3 vs 200.0), and was more likely to be an extended-release formulation (2.9% vs 0.7%, all P < 0.001). When compared with internal medicine, the adjusted odds of chronic use were highest with anesthesiology (odds ratio [OR] = 1.46) and neurology (OR = 1.43) and lowest with ophthalmology (OR = 0.33) and gynecology (OR = 0.37).

Eight point six percent of opioid-naïve individuals who received an opioid prescription developed chronic use. This rate varied depending on the specialty of the provider who wrote the prescription. The risk of chronic use increased with higher MME content of the initial prescription and use of extended-release opioids.

Eight point six percent of opioid-naïve individuals who received an opioid prescription developed chronic use. This rate varied depending on the specialty of the provider who wrote the prescription. The risk of chronic use increased with higher MME content of the initial prescription and use of extended-release opioids.

To determine the median effective dose (ED50) of prophylactic intravenous lidocaine for the prevention of propofol medium-chain triglyceride/long-chain triglyceride (MCT/LCT) emulsion injection pain.

Prospective trial, Dixon up-and-down sequential method.

Operating room of a single hospital.

Thirty patients aged 18-65years with American Society of Anesthesiologists (ASA) status I or II who were scheduled for elective surgery under general anesthesia (GA) were included.

The initial dose of prophylactic lidocaine before propofol MCT/LCT emulsion injection was set at 0.5mg/kg lean body weight (LBW). The lidocaine dose was adjusted according to the degree of patients’ injection pain using the Dixon up-and-down sequential method.

The ED50 and 95% confidence intervals (CIs) of lidocaine were calculated using the Dixon-Massey formula. Vital signs and adverse effects were recorded. In the postanesthesia care unit (PACU), patients were asked if they recalled feeling any injection pain with visual analog scale (VAS) evaluation.

The ED50 of lidocaine for the prevention of propofol MCT/LCT emulsion injection pain was 0.306mg/kg LBW (95% CI, 0.262-0.357mg/kg LBW). No adverse reactions to lidocaine occurred. In the PACU, 90.9% of patients who experienced injection pain recalled this pain (VAS score, 2.8±1.8).

Prophylactic intravenous lidocaine (0.306mg/kg LBW) effectively prevented propofol MCT/LCT emulsion injection pain in 50% of patients scheduled for elective surgery under GA with no adverse reaction occurring.

Prophylactic intravenous lidocaine (0.306 mg/kg LBW) effectively prevented propofol MCT/LCT emulsion injection pain in 50% of patients scheduled for elective surgery under GA with no adverse reaction occurring.

Current electrophysiology signal recording and mapping systems have limited dynamic range (DR) and bandwidth, which causes loss of valuable information during acquisition of cardiac signals. We evaluated a novel advanced signal processing platform with the objective to obtain and assess additional information of clinical importance.

Over 10 canines, we compared intracardiac recordings within all cardiac chambers, in various rhythms, in pacing and during radiofrequency (RF) ablation across two platforms; a conventional system and the PURE EP™ [(PEP); Bio Sig Technologies, Inc., Los Angeles, CA, USA]. Recording cardiac signals with varying amplitudes were consistently and reproducibly observed, without loss of detail or introduction of artefact. Further the amplitude of current of injury (COI) on the unipolar signals correlated with the instantaneous contact force (CF) recorded on the sensing catheter in all the animals (r2 = 0.94 in ventricle). The maximum change in the unipolar COI correlated with the change in local electrogram amplitude during non-irrigated RF ablation (r2 = 0.61 in atrium). Reduction in artefact attributable to pacing (20 sites) and noise during ablation (48 sites) was present on the PEP system. Within the PEP system, simultaneous display of identical signals, filtered differently, aided the visualization of discrete conduction tissue signals.

Compared to current system, the PEP system provided incremental information including identifying conduction tissue signals, estimates of CF and a surrogate for lesion formation. This novel signal processing platform with increased DR and minimal front-end filtering may be useful in clinical practice.

