Higher Adalimumab Concentration is Associated with Complete Fistula Healing in Patients with Perianal Fistulizing Crohn's Disease.

Perianal fistulas can develop in around 30% of patients with Crohn's disease (CD) and are associated with impaired quality of life and worse outcomes including increased rates of hospitalizations and surgeries.1 The cornerstone of pharmacologic treatment for perianal fistulizing CD is anti-tumor necrosis factor therapy, mainly infliximab and adalimumab (ADM).2 Therapeutic drug monitoring (TDM) can be used to identify potential pharmacokinetic and pharmacodynamic issues and avoid or manage unwanted outcomes, such as primary nonresponse and secondary loss of response.3 There are several exposure-response relationship data demonstrating a positive correlation between serum infliximab concentrations and favorable objective therapeutic outcomes in patients with perianal fistulizing CD.4 Nevertheless, there are only limited data, which is mostly from small retrospective studies regarding the association of ADM concentration and outcomes in patients with perianal fistulizing CD.4-8 Furthermore, the optimal ADM concentration for fistula healing still remains to be elucidated. This is clinically important because drug concentration cutoffs are used in reactive and proactive TDM algorithms to define therapeutic drug concentrations. This study investigates the association of maintenance ADM concentrations with complete fistula healing (CFH) and identifies an optimal ADM concentration threshold for CFH.

Hierarchically Doped Plasmonic Nanocrystal Metamaterials.

Assembling plasmonic nanocrystals in regular superlattices can produce effective optical properties not found in homogeneous materials. However, the range of these metamaterial properties is limited when a single nanocrystal composition is selected for the constituent meta-atoms. Here, we show how continuously varying doping at two length scales, the atomic and nanocrystal scales, enables tuning of both the frequency and bandwidth of the collective plasmon resonance in nanocrystal-based metasurfaces, while these features are inextricably linked in single-component superlattices. Varying the mixing ratio of indium tin oxide nanocrystals with different dopant concentrations, we use large-scale simulations to predict the emergence of a broad infrared spectral region with near-zero permittivity. Experimentally, tunable reflectance and absorption bands are observed, owing to in- and out-of-plane collective resonances. These spectral features and the predicted strong near-field enhancement establish this multiscale doping strategy as a powerful new approach to designing metamaterials for optical applications.

Plasmonic Response of Complex Nanoparticle Assemblies.

Optical properties of nanoparticle assemblies reflect distinctive characteristics of their building blocks and spatial organization, giving rise to emergent phenomena. Integrated experimental and computational studies have established design principles connecting the structure to properties for assembled clusters and superlattices. However, conventional electromagnetic simulations are too computationally expensive to treat more complex assemblies. Here we establish a fast, materials agnostic method to simulate the optical response of large nanoparticle assemblies incorporating both structural and compositional complexity. This many-bodied, mutual polarization method resolves limitations of established approaches, achieving rapid, accurate convergence for configurations including thousands of nanoparticles, with some overlapping. We demonstrate these capabilities by reproducing experimental trends and uncovering far- and near-field mechanisms governing the optical response of plasmonic semiconductor nanocrystal assemblies including structurally complex gel networks and compositionally complex mixed binary superlattices. This broadly applicable framework will facilitate the design of complex, hierarchically structured, and dynamic assemblies for desired optical characteristics.

Correction: Magnetic field enabled in situ control over the structure and dynamics of colloids interacting via SALR potentials.

Correction for 'Magnetic field enabled in situ control over the structure and dynamics of colloids interacting via SALR potentials' by Hashir M. Gauri et al., Soft Matter, 2023, 19, 4439-4448, https://doi.org/10.1039/D3SM00354J.

Magnetic field enabled in situ control over the structure and dynamics of colloids interacting via SALR potentials.

