Comorbidity clusters in patients with rheumatoid arthritis identify a patient phenotype with a favourable prognosis.

OBJECTIVES: We aimed to cluster patients with rheumatoid arthritis (RA) based on comorbidities and then examine the association between these clusters and RA disease activity and mortality. METHODS: In this population-based study, residents of an eight-county region with prevalent RA on 1 January 2015 were identified. Patients were followed for vital status until death, last contact or 31 December 2021. Diagnostic codes for 5 years before the prevalence date were used to define 55 comorbidities. Latent class analysis was used to cluster patients based on comorbidity patterns. Standardised mortality ratios were used to assess mortality. RESULTS: A total of 1643 patients with prevalent RA (72% female; 94% white; median age 64 years, median RA duration 7 years) were studied. Four clusters were identified. Cluster 1 (n=686) included patients with few comorbidities, and cluster 4 (n=134) included older patients with 10 or more comorbidities. Cluster 2 (n=200) included patients with five or more comorbidities and high prevalences of depression and obesity, while cluster 3 (n=623) included the remainder. RA disease activity and survival differed across the clusters, with cluster 1 demonstrating more remission and mortality comparable to the general population. CONCLUSIONS: More than 40% of patients with prevalent RA did not experience worse mortality than their peers without RA. The cluster with the worst prognosis (<10% of patients with prevalent RA) was older, had more comorbidities and had less disease-modifying antirheumatic drug and biological use compared with the other clusters. Comorbidity patterns may hold the key to moving beyond a one-size-fits-all perspective of RA prognosis.

Microfluidic dissolution of nanoemulsions in solvents.

We experimentally investigate the behavior of nanoemulsion and microscale emulsion jets flowing in solvents using coaxial microfluidic devices. The stability of colloidal dispersions made of oil droplets dispersed in water is significantly altered by the presence of a miscible solvent, which induces complex solutal and droplet coalescence instabilities over various timescales. We reveal intriguing microflow patterns of oil-in-water micro- and nanoemulsion threads in a continuous phase of isopropanol, including the dissolving, diffusive, gravitational, and stable thread regimes. We discuss the evolution of core-annular flow characteristics and develop scaling relationships to model thread dynamics through measurements of effective diameter as well as persistence and gravitational lengths. A microflow method based on dynamic similitude is developed to estimate the diffusion coefficients of nanoemulsions and microscale emulsions in miscible solvents. This work shows the possibility to process soft colloidal dispersions and control degradation mechanisms using microfluidic techniques.

A Brownian quasi-crystal of pre-assembled colloidal Penrose tiles.

Penrose's pentagonal P2 quasi-crystal1-4 is a beautiful, hierarchically organized multiscale structure in which kite- and dart-shaped tiles are arranged into local motifs, such as pentagonal stars, which are in turn arranged into various close-packed superstructural patterns that become increasingly complex at larger length scales. Although certain types of quasi-periodic structure have been observed in hard and soft matter, such structures are difficult to engineer, especially over large areas, because generating the necessary, highly specific interactions between constituent building blocks is challenging. Previously reported soft-matter quasi-crystals of dendrimers5, triblock copolymers6, nanoparticles7 and polymeric micelles8 have been limited to 12- or 18-fold symmetries. Because routes for self-assembling complex colloidal building blocks9-11 into low-defect dynamic superstructures remain limited12, alternative methods, such as using optical and directed assembly, are being explored13,14. Holographic laser tweezers15 and optical standing waves16 have been used to hold microspheres in local quasi-crystalline arrangements, and magnetic microspheres of two different sizes have been assembled into local five-fold-symmetric quasi-crystalline arrangements in two dimensions17. But a Penrose quasi-crystal of mobile colloidal tiles has hitherto not been fabricated over large areas. Here we report such a quasi-crystal in two dimensions, created using a highly parallelizable method of lithographic printing and subsequent release of pre-assembled kite- and dart-shaped tiles into a solution-dispersion containing a depletion agent. After release, the positions and orientations of the tiles within the quasi-crystal can fluctuate, and these tiles undergo random, Brownian motion in the monolayer owing to frequent collisions between neighbouring tiles, even after the system reaches equilibrium. Using optical microscopy, we study both the equilibrium fluctuations of the system at high tile densities and also the 'melting' of the pattern as the tile density is lowered. At high tile densities we find signatures of a five-fold pentatic liquid quasi-crystalline phase, analogous to a six-fold hexatic liquid crystal. Our fabrication approach is applicable to tiles of different sizes and shapes, and with different initial positions and orientations, enabling the creation of two-dimensional quasi-crystalline systems (and other systems that possess multiscale complexity at high tile densities) beyond those of current self- or directed-assembly methods18-20. We anticipate that our approach for generating lithographically pre-assembled monolayers could be extended to create three-dimensional Brownian systems of fluctuating particles with custom-designed shapes through holographic lithography21,22 or stereolithography23.

