Effects of Gestational Ozone Exposure on Privileged Placental and Brain Barrier Integrity

Ambient outdoor ozone, a common of component of photochemical smog and urban air pollution, is linked to various neurological and vascular pathologies. Its immediate reaction with lung surfactant after inhalation results in complete reactivity of the gas, with no active ozone passing into circulation. This indicates the presence of secondary and tertiary mediators in ozone-related systemic pathologies after pulmonary insult. In vasculature, ozone exposure is associated with an acute hypertensive phenotype apparent at least 24 hours after dose, such as experienced on a hot summer afternoon in a large metropolitan area like Los Angeles or Mexico City. However, the effects of ozone have been underexplored during gestation, when inducible teratogenesis during critical periods for development can result in catastrophic fetal outcomes, but also when more subtle impacts on placental supply can hamper sensitive developmental aspects such as in the brain. As the interface of maternal-fetal circulation, the placenta is a target organ of toxicological interest in hypertensive disorders of pregnancy such as preeclampsia. Moreover, the developing fetal blood-brain barrier (BBB) is underexplored, especially in relation to toxicological study. In the study at hand, proteomic analysis of amniotic fluid (AF) was assessed after exposure of pregnant Sprague-Dawley rats at two gestational timepoint representing critical periods during rat development. The AF proteome is an understudied window into the privileged amniotic environment and its response to toxicological stressors. Pregnant dams experienced a single 4-h exposure to ozone at GD10, a critical period of placental and BBB development, or at GD20, a period just prior to term and one of anatomical significance in brain development. AF samples were then collected at term for detailed proteomic analysis. Studies assessed: AF proteomic impacts between GD10 and GD20 time points; the differential response to 0.3 ppm or 1.0 ppm ozone dosage at GD20; and the overlap between AF proteomic and maternal serum proteomic responses to 0.3 ppm or 1.0 ppm GD20 ozone exposures. Subsequently, a plan was devised for targeted immunofluorescence microscopy assessments on the pathological effects within the placental and blood-brain barriers linked with the toxicological ozone response observed within the AF proteome. Overall, we identified 231 significant AF proteomic responses across all time points and ozone doses within the amniotic fluid. To our knowledge, this is the most comprehensive assessment of the AF proteome. Overlap was low between the AF proteomic responses to gestational exposure time or ozone dose, while considerably more consistent for maternal serum responses. The highly dynamic AF proteomic response to ozone, however, consistently related to extracellular matrix and vascular remodeling processes, many proteins with well-defined roles in the placenta and developing conceptus. Results with maternal serum indicated activation of the maternal compliment cascade system and systemic inflammation. Additionally, limited overlap between maternal serum and matched AF proteomes indicated the placenta or fetus as the primary contributors to the AF proteomic response to ozone. With placentation and cerebral angiogenesis just beginning in rat at GD10, we hypothesized a dramatic effect on these structures to be assessed with the devised immunofluorescence analysis. In placenta, we expect to observe conditions consistent with a hypertensive preeclamptic-like state. Our AF proteomic results showed significant fold changes in proteins associated with this disease such as galectin-1, MMP-2, TIMP-2, and osteopontin. In follow-up targeted analysis of these proteins in placenta, we expect to observe classic signs of preeclampsia and general placental dysfunction—shallow invasion of the maternal endometrial decidualized tissue layer and inadequate remodeling of the maternal spiral arteries resulting in inadequate fetal circulation. AF proteomic data also showed shifts in proteins important for vascular development in the fetal brain such as TGFβ, PKM and neuropilin-1. Thus, we devised follow-up studies to test for ozone-induced BBB barrier dysfunction within the fetal brain to include augmented tight-junction proteins, albumin leakage and promoted astrocytic and microglial reactivity proximal to the cerebrovasculature. Overall, the outlined studies have potential to demonstrate stark effects of critical-period ambient ozone exposure on the placenta and developing fetus

Prostate Cancer Nodal Staging: Using Deep Learning to Predict 68Ga-PSMA-Positivity from CT Imaging Alone

