Akute Auswirkungen von zwei verschiedenen Röntgenkontrastmitteln (Iodixanol im Vergleich zu Iopromid) nach wiederholter intraarterieller Applikation auf die renale Hämodynamik und den renalen Gewebesauerstoffpartialdruck: Randomisierte, explorative Vergleichsstudie in einem Großtiermodell (Deutsches Landschwein)

Ziel dieser Arbeit war eine explorative Untersuchung der akuten Effekte zweier unterschiedlicher Röntgenkontrastmittel mit unterschiedlichen Eigenschaften (LOCM vs. IOCM) am in vivo-Großtiermodell. Vor dem Hintergrund des noch nicht vollständig verstandenen Pathomechanismus des KM-ANV ist unsere Untersuchung der akuten Auswirkungen von zwei verschiedenen Röntgenkontrastmitteln (Iodixanol im Vergleich zu Iopromid) nach wiederholter intraarterieller Applikation auf die renale Hämodynamik und den renalen Gewebesauerstoffpartialdruck in einer randomisierten, explorativen Vergleichsstudie in einem Großtiermodell von großer Bedeutung für das tiefere Verständnis des KM-ANV und der Einordnung der bis dato vorliegenden in vitro-Ergebnisse, aber auch der Ergebnisse klinischer Vergleichs- und Beobachtungsstudien. Hierfür wurden bei insgesamt 16 anästhesierten Schweinen (pro Gruppe n=8) nach einem hochstandardisierten Protokoll mit Iodixanol bzw. Iopromid über die suprarenale Aorta behandelt und über den geschaffenen transperitonealen Zugang verschiedene Messungen zur Beurteilung der Perfusion und Sauerstoffversorgung - auch in Bezug auf die verschiedenen Zonen der Niere - durchgeführt: systemische hämodynamische Parameter (IBP-Messungen, Herzfrequenz), dopplersonographische Beurteilung (Resistive Index), CEUS-Messungen (TTP-Messung), pO¬2-Sonden-Messung (Licox) und oberflächliche O2-Fluoreszenzmessung. Für die systemischen hämodynamischen Parameter fanden sich bezogen auf den Blutdruck in beiden Gruppen gleichermaßen ansteigende Werte über den Verlauf des Versuchsprotokolls, am ehesten bedingt durch die chirurgischen und anästhesiologischen Störfaktoren. Bezogen auf die Herzfrequenz zeigte sich zwar keine Veränderung innerhalb beider Gruppen über die Zeit, jedoch gab es einen Unterschied zwischen den Gruppen. Da dieser Unterschied gleichblieb, war eine Vergleichbarkeit der Gruppen dennoch gegeben. Als interessantes Ergebnis war in der intraoperativen makroskopischen Beurteilung der Niere im Gruppenvergleich ein Marmorierungseffekt als hyperakuter Effekt an der Nierenoberfläche zu beobachten, was wiederum hinweisend für eine subkortikalen Perfusionsstörung war. Dieser hyperaktue Effekt war in der Iopromidgruppe signifikant häufiger zu beobachten. In beiden Gruppen kam es jedoch nach >3 Minuten zur äußerlich sichtbaren Normalisierung der Perfusion. Dies ist durch die noch junge und gesunde Gefäßarchitektur unserer Versuchstiere erklärbar. Dopplersonographisch zeigte sich die maximale systolische Geschwindigkeit augenscheinlich in beiden Gruppen gegenläufig im zeitlichen Verlauf. Während die PSV in der Iodixanolgruppe eher anstieg, kam es eher zum Abfallen in der Iopromidgruppe. Ein Anstieg der enddiastolischen Geschwindigkeit wäre für beide Gruppen bei ansteigendem Blutdruck über die Zeit zu erwarten gewesen, zeigte sich aber tendenziell in der Iopromid-Gruppe geringer ausgeprägt. Diese beiden Tendenzen spiegelten sich konsequenterweise im Resistive Index wider. Im direkten Verlgeich von dopplersonographischen Werten direkt vor mit direkt nach der jeweiligen RKM-Gabe zeigten sich nach der fünften und zehnten RKM-Gabe augenscheinliche Unterschiede, wobei sich in der Iodixanolgruppe eher ansteigende PSV- und EDV- bzw. abfallende RI-Werte zeigten. In der Iopromid-Gruppe verhielten sich die Veränderungen gegenläufig. Mit der Bestimmung der TTP für verschiedene renale Areale sollten direkte