Fluid dynamics alters liquid-liquid phase separation in confined aqueous two-phase systems.

Liquid-liquid phase separation is key to understanding aqueous two-phase systems (ATPS) arising throughout cell biology, medical science, and the pharmaceutical industry. Controlling the detailed morphology of phase-separating compound droplets leads to new technologies for efficient single-cell analysis, targeted drug delivery, and effective cell scaffolds for wound healing. We present a computational model of liquid-liquid phase separation relevant to recent laboratory experiments with gelatin-polyethylene glycol mixtures. We include buoyancy and surface-tension-driven finite viscosity fluid dynamics with thermally induced phase separation. We show that the fluid dynamics greatly alters the evolution and equilibria of the phase separation problem. Notably, buoyancy plays a critical role in driving the ATPS to energy-minimizing crescent-shaped morphologies, and shear flows can generate a tenfold speedup in particle formation. Neglecting fluid dynamics produces incorrect minimum-energy droplet shapes. The model allows for optimization of current manufacturing procedures for structured microparticles and improves understanding of ATPS evolution in confined and flowing settings important in biology and biotechnology.

Safety and effectiveness of the booster dose of mRNA COVID-19 vaccines in people with multiple sclerosis: A monocentric experience.

BACKGROUND: Long-term data on the effectiveness and safety of the booster dose of anti-SARS-CoV-2 vaccines in people affected by multiple sclerosis (pwMS) are lacking, hence a retrospective monocentric study exploring these issues was undertaken. MATERIALS AND METHODS: PwMS who had received the booster dose of anti-COVID19 mRNA vaccines (either Comirnaty or Spikevax) according to the national regulation were included. The occurrence of adverse events or disease reactivation and SARS-CoV-2 infection were recorded up to last follow-up. Factors predictive of COVID-19 were explored using logistic regression analyses. A two-tailed p-value <0.05 was considered significant. RESULTS: One hundred and fourteen pwMS were included: 80 females (70%); median age at the booster dose 42 years (range 21 - 73); 106/114 patients (93%) were receiving a disease-modifying treatment at vaccination. The median follow-up after the booster dose was 6 (range 2 - 7) months. Adverse events were experienced in 58% of the patients, being mild to moderate in most cases; 4 reactivations of MS were observed, two of which occurring within 4 weeks after the booster. SARS-CoV-2 infection was reported in 24/114 (21%) cases, occurring a median of 74 days (5-162) after the booster dose and requiring hospitalisation in 2 patients. Six cases received direct antiviral drugs. Age at vaccination and time between the primary vaccination cycle and the booster dose were independently and inversely associated with the risk of COVID-19 (HR 0.95 and 0.98, respectively). CONCLUSIONS: The administration of the booster dose in pwMS showed an overall good safety profile and protected 79% of the patients from SARS-CoV-2 infection. The observed association between the risk of infection after the booster dose and both younger age at vaccination and shorter interval period to the booster dose suggest that unobserved confounders, possibly including behavioural and social factors, play a relevant role in determining the individual propensity to get infected with COVID-19.

Post-Radiotherapy PET Image Outcome Prediction by Deep Learning Under Biological Model Guidance: A Feasibility Study of Oropharyngeal Cancer Application.

Purpose: To develop a method of biologically guided deep learning for post-radiation 18FDG-PET image outcome prediction based on pre-radiation images and radiotherapy dose information. Methods: Based on the classic reaction-diffusion mechanism, a novel biological model was proposed using a partial differential equation that incorporates spatial radiation dose distribution as a patient-specific treatment information variable. A 7-layer encoder-decoder-based convolutional neural network (CNN) was designed and trained to learn the proposed biological model. As such, the model could generate post-radiation 18FDG-PET image outcome predictions with breakdown biological components for enhanced explainability. The proposed method was developed using 64 oropharyngeal patients with paired 18FDG-PET studies before and after 20-Gy delivery (2 Gy/day fraction) by intensity-modulated radiotherapy (IMRT). In a two-branch deep learning execution, the proposed CNN learns specific terms in the biological model from paired 18FDG-PET images and spatial dose distribution in one branch, and the biological model generates post-20-Gy 18FDG-PET image prediction in the other branch. As in 2D execution, 718/233/230 axial slices from 38/13/13 patients were used for training/validation/independent test. The prediction image results in test cases were compared with the ground-truth results quantitatively. Results: The proposed method successfully generated post-20-Gy 18FDG-PET image outcome prediction with breakdown illustrations of biological model components. Standardized uptake value (SUV) mean values in 18FDG high-uptake regions of predicted images (2.45 ± 0.25) were similar to ground-truth results (2.51 ± 0.33). In 2D-based Gamma analysis, the median/mean Gamma Index (<1) passing rate of test images was 96.5%/92.8% using the 5%/5 mm criterion; such result was improved to 99.9%/99.6% when 10%/10 mm was adopted. Conclusion: The developed biologically guided deep learning method achieved post-20-Gy 18FDG-PET image outcome predictions in good agreement with ground-truth results. With the breakdown biological modeling components, the outcome image predictions could be used in adaptive radiotherapy decision-making to optimize personalized plans for the best outcome in the future.