Structural elucidation of polydopamine facilitated by ionic liquid solvation.

Minimal understanding of the formation mechanism and structure of polydopamine (pDA) and its natural analogue, eumelanin, impedes the practical application of these versatile polymers and limits our knowledge of the origin of melanoma. The lack of conclusive structural evidence stems from the insolubility of these materials, which has spawned significantly diverse suggestions of pDA's structure in the literature. We discovered that pDA is soluble in certain ionic liquids. Using these ionic liquids (ILs) as solvents, we present an experimental methodology to solvate pDA, enabling us to identify pDA's chemical structure. The resolved pDA structure consists of self-assembled supramolecular aggregates that contribute to the increasing complexity of the polymer. The underlying molecular energetics of pDA solvation and a macroscopic picture of the disruption of the aggregates using IL solvents have been investigated, along with studies of the aggregation mechanism in water.

Diffusing wave microrheology of highly scattering concentrated monodisperse emulsions.

Motivated by improvements in diffusing wave spectroscopy (DWS) for nonergodic, highly optically scattering soft matter and by cursory treatment of collective scattering effects in prior DWS microrheology experiments, we investigate the low-frequency plateau elastic shear moduli [Formula: see text] of concentrated, monodisperse, disordered oil-in-water emulsions as droplets jam. In such experiments, the droplets play dual roles both as optical probes and as the jammed objects that impart shear elasticity. Here, we demonstrate that collective scattering significantly affects DWS mean-square displacements (MSDs) in dense colloidal emulsions. By measuring and analyzing the scattering mean free path as a function of droplet volume fraction φ, we obtain a φ-dependent average structure factor. We use this to correct DWS MSDs by up to a factor of 4 and then calculate [Formula: see text] predicted by the generalized Stokes-Einstein relation. We show that DWS-microrheological [Formula: see text] agrees well with mechanically measured [Formula: see text] over about three orders of magnitude when droplets are jammed but only weakly deformed. Moreover, both of these measurements are consistent with predictions of an entropic-electrostatic-interfacial (EEI) model, based on quasi-equilibrium free-energy minimization of disordered, screened-charge-stabilized, deformable droplets, which accurately describes prior mechanical measurements of [Formula: see text] made on similar disordered monodisperse emulsions over a wide range of droplet radii and φ. This very good quantitative agreement between DWS microrheology, mechanical rheometry, and the EEI model provides a comprehensive and self-consistent view of weakly jammed emulsions. Extensions of this approach may improve DWS microrheology on other systems of dense, jammed colloids that are highly scattering.

Long-wavelength fluctuations and anomalous dynamics in 2-dimensional liquids.

In 2-dimensional systems at finite temperature, long-wavelength Mermin-Wagner fluctuations prevent the existence of translational long-range order. Their dynamical signature, which is the divergence of the vibrational amplitude with the system size, also affects disordered solids, and it washes out the transient solid-like response generally exhibited by liquids cooled below their melting temperatures. Through a combined numerical and experimental investigation, here we show that long-wavelength fluctuations are also relevant at high temperature, where the liquid dynamics do not reveal a transient solid-like response. In this regime, these fluctuations induce an unusual but ubiquitous decoupling between long-time diffusion coefficient D and structural relaxation time τ, where [Formula: see text], with [Formula: see text] Long-wavelength fluctuations have a negligible influence on the relaxation dynamics only at extremely high temperatures in molecular liquids or at extremely low densities in colloidal systems.

Prediction of lattice energy of benzene crystals: A robust theoretical approach.

