Nanoscopic Interfacial Hydrogel Viscoelasticity Revealed from Comparison of Macroscopic and Microscopic Rheology.

Deviations between macrorheological and particle-based microrheological measurements are often considered to be a nuisance and neglected. We study aqueous poly(ethylene oxide) (PEO) hydrogels for varying PEO concentrations and chain lengths that contain microscopic tracer particles and show that these deviations reveal the nanoscopic viscoelastic properties of the particle-hydrogel interface. Based on the transient Stokes equation, we first demonstrate that the deviations are not due to finite particle radius, compressibility, or surface-slip effects. Small-angle neutron scattering rules out hydrogel heterogeneities. Instead, we show that a generalized Stokes-Einstein relation, accounting for an interfacial shell around tracers with viscoelastic properties that deviate from bulk, consistently explains our macrorheological and microrheological measurements. The extracted shell diameter is comparable to the PEO end-to-end distance, indicating the importance of dangling chain ends. Our methodology reveals the nanoscopic interfacial rheology of hydrogels and is applicable to different kinds of viscoelastic fluids and particles.

Hysteretic Piezochromism in a Lead Iodide-Based Two-Dimensional Inorganic-Organic Hybrid Perovskite.

Two-dimensional inorganic-organic hybrid perovskites are in the limelight due to their potential applications in photonics and optoelectronics. They are environmentally stable, and their various chemical compositions offer a wide range of bandgap energies. Alternatively, crystal deformation enables in situ control over their optical properties. Here, we investigate (C6H9C2H4NH3)2PbI4, a hybrid perovskite whose organic linkers are 2-(1-cyclohexenyl)ethylammonium. Pressure-dependent optical absorption and emission spectroscopy reveal a hysteretic piezochromism that was not reported for other lead iodide-based 2D perovskites. We combine our optical studies with high-pressure X-ray diffraction experiments and first-principles calculations to demonstrate that the deformation of the inorganic lead iodide layers is the main reason for the observed changes in the optical bandgap.

How I treat and prevent venous thrombotic complications in patients with lymphoma.

Venous thromboembolism (VTE) is a common complication occurring in 5% to 10% of patients with lymphoma. As the complexity of lymphoma management has increased with novel therapies, so too has the treatment of VTE. Therapeutic options for the treatment of cancer-associated VTE have expanded from only warfarin and low-molecular-weight heparins (LMWHs) to include the direct oral anticoagulants (DOACs) apixaban, edoxaban and rivaroxaban. There have been no head-to-head trials comparing different DOACs in this setting, and randomized trials comparing a DOAC with LMWH dalteparin differ in trial design and results. Drug-drug interactions, drug-specific side effects, and patient selection are important considerations when prescribing anticoagulant therapy. In all patients, the relative risks of thrombosis and bleeding, the availability of the anticoagulant, and the life expectancy of the patient are vital elements in selecting the most appropriate anticoagulant (which can vary over time) for the individual patient. We describe the intricacies and challenges of treating thrombotic complications in patients with lymphoma with an emphasis on evidence and guideline-based care.

The incidence of transfusion-related acute lung injury using active surveillance: A systematic review and meta-analysis.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a leading cause of transfusion-related mortality. A concern with passive surveillance to detect transfusion reactions is underreporting. Our aim was to obtain evidence-based estimates of TRALI incidence using meta-analysis of active surveillance studies and to compare these estimates with passive surveillance. STUDY DESIGN AND METHODS: We performed a systematic review and meta-analysis of studies reporting TRALI rates. A search of Medline and Embase by a research librarian identified studies published between January 1, 1991 and January 20, 2023. Prospective and retrospective observational studies reporting TRALI by blood component (red blood cells [RBCs], platelets, or plasma) were identified and all inpatient and outpatient settings were eligible. Adult and pediatric, as well as general and specific clinical populations, were included. Platelets and plasma must have used at least one modern TRALI donor risk mitigation strategy. A random effects model estimated TRALI incidence by blood component for active and passive surveillance studies and heterogeneity was examined using meta-regression. RESULTS: Eighty studies were included with approximately 176-million blood components transfused. RBCs had the highest number of studies (n = 66) included, followed by platelets (n = 35) and plasma (n = 34). Pooled TRALI estimates for active surveillance studies were 0.17/10,000 (95% confidence intervals [CI]: 0.03-0.43; I2 = 79%) for RBCs, 0.31/10,000 (95% CI: 0.22-0.42; I2 = <1%) for platelets, and 3.19/10,000 (95% CI: 0.09-10.66; I2 = 86%) for plasma. Studies using passive surveillance ranged from 0.02 to 0.10/10,000 among the various blood components. DISCUSSION: In summary, these estimates may improve a quantitative understanding of TRALI risk, which is important for clinical decision-making weighing the risks and benefits of transfusion.

