Natural history and outcomes of patients with liver cirrhosis complicated by hepatic hydrothorax.

BACKGROUND: Hepatic hydrothorax (HH) is an uncommon and difficult-to-manage complication of cirrhosis with limited treatment options. AIM: To define the clinical outcomes of patients presenting with HH managed with current standards-of-care and to identify factors associated with mortality. METHODS: Cirrhotic patients with HH presenting to 3 tertiary centres from 2010 to 2018 were retrospectively identified. HH was defined as pleural effusion in the absence of cardiopulmonary disease. The primary outcomes were overall and transplant-free survival at 12-mo after the index admission. Cox proportional hazards analysis was used to determine factors associated with the primary outcomes. RESULTS: Overall, 84 patients were included (mean age, 58 years) with a mean model for end-stage liver disease score of 29. Management with diuretics alone achieved long-term resolution of HH in only 12% patients. At least one thoracocentesis was performed in 73.8% patients, transjugular intrahepatic portosystemic shunt insertion in 11.9% patients and 33% patients received liver transplantation within 12-mo of index admission. Overall patient survival and transplant-free survival at 12 mo were 68% and 41% respectively. At multivariable analysis, current smoking [hazard ratio (HR) = 8.65, 95% confidence interval (CI): 3.43-21.9, P < 0.001) and acute kidney injury (AKI) (HR = 2.91, 95%CI: 1.21-6.97, P = 0.017) were associated with a significantly increased risk of mortality. CONCLUSION: Cirrhotic patients with HH are a challenging population with a poor 12-mo survival despite current treatments. Current smoking and episodes of AKI are potential modifiable factors affecting survival. HH is often refractory of diuretic therapy and transplant assessment should be considered in all cases.

Publisher Correction: Noninvasive monitoring of single-cell mechanics by acoustic scattering.

The version of this paper originally published online contained an error in the x-axis of Fig. 2c: the LatB concentrations should be 0.4 and 1 µM, but during typesetting, the 1 µM label was incorrectly changed to 0.1 µM. The label is now correct in the print, PDF, and HTML versions of the paper. In addition, in the article's online Supplementary Information, Supplementary Video 2 was a duplicate of Supplementary Video 1. The correct versions of both videos are now available online.

Noninvasive monitoring of single-cell mechanics by acoustic scattering.

The monitoring of mechanics in a single cell throughout the cell cycle has been hampered by the invasiveness of mechanical measurements. Here we quantify mechanical properties via acoustic scattering of waves from a cell inside a fluid-filled vibrating cantilever with a temporal resolution of < 1 min. Through simulations, experiments with hydrogels and the use of chemically perturbed cells, we show that our readout, the size-normalized acoustic scattering (SNACS), measures stiffness. To demonstrate the noninvasiveness of SNACS over successive cell cycles, we used measurements that resulted in deformations of < 15 nm. The cells maintained constant SNACS throughout interphase but showed dynamic changes during mitosis. Our work provides a basis for understanding how growing cells maintain mechanical integrity, and demonstrates that acoustic scattering can be used to noninvasively probe subtle and transient dynamics.

Microfluidic platform for selective microparticle parking and paired particle isolation in droplet arrays.

Immobilizing microscale objects (e.g., cells, spheroids, and microparticles) in arrays for direct observation and analysis is a critical step of many biological and chemical assays; however, existing techniques are often limited in their ability to precisely capture, arrange, isolate, and recollect objects of interest. In this work, we present a microfluidic platform that selectively parks microparticles in hydrodynamic traps based on particle physical characteristics (size, stiffness, and internal structure). We present an accompanying scaling analysis for the particle parking process to enable rational design of microfluidic traps and selection of operating conditions for successful parking of desired particles with specific size and elastic modulus. Our platform also enables parking of encoded particle pairs in defined spatial arrangements and subsequent isolation of these pairs in aqueous droplets, creating distinct microenvironments with no cross-contamination. In addition, we demonstrate the ability to recollect objects of interest (i.e., one particle from each pair) after observation within the channel. This integrated device is ideal for multiplexed assays or microenvironment fabrication for controlled biological studies.

Microparticle parking and isolation for highly sensitive microRNA detection.

Isolating small objects, such as particles, cells, and molecules, in individual aqueous droplets is useful for chemical and biological assays. We have developed a simple microfluidic platform to immobilize (park) microparticles at defined locations, and isolate particles in monodisperse droplets surrounded by immiscible oil. While conventional methods can only achieve stochastic encapsulation of objects within larger droplets, our in situ method ensures that a single particle is entrapped in a similar-sized droplet, with ∼95% yield for parking and isolation. This enables time-lapse studies of reactions in confined volumes and can be used to perform enzymatic amplification of a desired signal to improve the sensitivity of diagnostic assays. To demonstrate the utility of our technique, we perform highly sensitive, multiplexed microRNA detection by isolating encoded, functional hydrogel microparticles in small aqueous droplets. Non-fouling hydrogel microparticles are attractive for microRNA detection due to favorable capture kinetics. By encapsulating these particles in droplets and employing a generalizable enzyme amplification scheme, we demonstrate an order of magnitude improvement in detection sensitivity compared to a non-amplified assay.

Effect of internal architecture on microgel deformation in microfluidic constrictions.

