Aspirin exposure and its association with metal stent patency in malignant distal biliary obstruction: a large international multicenter propensity score-matched study.

BACKGROUND AND AIMS: Stent dysfunction is common after ERCP with self-expandable metal stent (SEMS) insertion for malignant distal biliary obstruction (MDBO). Chronic aspirin (acetylsalicylic acid; ASA) exposure has been previously shown to potentially decrease this risk. We aim to further ascertain the protective effect of ASA and to identify other predictors of stent dysfunction. METHODS: This multicenter retrospective cohort study was conducted at 9 sites in Canada and 1 in the United States. Patients with MDBO who underwent ERCP with SEMS placement between January 2014 and December 2019 were included and divided into 2 cohorts: ASA exposed (ASA-E) and ASA unexposed (ASA-U). Propensity-score matching (PSM) was performed to limit selection bias. Matched variables were age, sex, tumor stage, and type of metal stent. The primary outcome was the hazard rate of stent dysfunction. A multivariable Cox proportional hazards model was used to identify independent predictors of stent dysfunction. RESULTS: Of 1396 patients assessed, after PSM 496 patients were analyzed (248 ASA-E and 248 ASA-U). ERCP with SEMS placement was associated with a high clinical success of 82.2% in ASA-E and 81.2% in ASA-U cohorts (P = .80). One hundred eighty-four patients had stent dysfunction with a mean stent patency time of 229.9 ± 306.2 days and 245.4 ± 241.4 days in ASA-E and ASA-U groups, respectively (P = .52). On multivariable analysis, ASA exposure did not protect against stent dysfunction (hazard ratio [HR], 1.25; 95% confidence interval [CI], .96-1.63). An etiology of pancreatic cancer (HR, 1.36; 95% CI, 1.15-1.61) predicted stent dysfunction, whereas cancer therapy was protective (HR, .73; 95% CI, .55-.96). Chronic ASA use was not associated with an increased risk for adverse events including bleeding, post-ERCP pancreatitis, and perforation. CONCLUSIONS: In this large, multicenter study using PSM, chronic exposure to ASA did not protect against stent dysfunction in MDBO. Instead, the analysis revealed that the etiology of pancreatic cancer was an independent predictor of stent dysfunction and cancer therapy was protective.

In situ aggregation and early states of gelation of gold nanoparticle dispersions.

The aggregation and onset of gelation of PEGylated gold nanoparticles dispersed in a glycerol-water mixture is studied by small-angle X-ray scattering and X-ray photon correlation spectroscopy. Tracking structural dynamics with sub-ms time resolution over a total experimental time of 8 hours corresponding to a time windows larger than 108 Brownian times and varying the temperature between 298 K and 266 K we can identify three regimes. First, while cooling to 275 K the particles show Brownian motion that slows down due to the increasing viscosity. Second, upon further cooling the static structure changes significantly, indicated by a broad structure factor peak. We attribute this to the formation of aggregates while the dynamics are still dominated by single-particle diffusion. Finally, the relaxation functions become more and more stretched accompanied by an increased slow down of the dynamics. At the same time the structure changes continuously indicating the onset of gelation. Our observations further suggest that the colloidal aggregation and gelation is characterized first by structural changes with a subsequent slowing down of the systems dynamics. The analysis also reveals that the details of the gelation process and the gel structure strongly depend on the thickness of the PEG-coating of the gold nanoparticles.

Emergence of anomalous dynamics in soft matter probed at the European XFEL.

Dynamics and kinetics in soft matter physics, biology, and nanoscience frequently occur on fast (sub)microsecond but not ultrafast timescales which are difficult to probe experimentally. The European X-ray Free-Electron Laser (European XFEL), a megahertz hard X-ray Free-Electron Laser source, enables such experiments via taking series of diffraction patterns at repetition rates of up to 4.5 MHz. Here, we demonstrate X-ray photon correlation spectroscopy (XPCS) with submicrosecond time resolution of soft matter samples at the European XFEL. We show that the XFEL driven by a superconducting accelerator provides unprecedented beam stability within a pulse train. We performed microsecond sequential XPCS experiments probing equilibrium and nonequilibrium diffusion dynamics in water. We find nonlinear heating on microsecond timescales with dynamics beyond hot Brownian motion and superheated water states persisting up to 100 µs at high fluences. At short times up to 20 µs we observe that the dynamics do not obey the Stokes-Einstein predictions.

Three-step colloidal gelation revealed by time-resolved x-ray photon correlation spectroscopy.

