Statistical Evaluation of the Material-Source Effects on the DSR Rheological Properties of Plant-Mix Extracted Asphalt-Binders

The work presented in this paper was carried out to statistically evaluate and quantify the material-source effect on the asphalt-binder’s rheological properties using Analysis of Variance (ANOVA) and Tukey’s Honestly Significant Difference (Tukey´s HSD) test. The study focused on the Asphalt-Binders’ high-temperature rheological properties, namely, the G*, δ, G*/Sin(δ) and G*/(1 − (1/Tan(δ)Sin(δ))) parameters, measured using the Dynamic Shear Rheometer (DSR) device. The DSR data analyzed in the study were extracted from the Texas flexible pavements and overlays database, namely, the Texas Data Storage System (DSS), covering two Asphalt-Binders (ABs), performance grade (PG) 64-22 and PG 76-22 plant-mix extracted ABs that were treated as rolling thin film oven (RTFO) residue, and sourced from 14 different suppliers. The study findings substantiate that material-source has an effect on the high-temperature rheological properties of ABs. Additionally, it was also concluded that in as much as performance superiority and costs are crucial issues in deciding the AB source/provider, consistency and quality aspects cannot be disregarded. Therefore, material-source effects should be inclusively evaluated from both performance (rheological properties) and quality (consistence) standpoints as well as cost considerations when choosing a supplier. In general, the study contributes to the state-of-the-art enrichment on aspects of material-source effects on RTFO residue ABs’ high-temperature rheological properties, consistency, variability, and data quality.     

A Comparative View of Reported Adverse Effects of Statins in Social Media,Regulatory Data,Drug Information Databases and Systematic Reviews

Introduction

There are few studies assessing how data on adverse drug events from consumers on social media compare with other sources.

Aim

The aim of this study was to assess the consistency of adverse event data of statin medications from social media as compared with other sources.

Methods

We collected data on the adverse events of statins from Twitter, the US FDA Adverse Event Reporting System (FAERS), the UK Medicines and Healthcare products Regulatory Agency (MHRA), drug information databases (DIDs) and systematic reviews. We manually annotated 12,649 tweets collected between June 2013 and August 2018. We collected 45,447 reports from FAERS, 10,415 from MHRA, identified 17 systematic reviews with relevant data and extracted data from Facts and Comparisons^® and Clinical Pharmacology^®. We compared the proportion, relative frequencies and rank of each category of adverse event from each source using MedDRA^® primary System Organ Class codes.

Results

Compared with other sources, patients on social media are proportionally far more likely to complain about musculoskeletal symptoms than other adverse events. Most adverse events showed a high level of agreement between Twitter and regulatory data. DIDs tend to demonstrate similar patterns but not as strongly. Systematic reviews tend to examine pre-specified adverse events or those reported by trial investigators.

Conclusions

Combining the data from multiple sources, albeit challenging, may provide a broader safety profile of any medication. Systematically collected social media reports may be able to contribute information on the most pertinent adverse effects to patients.

     

NMDA receptor–BK channel coupling regulates synaptic plasticity in the barrel cortex

Postsynaptic N-methyl-D-aspartate receptors (NMDARs) are crucial mediators of synaptic plasticity due to their ability to act as coincidence detectors of presynaptic and postsynaptic neuronal activity. However, NMDARs exist within the molecular context of a variety of postsynaptic signaling proteins, which can fine-tune their function. Here, we describe a form of NMDAR suppression by large-conductance Ca²⁺- and voltage-gated K⁺ (BK) channels in the basal dendrites of a subset of barrel cortex layer 5 pyramidal neurons. We show that NMDAR activation increases intracellular Ca²⁺ in the vicinity of BK channels, thus activating K⁺ efflux and strong negative feedback inhibition. We further show that neurons exhibiting such NMDAR–BK coupling serve as high-pass filters for incoming synaptic inputs, precluding the induction of spike timing–dependent plasticity. Together, these data suggest that NMDAR-localized BK channels regulate synaptic integration and provide input-specific synaptic diversity to a thalamocortical circuit.