Compared to current system, the PEP system provided incremental information including identifying conduction tissue signals, estimates of CF and a surrogate for lesion formation. This novel signal processing platform with increased DR and minimal front-end filtering may be useful in clinical practice.Folin-Ciocalteu and the more recent Fast Blue BB (FBBB) reactions are used for the quantification of total phenolics in food matrices. Despite its known interferences, Folin-Ciocalteu is still widely employed, considering Solid Phase Extraction (SPE) as clean-up step only in a few cases. Meanwhile, FBBB has shown no interferences for the determination of total phenolics in fruits and cereals, although its utilization in other popular matrices containing potential interferences, such as legumes, remains unexplored. In this study, the total phenolic content of 24 flours from legumes, cereals, fruits, nuts and plant seeds was evaluated by Folin-Ciocalteu and FBBB, with and without SPE. Folin-Ciocalteu showed interferences for 75% of the flours (attributed to reducing sugars and enediols), whereas FBBB only for legumes and nuts (attributed to the presence of tyrosine), both methods in those matrices requiring SPE. Although both SPE-FBBB and SPE-Folin-Ciocalteu presented excellent reproducibility, SPE-FBBB displayed 1.5 times higher sensitivity.Cooked rice (CR) is a staple diet for many people, but exhibits the high glycemic index that makes it difficult to control the blood glucose. Herein, instant green tea (IGT), instant black tea (IBT) and matcha (Mat) (1, 2 and 3% w/w, rice basis) were added to lower the in vitro starch digestibility and improve the eating quality of CR prepared with an electric rice cooker. The results showed that adding tea products at each level could remarkably reduce the in vitro starch digestibility of CR. Compared with IGT and IBT, 3% of Mat significantly decreased the contents of rapidly digestible starch (RDS) from 72.96% to 60.99%, the digestion rate constant (K) from 11.4 × 10-2 to 8.68 × 10-2 min-1 and the expected glycemic index (eGI) from 77.55 to 66.86. Furthermore, the gas chromatography-ion migration spectrum was analysed to confirm that the tea products endowed the cooked rice with a refreshing flavor by inducing the redistribution of the main aroma components. Moreover, it was found that increasing the ordered crystal structure of rice grains played a major role on lowering the starch digestion, which was demonstrated by the results of the Rapid Visco Analyser, scanning electron microscopy, X-ray diffraction and Fourier transform infrared spectroscopy. These findings suggested that cooking rice with tea products, especially Mat, can be useful in enhancing the palatability and slowing the in vitro digestion properties of CR.We show how an asymmetric elasto-magnetic system provides a novel integrated pumping solution for lab-on-a-chip and point of care devices. This monolithic pumping solution, inspired by Purcell’s 3-link swimmer, is integrated within a simple microfluidic device, bypassing the requirement of external connections. We experimentally prove that this system can provide tuneable fluid flow with a flow rate of up to 600 μL h-1. This fluid flow is achieved by actuating the pump using a weak, uniform, uniaxial, oscillating magnetic field, with field amplitudes in the range of 3-6 mT. Crucially, the fluid flow can be reversed by adjusting the driving frequency. We experimentally prove that this device can successfully operate on fluids with a range of viscosities, where pumping at higher viscosity correlates with a decreasing optimal driving frequency. The fluid flow produced by this device is understood here by examining the non-reciprocal motion of the elasto-magnetic component. This device has the capability to replace external pumping systems with a simple, integrated, lab-on-a-chip component.The ternary metal halide perovskites have gradually attracted attention for application in the optoelectronic field, owing to their tunable crystal structure and appropriate bandgap. Lead free Cs3Bi2I9 perovskite, with a 0D layered structure containing molecular [Bi2I9]3- dimers, exhibits prominent optical and electrical anisotropies. Here, the anisotropic properties of the Cs3Bi2I9 crystals were evaluated using terahertz time-domain spectroscopy (THz-TDS); meanwhile, the effect of phonon vibration on the THz transmission was confirmed using density functional perturbation theory (DFPT). Accordingly, the refractive index and extinction coefficient are estimated using THz-TDS, thanks to the high transmission in the range of 0.2-0.9 THz. The anisotropic refractive index was observed for the Cs3Bi2I9 crystals, and was found to be 3.2-3.7 for the (100) plane (CBI(100)) in contrast to 2.8-3.2 for the (001) plane (CBI(001)). Furthermore, the Lorentz model was employed to extract the dielectric constant of Cs3Bi2I9, in which anisotropy is obviously indicated by the static dielectric constant and the high-frequency dielectric constant. These anisotropic behaviors are determined by the dipole moment, which is attributed to the anisotropic packing density of [Bi2I9]3- dimers. This study is significant and provides a deeper insight into the anisotropic photoelectric properties of Cs3Bi2I9, thus contributing to the development of metal halide perovskites in the field of optoelectronics.Structure-guided engineering of Pseudomonas dacunhael-aspartate β-decarboxylase (AspBDC) resulted in a double mutant (R37A/T382G) with remarkable 15 400-fold improvement in specific activity reaching 216 mU mg-1, towards the target substrate 3(R)-benzyl-l-aspartate. A novel strategy for enzymatic synthesis of l-homophenylalanine was developed by using the variant as a biocatalyst affording 75% product yield within 12 h. Our results underscore the potential of engineered AspBDC for the biocatalytic synthesis of pharmaceutically relevant and value added unnatural l-amino acids.Metal organic frameworks (MOFs) have recently attracted considerable research interest in several fields from coordination chemistry and materials science to engineering and medicine not only due to energy and environmental issues but also due to the need for new paradigms of efficiency and sustainability according to the requirements of the 21st century global society. Because of their crystalline and organic-inorganic nature, they are able to crystallize constituting intergrown architectures ductile enough to be patterned, with the use of appropriate techniques, as nano- and micro-devices with multiple applications. This perspective comprehensively summarizes the recent state of the art in the use of top-down and bottom-up methodologies to create MOF structures