Extraction of Hidden Science from Nanoscale Images.

Scanning probe microscopies and spectroscopies enable investigation of surfaces and even buried interfaces down to the scale of chemical-bonding interactions, and this capability has been enhanced with the support of computational algorithms for data acquisition and image processing to explore physical, chemical, and biological phenomena. Here, we describe how scanning probe techniques have been enhanced by some of these recent algorithmic improvements. One improvement to the data acquisition algorithm is to advance beyond a simple rastering framework by using spirals at constant angular velocity then switching to constant linear velocity, which limits the piezo creep and hysteresis issues seen in traditional acquisition methods. One can also use image-processing techniques to model the distortions that appear from tip motion effects and to make corrections to these images. Another image-processing algorithm we discuss enables researchers to segment images by domains and subdomains, thereby highlighting reactive and interesting disordered sites at domain boundaries. Lastly, we discuss algorithms used to examine the dipole direction of individual molecules and surface domains, hydrogen bonding interactions, and molecular tilt. The computational algorithms used for scanning probe techniques are still improving rapidly and are incorporating machine learning at the next level of iteration. That said, the algorithms are not yet able to perform live adjustments during data recording that could enhance the microscopy and spectroscopic imaging methods significantly.

Effect of disease-modifying treatments on antibody-mediated response to anti-COVID19 vaccination in people with multiple sclerosis.

BACKGROUND: Few data are available so far on the antibody-mediated immune response to anti-SARS-Cov2 vaccination in people with multiple sclerosis (pwMS) treated with disease-modifying treatments (DMTs), therefore this issue was explored in a real-life cohort of pwMS. MATERIALS AND METHODS: Retrospective monocentric study on anti-spike protein antibody response in pwMS who had received vaccination for Sars-Cov2. Adverse events following vaccination were also recorded. RESULTS: One hundred and twenty pwMS were included: 83 females (69%); median age at vaccination 42 years (range 21-73); 112/120 patients (93%) were receiving DMTs at vaccination. Anti-spike protein IgG antibodies were detectable in 102/120 (85%) cases overall, being the proportion lower in pwMS receiving anti-CD20 antibodies (14/31, 45%) compared to non-depletive treatments (77/78, 99%), p < 0.0001. Median anti-spike titre was lower in anti-CD20 antibodies and fingolimod-treated pwMS compared to those receiving other DMTs, and it correlated with anti-CD20 treatment duration (R - 0.93, p < 0.0001) and with age at vaccination in pwMS not receiving depletive treatments (R - 0.25, p = 0.028). Baseline CD19+ cell count (where available) was higher in the responder group than in non-responders, p < 0.0001. Two symptomatic COVID-19 infections were diagnosed over a median follow-up of 5 months (range 2-7); adverse events were aligned with the published literature. CONCLUSION: Antibody response to anti-COVID-19 vaccines was detected in most of the pwMS analysed, but frequency of responders was reduced in those receiving CD20 depleting therapies compared to other DMTs-treated pwMS. Investigations on cell-mediated immune response are needed to assess whether a protective immune response is elicited also in non-antibody responders.

Suspendable Hydrogel Nanovials for Massively Parallel Single-Cell Functional Analysis and Sorting.

Techniques to analyze and sort single cells based on functional outputs, such as secreted products, have the potential to transform our understanding of cellular biology as well as accelerate the development of next-generation cell and antibody therapies. However, secreted molecules rapidly diffuse away from cells, and analysis of these products requires specialized equipment and expertise to compartmentalize individual cells and capture their secretions. Herein, we describe methods to fabricate hydrogel-based chemically functionalized microcontainers, which we call nanovials, and demonstrate their use for sorting single viable cells based on their secreted products at high-throughput using only commonly accessible laboratory infrastructure. These nanovials act as solid supports that facilitate attachment of a variety of adherent and suspension cell types, partition uniform aqueous compartments, and capture secreted proteins. Solutions can be exchanged around nanovials to perform fluorescence immunoassays on secreted proteins. Using this platform and commercial flow sorters, we demonstrate high-throughput screening of stably and transiently transfected producer cells based on relative IgG production. Chinese hamster ovary cells sorted based on IgG production regrew and maintained a high secretion phenotype over at least a week, yielding >40% increase in bulk IgG production rates. We also sorted hybridomas and B lymphocytes based on antigen-specific antibody production. Hybridoma cells secreting an antihen egg lysozyme antibody were recovered from background cells, enriching a population of ∼4% prevalence to >90% following sorting. Leveraging the high-speed sorting capabilities of standard sorters, we sorted >1 million events in <1 h. IgG secreting mouse B cells were also sorted and enriched based on antigen-specific binding. Successful sorting of antibody-secreting B cells combined with the ability to perform single-cell RT-PCR to recover sequence information suggests the potential to perform antibody discovery workflows. The reported nanovials can be easily stored and distributed among researchers, democratizing access to high-throughput functional cell screening.