We present an inexpensive and robust theoretical approach based on the fragment molecular orbital methodology and the spin-ratio scaled second-order Møller-Plesset perturbation theory to predict the lattice energy of benzene crystals within 2 kJ⋅mol-1 . Inspired by the Harrison method to estimate the Madelung constant, the proposed approach calculates the lattice energy as a sum of two- and three-body interaction energies between a reference molecule and the surrounding molecules arranged in a sphere. The lattice energy converges rapidly at a radius of 13 Å. Adding the corrections to account for a higher correlated level of theory and basis set superposition for the Hartree Fock (HF) level produced a lattice energy of -57.5 kJ⋅mol-1 for the benzene crystal structure at 138 K. This estimate is within 1.6 kJ⋅mol-1 off the best theoretical prediction of -55.9 kJ⋅mol-1 . We applied this approach to calculate lattice energies of the crystal structures of phase I and phase II-polymorphs of benzene-observed at a higher temperature of 295 K. The stability of these polymorphs was correctly predicted, with phase II being energetically preferred by 3.7 kJ⋅mol-1 over phase I. The proposed approach gives a tremendous potential to predict stability of other molecular crystal polymorphs.

Depletion torques between anisotropic colloidal particles.

We explore how the entropic notion of depletion forces between spheres, introduced by Asakura and Oosawa, can be extended to depletion torques that affect the orientations of colloidal particles having complex shapes. In prior experimental work, systems of microscale plate-like particles in the presence of a nanoscale depletion agent have been shown to form polymer-like columnar chains; restoring depletion torques act to align lithographically-structured platelets within a chain orientationally about the chain's axis. We consider depletion torques corresponding to parallel, face-to-face, near-contact pair interactions for complex-shaped, plate-like, prismatic lithographic particles in colloidal dispersions containing a spherical nanoscale depletion agent. We calculate depletion torques for a wide variety of such particles, including rotationally symmetric, asymmetric, achiral, chiral, and elongated particles. Moreover, we determine depletion torques between two non-parallel proximate square platelets connected by a lossless hinge along a common edge. Our investigations show that depletion torques can be tailored through lithographic or synthetic design of specific geometrical features in the shapes of particles.

Assembly of colloidal particles in solution.

Advances in both top-down and bottom-up syntheses of a wide variety of complex colloidal building blocks and also in methods of controlling their assembly in solution have led to new and interesting forms of highly controlled soft matter. In particular, top-down lithographic methods of producing monodisperse colloids now provide precise human-designed control over their sub-particle features, opening up a wide range of new possibilities for assembly structures that had been previously limited by the range of shapes available through bottom-up methods. Moreover, an increasing level of control over anisotropic interactions between these colloidal building blocks, which can be tailored through local geometries of sub-particle features as well as site-specific surface modifications, is giving rise to new demonstrations of massively parallel off-chip self-assembly of specific target structures with low defect rates. In particular, new experimental realizations of hierarchical self-assembly and control over the chiral purity of resulting assembly structures have been achieved. Increasingly, shape-dependent, shape-complementary, and roughness-controlled depletion attractions between non-spherical colloids are being used in novel ways to create assemblies that go far beyond early examples, such as fractal clusters formed by diffusion-limited and reaction-limited aggregation of spheres. As self-assembly methods have progressed, a wide variety of advanced directed assembly methods have also been developed; approaches based on microfluidic control and applying structured electromagnetic fields are particularly promising.

Influence of ionic constituents and electrical conductivity on the propagation of charged nanoscale objects in passivated gel electrophoresis.

When determining the electric field E acting on charged objects in gel electrophoresis, the electrical conductivity of the buffer solution is often overlooked; E is typically calculated by dividing the applied voltage by a separation distance between electrodes. However, as a consequence of electrolytic reactions, which occur at the electrodes, gradients in the ionic content of the buffer solution and its conductivity can potentially develop over time, thereby impacting E and affecting propagation velocities of charged objects, v, directly. Here, we explore how the types and concentrations of ionic constituents of the buffer solution, which largely control its conductivity, when used in passivated gel electrophoresis (P-gelEP), can influence E, thereby altering v of charged nanospheres propagating through large-pore gels. We measure the conductivity of the buffer solution in the center of the gel region near propagating bands of nanospheres, and we show that predictions of E based on conductivity closely correlate with v. We also explore P-gelEP involving two different types of passivation agents: nonionic polyethylene glycol (PEG) and anionic sodium dodecyl sulfate (SDS). Our observations indicate that using a conductivity model to determine E from the local current density and the conductivity where spheres are propagating can lead to a better estimate than the standard approach of a voltage divided by a separation. Moreover, this conductivity model also provides a starting point for interpreting the complex behavior created by amphiphilic ionic passivation agents, such as SDS, on propagating nanospheres used in some P-gelEP experiments.