with a defined pattern at the nano- and micro-scale.Hexagonal LaF3Yb3+/Ln3+ and tetragonal LaOFYb3+/Ln3+ (Ln = Ho, Tm, Er) have been successfully prepared via a two-step reaction, which includes a facile aqueous ligand free solution method and the following heat treatment of the as-prepared LaF3 precursor. The phase formation evolution from LaF3 to LaOF with different phase structures was characterized by X-ray diffraction (XRD), scanning electron microscopy, Fourier transform infrared, and Raman spectroscopy. At an annealing temperature of 500 °C pure hexagonal LaF3Yb3+/Ln3+ (Ln = Ho, Tm, Er) nanoparticles with an average size of 32 nm were obtained and they showed a strong visible upconversion and a modest infrared emission upon 976 nm laser excitation. Further, using an annealing temperature of 900 °C, tetragonal LaOFYb3+/Ln3+ (Ln = Ho, Tm, Er) nanoparticles with a size of around 44 nm were obtained (obtained from XRD) and an expressive enhancement in the emission of the VIS and near-infrared regions was observed. These results envision applications that require efficient emissions such as fluorescent and thermal images, and LaF3 nanocrystals have recently been widely explored for applications in biological systems.Polyelectrolyte complexes (PECs) are highly tunable materials that result from the phase separation that occurs upon mixing oppositely charged polymers. Over the years, they have gained interest due to their broad range of applications such as drug delivery systems, protective coatings, food packaging, and surface adhesives. In this review, we summarize the structure, phase transitions, chain dynamics, and rheological and thermal properties of PECs. Although most literature focuses upon the thermodynamics and application of PECs, this review highlights the fundamental role of salt and water on mechanical and thermal properties impacting the PEC’s dynamics. A special focus is placed upon experimental results and techniques. Specifically, the review examines phase behaviour and salt partitioning in PECs, as well as different techniques used to measure diffusion coefficients, relaxation times, various superpositioning principles, glass transitions, and water microenvironments in PECs. This review concludes with future areas of opportunity in fundamental studies and best practices in reporting.The electronic and local structural properties of CuO under pressure have been investigated by means of X-ray absorption spectroscopy (XAS) at Cu K edge and ab initio calculations, up to 17 GPa. The crystal structure of CuO consists of Cu motifs within CuO4 square planar units and two elongated apical Cu-O bonds. The CuO4 square planar units are stable in the studied pressure range, with Cu-O distances that are approximately constant up to 5 GPa, and then decrease slightly up to 17 GPa. In contrast, the elongated Cu-O apical distances decrease continuously with pressure in the studied range. An anomalous increase of the mean square relative displacement (EXAFS Debye-Waller, σ2) of the elongated Cu-O path is observed from 5 GPa up to 13 GPa, when a drastic reduction takes place in σ2. This is interpreted in terms of local dynamic disorder along the apical Cu-O path. At higher pressures (P > 13 GPa), the local structure of Cu2+ changes from a 4-fold square planar to a 4+2 Jahn-Teller distorted octahedral ion. We interpret these results in terms of the tendency of the Cu2+ ion to form favorable interactions with the apical O atoms. Also, the decrease in Cu-O apical distance caused by compression softens the normal mode associated with the out-of-plane Cu movement. CuO is predicted to have an anomalous rise in permittivity with pressure as well as modest piezoelectricity in the 5-13 GPa pressure range. In addition, the near edge features in our XAS experiment show a discontinuity and a change of tendency at 5 GPa. For P less then 5 GPa the evolution of the edge shoulder is ascribed to purely electronic effects which also affect the charge transfer integral. This is linked to a charge migration from the Cu to O, but also to an increase of the energy band gap, which show a change of tendency occurring also at 5 GPa.The luminescent and proton conductive Pt(ii) complex [PtCl(tpy-o-py)]Cl and its HCl adduct [PtCl(tpy-o-pyH)]Cl2 (o-Pt and o-Pt·HCl, respectively; tpy-o-py = 2,2’6′,2”-terpyridine-6′,2”’-pyridine) were synthesised and their crystal structures, vapochromic behaviour, and proton conduction, were investigated and compared to those of the para isomers [PtCl(tpy-p-py)]Cl and [PtCl(tpy-p-pyH)]Cl2 (p-Pt and p-Pt·HCl, respectively; tpy-p-py = 2,2’6′,2”-terpyridine-4′,4”’-pyridine). X-ray structure analysis revealed that the intermolecular metallophilic (PtPt) interaction was negligible in o-Pt but effective in o-Pt·HCl. Reversible transformation between o-Pt and o-Pt·HCl coupled with significant colour and luminescence changes was achieved by four different external stimuli, namely exposure of o-Pt to humid HCl gas to form o-Pt·HCl, heating, exposure to MeOH vapour, and finally drying in air to regenerate the original o-Pt. The intraligand π-π* orange emission observed for o-Pt exhibited negligible dependence on the relative humidity (RH). Conversely, o-Pt·HCl exhibited red metal-metal-to-ligand charge-transfer (MMLCT) phosphorescence at 725 nm, originating from effective intermolecular Pt-Pt interactions, and interesting vapochromic behaviour that was dependent on the RH. Notably, o-Pt·HCl presented higher conductivity than the p-Pt·HCl isomer at RH 80%, probably owing to the second water-adsorption-induced transformation of p-Pt·HCl. The cooperative phenomenon between the proton conduction and vapochromic behaviour observed for both o-Pt·HCl and p-Pt·HCl should allow the visualisation of the proton-conducting pathway, without the need for a bulk electrode, via the absorption and emission colours at both macroscopic and microscopic levels.We have performed the measurements of the optical Kerr effect signal time evolution up to 4 ns for a mixture of 1-alkyl-3-methyl-imidazolium hexafluorophosphate (BMIM PF6) ionic liquid and acetonitrile in the whole mole fractions range. The long delay line in our experimental setup allowed us to capture the complete reorientational dynamics of the ionic liquid. We have analysed the optical Kerr effect signal in the time and frequency domains with help of molecular dynamics simulations. In our approximation of the slow picosecond dynamics with a multi-exponential decay, we distinguish three relaxation times. The highest two are assigned to the reorientation of the cation and acetonitrile molecules that are in the vicinity of the imidazolium ring. The third one is recognized as originating from cation rotations