The gelation of PEGylated gold nanoparticles dispersed in a glycerol-water mixture is probed in situ by x-ray photon correlation spectroscopy. Following the evolution of structure and dynamics over 104 s, a three-step gelation process is found. First, a simultaneous increase of the Ornstein-Zernike length ξ and slowdown of dynamics is characterized by an anomalous q-dependence of the relaxation times of τ ∝ q-6 and strongly stretched intermediate scattering functions. After the structure of the gel network has been established, evidenced by a constant ξ, the dynamics show aging during the second gelation step accompanied by a change toward ballistic dynamics with τ ∝ q-1 and compressed correlation functions. In the third step, aging continues after the arrest of particle motion. Our observations further suggest that gelation is characterized by stress release as evidenced by anisotropic dynamics once gelation sets in.

Anisotropic and heterogeneous dynamics in an aging colloidal gel.

We investigate the out-of-equilibrium dynamics of a colloidal gel obtained by quenching a suspension of soft polymer-coated gold nanoparticles close to and below its gelation point using X-ray Photon Correlation Spectroscopy (XPCS). A faster relaxation process emergent from the localized motions of the nanoparticles reveals a dynamically-arrested network at the nanoscale as a key signature of the gelation process. We find that the slower network dynamics is hyperdiffusive with a compressed exponential form, consistent with stress-driven relaxation processes. Specifically, we use direction-dependent correlation functions to characterize the anisotropy in dynamics. We show that the anisotropy is greater for the gel close to its gelation point than at lower temperatures, and the anisotropy decreases as the gel ages. We quantify the anisotropic dynamical heterogeneities emergent in such a stress-driven dynamical system using higher order intensity correlations, and demonstrate that the aging phenomenon contributes significantly to the properties evaluated by the fluctuations in the intensity correlations. Our results provide important insights into the structural origin of the emergent anisotropic and cooperative heterogeneous dynamics, and we discuss analogies with previous work on other soft disordered systems.

Diffusive dynamics during the high-to-low density transition in amorphous ice.

Water exists in high- and low-density amorphous ice forms (HDA and LDA), which could correspond to the glassy states of high- (HDL) and low-density liquid (LDL) in the metastable part of the phase diagram. However, the nature of both the glass transition and the high-to-low-density transition are debated and new experimental evidence is needed. Here we combine wide-angle X-ray scattering (WAXS) with X-ray photon-correlation spectroscopy (XPCS) in the small-angle X-ray scattering (SAXS) geometry to probe both the structural and dynamical properties during the high-to-low-density transition in amorphous ice at 1 bar. By analyzing the structure factor and the radial distribution function, the coexistence of two structurally distinct domains is observed at T = 125 K. XPCS probes the dynamics in momentum space, which in the SAXS geometry reflects structural relaxation on the nanometer length scale. The dynamics of HDA are characterized by a slow component with a large time constant, arising from viscoelastic relaxation and stress release from nanometer-sized heterogeneities. Above 110 K a faster, strongly temperature-dependent component appears, with momentum transfer dependence pointing toward nanoscale diffusion. This dynamical component slows down after transition into the low-density form at 130 K, but remains diffusive. The diffusive character of both the high- and low-density forms is discussed among different interpretations and the results are most consistent with the hypothesis of a liquid-liquid transition in the ultraviscous regime.

X-ray spectroscopy with variable line spacing based on reflection zone plate optics.

X-ray spectroscopy is a method, ideally suited for investigating the electronic structure of matter, which has been enabled by the rapid developments in light sources and instruments. The x-ray fluorescence lines of life-relevant elements such as carbon, nitrogen, and oxygen are located in the soft x-ray regime and call for suitable spectrometer devices. In this Letter, we present a high-resolution spectrum of liquid water, recorded with a soft x-ray spectrometer based on a reflection zone plate (RZP) design. The RZP-based spectrometer with meridional variation of line space density from 2953 to 3757 l/mm offers extremely high detection efficiency and, at the same time, medium energy resolution. We can reproduce the well-known splitting of liquid water in the lone pair regime with 10 s acquisition time.

Impact of solvent granularity and layering on tracer hydrodynamics in confinement.