Lymphatic spread determines treatment decisions in prostate cancer (PCa) patients. 68Ga-PSMA-PET/CT can be performed, although cost remains high and availability is limited. Therefore, computed tomography (CT) continues to be the most used modality for PCa staging. We assessed if convolutional neural networks (CNNs) can be trained to determine 68Ga-PSMA-PET/CT-lymph node status from CT alone. In 549 patients with 68Ga-PSMA PET/CT imaging, 2616 lymph nodes were segmented. Using PET as a reference standard, three CNNs were trained. Training sets balanced for infiltration status, lymph node location and additionally, masked images, were used for training. CNNs were evaluated using a separate test set and performance was compared to radiologists' assessments and random forest classifiers. Heatmaps maps were used to identify the performance determining image regions. The CNNs performed with an Area-Under-the-Curve of 0.95 (status balanced) and 0.86 (location balanced, masked), compared to an AUC of 0.81 of experienced radiologists. Interestingly, CNNs used anatomical surroundings to increase their performance, "learning" the infiltration probabilities of anatomical locations. In conclusion, CNNs have the potential to build a well performing CT-based biomarker for lymph node metastases in PCa, with different types of class balancing strongly affecting CNN performance

Linearized Wasserstein dimensionality reduction with approximation guarantees

We introduce LOT Wassmap, a computationally feasible algorithm to uncover low-dimensional structures in the Wasserstein space. The algorithm is motivated by the observation that many datasets are naturally interpreted as probability measures rather than points in $\mathbb{R}^n$, and that finding low-dimensional descriptions of such datasets requires manifold learning algorithms in the Wasserstein space. Most available algorithms are based on computing the pairwise Wasserstein distance matrix, which can be computationally challenging for large datasets in high dimensions. Our algorithm leverages approximation schemes such as Sinkhorn distances and linearized optimal transport to speed-up computations, and in particular, avoids computing a pairwise distance matrix. We provide guarantees on the embedding quality under such approximations, including when explicit descriptions of the probability measures are not available and one must deal with finite samples instead. Experiments demonstrate that LOT Wassmap attains correct embeddings and that the quality improves with increased sample size. We also show how LOT Wassmap significantly reduces the computational cost when compared to algorithms that depend on pairwise distance computations.Comment: 38 pages, 10 figures. Submitte

Non-destructive analysis of fossil bones and insights into the evolution of osseous pathologies using computed tomography

