The roles of sub-micron and microscale roughness on shear-driven thrombosis on titanium alloy surfaces.

BACKGROUND: Continuous-flow ventricular assist devices (cfVADs) are implanted in patients with end-stage heart failure to assist with blood circulation. However, VAD implantation is associated with dangerous thrombotic complications. Our goal was to determine the impact of micron and sub-micron scale Ti6Al4V surface roughness on adherent platelet aggregate properties under clinically relevant shear rates. METHODS: We used fluorescence microscopy to visualize platelets in real time as they adhered to Ti6Al4V coupons of varying degrees of roughness, including a smooth control, in microfluidic channels and quantified deposition using an image processing algorithm. We systematically characterized roughness using spatial frequencies to generalize results for more blood-biomaterial contact applications. RESULTS: We observed that on the control and sub-micron rough surfaces, at 1000 s-1 , platelets adhered uniformly on the surface. At 2000 s-1 , we observed small and stably adherent platelet aggregates. At 5500 s-1 , platelet aggregates were large, unstable and interconnected via fibrillar structures. On a surface with micron-scale roughness features, at all three shear rates, platelets deposited in the troughs of the roughened surface, and formed aggregates. Thrombus height at 2000 s-1 and 5500 s-1 was greatest on the roughest surface and lowest on the mirror-finished surface, as indicated by the mean fluorescence intensity. CONCLUSIONS: These results demonstrated that at high shear rates, thrombi form regardless of surface topography at the scales applied. At lower shear rates, micron-scale surface features cause thrombus formation, whereas submicron features result in innocuous platelet adhesion. These findings have implications for manufacturing costs and other considerations.

Ledipasvir/Sofosbuvir for 8, 12, or 24 Weeks in Hepatitis C Patients Undergoing Dialysis for End-Stage Renal Disease.

INTRODUCTION: We evaluated 8, 12, or 24 weeks of ledipasvir/sofosbuvir in patients with hepatitis C virus and end-stage renal disease undergoing dialysis. METHODS: Primary efficacy end point was sustained virologic response 12 weeks after treatment. Primary safety end point was treatment discontinuation because of adverse events (AEs). RESULTS: Ninety-four percent (89/95) achieved sustained virologic response 12 weeks after treatment. Six patients died during treatment (n = 4) or before study completion (n = 2); no deaths were related to treatment. No patients discontinued treatment because of AEs. Thirteen percent had serious AEs; none were related to treatment. DISCUSSION: Treatment with ledipasvir/sofosbuvir was safe and effective in patients with end-stage renal disease undergoing dialysis.

Modifying Critical Exponents of Magnetic Phase Transitions via Nanoscale Materials Design.

We demonstrate a nanoscale materials design path that allows us to bypass universality in thin ferromagnetic films and enables us to tune the critical exponents of ferromagnetic phase transitions in a very wide parameter range, while at the same time preserving scaling in an extended phase space near the Curie temperature. Our detailed magnetometry results reveal that single crystal CoRu alloy films, in which the predefined depth dependent exchange coupling strength follows a V-shaped profile, exhibit critical scaling behavior over many orders of magnitude. Their critical exponents, however, can be designed and controlled by modifying their specific nanoscale structures, thus demonstrating full tunability of critical behavior. The reason for this tunability and the disappearance of universality is shown to be the competing relevance of collective versus interface propagating progression of ferromagnetic phase transitions, whose balance we find to be dependent on the specifics of the underlying exchange coupling strength profile.

Graded magnetic materials.

Graded magnetic materials represent a promising new avenue in modern material science from both fundamental and application points of view. Over the course of the last few years, remarkable results have been obtained in (epitaxial) heterostructures based on thin alloy films featuring diverse compositional depth profiles. As a result of the precise tailoring of such profiles, the exchange coupling, and the corresponding effective or local Curie temperatures can be controlled over tens of nm with an excellent precision. This topical review article reports the most recent advances in this emerging research field. Several aspects are covered, but the primary focus lies in the study of compositional gradients being transferred into depth dependent magnetic states in ferromagnets, while also reviewing other experimental attempts to create exchange graded films and materials in general. We account for the remarkable progress achieved in each sample and composition geometry by reporting the recent developments and by discussing the research highlights obtained by several groups. Finally, we conclude the review article with an outlook on future challenges in this field.

Effects of Selonsertib in Patients with Diabetic Kidney Disease.