How Chromophore Labels Shape the Structure and Dynamics of a Peptide Hydrogel.

Biocompatible and functionalizable hydrogels have a wide range of (potential) medicinal applications. The hydrogelation process, particularly for systems with very low polymer weight percentages (<1 wt %), remains poorly understood, making it challenging to predict the self-assembly of a given molecular building block into a hydrogel. This severely hinders the rational design of self-assembled hydrogels. In this study, we demonstrate the impact of an N-terminal group on the self-assembly and rheology of the peptide hydrogel hFF03 (hydrogelating, fibril forming peptide 03) using molecular dynamics simulations, oscillatory shear rheology, and circular dichroism spectroscopy. We find that the chromophore and even its specific regioisomers have a significant influence on the microscopic structure and dynamics of the self-assembled fibril, and on the macroscopic mechanical properties. This is because the chromophore influences the possible salt bridges, which form and stabilize the fibril formation. Furthermore, we find that the solvation shell fibrils by itself cannot explain the viscoelasticity of hFF03 hydrogels. Our atomistic model of the hFF03 fibril formation enables a more rational design of these hydrogels. In particular, altering the N-terminal chromophore emerges as a design strategy to tune the mechanic properties of these self-assembled peptide hydrogels.

Comprehensive Characterization of the Viscoelastic Properties of Bovine Submaxillary Mucin (BSM) Hydrogels and the Effect of Additives.

This study presents a comprehensive characterization of the viscoelastic and structural properties of bovine submaxillary mucin (BSM), which is widely used as a commercial source to conduct mucus-related research. We conducted concentration studies of BSM and examined the effects of various additives, NaCl, CaCl2, MgCl2, lysozyme, and DNA, on its rheological behavior. A notable connection between BSM concentration and viscoelastic properties was observed, particularly under varying ionic conditions. The rheological spectra could be well described by a fractional Kelvin-Voigt model with a minimum of model parameters. A detailed proteomics analysis provided insight into the protein, especially mucin composition within BSM, showing MUC19 as the main component. Cryo-scanning electron microscopy enabled the visualization of the porous BSM network structure. These investigations give us a more profound comprehension of the BSM properties, especially those pertaining to viscoelasticity, and how they are influenced by concentration and environmental conditions, aspects relevant to the field of mucus research.

Generalized vs. fractional: a comparative analysis of Maxwell models applied to entangled polymer solutions.

Fractional viscoelastic models provide an excellent description of rheological data for polymer systems with power-law behaviour. However, the physical interpretation of their model parameters, which carry fractional units of time, often remains elusive. We show that for poly(ethylene oxide) (PEO) solutions, the fractional Maxwell model (FMM) requires much fewer model parameters than the classical generalized Maxwell model for a good description of the data and that it can be applied consistently to solutions with varying degrees of viscoelasticity. Despite their fractional units, the parameters exhibit scaling laws similar to classical parameters as a function of polymer concentration.

SpaceGrow: efficient shape-based virtual screening of billion-sized combinatorial fragment spaces.

The growing size of make-on-demand chemical libraries is posing new challenges to cheminformatics. These ultra-large chemical libraries became too large for exhaustive enumeration. Using a combinatorial approach instead, the resource requirement scales approximately with the number of synthons instead of the number of molecules. This gives access to billions or trillions of compounds as so-called chemical spaces with moderate hardware and in a reasonable time frame. While extremely performant ligand-based 2D methods exist in this context, 3D methods still largely rely on exhaustive enumeration and therefore fail to apply. Here, we present SpaceGrow: a novel shape-based 3D approach for ligand-based virtual screening of billions of compounds within hours on a single CPU. Compared to a conventional superposition tool, SpaceGrow shows comparable pose reproduction capacity based on RMSD and superior ranking performance while being orders of magnitude faster. Result assessment of two differently sized subsets of the eXplore space reveals a higher probability of finding superior results in larger spaces highlighting the potential of searching in ultra-large spaces. Furthermore, the application of SpaceGrow in a drug discovery workflow was investigated in four examples involving G protein-coupled receptors (GPCRs) with the aim to identify compounds with similar binding capabilities and molecular novelty.

