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The multidrug resistance protein 4 (MRP4) is highly expressed in platelets and several lines of evidence point to an impact on platelet function. MRP4 represents a transporter for cyclic nucleotides as well as for certain lipid mediators. The aim of the present study was to comprehensively characterize the effect of a short-time specific pharmacological inhibition of MRP4 on signaling pathways in platelets. Transport assays in isolated membrane vesicles showed a concentrationdependent inhibition of MRP4-mediated transport of cyclic nucleotides, thromboxane (Tx)B2 and fluorescein (FITC)- labeled sphingosine-1-phosphate (S1P) by the selective MRP4 inhibitor Ceefourin-1. In ex vivo aggregometry studies in human platelets, Ceefourin-1 significantly inhibited platelet aggregation by about 30-50% when ADP or collagen was used as activating agents, respectively. Ceefourin-1 significantly lowered the ADP-induced activation of integrin aIIbb3, indicated by binding of FITC-fibrinogen (about 50% reduction at 50 mM Ceefourin-1), and reduced calcium influx. Furthermore, pre-incubation with Ceefourin-1 significantly increased PGE1- and cinaciguat-induced vasodilatorstimulated phosphoprotein (VASP) phosphorylation, indicating increased cytosolic cAMP as well as cGMP concentrations, respectively. The release of TxB2 from activated human platelets was also attenuated. Finally, selective MRP4 inhibition significantly reduced both the total area covered by thrombi and the average thrombus size by about 40% in a flow chamber model. In conclusion, selective MRP4 inhibition causes reduced platelet adhesion and thrombus formation under flow conditions. This finding is mechanistically supported by inhibition of integrin aIIbb3 activation, elevated VASP phosphorylation and reduced calcium influx, based on inhibited cyclic nucleotide and thromboxane transport as well as possible further mechanisms.
Synopsis
C+60 has been proposed to be responsible for two of the diffuse interstellar bands (DIBs), the absorption features observed in the visible-to-near-infrared spectra of the interstellar medium. However, a confirmation requires laboratory gas-phase spectra, which are so far not available. We plan to develop a novel spectroscopy technique that will allow us to obtain the first gas-phase spectra of C+60, and that will be applicable to other complex organic molecules such as polycyclic aromatic hydrocarbons. The current status of the experimental setup, the ideas behind the measurement scheme and the preparatory work toward its implementation will be presented.
AbstractFluctuations of electron cyclotron emission (ECE) signals are analyzed for differently heated Wendelstein 7-X plasmas. The fluctuations appear to travel predominantly on flux surfaces and are used as ‘tracers’ in multivariate time series. Different statistical techniques are assessed to reveal the coupling and information entropy-based coupling analysis are conducted. All these techniques provide evidence that the fluctuation analysis allows one to check the consistency of magneto-hydrodynamic (MHD) equilibrium calculations. Expanding the suite of techniques applied in fusion data analysis, partial mutual information (PMI) analysis is introduced. PMI generalizes traditional partial correlation (Frenzel and Pompe Phys. Rev. Lett.
99 204101) and also Schreiber’s transfer entropy (Schreiber 2000 Phys. Rev. Lett.
85 461). The main additional capability of PMI is to allow one to discount for specific spurious data. Since PMI analysis allows one to study the effect of common drivers, the influence of the electron cyclotron resonance heating on the mutual dependencies of simultaneous ECE measurements was assessed. Additionally, MHD mode activity was found to be coupled in a limited volume in the plasma core for different plasmas. The study reveals an experimental test for equilibrium calculations and ECE radiation transport.
Purpose
The German Retina.net ROP registry and its Europe-wide successor, the EU-ROP registry, collect data from patients treated for ROP. This analysis compares input parameters of these two registries to establish a procedure for joint analyses of different registry data using exemplary datasets from the two registries.
Methods
Exemplary datasets from the two databases over a 1-year period each (German Retina.net ROP Registry, 2011, 22 infants; EU-ROP Registry, 2021, 44 infants) were compared. The parameters documented in the two databases were aligned and analysed regarding demographic parameters, treatment modalities, complications within first 24 h and retreatments.
Results
The current analysis showed that data can be aligned for joint analyses with some adjustments within the data structure. The registry with more detailed data collection (EU-ROP) needs to be reduced regarding granularity in order to align the different registries, as the registry with lower granularity determines the level of analyses that can be performed in a comparative approach. In the exemplary datasets, we observed that the overall most common ROP severity in both registries was zone II, 3+ (2011: 70.5%; 2021: 65%), with decreasing numbers of clock hours showing preretinal neovascularisations (2011: 10–12 clock hours in 29% of cases, 2021: 4–6 clock hours in 38%). The most prevalent treatment method was laser coagulation in 2011 (75%) and anti-VEGF therapy in 2021 (86.1%). Within the anti-VEGF group, all patients were treated with bevacizumab in 2011 and with ranibizumab in 2021. Retreatment rates were comparable in 2011 and 2021.