BACKGROUND: Apoptosis signal-regulating kinase 1 (ASK1) activation in glomerular and tubular cells resulting from oxidative stress may drive kidney disease progression. Findings in animal models identified selonsertib, a selective ASK1 inhibitor, as a potential therapeutic agent. METHODS: In a phase 2 trial evaluating selonsertib's safety and efficacy in adults with type 2 diabetes and treatment-refractory moderate-to-advanced diabetic kidney disease, we randomly assigned 333 adults in a 1:1:1:1 allocation to selonsertib (oral daily doses of 2, 6, or 18 mg) or placebo. Primary outcome was change from baseline eGFR at 48 weeks. RESULTS: Selonsertib appeared safe, with no dose-dependent adverse effects over 48 weeks. Although mean eGFR for selonsertib and placebo groups did not differ significantly at 48 weeks, acute effects related to inhibition of creatinine secretion by selonsertib confounded eGFR differences at 48 weeks. Because of this unanticipated effect, we used piecewise linear regression, finding two dose-dependent effects: an acute and more pronounced eGFR decline from 0 to 4 weeks (creatinine secretion effect) and an attenuated eGFR decline between 4 and 48 weeks (therapeutic effect) with higher doses of selonsertib. A post hoc analysis (excluding data for 20 patients from two sites with Good Clinical Practice compliance-related issues) found that between 4 and 48 weeks, rate of eGFR decline was reduced 71% for the 18-mg group relative to placebo (difference 3.11±1.53 ml/min per 1.73 m2 annualized over 1 year; 95% confidence interval, 0.10-6.13; nominal P=0.043). Effects on urine albumin-to-creatinine ratio did not differ between selonsertib and placebo. CONCLUSIONS: Although the trial did not meet its primary endpoint, exploratory post hoc analyses suggest that selonsertib may slow diabetic kidney disease progression.

Emergent Magnetic State in (111)-Oriented Quasi-Two-Dimensional Spinel Oxides.

We report on the emergent magnetic state of (111)-oriented CoCr2O4 ultrathin films sandwiched between Al2O3 spacer layers in a quantum confined geometry. At the two-dimensional crossover, polarized neutron reflectometry reveals an anomalous enhancement of the total magnetization compared to the bulk value. Synchrotron X-ray magnetic circular dichroism measurements demonstrate the appearance of a long-range ferromagnetic ordering of spins on both Co and Cr sublattices. Brillouin function analyses and ab-initio density functional theory calculations further corroborate that the observed phenomena are due to the strongly altered magnetic frustration invoked by quantum confinement effects, manifested by the onset of a Yafet-Kittel-type ordering as the magnetic ground state in the ultrathin limit, which is unattainable in the bulk.

Sofosbuvir/velpatasvir for 12 weeks in hepatitis C virus-infected patients with end-stage renal disease undergoing dialysis.

BACKGROUND & AIMS: Although off-label use of sofosbuvir-containing regimens occurs regularly in patients with hepatitis C virus (HCV) infection undergoing dialysis for severe renal impairment or end-stage renal disease (ESRD), these regimens are not licensed for this indication, and there is an absence of dosing recommendations in this population. This study evaluated the safety and efficacy of sofosbuvir/velpatasvir in patients with HCV infection with ESRD undergoing dialysis. METHODS: In this phase II, single-arm study, 59 patients with genotype 1-6 HCV infection with ESRD undergoing hemodialysis or peritoneal dialysis received open-label sofosbuvir/velpatasvir (400 mg/100 mg) once daily for 12 weeks. Patients were HCV treatment naive or treatment experienced without cirrhosis or with compensated cirrhosis. Patients previously treated with any HCV NS5A inhibitor were not eligible. The primary efficacy endpoint was the proportion of patients achieving sustained virologic response (SVR) 12 weeks after discontinuation of treatment (SVR12). The primary safety endpoint was the proportion of patients who discontinued study drug due to adverse events. RESULTS: Overall, 56 of 59 patients achieved SVR12 (95%; 95% CI 86-99%). Of the 3 patients who did not achieve SVR12, 2 patients had virologic relapse determined at post-treatment Week 4 (including 1 who prematurely discontinued study treatment), and 1 patient died from suicide after achieving SVR through post-treatment Week 4. The most common adverse events were headache (17%), fatigue (14%), nausea (14%), and vomiting (14%). Serious adverse events were reported for 11 patients (19%), and all were deemed to be unrelated to sofosbuvir/velpatasvir. CONCLUSIONS: Treatment with sofosbuvir/velpatasvir for 12 weeks was safe and effective in patients with ESRD undergoing dialysis. LAY SUMMARY: Sofosbuvir/velpatasvir is a combination direct-acting antiviral that is approved for treatment of patients with hepatitis C virus (HCV) infection. Despite the lack of dosing recommendations, sofosbuvir-containing regimens (including sofosbuvir/velpatasvir) are frequently used for HCV-infected patients undergoing dialysis. This study evaluated the safety and efficacy of sofosbuvir/velpatasvir for 12 weeks in patients with HCV infection who were undergoing dialysis. Treatment with sofosbuvir/velpatasvir was safe and well tolerated, resulting in a cure rate of 95% in patients with HCV infection and end-stage renal disease. Clinical Trial Number: NCT03036852.