Impact of glycan nature on structure and viscoelastic properties of glycopeptide hydrogels.

Mucus is a complex biological hydrogel that acts as a barrier for almost everything entering or exiting the body. It is therefore of emerging interest for biomedical and pharmaceutical applications. Besides water, the most abundant components are the large and densely glycosylated mucins, glycoproteins of up to 20 MDa and carbohydrate content of up to 80 wt%. Here, we designed and explored a library of glycosylated peptides to deconstruct the complexity of mucus. Using the well-characterized hFF03 coiled-coil system as a hydrogel-forming peptide scaffold, we systematically probed the contribution of single glycans to the secondary structure as well as the formation and viscoelastic properties of the resulting hydrogels. We show that glycan-decoration does not affect α-helix and coiled-coil formation while it alters gel stiffness. By using oscillatory macrorheology, dynamic light scattering microrheology, and fluorescence lifetime-based nanorheology, we characterized the glycopeptide materials over several length scales. Molecular simulations revealed that the glycosylated linker may extend into the solvent, but more frequently interacts with the peptide, thereby likely modifying the stability of the self-assembled fibers. This systematic study highlights the interplay between glycan structure and hydrogel properties and may guide the development of synthetic mucus mimetics.

Low-Divergence hBN Single-Photon Source with a 3D-Printed Low-Fluorescence Elliptical Polymer Microlens.

Efficiently collecting light from single-photon emitters is crucial for photonic quantum technologies. Here, we develop and use an ultralow fluorescence photopolymer to three-dimensionally print micrometer-sized elliptical lenses on individual precharacterized single-photon emitters in hexagonal boron nitride (hBN) nanocrystals, operating in the visible regime. The elliptical lens design beams the light highly efficiently into the far field, rendering bulky objective lenses obsolete. Using back focal plane imaging, we confirm that the emission is collimated to a narrow low-divergence beam with a half width at half-maximum of 2.2°. Using photon correlation measurements, we demonstrate that the single-photon character remains undisturbed by the polymer lens. The strongly directed emission and increased collection efficiency is highly beneficial for quantum optical experiments. Furthermore, our approach paves the way for a highly parallel fiber-based detection of single photons from hBN nanocrystals.

Pressure Dependence of Intra- and Interlayer Excitons in 2H-MoS2 Bilayers.

The optical and electronic properties of multilayer transition metal dichalcogenides differ significantly from their monolayer counterparts due to interlayer interactions. The separation of individual layers can be tuned in a controlled way by applying pressure. Here, we use a diamond anvil cell to compress bilayers of 2H-MoS2 in the gigapascal range. By measuring optical transmission spectra, we find that increasing pressure leads to a decrease in the energy splitting between the A and the interlayer exciton. Comparing our experimental findings with ab initio calculations, we conclude that the observed changes are not due to the commonly assumed hydrostatic compression. This effect is attributed to the MoS2 bilayer adhering to the diamond, which reduces the in-plane compression. Moreover, we demonstrate that the distinct real-space distributions and resulting contributions from the valence band account for the different pressure dependencies of the inter- and intralayer excitons in compressed MoS2 bilayers.

Aberrant Phase Precession of Lateral Septal Cells in a Maternal Immune Activation Model of Schizophrenia Risk May Disrupt the Integration of Location with Reward.