Classic hydrodynamic arguments establish that when a spherical tracer particle is suspended between parallel walls, tracer-wall coupling mediated by the solvent will cause the tracer to exhibit position-dependent diffusivity. We investigate how the diffusivity profiles of confined tracers are impacted by the diameter size-ratio of the tracer to solvent: starting from the classic limit of infinite size-ratio (i.e., continuum solvent), we consider size-ratios of four or less to examine how hydrodynamic predictions are disrupted for systems where the tracer and solvent are of similar scale. We use computer simulations and techniques based on the Fokker-Planck formalism to calculate the diffusivity profiles of hard-sphere tracer particles in hard-sphere solvents, focusing on the dynamics perpendicular to the walls. Given wall separations of several tracer diameters, we first consider confinement between hard walls, where anisotropic structuring at the solvent lengthscale generates inhomogeneity in the tracer free-energy landscape and undermines hydrodynamic predictions locally. We then introduce confining planes that we term transparent walls, which restrict tracer and solvent center-accessibilities while completely eliminating static anisotropy, and reveal position-dependent signatures in tracer diffusivity solely attributable to confinement. With or without suppressing static heterogeneity, we find that tracer diffusivity increasingly deviates on a local basis from hydrodynamic predictions at smaller size-ratios. However, hydrodynamic theory still approximately captures spatially-averaged dynamics across the pores even for very small tracer-solvent size-ratios over a wide range of solvent densities and wall separations.

Communication: Local structure-mobility relationships of confined fluids reverse upon supercooling.

We examine the structural and dynamic properties of confined binary hard-sphere mixtures designed to mimic realizable colloidal thin films. Using computer simulations, governed by either Newtonian or overdamped Langevin dynamics, together with other techniques including a Fokker-Planck equation-based method, we measure the position-dependent and average diffusivities of particles along structurally isotropic and inhomogeneous dimensions of the fluids. At moderate packing fractions, local single-particle diffusivities normal to the direction of confinement are higher in regions of high total packing fraction; however, these trends are reversed as the film is supercooled at denser average packings. Auxiliary short-time measurements of particle displacements mirror data obtained for experimental supercooled colloidal systems. We find that average dynamics can be approximately predicted based on the distribution of available space for particle insertion across orders of magnitude in diffusivity regardless of the governing microscopic dynamics.

Tuning structure and mobility of solvation shells surrounding tracer additives.

Molecular dynamics simulations and a stochastic Fokker-Planck equation based approach are used to illuminate how position-dependent solvent mobility near one or more tracer particle(s) is affected when tracer-solvent interactions are rationally modified to affect corresponding solvation structure. For tracers in a dense hard-sphere fluid, we compare two types of tracer-solvent interactions: (1) a hard-sphere-like interaction, and (2) a soft repulsion extending beyond the hard core designed via statistical mechanical theory to enhance tracer mobility at infinite dilution by suppressing coordination-shell structure [Carmer et al., Soft Matter 8, 4083-4089 (2012)]. For the latter case, we show that the mobility of surrounding solvent particles is also increased by addition of the soft repulsive interaction, which helps to rationalize the mechanism underlying the tracer's enhanced diffusivity. However, if multiple tracer surfaces are in closer proximity (as at higher tracer concentrations), similar interactions that disrupt local solvation structure instead suppress the position-dependent solvent dynamics.

Effects of protein engineering and rational mutagenesis on crystal lattice of single chain antibody fragments.

Protein crystallization is dependent upon, and sensitive to, the intermolecular contacts that assist in ordering proteins into a three-dimensional lattice. Here we used protein engineering and mutagenesis to affect the crystallization of single chain antibody fragments (scFvs) that recognize the EE epitope (EYMPME) with high affinity. These hypercrystallizable scFvs are under development to assist difficult proteins, such as membrane proteins, in forming crystals, by acting as crystallization chaperones. Guided by analyses of intermolecular crystal lattice contacts, two second-generation anti-EE scFvs were produced, which bind to proteins with installed EE tags. Surprisingly, although noncomplementarity determining region (CDR) lattice residues from the parent scFv framework remained unchanged through the processes of protein engineering and rational design, crystal lattices of the derivative scFvs differ. Comparison of energy calculations and the experimentally-determined lattice interactions for this basis set provides insight into the complexity of the forces driving crystal lattice choice and demonstrates the availability of multiple well-ordered surface features in our scFvs capable of forming versatile crystal contacts.

Structure, thermodynamics, and position-dependent diffusivity in fluids with sinusoidal density variations.

Molecular dynamics simulations and a stochastic method based on the Fokker-Planck equation are used to explore the consequences of inhomogeneous density profiles on the thermodynamic and dynamic properties of the hard-sphere fluid and supercooled liquid water. Effects of the inhomogeneity length scale are systematically considered via the imposition of sinusoidal density profiles of various wavelengths. For long-wavelength density profiles, bulk-like relationships between local structure, thermodynamics, and diffusivity are observed as expected. However, for both systems, a crossover in behavior occurs as a function of wavelength, with qualitatively different correlations between the local static and dynamic quantities emerging as density variations approach the scale of a particle diameter. Irrespective of the density variation wavelength, average diffusivities of hard-sphere fluids in the inhomogeneous and homogeneous directions are coupled and approximately correlate with the volume available for insertion of another particle. Unfortunately, a quantitatively reliable static predictor of position-dependent dynamics has yet to be identified for even the simplest of inhomogeneous fluids.