Vibrational Modes and Dynamic Heterogeneity in a Near-Equilibrium 2D Glass of Colloidal Kites.

Using video microscopy and particle-tracking techniques developed for dense Brownian systems of polygons, we study the structure-dynamics relationship in a near-equilibrium 2D glass consisting of anisotropic Penrose kite-shaped colloids. Detailed vibrational properties of kite glasses, both translational and rotational, are obtained using covariance matrix techniques. Different from other colloidal glasses of spheres and ellipsoids, the vibrational modes of kite glasses at low frequencies show a strong translational character with spatially localized rotational modes and extended translational modes. Low-frequency quasilocalized soft modes commonly found in sphere glasses are absent in the translational phonon modes of kite glasses. Soft modes are observed predominantly in the rotational vibrations and correlate well with the spatial distribution of Debye-Waller factors. The local structural entropy field shows a strong correlation with the observed dynamic heterogeneity.

Surfactant Partitioning in Nanoemulsions.

Using a fractionated silicone oil-in-water nanoemulsion (NEM), which has a high ratio of surface area-to-volume, we investigate surfactant partitioning between the bulk continuous phase and the adsorbed interfacial phase. By adjusting the droplet volume fraction of this fractionated NEM and by using gravimetric and electrical conductivity methods, we measure the bulk and the surface concentrations of an ionic surfactant (sodium dodecyl sulfate, SDS), thereby obtaining a raw adsorption isotherm of SDS on the interfaces of the nanodroplets. To overcome significant uncertainties in the total surface area of this nanoemulsion, we have also measured the macroscopic interfacial tension (IFT) of silicone oil in contact with aqueous SDS solutions using the du Noüy ring method. We then scale the surface concentration of this raw isotherm using an appropriate Gibbs derivative based on the IFT measurement, yielding an adjusted isotherm. We show that this adjusted isotherm can be described using a simple Langmuir equation. In addition, we show that a significant and non-negligible percentage of surfactant typically partitions to nanodroplet interfaces after high-flow-rate emulsification (HFRE) has transformed a microscale premix emulsion into a NEM. We develop a model for predicting the final bulk surfactant concentration after HFRE given the initial bulk surfactant concentration before HFRE. We show that this model can be used to predict trends for surfactant partitioning in polydisperse nanoemulsions after HFRE.

Shape-designed frustration by local polymorphism in a near-equilibrium colloidal glass.

We show that hard, convex, lithographic, prismatic kite platelets, each having three 72° vertices and one 144° vertex, preferentially form a disordered and arrested 2D glass when concentrated quasi-statically in a monolayer while experiencing thermal Brownian fluctuations. By contrast with 2D systems of other hard convex shapes, such as squares, rhombs, and pentagons, which readily form crystals at high densities, 72° kites retain a liquid-like disordered structure that becomes frozen-in as their long-time translational and rotational diffusion become highly bounded, yielding a 2D colloidal glass. This robust glass-forming propensity arises from competition between highly diverse few-particle local polymorphic configurations (LPCs) that have incommensurate features and symmetries. Thus, entropy maximization is consistent with the preservation of highly diverse LPCs en route to the arrested glass.

Dimer crystallization of chiral proteoids.

Proteins can self-assemble into a variety of exquisitely organized structures through hierarchical reaction pathways. To examine how different core shapes of proteins and entropy combine to influence self-assembly, we create systems of lithographically fabricated proteomimetic colloids, or 'proteoids', and explore how Brownian monolayers of mobile proteoids, which have hard interactions, self-assemble as they are slowly crowded. Remarkably, chiral C-shaped proteoids having circular heads on only one side form enantiopure lock-and-key chiral dimers; these dimers have corrugated, shape-complementary perimeters, so they, in turn, form lock-and-key arrangements into chiral dimer crystals. Time-lapse video microscopy reveals the expulsion of monomers from the growing dimer crystals through tautomerization translocation reactions which expedite the crystallization kinetics. By lithographically mutating proteoids, we also tune the types and structures of the resulting dimer crystals. Thus, rational design of sub-particle features in hard-core colloidal shapes can be used to sterically select desired self-assembly pathways without introducing any site-specific attractions, thereby generating a striking degree of hierarchical self-ordering, reminiscent of protein crystallization.