Mitral Valve Segmentation Using Robust Nonnegative Matrix Factorization.

Analyzing and understanding the movement of the mitral valve is of vital importance in cardiology, as the treatment and prevention of several serious heart diseases depend on it. Unfortunately, large amounts of noise as well as a highly varying image quality make the automatic tracking and segmentation of the mitral valve in two-dimensional echocardiographic videos challenging. In this paper, we present a fully automatic and unsupervised method for segmentation of the mitral valve in two-dimensional echocardiographic videos, independently of the echocardiographic view. We propose a bias-free variant of the robust non-negative matrix factorization (RNMF) along with a window-based localization approach, that is able to identify the mitral valve in several challenging situations. We improve the average f1-score on our dataset of 10 echocardiographic videos by 0.18 to a f1-score of 0.56.

Capillary-Driven Rise of Well-Wetting Liquid on the Outer Surface of Cylindrical Nozzles.

Well-wetting liquids exiting small-diameter nozzles in the dripping regime can partially rise up along the outer nozzle surfaces. This is problematic for fuel injectors and other devices such as direct-contact heat and mass exchangers that incorporate arrays of nozzles to distribute liquids. We report our experimental and numerical study of the rising phenomenon for wide ranges of parameters. Our study shows that the interplay of three dimensionless numbers (the Bond number, the Weber number, and the Ohnesorge number) governs the capillary-driven rise dynamics. In general, as the flow rate or the viscosity increases, the capillary-driven rise height over each dripping period becomes smaller. We identify liquid flow rates below which the temporal evolution of the meniscus positions can be well approximated by a quasistatic model based on the Young-Laplace equation. Our analysis reveals two critical Bond numbers that give nozzle sizes, which correspond to the maximum meniscus rise and the onset of capillary-driven rise cessation. These critical Bond numbers are characterized as a function of the contact angle, regardless of the fluid type. Our study leads to a more efficient and optimized nozzle design in systems using wetting liquids by reducing both the risks of contamination and high pressure drop in such devices.

Statistical energy minimization theory for systems of drop-carrier particles.

Drop-carrier particles (DCPs) are solid microparticles designed to capture uniform microscale drops of a target solution without using costly microfluidic equipment and techniques. DCPs are useful for automated and high-throughput biological assays and reactions, as well as single-cell analyses. Surface energy minimization provides a theoretical prediction for the volume distribution in pairwise droplet splitting, showing good agreement with macroscale experiments. We develop a probabilistic pairwise interaction model for a system of such DCPs exchanging fluid volume to minimize surface energy. This leads to a theory for the number of pairwise interactions of DCPs needed to reach a uniform volume distribution. Heterogeneous mixtures of DCPs with different sized particles require fewer interactions to reach a minimum energy distribution for the system. We optimize the DCP geometry for minimal required target solution and uniformity in droplet volume.

Experimental study of a string-based counterflow wet electrostatic precipitator for collection of fine and ultrafine particles.

