Reduction-Induced Magnetic Behavior in LaFeO3-δ Thin Films.

The effect of oxygen reduction on the magnetic properties of LaFeO3-δ (LFO) thin films was studied to better understand the viability of LFO as a candidate for magnetoionic memory. Differences in the amount of oxygen lost by LFO and its magnetic behavior were observed in nominally identical LFO films grown on substrates prepared using different common methods. In an LFO film grown on as-received SrTiO3 (STO) substrate, the original perovskite film structure was preserved following reduction, and remnant magnetization was only seen at low temperatures. In a LFO film grown on annealed STO, the LFO lost significantly more oxygen and the microstructure decomposed into La- and Fe-rich regions with remnant magnetization that persisted up to room temperature. These results demonstrate an ability to access multiple, distinct magnetic states via oxygen reduction in the same starting material and suggest LFO may be a suitable materials platform for nonvolatile multistate memory.

Tunable coupling in magnetic thin film heterostructures with a magnetic phase transition.

The magnetic properties of permalloy-based trilayers of the form Py0.8Cu0.2/Py0.4Cu0.6/Py/IrMn were studied as the spacer layer undergoes a paramagnetic to ferromagnetic phase transition. We find the coupling between the free Py0.8Cu0.2 layer and the exchange bias pinned Py to be strongly temperature-dependent: there is negligible coupling above the Curie temperature of the Py0.4Cu0.6 spacer layer, strong ferromagnetic coupling below that temperature, and a tunable coupling between these extremes. Polarized neutron reflectometry was used to measure the depth profile of the magnetic order in the system, allowing us to correlate the order parameter with the coupling strength. The thickness dependence shows that these are interface effects with an inverse relationship to thickness, and that there is a magnetic proximity effect that enhances the Curie temperature of the spacer layer with characteristic length scale of about 7 nm. As a demonstration of potential functionality of such a system, the structure is shown to spontaneously flip from the antiparallel to parallel magnetic configuration once the spacer layer has developed long-range magnetic order.

Evaluation of the Potential for Cytochrome P450 and Transporter-Mediated Drug-Drug Interactions for Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor (FXR) Agonist.

BACKGROUND AND OBJECTIVE: Cilofexor is a selective farnesoid X receptor (FXR) agonist in development for the treatment of nonalcoholic steatohepatitis and primary sclerosing cholangitis. Our objective was to evaluate potential drug-drug interactions of cilofexor as a victim and as a perpetrator. METHODS: In this Phase 1 study, healthy adult participants (n = 18-24 per each of the 6 cohorts) were administered cilofexor in combination with either perpetrators or substrates of cytochrome P-450 (CYP) enzymes and drug transporters. RESULTS: In total, 131 participants completed the study. As a victim, cilofexor area under the curve (AUC) was 651%, 795%, and 175% when administered following single-dose cyclosporine (600 mg; organic anion transporting polypeptide [OATP]/P-glycoprotein [P-gp]/CYP3A inhibitor), single-dose rifampin (600 mg; OATP1B1/1B3 inhibitor), and multiple-dose gemfibrozil (600 mg twice daily [BID]; CYP2C8 inhibitor), respectively, compared with the administration of cilofexor alone. Cilofexor AUC was 33% when administered following multiple-dose rifampin (600 mg; OATP/CYP/P-gp inducer). Multiple-dose voriconazole (200 mg BID; CYP3A4 inhibitor) and grapefruit juice (16 ounces; intestinal OATP inhibitor) did not affect cilofexor exposure. As a perpetrator, multiple-dose cilofexor did not affect the exposure of midazolam (2 mg; CYP3A substrate), pravastatin (40 mg; OATP substrate), or dabigatran etexilate (75 mg; intestinal P-gp substrate), but atorvastatin (10 mg; OATP/CYP3A4 substrate) AUC was 139% compared with atorvastatin administered alone. CONCLUSION: Cilofexor may be coadministered with inhibitors of P-gp, CYP3A4, or CYP2C8 without the need for dose modification. Cilofexor may be coadministered with OATP, BCRP, P-gp, and/or CYP3A4 substrates-including statins-without dose modification. However, coadministration of cilofexor with strong hepatic OATP inhibitors, or with strong or moderate inducers of OATP/CYP2C8, is not recommended.