Colloidal suspensions are an ideal model for studying crystallization, nucleation, and glass transition mechanisms, due to the precise control of interparticle interactions by changing the shape, charge, or volume fraction of particles. However, these tuning parameters offer insufficient active control over interparticle interactions and reconfigurability of assembled structures. Dynamic control over the interparticle interactions can be obtained through the application of external magnetic fields that are contactless and chemically inert. In this work, we demonstrate the dual nature of magnetic nanoparticle dispersions to program interactions between suspended nonmagnetic microspheres using an external magnetic field. The nanoparticle dispersion simultaneously behaves as a continuous magnetic medium at the microscale and a discrete medium composed of individual particles at the nanoscale. This enables control over a depletion attractive potential and the introduction of a magnetic repulsive potential, allowing a reversible transition of colloidal structures within a rich phase diagram by applying an external magnetic field. Active control over competing interactions allows us to create a model system encompassing a range of states, from large fractal clusters to low-density Wigner glass states. Monitoring the dynamics of colloidal particles reveals dynamic heterogeneity and a marked slowdown associated with approaching the Wigner glass state.

Integration of Cirrhosis Best Practices Into Electronic Medical Record Documentation Associated With Reduction in 30-Day Mortality Following Hospitalization.

BACKGROUND: Hospital admissions for patients with cirrhosis continue to increase. In New York City, 25% to 30% of hospitalized cirrhotics are readmitted within 30 days. Rehospitalization is associated with increased mortality, poor quality of life, and financial burden to patients, hospitals, and payers. Preventable readmissions are partially accounted for by a well-documented quality gap between evidence-based guidelines for cirrhosis management and real-world adherence to these recommendations. METHODS: We performed a prospective cohort study that compared outcomes among cirrhotic patients admitted to 4 internal medicine teams over a 6-month period. An electronic medical record (EMR) note template that outlined best-practice measures for cirrhotics was developed. Inpatient providers on 2 teams were instructed to include it in daily progress notes and discharge summaries. The recommended practices included diagnostic paracentesis and diuretics for ascites, rifaximin, and lactulose for hepatic encephalopathy, beta blockers for esophageal varices, and antibiotic prophylaxis for spontaneous bacterial peritonitis. The remaining 2 teams continued the standard of care for cirrhotic patients. The primary outcome was 30-day readmissions. Secondary outcomes included in-hospital mortality, 30-day mortality, length of stay, and adherence to best-practice guidelines. RESULTS: Over a 6-month period, 108 cirrhotic patients were admitted, 83 in the interventional group and 25 in the control group. MELD-Na scores on admission did not differ between the groups (20.1 vs. 21.1, P =0.56). Thirty-day readmissions were not significantly different between the interventional and control groups (19.3% vs. 24%, P =0.61). However, 30-day mortality was significantly lower in the interventional group (8.4% vs. 28%, P =0.01). There was no difference between the 2 groups in in-hospital mortality (4.8% vs. 0%, P =0.27), 90-day mortality (15.7% vs. 28.0%, P =0.17) or length of stay (10.2 vs. 12.6 d, P =0.34). Adherence to best-practice metrics was similar between the groups, except for rates of diagnostic paracentesis, which were higher in the interventional group (98% vs. 80%, P =0.01). CONCLUSION: Implementation of an EMR note template with cirrhosis best practices was associated with lower 30-day mortality and higher rates of diagnostic paracentesis among admitted patients with cirrhosis. These findings suggest that the integration of best-practice measures into the EMR may improve outcomes in hospitalized cirrhotic patients. Larger studies are required to validate these findings.

Modular mixing in plasmonic metal oxide nanocrystal gels with thermoreversible links.

Gelation offers a powerful strategy to assemble plasmonic nanocrystal networks incorporating both the distinctive optical properties of constituent building blocks and customizable collective properties. Beyond what a single-component assembly can offer, the characteristics of nanocrystal networks can be tuned in a broader range when two or more components are intimately combined. Here, we demonstrate mixed nanocrystal gel networks using thermoresponsive metal-terpyridine links that enable rapid gel assembly and disassembly with thermal cycling. Plasmonic indium oxide nanocrystals with different sizes, doping concentrations, and shapes are reliably intermixed in linked gel assemblies, exhibiting collective infrared absorption that reflects the contributions of each component while also deviating systematically from a linear combination of the spectra for single-component gels. We extend a many-bodied, mutual polarization method to simulate the optical response of mixed nanocrystal gels, reproducing the experimental trends with no free parameters and revealing that spectral deviations originate from cross-coupling between nanocrystals with distinct plasmonic properties. Our thermoreversible linking strategy directs the assembly of mixed nanocrystal gels with continuously tunable far- and near-field optical properties that are distinct from those of the building blocks or mixed close-packed structures.