Wet electrostatic precipitators (WESP) have been widely studied for collecting fine and ultrafine particles, such as diesel particulate matter (DPM), which have deleterious effects on human health. Here, we report an experimental and numerical simulation study on a novel string-based two-stage WESP. Our new design incorporates grounded vertically aligned polymer strings, along which thin films of water flow down. The water beads, generated by intrinsic flow instability, travel down the strings and collect charged particles in the counterflowing gas stream. We performed experiments using two different geometric configurations of WESP: rectangular and cylindrical. We examined the effects of the WESP electrode bias voltage, air stream velocity, and water flow rate on the number-based fractional collection efficiency for particles of diameters ranging from 10 nm to 2.5 µm. The collection efficiency improves with increasing bias voltages or decreasing airflow rates. At liquid-to-gas (L/G) as low as approximately 0.0066, our design delivers a collection efficiency over 70% even for fine and ultrafine particles. The rectangular and cylindrical configurations exhibit similar collection efficiencies under nominally identical experimental conditions. We also compare the water-to-air mass flow rate ratio, air flow rate per unit collector volume, and collection efficiency of our string-based design with those of previously reported WESPs. The present work demonstrates a promising design for a highly efficient, compact, and scalable two-stage WESPs with minimal water consumption.Implications: Wet Electrostatic Precipitators (WESPs) are highly effective for collecting fine particles in exhaust air streams from various sources such as diesel engines, power plants, and oil refineries. However, their large-scale adoption has been limited by high water usage and reduced collection efficiencies for ultrafine particles. We perform experimental and numerical investigation to characterize the collection efficiency and water flow rate-dependence of a new design of WESP. The string-based counterflow WESP reported in this study offers number-based collection efficiencies >70% at air flow rates per collector volume as high as 4.36 (m3/s)/m3 for particles of diameters ranging from 10 nm - 2.5 µm, while significantly reducing water usage. Our work provides a basis for the design of more compact and water-efficient WESPs.

Monodisperse drops templated by 3D-structured microparticles.

The ability to create uniform subnanoliter compartments using microfluidic control has enabled new approaches for analysis of single cells and molecules. However, specialized instruments or expertise has been required, slowing the adoption of these cutting-edge applications. Here, we show that three dimensional-structured microparticles with sculpted surface chemistries template uniformly sized aqueous drops when simply mixed with two immiscible fluid phases. In contrast to traditional emulsions, particle-templated drops of a controlled volume occupy a minimum in the interfacial energy of the system, such that a stable monodisperse state results with simple and reproducible formation conditions. We describe techniques to manufacture microscale drop-carrier particles and show that emulsions created with these particles prevent molecular exchange, concentrating reactions within the drops, laying a foundation for sensitive compartmentalized molecular and cell-based assays with minimal instrumentation.

The challenges of modeling and forecasting the spread of COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic has placed epidemic modeling at the forefront of worldwide public policy making. Nonetheless, modeling and forecasting the spread of COVID-19 remains a challenge. Here, we detail three regional-scale models for forecasting and assessing the course of the pandemic. This work demonstrates the utility of parsimonious models for early-time data and provides an accessible framework for generating policy-relevant insights into its course. We show how these models can be connected to each other and to time series data for a particular region. Capable of measuring and forecasting the impacts of social distancing, these models highlight the dangers of relaxing nonpharmaceutical public health interventions in the absence of a vaccine or antiviral therapies.

Impact of social distancing during COVID-19 pandemic on crime in Los Angeles and Indianapolis.

Governments have implemented social distancing measures to address the ongoing COVID-19 pandemic. The measures include instructions that individuals maintain social distance when in public, school closures, limitations on gatherings and business operations, and instructions to remain at home. Social distancing may have an impact on the volume and distribution of crime. Crimes such as residential burglary may decrease as a byproduct of increased guardianship over personal space and property. Crimes such as domestic violence may increase because of extended periods of contact between potential offenders and victims. Understanding the impact of social distancing on crime is critical for ensuring the safety of police and government capacity to deal with the evolving crisis. Understanding how social distancing policies impact crime may also provide insights into whether people are complying with public health measures. Examination of the most recently available data from both Los Angeles, CA, and Indianapolis, IN, shows that social distancing has had a statistically significant impact on a few specific crime types. However, the overall effect is notably less than might be expected given the scale of the disruption to social and economic life.

Hyperspectral Image Unmixing With Endmember Bundles and Group Sparsity Inducing Mixed Norms.

Hyperspectral images provide much more information than conventional imaging techniques, allowing a precise identification of the materials in the observed scene, but because of the limited spatial resolution, the observations are usually mixtures of the contributions of several materials. The spectral unmixing problem aims at recovering the spectra of the pure materials of the scene (endmembers), along with their proportions (abundances) in each pixel. In order to deal with the intra-class variability of the materials and the induced spectral variability of the endmembers, several spectra per material, constituting endmember bundles, can be considered. However, the usual abundance estimation techniques do not take advantage of the particular structure of these bundles, organized into groups of spectra. In this paper, we propose to use group sparsity by introducing mixed norms in the abundance estimation optimization problem. In particular, we propose a new penalty, which simultaneously enforces group and within-group sparsity, to the cost of being nonconvex. All the proposed penalties are compatible with the abundance sum-to-one constraint, which is not the case with traditional sparse regression. We show on simulated and real datasets that well-chosen penalties can significantly improve the unmixing performance compared to classical sparse regression techniques or to the naive bundle approach.