Colloidal Lock-and-Key Dimerization Reactions of Hard Annular Sector Particles Controlled by Osmotic Pressure.

Colloidal annular sectors are a broad class of shapes that offer the interesting possibility of dimerization when osmotically compressed to high densities while undergoing Brownian motion in two dimensions (2D). Here, we lithographically create and form a stable aqueous dispersion of many microscale prismatic 270° annular sectors, and we explore their near-equilibrium behavior in a tilted 2D gravitational column. Near the top of the column where the 2D gravitational osmotic pressure Π(2D) is low, we observe a gas-like phase composed almost entirely of monomers. However, below the surface and deeper into the column where Π(2D) is higher, we observe a reaction zone where monomers and dimers coexist, followed by an arrested region containing a very high percentage of interpenetrating, lock-and-key dimers that are a racemic mixture of positive and negative chiralities. We determine particle area fractions of monomers and dimers as a function of depth and use these to obtain the system's 2D osmotic equation of state. In the reaction zone, where dimers transiently form and break up, we also use these to calculate the equilibrium constant K associated with the monomer-dimer reaction, which increases exponentially with Π(2D). This dependence can be attributed the reduction in number of accessible microstates for dimers as they become more tightly compressed.

Dual-energy CT for the diagnosis of gout: an accuracy and diagnostic yield study.

OBJECTIVES: To assess the accuracy of dual-energy CT (DECT) for diagnosing gout, and to explore whether it can have any impact on clinical decision making beyond the established diagnostic approach using polarising microscopy of synovial fluid (diagnostic yield). METHODS: Diagnostic single-centre study of 40 patients with active gout, and 41 individuals with other types of joint disease. Sensitivity and specificity of DECT for diagnosing gout was calculated against a combined reference standard (polarising and electron microscopy of synovial fluid). To explore the diagnostic yield of DECT scanning, a third cohort was assembled consisting of patients with inflammatory arthritis and risk factors for gout who had negative synovial fluid polarising microscopy results. Among these patients, the proportion of subjects with DECT findings indicating a diagnosis of gout was assessed. RESULTS: The sensitivity and specificity of DECT for diagnosing gout was 0.90 (95% CI 0.76 to 0.97) and 0.83 (95% CI 0.68 to 0.93), respectively. All false negative patients were observed among patients with acute, recent-onset gout. All false positive patients had advanced knee osteoarthritis. DECT in the diagnostic yield cohort revealed evidence of uric acid deposition in 14 out of 30 patients (46.7%). CONCLUSIONS: DECT provides good diagnostic accuracy for detection of monosodium urate (MSU) deposits in patients with gout. However, sensitivity is lower in patients with recent-onset disease. DECT has a significant impact on clinical decision making when gout is suspected, but polarising microscopy of synovial fluid fails to demonstrate the presence of MSU crystals.

Trajectories of probe spheres in generalized linear viscoelastic complex fluids.

We have developed a fast simulation that generates a random walk of an isolated probe sphere in a generalized linear viscoelastic complex fluid over a highly extended dynamic range. We introduce a coupled harmonically bound Brownian particle (c-HBBP) model, in which the relaxation modes of the viscoelastic medium are treated as harmonic wells. These wells are coupled to the probe sphere and perform Brownian motion in bound harmonic potentials corresponding to the next-longer relaxation mode, according to the relaxation spectrum of the viscoelastic material. We implement this c-HBBP model by generating variable temporal step sizes that have a uniform distribution in logarithmic time. We create and analyze trajectories for several different viscoelastic complex fluids: a polymer system at its gel point, a dense emulsion system, a blend of two monodisperse polystyrene polymers for which the relaxation spectrum has been measured, and a model anisotropic soft system that shows dense emulsion-like and gel-point behaviors along two orthogonal directions. Except for unusual viscoelastic materials, such as the polymer system at its gel point, the generated trajectories are neither self-similar nor self-affine. The resulting mean square displacements predicted by the c-HBBP model are consistent with the single-particle generalized Stokes-Einstein relation of linear passive microrheology.