Colloidal Nanocrystal Gels from Thermodynamic Principles.

Gels assembled from solvent-dispersed nanocrystals are of interest for functional materials because they promise the opportunity to retain distinctive properties of individual nanocrystals combined with tunable, structure-dependent collective behavior. By incorporating stimuli-responsive components, these materials could also be dynamically reconfigured between structurally distinct states. However, nanocrystal gels have so far been formed mostly through irreversible aggregation, which has limited the realization of these possibilities. Meanwhile, gelation strategies for larger colloidal microparticles have been developed using reversible physical or chemical interactions. These approaches have enabled the experimental navigation of theoretically predicted phase diagrams, helping to establish an understanding of how thermodynamic behavior can guide gel formation in these materials. However, the translation of these principles to the nanoscale poses both practical and fundamental challenges. The molecules guiding assembly can no longer be safely assumed to be vanishingly small compared to the particles nor large compared to the solvent.In this Account, we discuss recent progress toward the assembly of tunable nanocrystal gels using two strategies guided by equilibrium considerations: (1) reversible chemical bonding between functionalized nanocrystals and difunctional linker molecules and (2) nonspecific, polymer-induced depletion attractions. The effective nanocrystal attractions, mediated in both approaches by a secondary molecule, compete against stabilizing repulsions to promote reversible assembly. The structure and properties of the nanocrystal gels are controlled microscopically by the design of the secondary molecule and macroscopically by its concentration. This mode of control is compelling because it largely decouples nanocrystal synthesis and functionalization from the design of interactions that drive assembly. Statistical thermodynamic theory and computer simulation have been applied to simple models that describe the bonding motifs in these assembling systems, furnish predictions for conditions under which gelation is likely to occur, and suggest strategies for tuning and disassembling the gel networks. Insights from these models have guided experimental realizations of reversible gels with optical properties in the infrared range that are sensitive to the gel structure. This process avoids time-consuming and costly trial-and-error experimental investigations to accelerate the development of nanocrystal gel assemblies.These advances highlight the need to better understand interactions between nanocrystals, how interactions give rise to gel structure, and properties that emerge. Such an understanding could suggest new approaches for creating stimuli-responsive and dissipative assembled materials whose properties are tunable on demand through directed reconfiguration of the underlying gel microstructure. It may also make nanocrystal gels amenable to computationally guided design using inverse methods to rapidly optimize experimental parameters for targeted functionalities.

Wertheim's thermodynamic perturbation theory with double-bond association and its application to colloid-linker mixtures.

We extend Wertheim's thermodynamic perturbation theory to derive the association free energy of a multicomponent mixture for which double bonds can form between any two pairs of the molecules' arbitrary number of bonding sites. This generalization reduces in limiting cases to prior theories that restrict double bonding to at most one pair of sites per molecule. We apply the new theory to an associating mixture of colloidal particles ("colloids") and flexible chain molecules ("linkers"). The linkers have two functional end groups, each of which may bond to one of several sites on the colloids. Due to their flexibility, a significant fraction of linkers can "loop" with both ends bonding to sites on the same colloid instead of bridging sites on different colloids. We use the theory to show that the fraction of linkers in loops depends sensitively on the linker end-to-end distance relative to the colloid bonding-site distance, which suggests strategies for mitigating the loop formation that may otherwise hinder linker-mediated colloidal assembly.

Effects of linker flexibility on phase behavior and structure of linked colloidal gels.

Colloidal nanocrystal gels can be assembled using a difunctional "linker" molecule to mediate bonding between nanocrystals. The conditions for gelation and the structure of the gel are controlled macroscopically by the linker concentration and microscopically by the linker's molecular characteristics. Here, we demonstrate using a toy model for a colloid-linker mixture that linker flexibility plays a key role in determining both phase behavior and the structure of the mixture. We fix the linker length and systematically vary its bending stiffness to span the flexible, semiflexible, and rigid regimes. At fixed linker concentration, flexible-linker and rigid-linker mixtures phase separate at low colloid volume fractions, in agreement with predictions of first-order thermodynamic perturbation theory, but the semiflexible-linker mixtures do not. We correlate and attribute this qualitatively different behavior to undesirable "loop" linking motifs that are predicted to be more prevalent for linkers with end-to-end distances commensurate with the locations of chemical bonding sites on the colloids. Linker flexibility also influences the spacing between linked colloids, suggesting strategies to design gels with desired phase behavior, structure, and, by extension, structure-dependent properties.