Communication: Fine discretization of pair interactions and an approximate analytical strategy for predicting equilibrium behavior of complex fluids.

We study whether fine discretization (i.e., terracing) of continuous pair interactions, when used in combination with first-order mean-spherical approximation theory, can lead to a simple and general analytical strategy for predicting the equilibrium structure and thermodynamics of complex fluids. Specifically, we implement a version of this approach to predict how screened electrostatic repulsions, solute-mediated depletion attractions, or ramp-shaped repulsions modify the radial distribution function and the potential energy of reference hard-sphere fluids, and we compare the predictions to exact results from molecular simulations.

Communication: Phase behavior of materials with isotropic interactions designed by inverse strategies to favor diamond and simple cubic lattice ground states.

We use molecular simulation to construct equilibrium phase diagrams for two recently introduced model materials with isotropic, soft-repulsive pair interactions designed to favor diamond and simple cubic lattice ground states, respectively, over a wide range of densities [Jain et al., Soft Matter 9, 3866 (2013)]. We employ free energy based Monte Carlo simulation techniques to precisely trace the inter-crystal and fluid-crystal coexistence curves. We find that both model materials display rich polymorphic phase behavior featuring stable crystals corresponding to the target ground-state structures, as well as a variety of other crystalline (e.g., hexagonal and body-centered cubic) phases and multiple reentrant melting transitions.

Phage design and directed evolution to evolve phage for therapy.

Phage therapy or Phage treatment is the use of bacteriolysing phage in treating bacterial infections by using the viruses that infects and kills bacteria. This technique has been studied and practiced very long ago, but with the advent of antibiotics, it has been neglected. This foregone technique is now witnessing a revival due to development of bacterial resistance. Nowadays, with the awareness of genetic sequence of organisms, it is required that informed choices of phages have to be made for the most efficacious results. Furthermore, phages with the evolving genes are taken into consideration for the subsequent improvement in treating the patients for bacterial diseases. In addition, direct evolution methods are increasingly developing, since these are capable of creating new biological molecules having changed or unique activities, such as, improved target specificity, evolution of novel proteins with new catalytic properties or creation of nucleic acids that are capable of recognizing required pathogenic bacteria. This system is incorporates continuous evolution such as protein or genes are put under continuous evolution by providing continuous mutagenesis with least human intervention. Although, this system providing continuous directed evolution is very effective, it imposes some challenges due to requirement of heavy investment of time and resources. This chapter focuses on development of phage as a therapeutic agent against various bacteria causing diseases and it improvement using direct evolution of proteins and nucleic acids such that they target specific organisms.

Living on the EDGE: Canadian Experience With EUS-directed Transgastric ERCP (EDGE) in Patients With Roux-en-Y Gastric Bypass Anatomy.

Introduction: Roux-en-Y gastric bypass (RYGB) surgery imposes anatomic barriers to endoscopic retrograde cholangiopancreatography (ERCP). Potential options for biliary access in these patients include laparoscopic-assisted ERCP or balloon enteroscopy. However, these approaches require specialized equipment and/or operating room personnel and are associated with high rates of failure and adverse events compared to conventional ERCP. A recently described technique, EDGE, is an endoscopic approach which involves accessing the excluded stomach to facilitate ERCP. Objective: The objective of this study is to describe the results of EDGE procedures performed in Canada. Methods: Data were collected from patient cases who had undergone an EDGE procedure across centers in Canada. All patients had a history of RYGB bariatric surgery. In each procedure, a 20-mm diameter lumen-apposing metal stent (LAMS) was deployed under EUS guidance to allow access from the gastric remnant/proximal jejunum to the excluded stomach. Subsequently, during a separate procedure, a duodenoscope was passed through the LAMS to perform ERCP. Following ERCP, the LAMS was replaced with a pigtail stent or APC was used to facilitate closure of the gastro-jejunal/gastro-gastric fistula. Results: The indication for EDGE in the seven included cases was for the treatment of choledocholithiasis (six) or gallstone pancreatitis (one). The technical success rate of the EDGE procedure in these cases was 100%. Clinical success, defined by normalization of bilirubin and symptomatic relief, was observed in all cases. There were no adverse events reported. Conclusion: The results of this series support EDGE as a safe and minimally invasive approach to biliary access and therapy in patients with previous RYGB surgery.