Zielsetzung: In den vorliegenden Studien wurden Computertomographie (CT)- basierte Bildgebungsmethoden zur zerstörungsfreien Analyse fossiler Knochen entwickelt und im Kontext etablierter paläontologischer Verfahren für die Erforschung ossärer Pathologien evaluiert. Methoden: Sechs fossile Objekte, darunter die Tyrannosaurus rex (T. rex)- Exemplare „Sue“ und „Tristan Otto (TO)“, und das Femur eines rezenten Bos taurus (Rind) wurden untersucht. Zunächst erfolgte mittels CT die radiologische Diagnostik der pathologisch veränderten Fibula und der fusionierten Schwanzwirbel von T. rex "Sue". Anschließend wurden Daten zur Häufigkeit von korrespondierenden Pathologien bei phylogenetisch eng verwandten Arten auf Kladenebene aus der Literatur zum Vergleich herangezogen (144.277 bzw. 13.299 Vogel- und Reptilienpräparate), um die radiologischen Differentialdiagnosen mit Daten zur Wahrscheinlichkeit des Auftretens der Pathologien zu untermauern. Im Folgenden wurde die elementare Zusammensetzung des rezenten Rinderknochens und des Hämalbogens von T. rex "TO" mittels invasiver multimodaler Knochenanalyse analysiert. Diese diente anschließend als Grundlage für die Entwicklung eines quantitativen Dual-Energy (DE) CT-Algorithmus. Dieser wurde an in Sediment eingebetteten Fossilien validiert und schließlich an dem pathologisch veränderten Os dentale von T. rex "TO" angewendet, um Veränderungen der elementaren Zusammensetzung zerstörungsfrei zu charakterisieren. Ergebnisse: Die CT-Untersuchung des T. rex „Sue" zeigte Veränderungen, die radiologisch eine neoplastische oder infektiöse Genese nahelegen. Die Daten zur Häufigkeit von korrespondierenden Pathologien ergaben Neoplasieraten von 3% bei Vögeln und 2% bei Reptilien, während die Infektionsraten deutlich höher waren (32% und 54%) und somit die Diagnose einer Osteomyelitis nahelegten. Die multimodale Knochenanalyse der fossilen Knochen zeigte einen höheren Fluorgehalt als bei rezenten Knochen. Mittels fluorspezifischer DECT wurden ebenfalls höhere Fluorkonzentrationen im T. rex „TO" als im Bos taurus (p<0,001) detektiert. Der Fluorgehalt korrelierte zudem mit dem geologischen Alter der untersuchten terrestrischen Fossilien. Eine besonders hohe Fluorkonzentration wurde im pathologisch veränderten Os dentale von T. rex „TO" gemessen, welche in Zusammenschau mit der CT-Morphologie mit der Diagnose einer chronischen Osteomyelitis vereinbar ist. Schlussfolgerung: Die Kombination aus CT und Daten zur Häufigkeit von Erkrankungen bei phylogenetisch eng verwandter Arten konnte die Diagnose einer chronischen Osteomyelitis bei T. rex „Sue" und „TO" mit hoher diagnostischer Sicherheit stellen. Zudem wurde Fluor als Indikator für fossilen Knochen identifiziert und mittels eines innovativen DECT- Algorithmus quantifiziert. CT und fluorspezifische DECT eignen sich als nicht-invasive Werkzeuge zur Untersuchung fossiler Knochen und unterstreichen die Bedeutung innovativer radiologischer Bildgebung in den Naturwissenschaften.Objectives: In the present studies, computed tomography (CT)-based imaging methods were developed as non-destructive analysis tools for fossil bone and evaluated in the context of established paleontological methods for the study of osseous pathologies. Methods: A total of six fossil specimens, including the Tyrannosaurus rex (T. rex) specimens "Sue" and "Tristan Otto (TO)", and the femur of a extant Bos taurus (cattle) were subject to multimodal examination. First, CT imaging was applied to the pathologically altered fibula and fused caudal vertebrae of T. rex "Sue" was performed. Subsequently, pathology reports from phylogenetically closely related species at the clade level (phylogenetic disease bracketing) were reviewed and data on the occurrence of disease (144,277 and 13,299 avian and reptile specimens, respectively) was curated to determine the most plausible and likely diagnosis of the T. rex "Sue". Secondly, elementary compositions of the extant cattle bone and fossilized haemal arch of T. rex “TO” were analyzed invasively using established material characterization techniques. Identified elements in fossilized bone were used to develop a quantitative dual-energy (DE)CT algorithm for non-destructive bone characterization. Finally, the developed DECT algorithm was validated on sedimentembedded fossils and applied to the diseased jaw bone of T. rex "TO" to nondestructively characterize changes in elemental composition. Results: CT imaging of T. rex "Sue" revealed bone alterations suggestive of a neoplastic or infectious pathogenesis. Subsequent data review revealed neoplasia rates as low as 3% and 2% while infectious-disease rates were substantially higher with 32% and 54% in extant dinosaurs (birds) and non-avian reptiles, respectively, suggesting the diagnosis of osteomyelitis. Multimodal bone analysis revealed a higher fluorine content in fossilized bone than in extant and thus, a DECT algorithm for quantification of fluorine was developed. The fluorine-specific DECT also detected a higher fluorine concentration in T. rex "TO" compared to Bos taurus (p<0.001). Additionally, the fluorine content in the DECT analysis correlated with the geological age of the investigated terrestrial fossils. Finally, the diseased jaw bone of T. rex “TO” showed areas of particularly high fluorine concentrations on DECT, while pathomorphological features supported the diagnosis of chronic osteomyelitis. Conclusions: Using clinical CT and data on disease occurrence in phylogenetically related species allowed the diagnosis of chronic osteomyelitis in T. rex "Sue" and "TO" with a high diagnostic confidence. Moreover, fluorine was identified as an indicator of fossil bone and could be quantified using an innovative DECT algorithm. Thus, this work presents clinical CT and fluorine-specific DECT as non-destructive tools for the examination of fossil bones and highlight the importance of innovative radiological imaging techniques for natural sciences

Reading the Mind in the Eyes of Children Test (RME-C-T): Development and Validation of a Complex Emotion Recognition Test