Glutamate is the primary excitatory chemical transmitter in the mammalian central nervous system (CNS), where it is essential for neuronal viability, network function, and behavioral responses (1). Glutamate activates a variety of pre- and postsynaptic receptors, including ionotropic receptors (iGluRs) that form ligand-gated cation-permeable ion channels. The iGluR superfamily includes α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), kainate receptors, and N-methyl-D-aspartate receptors (NMDARs), all of which form tetrameric assemblies that are expressed throughout the CNS (2).NMDARs exhibit high sensitivity to glutamate (apparent half maximal effective concentration in the micromolar range) and a voltage-dependent block by Mg²⁺ (3, 4), slow gating kinetics (5), and high permeability to Ca²⁺ (6, 7) (for a review, see ref. 8). Together, these characteristics confer postsynaptic NMDARs with the ability to detect and decode coincidental activity of pre- and postsynaptic neurons: presynaptic glutamate release brings about the occupation of the agonist-binding site and AMPAR-driven postsynaptic depolarization, removing the voltage-dependent Mg²⁺ block. The coincidence of these two events leads to NMDAR activation and a Ca²⁺ influx through the channel (8, 9), which initiates several forms of synaptic plasticity (10, 11).Large-conductance Ca²⁺- and voltage-gated K⁺ (BK) channels are opened by a combination of membrane depolarization and relatively high levels of intracellular Ca²⁺ (12, 13). In CNS neurons, such micromolar Ca²⁺ increases are usually restricted to the immediate vicinity of Ca²⁺ sources, including voltage-gated Ca²⁺ channels (VGCCs) (14–16) and ryanodine receptors (RyRs) (17, 18). In addition, Ca²⁺ influx through nonselective cation-permeable channels, including NMDARs, has also been shown to activate BK channels in granule cells from the olfactory bulb and dentate gyrus (19–21). In these neurons, Ca²⁺ entry through NMDARs opens BK channels in somatic and perisomatic regions, causing the repolarization of the surrounding plasma membrane and subsequent closure of NMDARs. Because BK channel activation blunts NMDAR-mediated excitatory responses, it provides a negative feedback mechanism that modulates the excitability of these neurons (19, 20). Thus, the same characteristics that make NMDARs key components in excitatory synaptic transmission and plasticity can paradoxically give rise to an inhibitory response when NMDARs are located in the proximity of BK channels. However, it is unclear whether functional NMDAR–BK coupling is relevant at dendrites and dendritic spines.The barrel field area in the primary somatosensory cortex, also known as the barrel cortex (BC), processes information from peripheral sensory receptors for onward transmission to cortical and subcortical brain regions (22, 23). Sensory information is received in the BC from different nuclei of the thalamus. Among these nuclei, the ventral posterior medial nucleus, ventrobasal nucleus, and posterior medial nucleus are known to directly innervate layer 5 pyramidal neurons (BC-L5PNs) (24–27). In basal dendrites of BC-L5PN, the coactivation of neighboring dendritic inputs can initiate NMDAR-mediated dendritically restricted spikes characterized by large Ca²⁺ transients and long-lasting depolarizations (28–30), providing the appropriate environment for BK activation.To determine whether functional NMDAR–BK coupling plays a role in synaptic transmission, and potentially synaptic plasticity, we investigated the thalamocortical synapses at basal dendrites of BC-L5PNs. We found that the suppression of NMDAR activity by BK channels occurs in the basal dendrites of about 40% of BC-L5PNs, where NMDAR activation triggers strong negative feedback inhibition by delivering Ca²⁺ to nearby BK channels. This inhibition regulates the amplitude of postsynaptic responses and increases the threshold for the induction of synaptic plasticity. Our findings thus unveil a calibration mechanism that can decode the amount and frequency of afferent synaptic inputs by selectively attenuating synaptic plasticity and providing input-specific synaptic diversity to a thalamocortical circuit.     

Direct projections from the reticular formation of the medulla oblongata to the anterior cingulate cortex in the mouse and the rat

After injections of horseradish peroxidase into the anterior cingulate cortex of the mouse and the rat, labeled neurons were observed in different nuclei of the reticular formation of the rostral medulla oblongata: ventral part of the nucleus gigantocellularis, nucleus paragigantocellularis and nucleus lateralis reticularis. Other labeled neurons lay scattered outside the nuclear boundaries, often close to the ventral-most border of the medulla. The projection to the cingulate cortex is sparse, with rarely more than 3 cells per case, but constant. Injections into other cortical areas (visual, motor and somatosensory cortex) did not produce labeling in the medullary reticular formation.     

Pulsarperimetrie

We present a review and update on Pulsar perimetry, which combines temporal frequency, contrast and spatial frequency stimuli. The effects of age, visual acuity, and learning on results are described. Data on threshold fluctuation, signal-to-noise ratio, and the possibility of reducing noise with filtering techniques are provided. We describe its dynamic range and the possibility of compensating for profound defects. Finally, we show the results obtained in normal patients and in those with ocular hypertension or initial glaucoma, as well as an analysis of glaucoma progression. The English full-text version of this article is available at SpringerLink (under supplemental).     

Comparison of diagnostic ability between a fast strategy, tendency-oriented perimetry, and the standard bracketing strategy

PURPOSE: To compare the diagnostic abilities of the standard bracketing strategy (BR) and a fast strategy, the tendency-oriented perimetry (TOP). METHODS: Seventy-seven controls and 91 eyes from patients with glaucoma were analyzed with the strategies TOP and BR. Sensitivity (Se), specificity (Sp), the area under the receiver operating characteristic (ROC) curve (AC) and the optimum cutoff value (CO) were calculated for the visual field indices mean defect (MD), the square root of the loss variance (sLV) and the number of pathological points (NPP). RESULTS: In the glaucoma group, the mean MD value using TOP and BR was 7.5 and 8.3 dB, respectively. The mean sLV value using TOP and BR was 5.0 and 5.3 dB, respectively. Indices provided by TOP had higher ROC values than the ones provided by BR. Using TOP, the index with the best diagnostic ability was sLV (Sp = 94.8, Se = 90.1, AC = 0.966, CO = 2.5 dB), followed by NPP and MD. Using BR, the best results were obtained for MD (Sp = 92.2, Se = 81.3, AC = 0.900, CO = 2.5 dB) followed by sLV and NPP. CONCLUSIONS: A fast strategy, TOP, had superior diagnostic ability than the standard BR. Although TOP provided lower LV values than BR, the diagnostic ability of this index was higher than that of the conventional strategy.     

SARS-CoV-2–Specific Antibodies in Domestic Cats during First COVID-19 Wave,Europe

We conducted a severe acute respiratory syndrome coronavirus 2 antibody seroprevalence study among >2,000 domestic cats from 4 countries during the first coronavirus disease wave in Europe. We found 4.4% seroprevalence using a virus neutralization test and 4.3% using a receptor-binding domain ELISA, demonstrating probable human-to-cat transmission.