Scalable Synthesis of Switchable Assemblies of Gold Nanorod Lyotropic Liquid Crystal Nanocomposites.

A new class of solvent free, lyotropic liquid crystal nanocomposites based on gold nanorods (AuNRs) with high nanorod content is reported. Application of shear results in switchable, highly ordered alignment of the nanorods over several centimeters with excellent storage stability for months. For the synthesis, AuNRs are surface functionalized with a charged, covalently tethered corona, which induces fluid-like properties. This honey-like material can be deposited on a substrate and a high orientational order parameter of 0.72 is achieved using a simple shearing protocol. Switching shearing direction results in realignment of the AuNRs. For a film containing 75 wt% of AuNRs the alignment persists for several months. In addition to the lyotropic liquid crystal characteristics, the AuNRs films also exhibit anisotropic electrical conductivity with an order of magnitude difference between the conductivities in direction parallel and perpendicular to the alignment of the AuNRs.

Using Acoustic Perturbations to Dynamically Tune Shear Thickening in Colloidal Suspensions.

Colloidal suspensions in industrial processes often exhibit shear thickening that is difficult to control actively. Here, we use piezoelectric transducers to apply acoustic perturbations to dynamically tune the suspension viscosity in the shear-thickening regime. We attribute the mechanism of dethickening to the disruption of shear-induced force chains via perturbations that are large relative to the particle roughness scale. The ease with which this technique can be adapted to various flow geometries makes it a powerful tool for actively controlling suspension flow properties and investigating system dynamics.

anti-EGFR capture mitigates EMT- and chemoresistance-associated heterogeneity in a resistance-profiling CTC platform.

Capture and analysis of circulating tumor cells (CTCs) holds promise for diagnosing and guiding treatment of pancreatic cancer. To accurately monitor disease progression, capture platforms must be robust to processes that increase the phenotypic heterogeneity of CTCs. Most CTC-analysis technologies rely on the recognition of epithelial-specific markers for capture and identification, in particular the epithelial cell-adhesion molecule (EpCAM) and cytokeratin. As the epithelial-to-mesenchymal transition (EMT) and the acquisition of chemoresistance are both associated with loss of epithelial markers and characteristics, the effect of these processes on the expression of commonly used CTC markers, specifically EpCAM, EGFR and cytokeratin, requires further exploration. To determine this effect, we developed an in vitro model of EMT and acquired gemcitabine resistance in human pancreatic cancer cell lines. Using this model, we show that EMT-induction and acquired chemoresistance decrease EpCAM expression and microfluidic anti-EpCAM capture performance. Furthermore, we find that EGFR capture is more robust to these processes. By measuring the expression of known mediators of chemoresistance in captured cells using automated imaging and image processing, we demonstrate the ability to resistance-profile cells on-chip. We expect that this approach will allow for the development of improved non-invasive biomarkers of pancreatic cancer progression.

Tailoring exchange couplings in magnetic topological-insulator/antiferromagnet heterostructures.

Magnetic topological insulators such as Cr-doped (Bi,Sb)2Te3 provide a platform for the realization of versatile time-reversal symmetry-breaking physics. By constructing heterostructures exhibiting Néel order in an antiferromagnetic CrSb and ferromagnetic order in Cr-doped (Bi,Sb)2Te3, we realize emergent interfacial magnetic phenomena which can be tailored through artificial structural engineering. Through deliberate geometrical design of heterostructures and superlattices, we demonstrate the use of antiferromagnetic exchange coupling in manipulating the magnetic properties of magnetic topological insulators. Proximity effects are shown to induce an interfacial spin texture modulation and establish an effective long-range exchange coupling mediated by antiferromagnetism, which significantly enhances the magnetic ordering temperature in the superlattice. This work provides a new framework on integrating topological insulators with antiferromagnetic materials and unveils new avenues towards dissipationless topological antiferromagnetic spintronics.

Topological Transitions Induced by Antiferromagnetism in a Thin-Film Topological Insulator.