und indirekte Hinweise auf die Perfusion gewonnen werden. In der nachträglichen Auswertung der TTP für verschiedene Areale in der Niere, also der Zeit bis zu Anflutung des Ultraschallkontrastmittels, wurden insgesamt drei ROI-Protokolle angewendet. Im ROI-I-Protokoll fanden sich über den Aa. arcuatae in der Iodixanolgruppe über die vier Messungen konstante Werte, während sich in der Iopromidgruppe ein augenscheinlicher Anstieg bereits nach der fünften RKM-Gabe und ein vergleichbarer Wert für die zehnte RKM-Gabe zeigte. Die Unterschiede zwischen den Gruppen setzen sich tendenziell in den weiteren – dem Blutstrom sequentiell folgenden – ROI (Kortex, äußere Medulla, Papillenspitze) fort mit augenscheinlich höheren TTP in der Iopromidgruppe, v.a. nach der fünften und zehnten RKM-Gabe. In den Baseline-Messungen boten beide Gruppen vergleichbare TTP-Werte, so dass vor Behandlung eine Vergleichbarkeit gegeben war. Im ROI-II-Protokoll zeigten sich keine signifikanten Unterschiede (flächige, manuell geformte ROI). Der Tendenz nach waren aber die Werte vergleichbar mit den ROI-I-Werten, auch bei Mittelung über die gesamte Nierenhälfte. Konsistent hierzu waren die Ergebnisse im ROI-III-Protokoll, welches in unserer Arbeitsgruppe ausgewertet und von Lamby et al. (2017) veröffentlicht wurde. Es fanden sich keine signifikanten Unterschiede zwischen den Gruppen bei Vermessung der Gefäßdurchmesser (Aa. arcuatae). Speziell im Verlauf nivellierten sich sogar tendenzielle Unterschiede. Letztlich wird hier sichtbar, dass die Effekte der RI- und CEUS-Messungen im mikrozirkulatorischen Bereich zu verorten sind. Bei Auswertung der oberflächlichen O2-Flux-Messung mittels Sensorfolie war zwar eine Reihe von Messungen nicht auswertbar, die Anzahl der nicht auswertbaren Messungen war jedoch zwischen den Gruppen annähernd gleich. Es boten sich augenscheinliche Gruppenunterschiede mit allzeit niedrigeren Fluxwerten in der Iodixanolgruppe und teils signifikanten Mittelwertunterschieden zwischen den Gruppen. Im beispielhaften Einzelfall konnte eine Koinzidenz der Marmorierung mit einem hohen Flux beobachtet werden. Zur Vollständigkeit wurden die Ergebnisse der Messung des Sauerstoffpartialdrucks im kortikomedullären Übergang mittels Licox-Sonde dargestellt, welche bereits von Lamby et al. (2019) veröffentlicht wurden. Statistisch signifikante Gruppenunterschiede konnten hier nicht beobachtet werden. Tendenziell zeigte sich in der Iopromid-Gruppe jedoch im 200-Sekunden-Beobachtungszeitraum ein irreversibler Abfall des Sauerstoffpartialdrucks im kortikomedullären Übergangsbereich. Zusammenfassend zeigten sich für alle Messungen konsistente Ergebnisse, wobei Iopromid in der Akutbetrachtung und nach mehrmaliger Gabe eine Veränderung und Verschlechterung der renalen Perfusion in verschiedenen Arealen der Niere verursachte. Der bisher noch nicht beschriebene, hyperakute Effekt der Marmorierung nach RKM-Gabe zeigte sich vor allem in der Iopromid-Gruppe und konnte mit anderen gemessenen Parametern in Einklang gebracht werden. Die Verwendung verschiedener Messtechniken stellt zwar eine Herausforderung in der Durchführung und Interpretation dar, jedoch wurde die Verwendung einzelner Methoden (z.B. O2-Fluoreszenz-Messung) in diesem Setup an der Niere noch nie zuvor durchgeführt. Die Beobachtung von derart ausgeprägten vaskulären Reaktionen bei jungen und gesunden Nieren nach RKM-Gabe mit anschließender Normalisierung stellt erstens die unerwünschten Nebenwirkungen von RKM (speziell Iopromid) dar, zweitens zeigt es die Reversibilität bei ausreichend gesunden Nieren und drittens kann es so die schädlichen Auswirkungen von RKM bei chronisch geschädigten Nieren erklären und als Ausgangspunkt eines KM-ANV gewertet werden