Extracting Mural and Volumetric Growth Patterns of Platelet Aggregates on Engineered Surfaces by Use of an Entity Tracking Algorithm.

Thrombosis is a major complication that can occur in both blood-contacting devices and regions and in regions of vascular damage. Microfluidic devices are popular templates to model various thrombogenic settings and to assess conditions that lead to bulk channel occlusion. However, area-averaged measurements miss the opportunity to extract real-time information on thrombus evolution and early dynamics of thrombus formation and propagation, which result in late-stage bulk channel occlusion. To clarify these dynamics, we have developed a standalone tracking algorithm that uses consecutive image connectivity and minimal centroid distance mappings to uniquely index all appearing thrombi in fluorescence time-lapse videos http://links.lww.com/ASAIO/A887 , and http://links.lww.com/ASAIO/A888 . This leads to measurements of all individual aggregates that can in turn be studied as ensembles. We applied tracking to fluorescence time-lapse videos http://links.lww.com/ASAIO/A887 , and http://links.lww.com/ASAIO/A888 of thrombosis across both collagen-functionalized substrate and across the surface of a roughened titanium alloy (Ti6Al4V) at a shear rate of 4000 s -1 . When comparing ensemble-averaged measurements to area-averaged metrics, we unveil immediate, steady thrombus growth at early phases on collagen surfaces and unstable thrombus attachment to roughened Ti6Al4V surfaces on Ti6Al4V surfaces. Additionally, we introduce tracked thrombus eccentricity and fluorescence intensity as additional volumetric measures of thrombus growth that relate back to the primary thrombosis mechanism at play. This work advocates for the complementation of surface macrostate metrics with characteristic thrombus microstate growth patterns to accurately predict critical thrombosis events.

Pharmacokinetics, pharmacodynamics, safety and tolerability of cilofexor, a novel nonsteroidal Farnesoid X receptor agonist, in healthy volunteers.

Cilofexor is a nonsteroidal farnesoid X receptor (FXR) agonist being evaluated for treatment of nonalcoholic steatohepatitis (NASH) and primary sclerosing cholangitis (PSC). This work characterized the pharmacokinetics, pharmacodynamic, safety, and tolerability of cilofexor in healthy participants. Cilofexor single and multiple once-daily doses (10 to 300 mg fasting or fed and twice-daily doses [15 and 50 mg; fed]; tablet formulation) were evaluated. In each cohort, participants were randomized to active drug or placebo in a 4:1 ratio (planned n = 15/cohort). Multiple dosing was for 14 days. Pharmacokinetic and pharmacodynamic samples were collected and safety and tolerability were assessed. Overall, 120 participants were enrolled in the study and 118 participants received at least one dose of study drug. Cilofexor pharmacokinetics followed bi-exponential disposition and its exposure increased in a less-than-dose-proportional manner over the 10 to 300 mg dose range, with no significant accumulation with repeated dosing. Moderate-fat meal reduced cilofexor area under the plasma concentration versus time curve (AUC) by 21% to 45%. Cilofexor increased plasma levels of fibroblast growth factor19 (FGF19) and reduced the serum bile acid intermediate 7α-hydroxy-4-cholesten-3-one (C4) and bile acids in an exposure-dependent manner. Cilofexor doses >30 mg appeared to achieve the plateau of intestinal FXR activation. Cilofexor was generally well tolerated; all treatment-emergent adverse events (TEAEs) were mild or moderate in severity, with headache being the most frequently observed TEAE. The pharmacokinetics pharmacodynamic safety, and tolerability results from this study supported further evaluations, and informed dose selection, of cilofexor in phase II studies in patients with NASH and PSC.

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.

Room-temperature valence transition in a strain-tuned perovskite oxide.

Cobalt oxides have long been understood to display intriguing phenomena known as spin-state crossovers, where the cobalt ion spin changes vs. temperature, pressure, etc. A very different situation was recently uncovered in praseodymium-containing cobalt oxides, where a first-order coupled spin-state/structural/metal-insulator transition occurs, driven by a remarkable praseodymium valence transition. Such valence transitions, particularly when triggering spin-state and metal-insulator transitions, offer highly appealing functionality, but have thus far been confined to cryogenic temperatures in bulk materials (e.g., 90 K in Pr1-xCaxCoO3). Here, we show that in thin films of the complex perovskite (Pr1-yYy)1-xCaxCoO3-δ, heteroepitaxial strain tuning enables stabilization of valence-driven spin-state/structural/metal-insulator transitions to at least 291 K, i.e., around room temperature. The technological implications of this result are accompanied by fundamental prospects, as complete strain control of the electronic ground state is demonstrated, from ferromagnetic metal under tension to nonmagnetic insulator under compression, thereby exposing a potential novel quantum critical point.