Magnetism in topological insulators (TIs) opens a topologically nontrivial exchange band gap, providing an exciting platform for manipulating the topological order through an external magnetic field. Here, we show that the surface of an antiferromagnetic thin film can magnetize the top and the bottom TI surface states through interfacial couplings. During the magnetization reversal, intermediate spin configurations are ascribed from unsynchronized magnetic switchings. This unsynchronized switching develops antisymmetric magnetoresistance spikes during magnetization reversals, which might originate from a series of topological transitions. With the high Néel ordering temperature provided by the antiferromagnetic layers, the signature of the induced topological transition persists up to ∼90 K.

Separation of 300 and 100 nm Particles in Fabry-Perot Acoustofluidic Resonators.

Separation of particles on the order of 100 nm with acoustophoresis has been challenging to date because of the competing natures of the acoustic radiation force and acoustic streaming on the particles. In this work, we present a surface acoustic wave (SAW)-based device that integrates a Fabry-Perot type acoustic resonator into a microfluidic channel to separate submicrometer particles. This configuration enhances the overall acoustic radiation force on the particles and thereby offers controlled manipulation of particles as small as 300 nm. Additionally, SAW-based excitation generates high-frequency acoustic waves in the system relative to bulk acoustic wave (BAW)-based actuation, which suppresses Rayleigh streaming effects on the submicrometer particles. We demonstrate a continuous-flow acoustophoretic separation of 300 and 100 nm particles in our device with a separation efficiency of 86.3%. We also present an analytical stochastic method to model the transport of submicrometer particles in the device and predict the migration trajectories as a function of acoustic and velocity potential field strengths. Our model incorporates particle diffusion, which is important for small particles, and successfully predicts the size-dependent separation modality of our system. This device can be used for several applications in microfluidics that require sorting of the submicrometer particles, and the analytical method can also be extended to predict the particle transport in other systems.

Lateral Magnetically Modulated Multilayers by Combining Ion Implantation and Lithography.

The combination of lithography and ion implantation is demonstrated to be a suitable method to prepare lateral multilayers. A laterally, compositionally, and magnetically modulated microscale pattern consisting of alternating Co (1.6 µm wide) and Co-CoO (2.4 µm wide) lines has been obtained by oxygen ion implantation into a lithographically masked Au-sandwiched Co thin film. Magnetoresistance along the lines (i.e., current and applied magnetic field are parallel to the lines) reveals an effective positive giant magnetoresistance (GMR) behavior at room temperature. Conversely, anisotropic magnetoresistance and GMR contributions are distinguished at low temperature (i.e., 10 K) since the O-implanted areas become exchange coupled. This planar GMR is principally ascribed to the spatial modulation of coercivity in a spring-magnet-type configuration, which results in 180° Néel extrinsic domain walls at the Co/Co-CoO interfaces. The versatility, in terms of pattern size, morphology, and composition adjustment, of this method offers a unique route to fabricate planar systems for, among others, spintronic research and applications.

Comparison and optimization of machine learning methods for automated classification of circulating tumor cells.

Advances in rare cell capture technology have made possible the interrogation of circulating tumor cells (CTCs) captured from whole patient blood. However, locating captured cells in the device by manual counting bottlenecks data processing by being tedious (hours per sample) and compromises the results by being inconsistent and prone to user bias. Some recent work has been done to automate the cell location and classification process to address these problems, employing image processing and machine learning (ML) algorithms to locate and classify cells in fluorescent microscope images. However, the type of machine learning method used is a part of the design space that has not been thoroughly explored. Thus, we have trained four ML algorithms on three different datasets. The trained ML algorithms locate and classify thousands of possible cells in a few minutes rather than a few hours, representing an order of magnitude increase in processing speed. Furthermore, some algorithms have a significantly (P < 0.05) higher area under the receiver operating characteristic curve than do other algorithms. Additionally, significant (P < 0.05) losses to performance occur when training on cell lines and testing on CTCs (and vice versa), indicating the need to train on a system that is representative of future unlabeled data. Optimal algorithm selection depends on the peculiarities of the individual dataset, indicating the need of a careful comparison and optimization of algorithms for individual image classification tasks. © 2016 International Society for Advancement of Cytometry.

Surface conductivity in electrokinetic systems with porous and charged interfaces: Analytical approximations and numerical results.

We derive an approximate analytical representation of the conductivity for a 1D system with porous and charged layers grafted onto parallel plates. Our theory improves on prior work by developing approximate analytical expressions applicable over an arbitrary range of potentials, both large and small as compared to the thermal voltage (RTF). Further, we describe these results in a framework of simplifying nondimensional parameters, indicating the relative dominance of various physicochemical processes. We demonstrate the efficacy of our approximate expression with comparisons to numerical representations of the exact analytical conductivity. Finally, we utilize this conductivity expression, in concert with other components of the electrokinetic coupling matrix, to describe the streaming potential and electroviscous effect in systems with porous and charged layers.