CXCR2-Blocking Has Context-Sensitive Effects on Rat Glioblastoma Cell Line Outgrowth (S635) in an Organotypic Rat Brain Slice Culture Depending on Microglia-Depletion (PLX5622) and Dexamethasone Treatment

In glioblastoma (GBM), the interplay of different immune cell subtypes, cytokines, and/or drugs shows high context-dependencies. Interrelations between the routinely applied dexamethasone (Dex) and microglia remain elusive. Here, we exploited rat organotypic brain slice co-cultures (OBSC) to examine the effects on a rat GBM cell line (S635) outgrowth resulting from the presence of Dex and pretreatment with the colony-stimulating factor receptor 1 (CSF1-R) inhibitor PLX5622: in native OBSC (without PLX5622-pretreatment), a diminished S635 spheroid outgrowth was observable, whereas Dex-treatment enhanced outgrowth in this condition compared to PLX5622-pretreated OBSC. Screening the supernatants of our model with a proteome profiler, we found that CXCL2 was differentially secreted in a Dex- and PLX5622-dependent fashion. To analyze causal interrelations, we interrupted the CXCL2/CXCR2-axis: in the native OBSC condition, CXCR2-blocking resulted in increased outgrowth, in combination with Dex, we found potentiated outgrowth. No effect was found in the PLX5622-pretreated. Our method allowed us to study the influence of three different factors—dexamethasone, PLX5622, and CXCL2—in a well-controlled, simplified, and straight-forward mechanistic manner, and at the same time in a more realistic ex vivo scenario compared to in vitro studies. In our model, we showed a GBM outgrowth enhancing synergism between CXCR2-blocking and Dex-treatment in the native condition, which was levelled by PLX5622-pretreatment

Pathogenic lipid-binding antiphospholipid antibodies are associated with severity of COVID-19

Background Coronavirus disease 19 (COVID-19)–associated coagulopathy is a hallmark of disease severity and poor prognosis. The key manifestations of this prothrombotic syndrome—microvascular thrombosis, stroke, and venous and pulmonary clots—are also observed in severe and catastrophic antiphospholipid syndrome. Antiphospholipid antibodies (aPL) are detectable in COVID-19 patients, but their association with the clinical course of COVID-19 remains unproven. Objectives To analyze the presence and relevance of lipid-binding aPL in hospitalized COVID-19 patients. Methods Two cohorts of 53 and 121 patients from a single center hospitalized for PCR-proven severe acute respiratory syndrome–coronavirus 2 infection were analyzed for the presence of aPL and clinical severity of COVID-19. Results We here demonstrate that lipid-binding aPL are common in COVID-19. COVID-19 patients with lipid-binding aPL have higher median concentrations of C-reactive protein and D-dimer, and are more likely to have a critical clinical course and fatal outcome. Lipid-binding aPL isolated from COVID-19 patients target the recently described cell surface complex of lysobisphosphatidic acid (LBPA) with the protein C receptor (EPCR) to induce prothrombotic and inflammatory responses in monocytes and endothelial cells. We show that B1a cells producing lipid-reactive aPL of the IgG isotype circulate in the blood of COVID-19 patients. In vivo, COVID-19 aPL accelerate thrombus formation in an experimental mouse model dependent on the recently delineated signaling pathway involving EPCR-LBPA. Conclusions COVID-19 patients rapidly expand B1a cells secreting pathogenic lipid-binding aPL with broad thrombotic and inflammatory effects. The association with markers of inflammation and coagulation, clinical severity, and mortality suggests a causal role of aPL in COVID-19–associated coagulopathy

Brain plasticity and neuroinflammatory protein biomarkers with circulating MicroRNAs as predictors of acute brain injury outcome – A prospective cohort study