and reorientation of acetonitrile molecules in the bulk or in the vicinity of the aliphatic chains of the cation. With help of the simulation we interpret the intermolecular band in the reduced spectral density, obtained from Kerr signal, as follows its low-frequency side results from oscillations of one of the components in the cage formed by its neighbors, while the high-frequency side is attributed to the librations of the cation and acetonitrile molecule as well as the intermolecular oscillations of system components involved in specific interactions. We use this assignment and concentration dependence of the spectra obtained from velocity and angular velocity correlations to explain the mole fraction dependence of Kerr reduced spectral density.To ensure the ultimate high-quality imaging of super-resolution fluorescence microscopy with increasingly high resolution, it is significant to use small specific fluorescent probes. Compared with the common biological fluorescent labeling technology, because of small size, strong specificity, abundance and special binding sites, single-targeted small-molecule inhibitors (SMIs) can link with organic dyes to form small fluorescent probes for various biomolecules. Herein, to confirm the feasibility of the SMI-probes, epidermal growth factor (EGF) receptor (EGFR)-targeted tyrosine kinase inhibitor Gefitinib was selected for modification with the fluorescent dye to form Gefitinib-probe. Then, the labeling superiority of Gefitinib-probe was revealed by comparing the direct stochastic optical reconstruction microscopy (dSTORM) images of EGFR labeled with different probes. Additionally, a high co-localization of fluorescent points from Gefitinib-probe and EGF-probe labeling indicated a high specificity of Gefitinib-probe to EGFR. Finally, higher co-localization of EGFR and HER3 labeled with the probe pair containing Gefitinib-probe than with the antibody-probe pair suggested that Gefitinib-probe with a cytoplasmic binding site benefited dual-color imaging. These results indicate that the SMI-probes are able to serve as versatile labeling tools for high-quality super-resolution imaging.Yield stress fluids are widely used in industrial application to arrest dense solid particles, which can be studied by using a concentrated emulsion as a model fluid. We show in experiments that particle sedimentation in emulsions cannot be predicted by the classical criterion for spheres embedded in a yield stress fluid. Phase separation processes take place, where a liquid layer forms and particle sedimentation is enhanced by the emulsion drainage. In addition, emulsion drainage can be arrested or enhanced by the amount of particles embedded in the emulsion. A minimal mathematical model is developed and solved in numerical simulations to describe the emulsion drainage in the presence of particles, which favorably compares with the experimental stability diagram and the sedimentation dynamics.Correction for 'Aqueous surface gels as low friction interfaces to mitigate implant-associated inflammation’ by Allison L. Chau et al., J. Mater. Chem. B, 2020, 8, 6782-6791, DOI .Formaldehyde levels in the atmosphere are a concern in the indoor and outdoor air and many methods for determining this compound have been developed. The use of 2,4-dinitrophenylhydrazine (DNPH) for reaction with formaldehyde, catalyzed by acid, forming a hydrazone derivative in cartridges is considered the standard method for analyzing formaldehyde compounds in the air. However, formaldehyde is quantified using an analytical curve, created by diluting liquid standards of the formaldehyde-DNPH product. The analysis aims to quantify the gas phase formaldehyde, and it may be subject to experimental biases from the differences in the matrix of the sample (gas) and calibration standard (liquid). The objective of this work was to build an analytical curve in the gaseous phase using a synthetic air/formaldehyde mixing system (SFMS) and sampling with SPE-DNPH-tubes, comparing with the analytical curve in the liquid phase adopted by the Environmental Protection Agency (EPA). Parameters of linearity, sensitivity, limit of detection (LOD), limit of quantification (LOQ), precision and accuracy (recovery) were determined from the analytical curve in the gaseous phase. The best recovery in DNPH-tubes was obtained using the range of 400-1600 mL min-1 of flow rates in the gaseous phase. The sampling and reaction/elution of formaldehyde using DNPH-tubes presented adequate linearity and a similar sensitivity in the liquid analytical curve. Considering the LOD and LOQ in the gaseous phase, the values in nanograms are higher than those in the liquid phase. This study suggests that the quantification of formaldehyde in ambient air may be subject to bias due to differences in derivatization reaction efficiency. However, the results prove the efficiency of formaldehyde recovery from the atmosphere and the validity of the use of this DNPH-tube method.This work presents a novel deep learning method to combine segmentation and motion tracking in 4D echocardiography. The network iteratively trains a motion branch and a segmentation branch. The motion branch is initially trained entirely unsupervised and learns to roughly map the displacements between a source and a target frame. The estimated displacement maps are then used to generate pseudo-ground truth labels to train the segmentation branch. The labels predicted by the trained segmentation branch are fed back into the motion branch and act as landmarks to help retrain the branch to produce smoother displacement estimations. These smoothed out displacements are then used to obtain smoother pseudo-labels to retrain the segmentation branch. Additionally, a biomechanically-inspired incompressibility constraint is implemented in order to encourage more realistic cardiac motion. The proposed method is evaluated against other approaches using synthetic and in-vivo canine studies. Both the segmentation and motion tracking results of our model perform favorably against competing methods.Unfolded protein response (UPR) suppression by Kifunensine has been associated with lung hyperpermeability, the hallmark of Acute Respiratory Distress Syndrome. The present study investigates the effects of the heat shock protein 90 inhibitor Luminespib (AUY-922) towards the Kifunensine-triggered lung endothelial dysfunction. Our results indicate that the UPR inducer Luminespib counteracts the effects of Kifunensine in both human and bovine lung endothelial cells. Hence, we suggest that UPR manipulation may serve as a promising therapeutic strategy against potentially lethal respiratory disorders, including the ARDS related to COVID-19.Naturally occurring