Sofosbuvir plus ribavirin for the treatment of chronic genotype 4 hepatitis C virus infection in patients of Egyptian ancestry.

BACKGROUND & AIMS: We conducted an open-label phase 2 study to assess the efficacy and safety of the oral nucleotide polymerase inhibitor sofosbuvir in combination with ribavirin in patients of Egyptian ancestry, chronically infected with genotype 4 hepatitis C virus (HCV). METHODS: Treatment-naive and previously treated patients with genotype 4 HCV were randomly allocated in a 1:1 ratio to receive sofosbuvir 400mg and weight-based ribavirin, for 12 or 24 weeks. The primary efficacy endpoint was the proportion of patients with sustained virologic response (HCV RNA <25IU/ml) 12 weeks after cessation of therapy (SVR12). RESULTS: Thirty treatment-naive and thirty previously treated patients were enrolled and treated for 12 weeks (n=31) or 24 weeks (n=29). Overall, 23% of patients had cirrhosis and 38% had diabetes. 14% of treatment-naive patients were interferon ineligible and 63% of treatment-experienced patients had prior non-response. SVR12 was achieved by 68% of patients (95% CI, 49-83%) in the 12-week group, and by 93% of patients (95% CI, 77-99%) in the 24-week group. The most common adverse events were headache, insomnia, and fatigue. No patient discontinued treatment due to an adverse event. CONCLUSIONS: The findings from the present study suggest that 24 weeks of sofosbuvir plus ribavirin is an efficacious and well tolerated treatment in patients with HCV genotype 4 infection.

Detection of circulating pancreas epithelial cells in patients with pancreatic cystic lesions.

Hematogenous dissemination is thought to be a late event in cancer progression. We recently showed in a genetic model of pancreatic ductal adenocarcinoma that pancreas cells can be detected in the bloodstream before tumor formation. To confirm these findings in humans, we used microfluidic geometrically enhanced differential immunocapture to detect circulating pancreas epithelial cells in patient blood samples. We captured more than 3 circulating pancreas epithelial cells/mL in 7 of 21 (33%) patients with cystic lesions and no clinical diagnosis of cancer (Sendai criteria negative), 8 of 11 (73%) with pancreatic ductal adenocarcinoma, and in 0 of 19 patients without cysts or cancer (controls). These findings indicate that cancer cells are present in the circulation of patients before tumors are detected, which might be used in risk assessment.

Proximity-Driven Enhanced Magnetic Order at Ferromagnetic-Insulator-Magnetic-Topological-Insulator Interface.

Magnetic exchange driven proximity effect at a magnetic-insulator-topological-insulator (MI-TI) interface provides a rich playground for novel phenomena as well as a way to realize low energy dissipation quantum devices. Here we report a dramatic enhancement of proximity exchange coupling in the MI/magnetic-TI EuS/Sb(2-x)V(x)Te3 hybrid heterostructure, where V doping is used to drive the TI (Sb2Te3) magnetic. We observe an artificial antiferromagneticlike structure near the MI-TI interface, which may account for the enhanced proximity coupling. The interplay between the proximity effect and doping in a hybrid heterostructure provides insights into the engineering of magnetic ordering.

A transfer function approach for predicting rare cell capture microdevice performance.

Rare cells have the potential to improve our understanding of biological systems and the treatment of a variety of diseases; each of those applications requires a different balance of throughput, capture efficiency, and sample purity. Those challenges, coupled with the limited availability of patient samples and the costs of repeated design iterations, motivate the need for a robust set of engineering tools to optimize application-specific geometries. Here, we present a transfer function approach for predicting rare cell capture in microfluidic obstacle arrays. Existing computational fluid dynamics (CFD) tools are limited to simulating a subset of these arrays, owing to computational costs; a transfer function leverages the deterministic nature of cell transport in these arrays, extending limited CFD simulations into larger, more complicated geometries. We show that the transfer function approximation matches a full CFD simulation within 1.34 %, at a 74-fold reduction in computational cost. Taking advantage of these computational savings, we apply the transfer function simulations to simulate reversing array geometries that generate a "notch filter" effect, reducing the collision frequency of cells outside of a specified diameter range. We adapt the transfer function to study the effect of off-design boundary conditions (such as a clogged inlet in a microdevice) on overall performance. Finally, we have validated the transfer function's predictions for lateral displacement within the array using particle tracking and polystyrene beads in a microdevice.