Improving Colonoscopy Bowel Preparation and Reducing Patient Anxiety Through Recently Developed Online Information Resource: A Cross-sectional Study.

Introduction: Invasive medical procedures such as colonoscopies can cause psychological distress and anxiety. Mycolonoscopy.ca is a multilanguage website that provides online written and video information (individual items reported in prior publications to be highly rated by patients) regarding preparation and what to expect before, during, and after colonoscopy. Information about how to access the website is included with all colonoscopy appointment materials in Winnipeg, Manitoba. We evaluated the use of mycolonoscopy.ca among patients undergoing colonoscopy and examined the association between visitation to the website and patient outcomes. Methods: A paper-based survey was distributed to patients attending their colonoscopy appointments between 11/2019 and 3/2020. Logistic regression analyses were performed to determine the factors associated with website visitation, procedural worry, and bowel preparation scores. Results: Five hundred and ninety-three surveys were distributed, of which 506 were completed. 17.4% of participants had visited the website before their colonoscopy. Visitors to mycolonoscopy.ca were more likely to consume a split-dose bowel preparation (63.9%) compared with non-visitors (52.5%) (P = 0.006). 31.3% of website visitors were very/extremely worried about their colonoscopy compared with 17.9% of non-visitors. 76.6% of individuals agreed/strongly agreed that visiting the website helped them prepare for their colonoscopy and 69.7% who visited the website agreed/strongly agreed that it helped to reduce their stress/anxiety for the procedure. In multivariable analyses, visitation to website was associated with higher adequate bowel preparation (OR:10.55; 95% CI:1.35 to 82.4). Conclusion: Use of an informative online platform such as mycolonoscopy.ca can help to improve patient education before colonoscopy, reduce worry surrounding the procedure, and improve bowel preparation.

Comparison of two behavioral tests for tinnitus assessment in mice.

Animal research focused on chronic tinnitus associated with noise-induced hearing loss can be expensive and time-consuming as a result of the behavioral training required. Although there exist a number of behavioral tests for tinnitus; there have been few formal direct comparisons of these tests. Here, we evaluated animals in two different tinnitus assessment methods. CBA/CaJ mice were trained in an operant conditioning, active avoidance (AA) test, and a reflexive, gap-induced pre-pulse inhibition of acoustic startle (GPIAS) test, or both. Tinnitus was induced in awake mice by unilateral continuous sound exposure using a 2-kHz- or 1 2 octave-wide noise centered at 16 kHz and presented at 113- or 116-dB SPL. Tinnitus was assessed 8 weeks after sound overexposure. Most mice had evidence of tinnitus behavior in at least one of the two behaviors. Of the mice evaluated in AA, over half (55%) had tinnitus positive behavior. In GPIAS, fewer animals (13%) were positive than were identified using the AA test. Few mice were positive in both tests (10%), and only one was positive for tinnitus behavior at the same spectral frequency in both tests. When the association between tinnitus behavior and spontaneous activity recorded in the inferior colliculus was compared, animals with tinnitus behavior in AA exhibited increased spontaneous activity, while those positive in GPIAS did not. Thus, it appears that operant conditioning tests, like AA, maybe more reliable and accurate tests for tinnitus than reflexive tests.

Recurrent Encephalopathy and Severe Anion Gap Metabolic Acidosis in a Patient with Short Bowel: It Is D-Lactic Acidosis.

D-lactic acidosis is a rare and potentially underrecognized condition in patients with short bowel syndrome. We present the case of a 61-year-old female with a history of an ileojejunal bypass at age 18 who presented to hospital with acute-onset encephalopathy, ataxia, and severe anion gap metabolic acidosis (AGMA). On initial investigations there were no identifiable etiologies for the AGMA. Further history revealed that she had been experiencing these symptoms on a recurrent basis for the past 40 years. An oral carbohydrate load was given to the patient in hospital which reproduced her symptoms and the AGMA. A serum D-lactate level returned elevated several weeks later. A 2-month follow-up revealed that all her symptoms had ceased with limitation of carbohydrates to 150 g per day. Patients with short bowel syndrome are susceptible to developing D-lactic acidosis due to the large carbohydrate loads that are delivered to the colon, where they are then metabolized. Due to its rarity, it is likely that there is a delay in recognition of this condition. This case report describes a common clinical presentation of this rare condition and describes the pathophysiology, diagnosis, and management of D-lactic acidosis in small bowel syndrome.