Conclusion
Data from two different ROP registries can be aligned and jointly analysed. The analysis reveals a paradigm shift in treatment modalities, from predominantly laser to anti-VEGF, and within the anti-VEGF group from bevacizumab to ranibizumab in Germany. In addition, there was a trend towards earlier treatment in 2021.
Background/Aims
Prematurely born infants undergo costly, stressful eye examinations to uncover the small fraction with retinopathy of prematurity (ROP) that needs treatment to prevent blindness. The aim was to develop a prediction tool (DIGIROP-Screen) with 100% sensitivity and high specificity to safely reduce screening of those infants not needing treatment. DIGIROP-Screen was compared with four other ROP models based on longitudinal weights.
Methods
Data, including infants born at 24–30 weeks of gestational age (GA), for DIGIROP-Screen development (DevGroup, N=6991) originate from the Swedish National Registry for ROP. Three international cohorts comprised the external validation groups (ValGroups, N=1241). Multivariable logistic regressions, over postnatal ages (PNAs) 6–14 weeks, were validated. Predictors were birth characteristics, status and age at first diagnosed ROP and essential interactions.
Results
ROP treatment was required in 287 (4.1%)/6991 infants in DevGroup and 49 (3.9%)/1241 in ValGroups. To allow 100% sensitivity in DevGroup, specificity at birth was 53.1% and cumulatively 60.5% at PNA 8 weeks. Applying the same cut-offs in ValGroups, specificities were similar (46.3% and 53.5%). One infant with severe malformations in ValGroups was incorrectly classified as not needing screening. For all other infants, at PNA 6–14 weeks, sensitivity was 100%. In other published models, sensitivity ranged from 88.5% to 100% and specificity ranged from 9.6% to 45.2%.
Conclusions
DIGIROP-Screen, a clinical decision support tool using readily available birth and ROP screening data for infants born GA 24–30 weeks, in the European and North American populations tested can safely identify infants not needing ROP screening. DIGIROP-Screen had equal or higher sensitivity and specificity compared with other models. DIGIROP-Screen should be tested in any new cohort for validation and if not validated it can be modified using the same statistical approaches applied to a specific clinical setting.
Importance: One of the biggest challenges when using anti–vascular endothelial growth factor (VEGF) agents to treat retinopathy of prematurity (ROP) is the need to perform long-term follow-up examinations to identify eyes at risk of ROP reactivation requiring retreatment.
Objective: To evaluate whether an artificial intelligence (AI)–based vascular severity score (VSS) can be used to analyze ROP regression and reactivation after anti-VEGF treatment and potentially identify eyes at risk of ROP reactivation requiring retreatment.
Design, Setting, and Participants: This prognostic study was a secondary analysis of posterior pole fundus images collected during the multicenter, double-blind, investigator-initiated Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity (CARE-ROP) randomized clinical trial, which compared 2 different doses of ranibizumab (0.12 mg vs 0.20 mg) for the treatment of ROP. The CARE-ROP trial screened and enrolled infants between September 5, 2014, and July 14, 2016. A total of 1046 wide-angle fundus images obtained from 19 infants at predefined study time points were analyzed. The analyses of VSS were performed between January 20, 2021, and November 18, 2022.
Interventions: An AI-based algorithm assigned a VSS between 1 (normal) and 9 (most severe) to fundus images.
Main Outcomes and Measures: Analysis of VSS in infants with ROP over time and VSS comparisons between the 2 treatment groups (0.12 mg vs 0.20 mg of ranibizumab) and between infants who did and did not receive retreatment for ROP reactivation.
Results: Among 19 infants with ROP in the CARE-ROP randomized clinical trial, the median (range) postmenstrual age at first treatment was 36.4 (34.7-39.7) weeks; 10 infants (52.6%) were male, and 18 (94.7%) were White. The mean (SD) VSS was 6.7 (1.9) at baseline and significantly decreased to 2.7 (1.9) at week 1 (P < .001) and 2.9 (1.3) at week 4 (P < .001). The mean (SD) VSS of infants with ROP reactivation requiring retreatment was 6.5 (1.9) at the time of retreatment, which was significantly higher than the VSS at week 4 (P < .001). No significant difference was found in VSS between the 2 treatment groups, but the change in VSS between baseline and week 1 was higher for infants who later required retreatment (mean [SD], 7.8 [1.3] at baseline vs 1.7 [0.7] at week 1) vs infants who did not (mean [SD], 6.4 [1.9] at baseline vs 3.0 [2.0] at week 1). In eyes requiring retreatment, higher baseline VSS was correlated with earlier time of retreatment (Pearson r = −0.9997; P < .001).
Conclusions and Relevance: In this study, VSS decreased after ranibizumab treatment, consistent with clinical disease regression. In cases of ROP reactivation requiring retreatment, VSS increased again to values comparable with baseline values. In addition, a greater change in VSS during the first week after initial treatment was found to be associated with a higher risk of later ROP reactivation, and high baseline VSS was correlated with earlier retreatment. These findings may have implications for monitoring ROP regression and reactivation after anti-VEGF treatment.