The study of how soft particles deform to pass through narrow openings is important for understanding the transit of biological cells, as well as for designing deformable drug delivery carriers. In this work, we systematically explore how soft microparticles with various internal architectures deform during passage through microfluidic constrictions. We synthesize hydrogel particles with well-defined internal structure using lithography-based UV polymerization in microfluidic channels (stop-flow lithography). Using this in situ technique, we explore a range of 2D particle architectures and their effect on particle deformation. We observe that particles undergo buckling of internal supports and reorient at the constriction entrance in order to adopt preferred shapes that correspond to minimum energy configurations. Using finite element simulations of elastic deformation under compression, we accurately predict the optimal deformation configuration of these structured particles.

The association between benzodiazepine use and sleep quality in residential aged care facilities: a cross-sectional study.

BACKGROUND: Benzodiazepines are commonly prescribed in residential aged care facilities (RACFs) for their sedative and anxiolytic effects. The objective of this study was to investigate the association between benzodiazepine use and sleep quality in residents of RACFs. METHODS: A cross-sectional study involving 383 participants was conducted in six Australian RACFs. Night-time sleep quality, day-time drowsiness and day-time napping behavior were assessed using a validated questionnaire. Logistic regression was used to compute adjusted odds ratios (AORs) and 95% confidence intervals (CIs) for the association between benzodiazepine use and sleep quality. Covariates included pain, dementia severity, depression, insomnia and other sedative use. RESULTS: Of the 383 residents (mean age 87.5 years, 77.5% female), 96(25.1%) used a benzodiazepine on a regular basis. Residents who used long-acting benzodiazepines on a regular basis had higher night-time sleep quality than non-users (AOR = 4.00, 95%CI 1.06 - 15.15). Residents who used short-acting benzodiazepines on a PRN only basis had longer daytime napping times than non-users (AOR = 1.77, 95%CI 1.01 - 3.08). No benzodiazepine category was associated with day-time drowsiness. CONCLUSIONS: The association between benzodiazepine use and sleep quality is dependent on the half-life and prescribing pattern of the benzodiazepine. Short-acting PRN benzodiazepines were associated with lower night time sleep quality and longer day-time napping compared to long-acting regular benzodiazepines. Longitudinal studies are needed to determine whether these findings reflect channeling of short-acting agents to residents at higher risk of sleep disorders.

Flexible Octopus-Shaped Hydrogel Particles for Specific Cell Capture.

Multiarm hydrogel microparticles with varying geometry are fabricated to specifically capture cells expressing epithelial cell adhesion molecule. Results show that particle shape influences cell-capture efficiency due to differences in surface area, hydrodynamic effects, and steric constraints. These findings can lead to improved particle design for cell separation and diagnostic applications.

Synthesis of Nonspherical Microcapsules through Controlled Polyelectrolyte Coating of Hydrogel Templates.

We report a simple approach to fabricate custom-shape microcapsules using hydrogel templates synthesized by stop flow lithography. Cargo-containing microcapsules were made by coating hydrogel particles with a single layer of poly-l-lysine followed by a one-step core degradation and capsule cross-linking procedure. We determined appropriate coating conditions by investigating the effect of pH, ionic strength, and prepolymer composition on the diffusion of polyelectrolytes into the oppositely charged hydrogel template. We also characterized the degradation of the templating core by tracking the diffusivity of nanoparticles embedded within the hydrogel. Unlike any other technique, this approach allows for easy fabrication of microcapsules with internal features (e.g., toroids) and selective surface modification of Janus particles using any polyelectrolyte. These soft, flexible capsules may be useful for therapeutic applications as well as fundamental studies of membrane mechanics.

Synthesis of colloidal microgels using oxygen-controlled flow lithography.

We report a synthesis approach based on stop-flow lithography (SFL) for fabricating colloidal microparticles with any arbitrary 2D-extruded shape. By modulating the degree of oxygen inhibition during synthesis, we achieved previously unattainable particle sizes. Brownian diffusion of colloidal discs in bulk suggests the out-of-plane dimension can be as small as 0.8 µm, which agrees with confocal microscopy measurements. We measured the hindered diffusion of microdiscs near a solid surface and compared our results to theoretical predictions. These colloidal particles can also flow through physiological microvascular networks formed by endothelial cells undergoing vasculogensis under minimal hydrostatic pressure (∼5 mm H2O). This versatile platform creates future opportunities for on-chip parametric studies of particle geometry effects on particle passage properties, distribution and cellular interactions.

Self-assembled hydrogel fibers for sensing the multi-compartment intracellular milieu.

Targeted delivery of drugs and sensors into cells is an attractive technology with both medical and scientific applications. Existing delivery vehicles are generally limited by the complexity of their design, dependence on active transport, and inability to function within cellular compartments. Here, we developed self-assembled nanofibrous hydrogel fibers using a biologically inert, low-molecular-weight amphiphile. Self-assembled nanofibrous hydrogels offer unique physical/mechanical properties and can easily be loaded with a diverse range of payloads. Unlike commercially available E. coli membrane particles covalently bound to the pH reporting dye pHrodo, pHrodo encapsulated in self-assembled hydrogel-fibers internalizes into macrophages at both physiologic (37°C) and sub-physiologic (4°C) temperatures through an energy-independent, passive process. Unlike dye alone or pHrodo complexed to E. coli, pHrodo-SAFs report pH in both the cytoplasm and phagosomes, as well the nucleus. This new class of materials should be useful for next-generation sensing of the intracellular milieu.