Background: Brain recovery mechanisms after injuries like aneurysmal subarachnoid hemorrhage (aSAH), ischemic stroke (IS), and traumatic brain injury (TBI) involve brain plasticity, synaptic regeneration, and neuroinflammation. We hypothesized that serum levels of the p75 neurotrophic receptor (p75NTR) and associated signaling proteins, as well as differentially expressed (DE) microRNAs, could predict recovery outcomes irrespective of injury type. Methods: A prospective patient cohort with ischemic stroke (IS, n = 30), aneurysmal subarachnoid hemorrhage (aSAH, n = 31), and traumatic brain injury (TBI, n = 13) were evaluated (total n = 74). Serum samples were collected at two post-injury intervals (early: 1-3 days, late: 4-8 days), and outcomes were assessed after three months using the modified Rankin Scale (mRS), categorizing outcomes as favorable (mRS 0-3) or unfavorable (mRS 4-6). Six proteins were measured using ELISAs: p75NTR, NGF, sortilin, IL1β, TNFα, and cyclophilin. DE microRNAs were identified using DESeq2, and their target genes were predicted. Serum molecules between patients with differing outcomes were compared using a Kolmogorov-Smirnov test, 2-tailed t-test and multivariate linear discriminant analysis (LDA). Results: Favorable (n = 46) and unfavorable (n = 28) outcome cohorts were balanced with age and sex (p = 0.25 and 0.63). None of the studied proteins correlated with age. Combinatory LDA of the six protein biomarkers indicated strong prognostic value for favorable outcomes (OR 2.09; AUC = 70.3%, p = 0.0058). MicroRNA expression changes over time were identified in the aSAH, TBI, and IS groups (p Conclusions: The combined prognostic microRNA and protein biomarker models demonstrated accurate outcome prognostication across diverse injury types, implying the presence of a common recovery mechanism. DE microRNAs were found to target the studied molecules, suggesting a potential mechanistic role in recovery. Further investigation is warranted to study these molecules in prognostication, as well as therapeutic targets for enhancing recovery.</p

Histological and SEM Assessment of Blood Stasis in Kidney Blood Vessels after Repeated Intra-Arterial Application of Radiographic Contrast Media

Background: After application of iodinated contrast media (CM), a pronounced deterioration of the microcirculation in skin and myocardium was reported. Clinically, the repeated application of CM, especially, led to an increase of the renal resistance index (RRI). With respect to the transiency of the RRI increase, it is reasonable to assume that the deterioration of blood flow could be due to transient blood stasis caused by reversible morphologic cell alterations due to osmotic discrepancies between CM and human blood. Therefore, the hypothesis was investigated whether CM are able to induce in vivo such blood stasis and cell deformations in the renal vasculature of well-hydrated pigs. Methods: The in vivo study was performed as a prospective randomized examination to compare the effects of two different CM in 16 pigs (German Landrace). Pigs were randomized to receive either Iodixanol (n= 8), or Iopromide (n= 8). Each animal received 10 injections separated by 5-min intervals via the suprarenal aorta at a rate of 10 mL/s according to the usual procedure during a cardiac catheter examination. Finally, the kidneys were explanted and processed for histology (H & E staining and fibrin staining according to Weigert) as well as for scanning electron microscopy (SEM) with regards to morphologic correlates explaining the changes in the microcirculation. Results: In each of the predefined four categories of vascular diameters, blood stasis were found, but clearly more often after application of Iopromide than after application of Iodixanol (p< 0.001). In addition, Iopromide induced more blood stasis in all of the examined kidney regions compared to Iodixanol (p= 0.0001). There were no obstructive events in the middle cortex following the application of Iodixanol. Except for the region around a puncture channel of a placed-in catheter probe, no fibrin was detected in Weigert's fibrin-stained samples, neither around the histologically assessed thrombi nor in vessels with blood stasis. Complementary SEM analyses revealed in a few cases only a slight generation of fibrin and thrombi and deformations, such as echinocyte and "box-like" deformations. Conclusions: According to previous in vitro studies, pathological erythrocyte deformations, such as echinocyte and box-like formation of erythrocytes, were observed also in vivo. In addition, blood stasis and/or thrombi could be detected in histological samples from explanted kidneys from young pigs after repeated in vivo administration of CM. In only a few cases, mural platelet aggregates within minimal fibrin meshes occurred only after the application of Iopromide