Universal Gelation of Metal Oxide Nanocrystals via Depletion Attractions.

Nanocrystal gelation provides a powerful framework to translate nanoscale properties into bulk materials and to engineer emergent properties through the assembled microstructure. However, many established gelation strategies rely on chemical reactions and specific interactions, e.g., stabilizing ligands or ions on the nanocrystals' surfaces, and are therefore not easily transferable. Here, we report a general gelation strategy via nonspecific and purely entropic depletion attractions applied to three types of metal oxide nanocrystals. The gelation thresholds of two compositionally distinct spherical nanocrystals agree quantitatively, demonstrating the adaptability of the approach for different chemistries. Consistent with theoretical phase behavior predictions, nanocrystal cubes form gels at a lower polymer concentration than nanocrystal spheres, allowing shape to serve as a handle to control gelation. These results suggest that the fundamental underpinnings of depletion-driven assembly, traditionally associated with larger colloidal particles, are also applicable at the nanoscale.

Spontaneous Electrokinetic Magnus Effect.

Colloids dispersed in electrolytes and exposed to an electric field produce a locally polarized cloud of ions around them. Above a critical electric field strength, an instability occurs causing these ion clouds to break symmetry leading to spontaneous rotation of particles about an axis orthogonal to the applied field, a phenomenon named Quincke rotation. In this Letter, we characterize a new mode of electrokinetic transport. If the colloids have a net charge, Quincke rotation couples with electrophoretic motion and propels particles in a direction orthogonal to both the applied field and the axis of rotation. This motion is a spontaneous, electrokinetic analogue to the well-known Magnus effect. Typically, motion orthogonal to a field requires anisotropy in particle shape, dielectric properties, or boundary geometry. Here, the electrokinetic Magnus (EKM) effect occurs for spheres with isotropic properties in an unbounded environment, with the Quincke rotation instability providing the broken symmetry needed to drive orthogonal motion. We study the EKM effect using explicit ion, Brownian dynamics simulations and develop a simple, continuum, analytic electrokinetic theory, which are in agreement. We also explain how nonlinearities in the theoretical description of the ions affect Quincke rotation and the EKM effect.

Inverse methods for design of soft materials.

Functional soft materials, comprising colloidal and molecular building blocks that self-organize into complex structures as a result of their tunable interactions, enable a wide array of technological applications. Inverse methods provide a systematic means for navigating their inherently high-dimensional design spaces to create materials with targeted properties. While multiple physically motivated inverse strategies have been successfully implemented in silico, their translation to guiding experimental materials discovery has thus far been limited to a handful of proof-of-concept studies. In this perspective, we discuss recent advances in inverse methods for design of soft materials that address two challenges: (1) methodological limitations that prevent such approaches from satisfying design constraints and (2) computational challenges that limit the size and complexity of systems that can be addressed. Strategies that leverage machine learning have proven particularly effective, including methods to discover order parameters that characterize complex structural motifs and schemes to efficiently compute macroscopic properties from the underlying structure. We also highlight promising opportunities to improve the experimental realizability of materials designed computationally, including discovery of materials with functionality at multiple thermodynamic states, design of externally directed assembly protocols that are simple to implement in experiments, and strategies to improve the accuracy and computational efficiency of experimentally relevant models.

Reduced Cell Division Control Protein 42 Activity Compromises Hematopoiesis-Supportive Function of Fanconi Anemia Mesenchymal Stromal Cells.