phyllosilicate minerals such as talc and vermiculite in conjunction with n-tetra butyl ammonium bromide (TBAB) co-catalyst were found to be efficient in the coupling of CO2 with epoxides to form cyclic carbonates. The reaction was carried out in a pressurized autoclave reactor at moderate pressures of 10-35 bars and temperatures of 100-150 °C. The optimized catalyst system exhibited > 90% conversion of the epoxides and > 90% selectivity for the desired cyclic carbonates, in the presence or absence of a solvent. The selectivity of the catalytic system could be improved with heat pre-treatment of the phyllosilicates albeit this resulted in slightly lower epoxide conversion. The results obtained using the heat treated phyllosilicates strongly support the hydrogen bond assisted mechanism for the cycloaddition of epoxides and CO2. The cycloaddition reaction could also be carried out in the absence of TBAB, although lower cyclic carbonate yields were observed. The phyllosilicate part of the catalyst system is heterogeneous, easy to separate after completion of reactions and reusable a number of runs without loss of activity.Identification of an active center of catalysts under realistic working conditions of oxygen reduction reaction (ORR) still remains a great challenge and unclear. Herein, we synthesize the Cu single atom embedded on nitrogen-doped graphene-like matrix electrocatalyst (abbreviated as SA-Cu/NG). The results show that SA-Cu/NG possesses a higher ORR capability than 20% Pt/C at alkaline solution while the inferior activity to 20% Pt/C at acidic medium. Based on the experiment and simulation calculation, we identify the atomic structure of Cu-N2C2 in SA-Cu/NG and for the first time unravels that the oxygen-reconstituted Cu-N2C2-O structure is really the active species of alkaline ORR, while the oxygen reconstitution does not happen at acidic medium. The finding of oxygen-reconstituted active species of SA-Cu/NG at alkaline media successfully unveils the bottleneck puzzle of why the performance of ORR catalysts at alkaline solution is better than that at acidic media, which provides new physical insight into the development of new ORR catalysts.Binding motifs for transcription factors, RNA-binding proteins, microRNAs (miRNAs), etc. are vital for proper gene transcription and translation regulation. Sequence alteration mechanisms including single nucleotide mutations, insertion, deletion, RNA editing and single nucleotide polymorphism can lead to gains and losses of binding motifs; such consequentially emerged or vanished binding motifs are termed 'somatic motifs’ by us. Somatic motifs have been studied sporadically but have never been curated into a comprehensive resource. By analyzing various types of sequence altering data from large consortiums, we successfully identified millions of somatic motifs, including those for important transcription factors, RNA-binding proteins, miRNA seeds and miRNA-mRNA 3′-UTR target motifs. While a few of these somatic motifs have been well studied, our results contain many novel somatic motifs that occur at high frequency and are thus likely to cause important biological repercussions. Genes targeted by these altered motifs are excellent candidates for further mechanism studies. Here, we present the first database that hosts millions of somatic motifs ascribed to a variety of sequence alteration mechanisms.Diffuse large B-cell lymphoma (DLBCL) is a molecularly heterogeneous group of malignancies with frequent genetic abnormalities. G-quadruplex (G4) DNA structures may facilitate this genomic instability through association with activation-induced cytidine deaminase (AID), an antibody diversification enzyme implicated in mutation of oncogenes in B-cell lymphomas. Chromatin immunoprecipitation sequencing analyses in this study revealed that AID hotspots in both activated B cells and lymphoma cells in vitro were highly enriched for G4 elements. A representative set of these targeted sequences was validated for characteristic, stable G4 structure formation including previously unknown G4s in lymphoma-associated genes, CBFA2T3, SPIB, BCL6, HLA-DRB5 and MEF2C, along with the established BCL2 and MYC structures. Frequent genome-wide G4 formation was also detected for the first time in DLBCL patient-derived tissues using BG4, a structure-specific G4 antibody. Tumors with greater staining were more likely to have concurrent BCL2 and MYC oncogene amplification and BCL2 mutations. Ninety-seven percent of the BCL2 mutations occurred within G4 sites that overlapped with AID binding. G4 localization at sites of mutation, and within aggressive DLBCL tumors harboring amplified BCL2 and MYC, supports a role for G4 structures in events that lead to a loss of genomic integrity, a critical step in B-cell lymphomagenesis.APOBEC1 (APO1), a member of AID/APOBEC nucleic acid cytosine deaminase family, can edit apolipoprotein B mRNA to regulate cholesterol metabolism. This APO1 RNA editing activity requires a cellular cofactor to achieve tight regulation. However, no cofactors are required for deamination on DNA by APO1 and other AID/APOBEC members, and aberrant deamination on genomic DNA by AID/APOBEC deaminases has been linked to cancer. Here, we present the crystal structure of APO1, which reveals a typical APOBEC deaminase core structure, plus a unique well-folded C-terminal domain that is highly hydrophobic. This APO1 C-terminal hydrophobic domain (A1HD) interacts to form a stable dimer mainly through hydrophobic interactions within the dimer interface to create a four-stranded β-sheet positively charged surface. Structure-guided mutagenesis within this and other regions of APO1 clarified the importance of the A1HD in directing RNA and cofactor interactions, providing insights into the structural basis of selectivity on DNA or RNA substrates.The pathological deposition of the transactive response DNA-binding protein of 43 kDa occurs in the majority (∼97%) of amyotrophic lateral sclerosis and in around 45% of frontotemporal lobar degeneration cases. Amyotrophic lateral sclerosis and frontotemporal lobar degeneration clinically overlap, presenting a continuum of phenotypes. Both amyotrophic lateral sclerosis and frontotemporal lobar degeneration lack treatments capable of interfering with the underlying pathological process and early detection of transactive response DNA-binding protein of 43 kDa pathology would facilitate the development of disease-modifying drugs. The real-time quaking-induced conversion reaction showed the ability to detect prions in several peripheral tissues of patients with different forms of prion and prion-like diseases. Despite transactive response DNA-binding protein of 43 kDa displays