Spatial memory and reward processing are known to be disrupted in schizophrenia. Since the lateral septum (LS) may play an important role in the integration of location and reward, we examined the effect of maternal immune activation (MIA), a known schizophrenia risk factor, on spatial representation in the rat LS. In support of a previous study, we found that spatial location is represented as a phase code in the rostral LS of adult male rats, so that LS cell spiking shifts systematically against the phase of the hippocampal, theta-frequency, local field potential as an animal moves along a track toward a reward (phase precession). Whereas shallow precession slopes were observed in control group cells, they were steeper in the MIA animals, such that firing frequently precessed across several theta cycles as the animal moved along the length of the apparatus, with subsequent ambiguity in the phase representation of location. Furthermore, an analysis of the phase trajectories of the control group cells revealed that the population tended to converge toward a common firing phase as the animal approached the reward location. This suggested that phase coding in these cells might signal both reward location and the distance to reward. By comparison, the degree of phase convergence in the MIA-group cells was weak, and the region of peak convergence was distal to the reward location. These findings suggest that a schizophrenia risk factor disrupts the phase-based encoding of location-reward relationships in the LS, potentially smearing reward representations across space.SIGNIFICANCE STATEMENT It is unclear how spatial or contextual information generated by hippocampal cells is converted to a code that can be used to signal reward location in regions, such as the VTA. Here we provide evidence that the firing phase of cells in the lateral septum, a region that links the two areas, may code reward location in the firing phase of cells. This phase coding is disrupted in a maternal immune activation model of schizophrenia risk such that representations of reward may be smeared across space in maternal immune activation animals. This could potentially underlie erroneous reward processing and misattribution of salience in schizophrenia.

Two modes of midfrontal theta suggest a role in conflict and error processing.

Midfrontal theta increases during scenarios when conflicts are successfully resolved. Often considered a generic signal of cognitive control, its temporal nature has hardly been investigated. Using advanced spatiotemporal techniques, we uncover that midfrontal theta occurs as a transient oscillation or "event" at single trials with their timing reflecting computationally distinct modes. Single-trial analyses of electrophysiological data from participants performing the Flanker (N = 24) and Simon task (N = 15) were used to probe the relationship between theta and metrics of stimulus-response conflict. We specifically investigated "partial errors", in which a small burst of muscle activity in the incorrect response effector occurred, quickly followed by a correction. We found that transient theta events in single trials could be categorized into two distinct theta modes based on their relative timing to different task events. Theta events from the first mode occurred briefly after the task stimulus and might reflect conflict-related processing of the stimulus. In contrast, theta events from the second mode were more likely to occur around the time partial errors were committed, suggesting they were elicited by a potential upcoming error. Importantly, in trials in which a full error was committed, this "error-related theta" occurred too late with respect to the onset of the erroneous muscle response, supporting the role of theta also in error correction. We conclude that different modes of transient midfrontal theta can be adopted in single trials not only to process stimulus-response conflict, but also to correct erroneous responses.

Schwann Cell Remyelination in the Multiple Sclerosis Central Nervous System.

Multiple sclerosis (MS) is a central nervous system (CNS) demyelinating disease. Failure to remyelinate successfully is common in MS lesions, often with consequent neuronal/axonal damage. CNS myelin is normally produced by oligodendroglial cells. Remyelination by Schwann cells (SchC) has been reported in spinal cord demyelination, in which SchCs are in close proximity to CNS myelin. We identified an MS cerebral lesion that was remyelinated by SchCs. This prompted us to query the extent of SchC remyelination in the brain and spinal cords of additional autopsied MS specimens. CNS tissues were obtained from the autopsies of 14 MS cases. Remyelinated lesions were identified by Luxol fast blue-periodic-acid Schiff and solochrome cyanine staining. Deparaffinized sections containing remyelinated lesions were stained with anti-glial fibrillary acid protein to identify reactive astrocytes. Glycoprotein P zero (P0) is a protein exclusive to peripheral but not CNS myelin. Areas of SchC remyelination were identified by staining with anti-P0. Myelinated regions in the index case cerebral lesion were confirmed to be of SchC origin using anti-P0 staining. Subsequently, 64 MS lesions from 14 autopsied MS cases were examined, and 23 lesions in 6 cases showed remyelination by SchCs. Lesions from the cerebrum, brainstem, and spinal cord were examined in each case. When present, SchC remyelination was most commonly located adjacent to the venules and associated with a lower surrounding density of glial fibrillary acid protein+ reactive astrocytes than areas of only oligodendroglial cell remyelination. The difference was significant only for spinal cord and brainstem lesions but not for lesions located in the brain. In conclusion, we demonstrated SchC remyelination in the cerebrum, brainstem, and spinal cord of 6 autopsied MS cases. To our knowledge, this is the first report of supratentorial SchC remyelination in MS.