Isotope effect and bond-stretching phonon anomaly in high-Tc cuprates

We analyse a model where the anomalies of the bond-stretching LO phonon mode are caused by the coupling to electron dynamic response in the form of a damped oscillator and explore the possibility to reconstruct the spectrum of the latter from the phonon measurements. Preliminary estimates point to its location in the mid infrared region and we show how the required additional information can be extracted from the oxygen isotope effect on the phonon spectrum. The model predicts a significant measurable deviation from the "standard value" of the isotope effect even if the phonon frequency is far below the electron spectrum, provided the latter is strongly incoherent. In this regime, which corresponds to the "mid infrared scenario", the phonon linewidth becomes a sensitive and informative probe of the isotope effect.Comment: 10 pages, 2 figures, added reference

COVID-19 trajectories among 57 million adults in England: a cohort study using electronic health records

BACKGROUND: Updatable estimates of COVID-19 onset, progression, and trajectories underpin pandemic mitigation efforts. To identify and characterise disease trajectories, we aimed to define and validate ten COVID-19 phenotypes from nationwide linked electronic health records (EHR) using an extensible framework. METHODS: In this cohort study, we used eight linked National Health Service (NHS) datasets for people in England alive on Jan 23, 2020. Data on COVID-19 testing, vaccination, primary and secondary care records, and death registrations were collected until Nov 30, 2021. We defined ten COVID-19 phenotypes reflecting clinically relevant stages of disease severity and encompassing five categories: positive SARS-CoV-2 test, primary care diagnosis, hospital admission, ventilation modality (four phenotypes), and death (three phenotypes). We constructed patient trajectories illustrating transition frequency and duration between phenotypes. Analyses were stratified by pandemic waves and vaccination status. FINDINGS: Among 57 032 174 individuals included in the cohort, 13 990 423 COVID-19 events were identified in 7 244 925 individuals, equating to an infection rate of 12·7% during the study period. Of 7 244 925 individuals, 460 737 (6·4%) were admitted to hospital and 158 020 (2·2%) died. Of 460 737 individuals who were admitted to hospital, 48 847 (10·6%) were admitted to the intensive care unit (ICU), 69 090 (15·0%) received non-invasive ventilation, and 25 928 (5·6%) received invasive ventilation. Among 384 135 patients who were admitted to hospital but did not require ventilation, mortality was higher in wave 1 (23 485 [30·4%] of 77 202 patients) than wave 2 (44 220 [23·1%] of 191 528 patients), but remained unchanged for patients admitted to the ICU. Mortality was highest among patients who received ventilatory support outside of the ICU in wave 1 (2569 [50·7%] of 5063 patients). 15 486 (9·8%) of 158 020 COVID-19-related deaths occurred within 28 days of the first COVID-19 event without a COVID-19 diagnoses on the death certificate. 10 884 (6·9%) of 158 020 deaths were identified exclusively from mortality data with no previous COVID-19 phenotype recorded. We observed longer patient trajectories in wave 2 than wave 1. INTERPRETATION: Our analyses illustrate the wide spectrum of disease trajectories as shown by differences in incidence, survival, and clinical pathways. We have provided a modular analytical framework that can be used to monitor the impact of the pandemic and generate evidence of clinical and policy relevance using multiple EHR sources. FUNDING: British Heart Foundation Data Science Centre, led by Health Data Research UK

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Visuo-Spatial Performance in Autism: A Meta-analysis

Visuo-spatial skills are believed to be enhanced in autism spectrum disorders (ASDs). This meta-analysis tests the current state of evidence for Figure Disembedding, Block Design, Mental Rotation and Navon tasks in ASD and neurotypicals. Block Design (d = 0.32) and Figure Disembedding (d = 0.26) showed superior performance for ASD with large heterogeneity that is unaccounted for. No clear differences were found for Mental Rotation. ASD samples showed a stronger local processing preference for Navon tasks (d = 0.35); less clear evidence for performance differences of a similar magnitude emerged. We discuss the meta-analysis results together with other findings relating to visuo-spatial processing and three cognitive theories of ASD: Weak Central Coherence, Enhanced Perceptual Functioning and Extreme Male Brain theory