Much research has been devoted to the development of emotion recognition tests that can be used to investigate how individuals identify and discriminate emotional expressions of other individuals. One of the most prominent emotion recognition tests is the Reading the Mind in the Eyes Test (RME-T). The original RME-T has been widely used to investigate how individuals recognize complex emotional expressions from the eye region of adult faces. However, the RME-T can only be used to investigate inter-individual differences in complex emotion recognition during the processing of adult faces. To extend its usefulness, we developed a modified version of the RME-T, the Reading the Mind in the Eyes of Children Test (RME-C-T). The RME-C-T can be used to investigate how individuals recognize complex emotional expressions from the eye region of child faces. However, the validity of the RME-C-T has not been evaluated yet. We, thus, administered the RME-C-T together with the RME-T to a sample of healthy adult participants (n = 119). The Interpersonal Reactivity Index (IRI) and the Toronto Alexithymia Scale (TAS) were also administered. Participants’ RME-C-T performance correlated with participants’ RME-T performance, implying that the RME-C-T measures similar emotion recognition abilities as the RME-T. Participants’ RME-C-T performance also correlated with participants’ IRI and TAS scores, indicating that these emotion recognition abilities are affected by empathetic and alexithymic traits. Moreover, participants’ RME-C-T performance differed between participants with high and low TAS scores, suggesting that the RME-C-T is sensitive enough to detect impairments in these emotion recognition abilities. The RME-C-T, thus, turned out to be a valid measure of inter-individual differences in complex emotion recognition during the processing of child faces

Clinical utility of postprocessed low-dose radiographs in skeletal imaging

Objectives: Radiography remains the mainstay of diagnostic and follow-up imaging. In view of the risks and the increasing use of ionizing radiation, dose reduction is a key issue for research and development. The introduction of digital radiography and the associated access to image postprocessing have opened up new opportunities to minimize the radiation dosage. These advances are contingent upon quality controls to ensure adequate image detail and maintenance of diagnostic confidence. The purpose of this study was to investigate the clinical applicability of postprocessed low-dose images in skeletal radiography. Methods: In our study setting, the median radiation dose for full dose X-rays was 9.61 dGy*cm2 for pelvis, 1.20 dGy*cm2 for shoulder and 18.64 dGy*cm2 for lumbar spine exams. Based on these values, we obtained 200 radiographs for each anatomic region in four consecutive steps, gradually reducing the dose to 84%, 71%, 60% and 50% of the baseline using an automatic exposure control (AEC). 549 patients were enrolled for a total of 600 images. All X-rays were postprocessed with a spatial noise reduction algorithm. Two radiologists assessed the diagnostic value of the radiographs by rating the visualization of anatomical landmarks and image elements on a five-point Likert scale. A mean-sum score was calculated by averaging the two reader's total scores. Given the non-parametric distribution, we used the Mann-Whitney U test to evaluate the scores. Results: Median dosage at full dose accounted for 38.4%, 48 and 53.2% of the German reference dose area product for shoulder, pelvis and lumbar spine, respectively. The applied radiation was incrementally reduced to 21.5%, 18.4% and 18.7% of the respective reference value for shoulder, pelvis and lumbar spine. Throughout the study, we observed an estimable tendency of superior quality at higher dosage in overall image quality. Statistically significant differences in image quality were restricted to the 50% dose groups in shoulder and lumbar spine images. Regardless of the applied dosage, 598 out of 600 images were of sufficient diagnostic value. Conclusion: In digital radiography image postprocessing allows for extensive reduction of radiation dosage. Despite a trend of superior image detail at higher dose levels, overall quality and, more importantly, diagnostic utility of low-dose images was not significantly affected. Therefore, our results not only confirm the clinical utility of postprocessed low-dose radiographs, but also suggest a widespread deployment of this advanced technology to ensure further dose limitations in clinical practice. Advances in knowledge: The diagnostic image quality of postprocessed skeletal radiographs is not significantly impaired even after extensive dose reduction by up to 20% of the reference value

A radiomics-based model to classify the etiology of liver cirrhosis using gadoxetic acid-enhanced MRI

The implementation of radiomics in radiology is gaining interest due to its wide range of applications. To develop a radiomics-based model for classifying the etiology of liver cirrhosis using gadoxetic acid-enhanced MRI, 248 patients with a known etiology of liver cirrhosis who underwent 306 gadoxetic acid-enhanced MRI examinations were included in the analysis. MRI examinations were classified into 6 groups according to the etiology of liver cirrhosis: alcoholic cirrhosis, viral hepatitis, cholestatic liver disease, nonalcoholic steatohepatitis (NASH), autoimmune hepatitis, and other. MRI examinations were randomized into training and testing subsets. Radiomics features were extracted from regions of interest segmented in the hepatobiliary phase images. The fivefold cross-validated models (2-dimensional-(2D) and 3-dimensional-(3D) based) differentiating cholestatic cirrhosis from noncholestatic etiologies had the best accuracy (87.5%, 85.6%), sensitivity (97.6%, 95.6%), predictive value (0.883, 0.877), and area under curve (AUC) (0.960, 0.910). The AUC was larger in the 2D-model for viral hepatitis, cholestatic cirrhosis, and NASH-associated cirrhosis (P-value of 0.05, 0.05, 0.87, respectively). In alcoholic cirrhosis, the AUC for the 3D model was larger (P=0.01). The overall intra-class correlation coefficient (ICC) estimates and their 95% confident intervals (CI) for all features combined was 0.68 (CI 0.56-0.87) for 2D and 0.71 (CI 0.61-0.93) for 3D measurements suggesting moderate reliability. Radiomics-based analysis of hepatobiliary phase images of gadoxetic acid-enhanced MRI may be a promising noninvasive method for identifying the etiology of liver cirrhosis with better performance of the 2D- compared with the 3D-generated models