Using insurance claims to predict and improve hospitalizations and biologics use in members with inflammatory bowel diseases.

OBJECTIVE: Inflammatory Bowel Disease (IBD) is an inflammatory disorder of the gastrointestinal tract that can necessitate hospitalization and the use of expensive biologics. Models predicting these interventions may improve patient quality of life and reduce expenditures. MATERIALS AND METHODS: We used insurance claims from 2011 to 2013 to predict IBD-related hospitalizations and the initiation of biologics. We derived and optimized our model from a 2011 training set of 7771 members, predicting their outcomes the following year. The best-performing model was then applied to a 2012 validation set of 7450 members to predict their outcomes in 2013. RESULTS: Our models predicted both IBD-related hospitalizations and the initiation of biologics, with average positive predictive values of 17% and 11%, respectively - each a 200% improvement over chance. Further, when we used topic modeling to identify four member subpopulations, the positive predictive value of predicting hospitalization increased to 20%. DISCUSSION: We show that our hospitalization model, in concert with a mildly-effective interventional treatment plan for members identified as high-risk, may both improve patient outcomes and reduce insurance expenditures. CONCLUSION: The success of our approach provides a roadmap for how claims data can complement traditional medical decision making with personalized, data-driven predictive medicine.

Mapping Buried Hydrogen-Bonding Networks.

We map buried hydrogen-bonding networks within self-assembled monolayers of 3-mercapto-N-nonylpropionamide on Au{111}. The contributing interactions include the buried S-Au bonds at the substrate surface and the buried plane of linear networks of hydrogen bonds. Both are simultaneously mapped with submolecular resolution, in addition to the exposed interface, to determine the orientations of molecular segments and directional bonding. Two-dimensional mode-decomposition techniques are used to elucidate the directionality of these networks. We find that amide-based hydrogen bonds cross molecular domain boundaries and areas of local disorder.

Growth and containment of a hierarchical criminal network.

We model the hierarchical evolution of an organized criminal network via antagonistic recruitment and pursuit processes. Within the recruitment phase, a criminal kingpin enlists new members into the network, who in turn seek out other affiliates. New recruits are linked to established criminals according to a probability distribution that depends on the current network structure. At the same time, law enforcement agents attempt to dismantle the growing organization using pursuit strategies that initiate on the lower level nodes and that unfold as self-avoiding random walks. The global details of the organization are unknown to law enforcement, who must explore the hierarchy node by node. We halt the pursuit when certain local criteria of the network are uncovered, encoding if and when an arrest is made; the criminal network is assumed to be eradicated if the kingpin is arrested. We first analyze recruitment and study the large scale properties of the growing network; later we add pursuit and use numerical simulations to study the eradication probability in the case of three pursuit strategies, the time to first eradication, and related costs. Within the context of this model, we find that eradication becomes increasingly costly as the network increases in size and that the optimal way of arresting the kingpin is to intervene at the early stages of network formation. We discuss our results in the context of dark network disruption and their implications on possible law enforcement strategies.

Height drift correction in non-raster atomic force microscopy.

We propose a novel method to detect and correct drift in non-raster scanning probe microscopy. In conventional raster scanning drift is usually corrected by subtracting a fitted polynomial from each scan line, but sample tilt or large topographic features can result in severe artifacts. Our method uses self-intersecting scan paths to distinguish drift from topographic features. Observing the height differences when passing the same position at different times enables the reconstruction of a continuous function of drift. We show that a small number of self-intersections is adequate for automatic and reliable drift correction. Additionally, we introduce a fitness function which provides a quantitative measure of drift correctability for any arbitrary scan shape.

Multiclass Data Segmentation Using Diffuse Interface Methods on Graphs.

We present two graph-based algorithms for multiclass segmentation of high-dimensional data on graphs. The algorithms use a diffuse interface model based on the Ginzburg-Landau functional, related to total variation and graph cuts. A multiclass extension is introduced using the Gibbs simplex, with the functional's double-well potential modified to handle the multiclass case. The first algorithm minimizes the functional using a convex splitting numerical scheme. The second algorithm uses a graph adaptation of the classical numerical Merriman-Bence-Osher (MBO) scheme, which alternates between diffusion and thresholding. We demonstrate the performance of both algorithms experimentally on synthetic data, image labeling, and several benchmark data sets such as MNIST, COIL and WebKB. We also make use of fast numerical solvers for finding the eigenvectors and eigenvalues of the graph Laplacian, and take advantage of the sparsity of the matrix. Experiments indicate that the results are competitive with or better than the current state-of-the-art in multiclass graph-based segmentation algorithms for high-dimensional data.