prion-like properties, to date the real-time quaking-induced conversion reaction technology has not yet been adapted to this protein. The by amyotrophic lateral sclerosis and frontotemporal lobar degeneration and age-matched controls with a total sensitivity of 94% and a specificity of 85%. Our data give a proof-of-concept that transactive response DNA-binding protein of 43 kDa is a suitable substrate for the real-time quaking-induced conversion reaction. Transactive response DNA-binding protein of 43 kDa real-time quaking-induced conversion reaction could be an innovative and useful tool for diagnosis and drug development in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. The cerebrospinal fluid detection of transactive response DNA-binding protein of 43 kDa pathological aggregates may be exploited as a disease biomarker for amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients.Stroke is a leading cause of acute death related in part to brain oedema, blood-brain barrier disruption and glial inflammation. A cyclin-dependant kinase inhibitor, (S)-roscovitine, was administered 90 min after onset on a model of rat focal cerebral ischaemia. Brain swelling and Evans Blue tissue extravasation were quantified after Evans Blue injection. Combined tissue Evans Blue fluorescence and immunofluorescence of endothelial cells (RECA1), microglia (isolectin-IB4) and astrocytes (glial fibrillary acidic protein) were analysed. Using a Student’s t-test or Mann-Whitney test, (S)-roscovitine improved recovery by more than 50% compared to vehicle (Mann-Whitney, P  less then  0.001), decreased significantly brain swelling by 50% (t-test, P = 0.0128) mostly in the rostral part of the brain. Main analysis was therefore performed on rostral cut for immunofluorescence to maximize biological observations (cut B). Evans Blue fluorescence decreased in (S)-roscovitine group compared to vehicle (60%, t-test, P = 0. in the treated animals, and positive values in the non-treated animals. Interestingly, stroke recovery presented a negative correlation with this dimension, while all other biological variables showed a positive correlation. Dimensions 1 and 2 allowed the identification of two groups of co-varying variables endothelial cells, microglia number and Evans Blue with positive values on both dimensions, and astrocyte number, astrogliosis and brain swelling with negative values on dimension 2. This partition suggests different mechanisms. Correlation matrix analysis was concordant with principal component analysis results. Because of its pleiotropic complex action on different elements of the NeuroVascular Unit response, (S)-roscovitine may represent an effective treatment against oedema in stroke.Various studies have suggested that a neurotoxic cerebrospinal fluid profile could be implicated in amyotrophic lateral sclerosis. Here, we systematically review the evidence for cerebrospinal fluid cytotoxicity in amyotrophic lateral sclerosis and explore its clinical correlates. We searched the following databases with no restrictions on publication date PubMed, Embase and Web of Science. All studies that investigated cytotoxicity in vitro following exposure to cerebrospinal fluid from amyotrophic lateral sclerosis patients were considered for inclusion. Meta-analysis could not be performed, and findings were instead narratively summarized. Twenty-eight studies were included in our analysis. Both participant characteristics and study conditions including cerebrospinal fluid concentration, exposure time and culture model varied considerably across studies. Of 22 studies assessing cell viability relative to controls, 19 studies reported a significant decrease following exposure to cerebrospinal fluid from patients with amyotrophic lateral sclerosis, while three early studies failed to observe any difference. Seven of eight studies evaluating apoptosis observed significant increases in the levels of apoptotic markers following exposure to cerebrospinal fluid from patients with amyotrophic lateral sclerosis, with the remaining study reporting a qualitative difference. Although five studies investigated the possible relationship between cerebrospinal fluid cytotoxicity and patient characteristics, such as age, gender and disease duration, none demonstrated an association with any of the factors. In conclusion, our analysis suggests that cerebrospinal fluid cytotoxicity is a feature of sporadic and possibly also of familial forms of amyotrophic lateral sclerosis. Further research is, however, required to better characterize its underlying mechanisms and to establish its possible contribution to amyotrophic lateral sclerosis pathophysiology.Monitoring epileptic activity in the absence of interictal discharges is a major need given the well-established lack of reliability of patients’ reports of their seizures. Up to now, there are no other tools than reviewing the seizure diary; however, seizures may not be remembered or dismissed voluntarily. In the present study, we set out to determine if EEG voltage maps of epileptogenic activity in individual patients can help to identify disease activity, even if their scalp EEG appears normal. Twenty-five patients with pharmacoresistant focal epilepsy were included. For each patient, 6 min of EEG with spikes (yes-spike) and without visually detectable epileptogenic discharges (no-spike) were selected from long-term monitoring recordings (EEG 31-37 channels). For each patient, we identified typical discharges, calculated their average and the corresponding scalp voltage map (’spike-map’). We then fitted the spike-map for each patient on their (i) EEG epochs with visible spikes, (ii) epochs without any visible spike and (iii) EEGs of 48 controls. The global explained variance was used to estimate the presence of the spike-maps. The individual spike-map occurred more often in the spike-free EEGs of patients compared to EEGs of healthy controls (P = 0.001). Not surprisingly, this difference was higher if the EEGs contained spikes (P  less then  0.001). In patients, spike-maps were more frequent per second (P  less then  0.001) but with a shorter mean duration (P  less then  0.001) than in controls, for both no-spike and yes-spike EEGs. The amount of spike-maps was unrelated to clinical variables, like epilepsy severity, drug load or vigilance state. Voltage maps of spike activity are present very frequently in the scalp EEG of patients, even in presumably normal EEG. We conclude that spike-maps are a robust and potentially powerful marker to monitor subtle epileptogenic activity.A healthy mitochondrial network is essential for the maintenance of neuronal synaptic integrity. Mitochondrial and metabolic dysfunction contributes to