Die Bedeutung veganer Bioprodukte für die ökologische Landwirtschaft

Vegane Lebensmittel haben in den letzten Jahren deutlich an Stellenwert gewonnen. Im Projekt wurde untersucht, welche Bedeutung der Vegan-Trend für die Öko-Branche hat und wie diese auf den Vegan-Trend reagieren kann. Hierzu wurden Befragungen und Workshops mit Akteuren entlang der Wertschöpfungskette durchgeführt. In einer Verbraucherbefragung wurden 503 Personen mit unterschiedlichen Ernährungsstilen nach ihren Einstellungen zu veganen Lebensmitteln und ihrer Zahlungsbereitschaft für diese befragt. Für Personen, die auch Fleisch essen, spielten Umweltvorteile veganer Lebensmittel kaum eine Rolle und der Geschmack veganer Lebensmittel stellte ein Kaufhemmnis dar. Auch wenn die Befragten vegane Lebensmittel eher als teuer wahrnahmen, waren viele Verbraucher bereit, mehr Geld für vegane Produkte zu bezahlen. Öko-Hersteller und -händler sahen das Potenzial für vegane Produkte noch nicht ausgeschöpft, wenngleich eine fehlende Vernetzung ein Hemmnis darstellte. Eine Analyse von Webseiten zu veganen Lebensmitteln zeigte, dass auf diesen der gute Geschmack veganer Lebensmittel und Vorteile für Gesundheit und Umwelt betont werden. Bei einer veganen Landbewirtschaftung besteht besonders hinsichtlich der langfristigen Auswirkungen auf Nährstoff- und Humusgehalte der Böden noch Forschungsbedarf. Für Produkte aus veganem Anbau waren Verbraucher bereit, Preisaufschläge zu bezahlen, wenn ihnen zuvor die Besonderheiten der Anbauform vermittelt wurden. Herstellern veganer Öko-Lebensmittel ist u.a. zu empfehlen, in Kooperation mit dem Handel eine gemeinsame Marketingkampagne für vegane Öko-Lebensmittel zu starten. Landwirtschaftliche Öko-Betriebe können sich mit veganem Öko-Landbau im Wettbewerb abheben und Pioniervorteile erzielen. Im Bereich der Außer-Haus-Verpflegung sollte die Kompetenz der Köche im Umgang mit veganen Lebensmitteln gestärkt werden

Predictors of early and late left atrial tachycardia and left atrial flutter after catheter ablation of atrial fibrillation: Long-term follow-up

Background: The aim of the study was identification of the predictors of left atrial tachycardia and left atrial flutter (LATAFL) after radiofrequency catheter ablation of atrial fibrillation (CAAF). Methods: We followed 598 patients (71% male, 41% paroxysmal AF; median follow-up: 36 months) after a single step-wise CAAF procedure. The time to first documented LATAFL lasting longer than 30 s, documented in any kind of electrocardiography (ECG), was defined as an end-point. Results: A single CAAF procedure resulted in LATAF in 58 (10%) patients. Additional lesions were performed in 275 (46%) patients. Early LATAFL recurrence (£ 3 months since the index procedure) was observed in 11 (2%) patients. Late LATAFL (&gt; 3 months) was noted in 47 (8%) patients. The univariate predictors of LATAFL recurrence were: type of AF (p = 0.003), the size of LA (p = 0.002) and the type of procedure (p = 0.0001). The identified single independent predictors of LATAFL recurrence were enlarged LA (p = 0.001) and mul­tiple (≥ 2) additional lesions performed during the index procedure (p &lt; 0.0001). Conclusions: Higher rate of LATAFL recurrence was observed in patients with non-paroxysmal AF, enlarged LA and any additional lesions performed. Two independent predictors of LATAFL recurrence after CAAF were: the enlarged LA and multiple (≥ 2) additional lesions performed during the index procedure