Hematopoietic stem cells preserve their ability to self-renew and differentiate to different lineages in the bone marrow (BM) niche, which is composed in large part by BM stromal cells. Studies have shown that altered signaling in the BM niche results in leukemia initiation or progression. Fanconi anemia (FA) is an inherited BM failure syndrome associated with extremely high risk of leukemic transformation. By using two FA mouse models, here we have investigated the hematopoiesis-supportive function of FA BM mesenchymal stroma cells (MSCs). We found that MSCs deficient for Fanca or Fancc gene are defective in proliferation and prone to undergo senescence in vitro. Mechanistically, we show that the activity of cell division control protein 42 (Cdc42), a Rho GTPase known to be a critical regulator for cytoskeleton organization, is significantly reduced in FA MSCs. Furthermore, we demonstrate that this reduction in Cdc42 activity plays a causal role in defective hematopoiesis-supportive function of the FA MSCs. The progenies of wild-type hematopoietic stem and progenitor cells cocultured on FA MSCs exhibit compromised self-renewal capacity both in vitro and in vivo. Genetic correction of FA deficiency restores Cdc42 activity and improves the hematopoiesis-supportive capacity of FA MSC. Finally, ectopic expression of a constitutively active Cdc42 mutant, Cdc42F28L, or pretreatment with Wnt5a, increases the active Cdc42 level and rescues the hematopoietic supportive defects of FA MSCs. Taken together, our results identify a novel link between Cdc42 activity and the hematopoiesis-supportive function of MSCs and suggest that a niche-specific increase of Cdc42 activity may be beneficial for FA therapy. Stem Cells 2018;36:785-795.

Colloidal Gelation through Thermally Triggered Surfactant Displacement.

Colloidal systems that undergo gelation attract much attention in both fundamental studies and practical applications. Rational tuning of interparticle interactions allows researchers to precisely engineer colloidal material properties and microstructures. Here, contrary to the traditional approaches where modulating attractive interactions is the major focus, we present a platform wherein colloidal gelation is controlled by tuning repulsive interactions. By including amphiphilic oligomers in colloidal suspensions, the ionic surfactants on the colloids are replaced by the nonionic oligomer surfactants at elevated temperatures, leading to a decrease in electrostatic repulsion. The mechanism is examined by carefully characterizing the colloids, and subsequently allowing the construction of interparticle potentials to capture the material behaviors. With the thermally triggered surfactant displacement, the dispersion assembles into a macroporous viscoelastic network and the gelling mechanism is robust over a wide range of compositions, colloid sizes, and component chemistries. This stimulus-responsive gelation platform is general and offers new strategies to engineer complex viscoelastic soft materials.

Enhanced diffusion and magnetophoresis of paramagnetic colloidal particles in rotating magnetic fields.

Dispersions of paramagnetic colloids can be manipulated with external magnetic fields to assemble structures via dipolar assembly and control transport via magnetophoresis. For fields held steady in time, the dispersion structure and dynamic properties are coupled. This coupling can be problematic when designing processes involving field-induced forces, as particle aggregation competes against and hinders particle transport. Time-varying fields drive dispersions out-of-equilibrium, allowing the structure and dynamics to be tuned independently. Rotating the magnetic field direction using two biaxial fields is a particularly effective mode of time-variation and has been used experimentally to enhance particle transport. Fundamental transport properties, like the diffusivity and magnetophoretic mobility, dictate dispersions' out-of-equilibrium responses to such time-varying fields, and are therefore crucial to understand to effectively design processes utilizing rotating fields. However, a systematic study of these dynamic quantities in rotating fields has not been performed. Here, we investigate the transport properties of dispersions of paramagnetic colloids in rotating magnetic fields using dynamic simulations. We find that self-diffusion of particles is enhanced in rotating fields compared to steady fields, and that the self-diffusivity in the plane of rotation reaches a maximum value at intermediate rotation frequencies that is larger than the Stokes-Einstein diffusivity of an isolated particle. We also show that, while the magnetophoretic velocity of particles through the bulk in a field gradient decreases with increasing rotation frequency, the enhanced in-plane diffusion allows for faster magnetophoretic transport through porous materials in rotating fields. We examine the effect of porous confinement on the transport properties in rotating fields and find enhanced diffusion at all pore sizes. The confined and bulk values of the transport properties are leveraged in simple models of magnetophoresis through tortuous porous media.

Phase Separation Kinetics of Dynamically Self-Assembling Nanoparticles with Toggled Interactions.