the pathogenesis of many neurodegenerative diseases including dementia. OPA1 is the master regulator of mitochondrial fusion and fission and is likely to play an important role during neurodegenerative events. To explore this, we quantified hippocampal dendritic and synaptic integrity and the learning and memory performance of aged Opa1 haploinsufficient mice carrying the Opa1Q285X mutation (B6; C3-Opa1Q285STOP ; Opa1+/- ). We demonstrate that heterozygous loss of Opa1 results in premature age-related loss of spines in hippocampal pyramidal CA1 neurons and a reduction in synaptic density in the hippocampus. This loss is associated with subtle memory deficits in both spatial novelty and object recognition. We hypothesize that metabolic failure to maintain normal neuronal activity at the level of a single spine leads to premature age-related memory deficits. These results highlight the importance of mitochondrial homeostasis for maintenance of neuronal function during ageing.Co-occurrence of tau and α-synuclein pathologies in a subset of Alzheimer’s disease patients has led to the idea that mixed pathologies may play a unique characteristic role in the Alzheimer’s disease neurodegenerative cascade. To understand the aetiology of such mixed pathologies, we investigated cross-seeding by human recombinant tau and human recombinant α-synuclein fibrillar species in a mouse model of tauopathy (Line PS19) or synucleinopathy (Line M20). Unilateral hippocampal injection of tau fibrils or α-synuclein fibrils, and to a lesser extent tau + α-synuclein copolymer fibrils prepared from co-incubating individual recombinant monomers, induced robust phosphorylated tau pathology in PS19 mice relative to control mice. Though the tau + α-synuclein copolymer fibrils did not modulate induction of pathologies at the site of injection, examination of the whole brain showed that these copolymers exacerbated neuroanatomic transmission of seeded tau pathology compared to tau fibril-injected mice. Only α-syn the whole brain of M20 mice showed that tau + α-synuclein copolymer-injected mice had lower abundance of bilaterally transmitted α-synuclein pathologies relative to α-synuclein fibril-injected mice. Thus, the tau + α-synuclein copolymer fibrils show robust transmission properties preferentially in rodent model of tauopathies but not in synucleinopathy, probably signifying an enhanced cooperative relationship between tau and α-synuclein in the tau seeding process. Together, our data highlight the unique cross-seeding properties of tau and αSyn in neurodegenerative proteinopathies.Regulation of actin cytoskeleton dynamics in dendritic spines is crucial for learning and memory formation. Hence, defects in the actin cytoskeleton pathways are a biological trait of several brain diseases, including Alzheimer’s disease. Here, we describe a novel synaptic mechanism governed by the cyclase-associated protein 2, which is required for structural plasticity phenomena and completely disrupted in Alzheimer’s disease. We report that the formation of cyclase-associated protein 2 dimers through its Cys32 is important for cyclase-associated protein 2 binding to cofilin and for actin turnover. The Cys32-dependent cyclase-associated protein 2 homodimerization and association to cofilin are triggered by long-term potentiation and are required for long-term potentiation-induced cofilin translocation into spines, spine remodelling and the potentiation of synaptic transmission. This mechanism is specifically affected in the hippocampus, but not in the superior frontal gyrus, of both Alzheimer’s disease patients and APP/PS1 mice, where cyclase-associated protein 2 is down-regulated and cyclase-associated protein 2 dimer synaptic levels are reduced. Notably, cyclase-associated protein 2 levels in the cerebrospinal fluid are significantly increased in Alzheimer’s disease patients but not in subjects affected by frontotemporal dementia. In Alzheimer’s disease hippocampi, cofilin association to cyclase-associated protein 2 dimer/monomer is altered and cofilin is aberrantly localized in spines. Taken together, these results provide novel insights into structural plasticity mechanisms that are defective in Alzheimer’s disease.Alport syndrome affects up to 60,000 people in the United States. The proposed reclassification of thin basement membrane nephropathy and some cases of focal segmental glomerulosclerosis as Alport syndrome could substantially increase the affected population. The reclassification scheme categorizes Alport syndrome as 3 distinct diseases of type IV collagen α3/4/5 based on a genetic evaluation X-linked, autosomal, and digenic. This approach has the advantage of identifying patients at risk for progressive loss of kidney function. Furthermore, the shared molecular cause of Alport syndrome and thin basement membrane nephropathy arises from mutations in the COL4A3, COL4A4, and COL4A5 genes, which contribute to downstream pathophysiologic consequences, including chronic kidney inflammation. Recent evidence indicates that chronic inflammation and its regulation through anti-inflammatory nuclear factor erythroid 2-related factor 2 (Nrf2) and proinflammatory nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) transcription factors plays a central role in renal tubular and glomerular cell responses to injury. Crosstalk between the Nrf2 and NF-κB pathways is important in the regulation of inflammation in patients with chronic kidney disease; moreover, there is evidence that an insufficient Nrf2 response to inflammation contributes to disease progression. Given the association between type IV collagen abnormalities and chronic inflammation, there is renewed interest in targeted anti-inflammatory therapies in Alport syndrome and other forms of progressive chronic kidney disease.There is a well-established yet unexplained high prevalence of cardiovascular morbidity and mortality in individuals with end-stage kidney disease receiving dialysis. Potential causes include changes in cardiac structure and function, with increased left ventricular mass index as the best established cardiac structural change associated with this increase in mortality. However, in recent years, new echocardiographic and cardiac magnetic resonance imaging techniques have emerged that may provide novel markers that may better explain the mechanisms underlying the cardiovascular morbidity and mortality observed in end-stage kidney disease. This review outlines advances in cardiac imaging and the current status of imaging modalities, including echocardiography, cardiac magnetic resonance imaging, and cardiac positron emission tomography, to identify dialysis patients at high risk for cardiovascular mortality.