Schwann cells and myelin in human peripheral nerve: Major protein components vary with age, axon size and pathology.

AIMS: We examined major protein components of Schwann cells (SCs) and myelin in normal and diseased human peripheral nerves. METHODS: We evaluated distributions of neural cell adhesion molecule (NCAM), P0 protein (P0) and myelin basic protein (MBP) in frozen sections of 98 sural nerves. RESULTS: Non-myelinating SC in normal adults contained NCAM, but not P0 or MBP. With chronic axon loss, SC without associated axons (Büngner band cells) often co-stained for both NCAM and P0. Onion bulb cells also co-stained for both P0 and NCAM. Infants had many SC with MBP but no P0. All myelin sheaths contained P0. Myelin around large, and some intermediate-sized, axons co-stained for both MBP and P0. Myelin on other intermediate-sized axons had P0, but no MBP. Regenerated axons often had sheaths with MBP, P0 and some NCAM. During active axon degeneration, myelin ovoids often co-stained for MBP, P0 and NCAM. Demyelinating neuropathy patterns included SC (NCAM) loss, and myelin with abnormally distributed, or reduced, P0. CONCLUSIONS: Peripheral nerve SC and myelin have varied molecular phenotypes, related to age, axon size and nerve pathology. In normal adult peripheral nerve, myelin has two different patterns of molecular composition. MBP is mostly absent from myelin around a population of intermediate-sized axons, whereas P0 is present in myelin around all axons. Denervated SCs have a molecular signature that differs from normal SC types. With acute denervation, SCs may stain for both NCAM and MBP. Chronically denervated SCs often stain for both NCAM and P0.

The epidemiology of transfusion-related acute lung injury: A scoping review and analysis.

BACKGROUND: The purpose of this scoping review was to identify available sources of evidence on the epidemiology of transfusion-related acute lung injury (TRALI) and whether meta-analysis on the incidence of TRALI is feasible. TRALI is a serious complication and the second leading cause of death related to blood transfusion. Estimates of the incidence of TRALI would provide a useful benchmark for research to reduce TRALI. STUDY DESIGN AND METHODS: We searched the Medline, EMBASE, and PubMed databases for publications related to the incidence of TRALI and hemovigilance. We included all studies irrespective of language or country. Both full-text articles and conference abstracts were included. Participants of the studies must all have received a blood transfusion. Reviews and case studies were excluded. RESULTS: We identified 427 articles or abstracts to include for review. More than half were abstracts, and the majority were published after 2010. Reported TRALI definitions varied, but only 27.2% of studies reported any definition for TRALI. TRALI rates were reported using different denominators, such as per blood unit (54.1%), patient (34.4%), and transfusion episode (14.8%). Study populations and contexts were mostly general (75.6% and 80.3%, respectively). There was also variation in study design with most being observational (90.6%) and only 13.1% of all studies used modern donor restriction policies. DISCUSSION: There was substantial variation in reporting in studies on TRALI incidence. Meta-analysis of TRALI rates may be feasible in specific circumstances where reporting is clear. Future studies should clearly report key items, such as a TRALI definition.

Meta-analysis of bacterial growth characteristics in platelet components: Refining the inputs of a simulation analysis comparing the relative safety of testing strategies.

BACKGROUND: The relative safety of bacterial risk control strategies for platelets that include culture with or without rapid testing has been compared using simulation analysis. A wide range of bacterial lag and doubling times were included. However, published data on growth rates are available and these data have not been synthesized. We conducted a systematic review and meta-analysis to estimate growth rates and used these estimates to refine a comparative safety analysis of bacterial risk control strategies in the FDA guidance STUDY DESIGN AND METHODS: Data were extracted from published studies on bacterial growth rates in platelet components during storage. These data were used to estimate the practical range of growth rates. This refined the inputs for a simulation model comparing the safety of the testing strategies. RESULTS: In total, 108 growth curves for 11 different aerobic organisms were obtained. Doubling times ranged from 0.8 to 12 h, but the lower 90% range was approximately 1-5 h. The revised comparative safety simulation using the narrower 1-5-h range showed similar rankings to the prior simulation, with 48-h large-volume delayed sampling with 7-day expiration (48C-7) demonstrating the lowest-ranking relative performance at the 103 and 105 colony forming unit (CFU)/mL exposure thresholds. DISCUSSION: This was a two-step study. First, meta-analysis of published data on aerobic bacterial growth rates in stored platelets showed the vast majority of doubling times were 1-5 h. Next, an updated comparative safety simulation yielded similar results to a prior study, with 48C-7 showing the least favorable relative safety performance.