Self-limiting droplet fusion in ionic emulsions.

We make an oil-in-water emulsion, which is initially stabilized using a first ionic surfactant, and mix it with a solution of a second ionic surfactant having the opposite charge, thereby inducing massively parallel droplet fusion. A transient disruption of the screened-charge repulsive barrier between interacting droplets, caused by the second ionic surfactant, arises from significant yet temporary charge neutralization of the first ionic surfactant on the surfaces of the oil droplets while mixing occurs. Interestingly, if a moderate molar excess of one surfactant exists, then the resulting emulsion re-stabilizes after limited droplet fusion. By adjusting the droplet volume fraction, concentrations of first and second surfactants, and volumes of the emulsion and the solution of the second surfactant, we control the degree of droplet coalescence and achieve a self-limiting droplet fusion process. Using optical microscopy, we observe that flat, thin, crystalline films can form between the two oil compartments after fusion of two or more immiscible microscale droplets. However, no such crystalline films are seen on the highly curved oil-oil interfaces inside nanoscale droplets that are composed of two or more immiscible oils and have been fused in the same manner, as revealed by cryogenic transmission electron microscopy.

Entropic chiral symmetry breaking in self-organized two-dimensional colloidal crystals.

Long-range chiral symmetry breaking (CSB) has been recently observed in 2D self-organized rhombic crystals of hard, achiral, 72 degree rhombic microparticles. However, purely entropic selection of a CSB crystal in an idealized system of hard achiral shapes, in which attractions are entirely absent and the shape does not dictate a chiral tiling, has not yet been quantitatively predicted. Overcoming limitations of a purely rotational cage model, we investigate a translational-rotational cage model (TRCM) of dense systems of hard achiral rhombs and quantitatively demonstrate that entropy can spontaneously drive the preferential self-organization of a chiral crystal composed of achiral shapes that also tile into an achiral crystal. At different particle area fractions, ϕA, we calculate the number of accessible translational-rotational microstates, Ω, of a mobile central rhomb in a static cage of neighboring rhombs, which can have different orientation angles, γ, relative to the bisector of the crystalline axes. As we raise ϕA, two maxima emerge in Ω(γ) at non-zero cage orientation angles, ±Î³max. These maxima correspond to additional translational microstates that become accessible in the CSB crystalline polymorph through reduced translational tip-tip interference. Thus, entropy, often associated with structural disorder, can drive CSB in condensed phase systems of non-attractive achiral objects that do not tile into chiral structures. The success of the TRCM in explaining the entropic origin of CSB in systems of hard rhombs indicates that the TRCM will have significant utility in predicting the self-organized behavior of dense systems of other hard shapes in 2D.

Crossover between entropic and interfacial elasticity and osmotic pressure in uniform disordered emulsions.

We develop a simple predictive model of the osmotic pressure Π and linear shear elastic modulus G of uniform disordered emulsions that includes energetic contributions from entropy and interfacial deformation. This model yields a smooth crossover between an entropically dominated G ∼ kBT/a(3) for droplet volume fractions ϕ below a jamming threshold for spheres, ϕc, and an interfacially dominated G ∼ σ/a for ϕ above ϕc, where a and σ are the undeformed radius and interfacial tension, respectively, of a droplet and T is the temperature. We show that this model reduces to the known ϕ-dependent jamming behavior G(ϕ) ∼ (σ/a)ϕ(ϕ - ϕc) as T → 0 for ϕ > ϕc of disordered uniform emulsions, and it also produces the known divergence for disordered hard spheres G(ϕ) ∼ (kBT/a(3))ϕ/(ϕc - ϕ) for ϕ < ϕc when σ → ∞. We compare predictions of this model to data for disordered uniform microscale emulsion droplets, corrected for electrostatic repulsions. The smooth crossover captures the observed trends in G and Π below ϕc better than existing analytic models of disordered emulsions, which do not make predictions below ϕc. Moreover, the model predicts that entropic contributions to the shear modulus can become more significant for nanoemulsions as compared to microscale emulsions.