Left ventricular (LV) mass (LVM) is a predictor of cardiovascular morbidity and mortality and commonly calculated using 1-dimensional (1D) echocardiographic methods. These methods are vulnerable to small measurement errors and LVM may wrongly change according to changes in LV volume (LVV). Less commonly used 2-dimensional (2D) methods can accommodate to the changes in LVV and may be a better alternative among patients receiving hemodialysis (HD) with large fluid fluctuations.

Observational study.

Patients with end-stage kidney disease receiving HD.

One HD session.

Transthoracic echocardiography was performed right before and after HD. LVM was calculated using 1D (Devereux, Penn, and Teichholz) and 2D methods (truncated ellipsoid and area-length).

Significant differences in LVM after HD.

We compared dimensions, LVV and LVM, in 53 patients (mean age, 63±15 years; 66% men). For each 1-L increase in ultrafiltration volume (UFV), LV internal diameter decreased 1.1mm (95% CI, 0.5-1.7mm;

=0.001). Paty fluctuations in fluid and LVV, in contrast to 1D methods. Complementary LVM calculation using 2D methods is encouraged, especially in patients with large fluid fluctuations in which increased LVM using a 1D method has been detected.

Recent evidence suggests that adults with cerebral palsy have an elevated risk for developing advanced chronic kidney disease (CKD). To develop effective interventions, the objective was to identify whether demographics and preexisting medical conditions are risk factors for advanced CKD among adults with cerebral palsy.

Retrospective cohort study.

Data were from the Optum Clinformatics Data Mart. Adults 18 years or older with cerebral palsy and without advanced CKD (CKD stage 4 or later) were identified from 2013 and subsequently followed up from January 1, 2014, to the development of advanced CKD, death, loss to follow-up, or end of the study period (December 31, 2017), whichever came first. Diagnostic, procedure, and diagnosis-related group codes were used to identify cerebral palsy, incident cases of advanced CKD, comorbid intellectual disability, and 10 preexisting medical conditions.

Demographic variables and 10 preexisting medical conditions CKD stages 1-3, hypertension, diabetes, heart and cer, and non-CKD urologic conditions (HR, 1.39; 95% CI, 1.05-1.84).

Private insurance database, short follow-up period, and lack of laboratory values, such as albuminuria/proteinuria.

Advanced CKD was common among adults with cerebral palsy and its development was associated with both traditional and nontraditional urologic risk factors.

Advanced CKD was common among adults with cerebral palsy and its development was associated with both traditional and nontraditional urologic risk factors.

The response to corticosteroid therapy may differ among patients with minimal change disease (MCD). Previous studies have suggested that glomerular hypertrophy or low areal glomerular density in biopsy specimens, which may be related to fewer nephrons, is associated with such a difference. We examined the associations between nephron number and the therapeutic response to corticosteroids in patients with MCD.

Retrospective cohort study.

75 adult patients with a histologic diagnosis of MCD.

Nephron number per kidney estimated based on the combination of unenhanced computed tomography and nonsclerotic volumetric glomerular density in kidney biopsy specimens.

Complete remission and relapse following corticosteroid therapy.

Multivariable Cox proportional hazard analyses of associations between factors, including nephron number, and outcomes.

Mean age of patients was 45.9 years and 60.0% were men. Patients had an estimated glomerular filtration rate of 64.6mL/min/1.73m

and proteinuria of 8.7g/d. Thte remission.

Attention to geriatric impairments is not routinely provided to older adults receiving dialysis. Our objective was to identify patient and personnel perspectives on experiences with geriatric problems, unmet needs that may affect a patient’s ability to maintain his or her functional status, and preferences for design of a geriatric model of care tailored to address the unmet needs.

Qualitative study using semi-structured interviews and focus groups.

14 hemodialysis patients 55 years and older and 24 dialysis unit personnel (eg, nephrologists, nurses, patient care technicians, and social workers) representing 5 dialysis units.

Content analysis to identify themes reflecting unmet needs and design considerations for a geriatric model of care for older adults receiving dialysis.

4 themes (or unmet needs) identified from both patient and personnel transcripts were (1) mobility, which referred to the insufficient mobility assessment and transportation services; (2) medications, which referred to insufficicient attention to mobility, medication management, social support, and communication needs for older adults receiving in-center hemodialysis. Addressing these unmet needs in a geriatric model of care and measuring its effectiveness are areas of future research.Grazing-based dairy operations require productive, high-quality forages capable of supporting the nutritional needs of mid-lactation dairy cows. Our objectives were to evaluate primary and regrowth harvests of two cultivars of sudangrass (SU), sorghum-sudangrass (S×SU), and pearl millet (PM) forages for growth and nutritive characteristics within the specific context of suitability for grazing by dairy cows. Three harvest cycles, including primary and regrowth cycles in 2016, and a single harvest cycle of primary growth in 2017, were evaluated at two locations (Prairie du Sac and Marshfield, WI). Within each cycle, sampling was initiated when canopy height was about 41 cm and continued thereafter on weekly intervals for 5 weeks, resulting in six equally spaced sampling dates per harvest cycle. Data were analyzed as a split-plot design with cultivars (6) as whole-plots arranged in randomized complete blocks and weekly harvest dates (6) as subplots. Yields of dry matter (DM) were less consistent at the more northern location (Marshfield), which is known for its heavier, poorly drained soils.