Bacterial culture time to detection in platelet components: An evidence synthesis and estimation of detection failures.

BACKGROUND: Non-pathogen reduction platelet bacterial risk control strategies in the US FDA guidance include at least one culture. Almost all of these strategies have a culture hold time of ≥12 h. Studies have reported time to detection (TTD) of bacterial cultures inoculated with bacteria from contaminated platelets, but these data and estimates of risk associated with detection failures have not been synthesized. METHODS: We performed a literature search to identify studies reporting TTD for samples obtained from spiked platelet components. Using extracted data, regression analysis was used to estimate TTD for culture bottles at different inoculum sizes. Detection failures were defined as events in which contaminated components are transfused to a patient. We then used published data on time of transfusion (ToT) to estimate the risk of detection failures in practice. RESULTS: The search identified 1427 studies, of which 16 were included for analysis. TTD data were available for 16 different organisms, including 14 in aerobic cultures and 11 in anaerobic cultures. For inocula of 1 colony forming unit (CFU), the average TTD for aerobic organisms was 19.2 h while it was 24.9 h in anaerobic organisms, but there was substantial overall variation. A hold time of 12 versus 24 h had minimal effect for most organisms. CONCLUSION: TTD variation occurs between bacterial species and within a particular species. Under typical inventory management, the relative contribution of culture detection failures is much smaller than the residual risk from sampling failures. Increasing the hold period beyond 12 h has limited value.

Modifying the Properties of Microemulsion Droplets by Addition of Thermoresponsive BAB* Copolymers.

Oil-in-water (O/W) microemulsions (ME) typically feature a low viscosity and exhibit ordinary viscosity reduction as a function of temperature. However, for certain applications, avoiding or even reverting the temperature trend might be required. This can be conceived by adding thermoresponsive (TR) block copolymers that induce network formation as the temperature increases. Accordingly, various ME-polymer mixtures were studied for which three different block copolymer architectures of BAB*-, B2AB*-, and B(AB*)2-types were employed. Here, "B" represents a permanently hydrophobic, "A" a permanently hydrophilic, and "B*" a TR block. For the TR-block, three different poly(acrylamide)s, namely poly(N-n-propylacrylamide) (pNPAm), poly(N,N-diethylacrylamide) (pDEAm), and poly(N-isopropylacrylamide) (pNiPAm), were used, which all exhibit a lower critical solution temperature. For a well-selected ME concentration, these block copolymers lead to a viscosity enhancement with increasing temperature. At a polymer concentration of about 22 g L-1, the most pronounced enhancement was observed for the pNPAm-based systems with factors up to 3, 5, and 8 for BAB*, B2AB*, and B(AB*)2, respectively. This phenomenon is caused by the formation of a transitory network mediated by TR-blocks, as evidenced by the direct correlation between the attraction strength and the viscosity enhancement. For applications requiring a high hydrophobic payload, which is attained via ME droplets, this kind of tailored temperature-dependent viscosity control of surfactant systems should therefore be advantageous.

Precision quality control: a dynamic model for risk-based analysis of analytical quality.

OBJECTIVES: There is continuing pressure to improve the cost effectiveness of quality control (QC) for clinical laboratory testing. Risk-based approaches are promising but recent research has uncovered problems in some common methods. There is a need for improvements in risk-based methods for quality control. METHODS: We provide an overview of a dynamic model for assay behavior. We demonstrate the practical application of the model using simulation and compare the performance of simple Shewhart QC monitoring against Westgard rules. We also demonstrate the utility of trade-off curves for analysis of QC performance. RESULTS: Westgard rules outperform simple Shewhart control over a narrow range of the trade-off curve of false-positive and false negative risk. The risk trade-off can be visualized in terms of risk, risk vs. cost, or in terms of cost. Risk trade-off curves can be "smoothed" by log transformation. CONCLUSIONS: Dynamic risk-models may provide advantages relative to static models for risk-based QC analysis.