Acquired chemoresistance drives spatial heterogeneity, chemoprotection and collective migration in pancreatic tumor spheroids.

Tumors display rich cellular heterogeneity and typically consist of multiple co-existing clones with distinct genotypic and phenotypic characteristics. The acquisition of resistance to chemotherapy has been shown to contribute to the development of aggressive cancer traits, such as increased migration, invasion and stemness. It has been hypothesized that collective cellular behavior and cooperation of cancer cell populations may directly contribute to disease progression and lack of response to treatment. Here we show that the spontaneous emergence of chemoresistance in a cancer cell population exposed to the selective pressure of a chemotherapeutic agent can result in the emergence of collective cell behavior, including cell-sorting, chemoprotection and collective migration. We derived several gemcitabine resistant subclones from the human pancreatic cancer cell line BxPC3 and determined that the observed chemoresistance was driven of a focal amplification of the chr11p15.4 genomic region, resulting in over-expression of the ribonucleotide reductase (RNR) subunit RRM1. Interestingly, these subclones display a rich cell-sorting behavior when cultured as mixed tumor spheroids. Furthermore, we show that chemoresistant cells are able to exert a chemoprotective effect on non-resistant cells in spheroid co-culture, whereas no protective effect is seen in conventional 2D culture. We also demonstrate that the co-culture of resistant and non-resistant cells leads to collective migration where resistant cells enable migration of otherwise non-migratory cells.

Randomised clinical trial: a phase 1b study of GB004, an oral HIF-1α stabiliser, for treatment of ulcerative colitis.

BACKGROUND: Epithelial barrier dysfunction contributes to a dysregulated intestinal immune response in ulcerative colitis (UC). GB004 is an orally administered, small molecule, gut-targeted stabiliser of hypoxia-inducible factor-1α, a transcription factor with protective roles at the epithelial layer of the inflamed gut. AIMS: To evaluate safety, pharmacokinetics, pharmacodynamics and efficacy of GB004 in patients with active UC. METHODS: This double-blind, placebo-controlled study randomised patients 2:1 to receive an oral solution of GB004 120 mg or placebo once daily for 28 days. Eligible patients had a Robarts Histopathology Index score ≥4 with neutrophils in the epithelium, total Mayo Clinic score 3-12, Mayo Clinic endoscopic subscore ≥1, and blood in the stool, despite treatment with 5-aminosalicylates, corticosteroids or immunosuppressants. RESULTS: Thirty-four patients were randomised. GB004 120 mg for 28 days was generally well-tolerated. Adverse events occurred in 27.3% (3/11) and 39.1% (9/23) of patients in the placebo and GB004 groups respectively. Nausea and dysgeusia were most commonly reported in the GB004 group (0% for placebo and 21.7% [5/23] and 13.0% [3/23] respectively for GB004). There were no treatment-related serious adverse events or deaths. GB004 exhibited minimal accumulation, with higher colonic concentrations relative to plasma. Exploratory pharmacodynamic and efficacy analyses demonstrated GB004 target engagement and numerically higher proportions of patients achieving improvement in multiple measures of disease activity, respectively, at day 28 for GB004 compared to placebo. CONCLUSION: Results from this phase 1b trial support evaluation of the full therapeutic potential of GB004 for the treatment of UC. A phase 2 study (NCT04556383) is ongoing. Clinicaltrials.gov NCT03860896.

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.

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.

Electrically Enhanced Exchange Bias via Solid-State Magneto-ionics.