Ordered materials passively self-assembled from dispersions of nanoparticles with steady interactions are subject to thermodynamic constraints on their phase separation kinetics forcing a trade-off between throughput and quality. Dynamically self-assembling dispersions whose interactions vary in a controlled way with time do not have these constraints and can rapidly form ordered structures while avoiding kinetic arrest. These out-of-equilibrium processes cannot be understood in terms of equilibrium thermodynamics or kinetic models derived from equilibrium thermodynamics, so new theories must be developed before dynamic self-assembly can be used to reliably fabricate nanomaterials. Here, we use dynamic simulation and theory to study the self-assembly kinetics of a monodisperse suspension of spherical nanoparticles interacting with a short-ranged, isotropic attraction that is toggled on and off cyclically in time. The rate of phase separation, local and global quality of the self-assembled structures, and range of tunable parameters leading to acceptable self-assembly are all enhanced with toggled attractions compared to steady attractions. The kinetic mechanism and rate of assembly can be easily controlled with the temporal toggling parameters. We develop simple phenomenological expressions to describe and predict the self-assembly rates for two predominant kinetic mechanisms. The first model describes the coarsening of percolated, gel-like networks, and the second describes the nucleation and growth of dense phases.

Field-Directed Self-Assembly of Mutually Polarizable Nanoparticles.

Directed assembly of dielectric and paramagnetic nanoparticles can be used to synthesize diverse functional materials that polarize in response to an externally applied electric or magnetic field. However, theories capable of predicting the self-assembled states are lacking. In the proposed work, we develop a complete thermodynamic description of such assemblies for spherical nanoparticles. We show how an important physical feature of these types of particles, mutual polarization, sculpts the free energy landscape and has a remarkably strong influence on the nature of the self-assembled states. Modeling the mutual polarization among nanoparticles requires solving a many-bodied problem for the particle dipole moments. Typically, this computationally expensive task is avoided by neglecting mutual polarization and assuming that each particle in a concentrated dispersion acquires the same dipole moment as a single, isolated particle. Although valid in the limit of small dielectric or permeability contrasts between particles and solvent, this constant dipole assumption leads to qualitatively incorrect predictions for coexisting phases in equilibrium at large dielectric or permeability contrasts. Correctly accounting for mutual polarization enables a thermodynamic theory that describes the equilibrium phase diagram of polarizable dispersions in terms of experimentally controllable variables. Our theoretical predictions agree with the phase behavior we observe in dynamic simulations of these dispersions as well as that in experiments of field-directed structural transitions. In contrast to predictions of a constant dipole model, we find that dispersions of particles with different dielectric constants or magnetic permeabilities exhibit qualitatively different phase behavior. This new model also predicts the existence of a eutectic point at which two crystalline phases and a disordered phase of nanoparticles all simultaneously coexist.

Illuminating Disorder: Optical Properties of Complex Plasmonic Assemblies.

The optical properties of disordered plasmonic nanoparticle assemblies can be continuously tuned through the structural organization and composition of their colloidal building blocks. However, progress in the design and experimental realization of these materials has been limited by challenges associated with controlling and characterizing disordered assemblies and predicting their optical properties. This Perspective discusses integrated studies of experimental assembly of disordered optical materials, such as doped metal oxide nanocrystal gels and metasurfaces, with electromagnetic computations on large-scale simulated structures. The simulations prove vital for connecting experimental parameters to disordered structural motifs and optical properties, revealing structure-property relations that inform design choices. Opportunities are identified for optimizing optical property designs for disordered materials using computational inverse methods and tools from machine learning.

Structural Control of Plasmon Resonance in Molecularly Linked Metal Oxide Nanocrystal Gel Assemblies.

Nanocrystal gels exhibit collective optical phenomena based on interactions among their constituent building blocks. However, their inherently disordered structures have made it challenging to understand, predict, or design properties such as optical absorption spectra that are sensitive to the coupling between the plasmon resonances of the individual nanocrystals. Here, we bring indium tin oxide nanocrystal gels under chemical control and show that their infrared absorption can be predicted and systematically tuned by selecting the nanocrystal sizes and compositions and molecular structures of the link-mediating surface ligands. Thermoreversible assemblies with metal-terpyridine links form reproducible gel architectures, enabling us to derive a plasmon ruler that governs the spectral shifts upon gelation, predicated on the nanocrystal and ligand compositions. This empirical guide is validated using large-scale, many-bodied simulations to compute the optical spectra of gels with varied structural parameters. Based on the derived plasmon ruler, we design and demonstrate a nanocrystal mixture whose spectrum exhibits distinctive line narrowing upon assembly.