Electrically induced ionic motion offers a new way to realize voltage-controlled magnetism, opening the door to a new generation of logic, sensor, and data storage technologies. Here, we demonstrate an effective approach to magneto-ionically and electrically tune the exchange bias in Gd/Ni1-xCoxO thin films (x = 0.50 and 0.67), where neither of the layers alone is ferromagnetic at room temperature. The Gd capping layer deposited onto antiferromagnetic Ni1-xCoxO initiates a solid-state redox reaction that reduces an interfacial region of the oxide to ferromagnetic NiCo. An exchange bias is established after field cooling (FC), which can be enhanced by up to 35% after a voltage conditioning and subsequently reset with a second FC. These effects are caused by the presence of an interfacial ferromagnetic NiCo layer, which further alloys with the Gd layer upon FC and voltage application, as confirmed by electron microscopy and polarized neutron reflectometry studies. These results highlight the viability of the solid-state magneto-ionic approach to achieve electric control of exchange bias, with potential for energy-efficient magneto-ionic devices.

Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of Remdesivir, a SARS-CoV-2 Replication Inhibitor.

Remdesivir (RDV, Veklury®) is a once-daily, nucleoside ribonucleic acid polymerase inhibitor of severe acute respiratory syndrome coronavirus 2 replication. Remdesivir has been granted approvals in several countries for use in adults and children hospitalized with severe coronavirus disease 2019 (COVID-19). Inside the cell, remdesivir undergoes metabolic activation to form the intracellular active triphosphate metabolite, GS-443902 (detected in peripheral blood mononuclear cells), and ultimately, the renally eliminated plasma metabolite GS-441524. This review discusses the pre-clinical pharmacology of RDV, clinical pharmacokinetics, pharmacodynamics/concentration-QT analysis, rationale for dose selection for treatment of patients with COVID-19, and drug-drug interaction potential based on available in vitro and clinical data in healthy volunteers. Following single-dose intravenous administration over 2 h of an RDV solution formulation across the dose range of 3-225 mg in healthy participants, RDV and its metabolites (GS-704277and GS-441524) exhibit linear pharmacokinetics. Following multiple doses of RDV 150 mg once daily for 7 or 14 days, major metabolite GS-441524 accumulates approximately 1.9-fold in plasma. Based on pharmacokinetic bridging from animal data and available human data in healthy volunteers, the RDV clinical dose regimen of a 200-mg loading dose on day 1 followed by 100-mg maintenance doses for 4 or 9 days was selected for further evaluation of pharmacokinetics and safety. Results showed high intracellular concentrations of GS-443902 suggestive of efficient conversion from RDV into the triphosphate form, and further supporting this clinical dosing regimen for the treatment of COVID-19. Mathematical drug-drug interaction liability predictions, based on in vitro and phase I data, suggest RDV has low potential for drug-drug interactions, as the impact of inducers or inhibitors on RDV disposition is minimized by the parenteral route of administration and extensive extraction. Using physiologically based pharmacokinetic modeling, RDV is not predicted to be a clinically significant inhibitor of drug-metabolizing enzymes or transporters in patients infected with COVID-19 at therapeutic RDV doses.

Physiologically-Based Pharmacokinetic Modeling of Remdesivir and Its Metabolites to Support Dose Selection for the Treatment of Pediatric Patients With COVID-19.

Severe coronavirus disease 2019 (COVID-19) disease, including multisystem inflammatory syndrome, has been reported in children. This report summarizes development of a remdesivir physiologically-based pharmacokinetic (PBPK) model that accurately describes observed adult remdesivir and metabolites exposure and predicts pediatric remdesivir and metabolites exposure. The adult PBPK model was applied to predict pediatric remdesivir and metabolites steady-state exposures using the Pediatric Population Model in SimCYP and incorporated the relevant physiologic and mechanistic information. Model development was based on adult phase I exposure data in healthy volunteers who were administered a 200-mg loading dose of remdesivir intravenous (IV) over 0.5 hours on Day 1, then 100-mg daily maintenance doses of IV over 0.5 hours starting on Day 2 and continuing through Days 5 or 10. Simulations indicated that use of the adult therapeutic remdesivir dosage regimen (200-mg loading dose on Day 1 then 100-mg daily maintenance dose starting on Day 2) in pediatric patients ≥ 40 kg and a weight-based remdesivir dosage regimen (5-mg/kg loading dose on Day 1 then 2.5-mg/kg daily maintenance dose starting on Day 2) in pediatric patients weighing 2.5 to < 40 kg is predicted to maintain therapeutic exposures of remdesivir and its metabolites. The comprehensive PBPK model described in this report supported remdesivir dosing in planned pediatric clinical studies and dosing in the emergency use authorization and pediatric compassionate use programs that were initiated to support remdesivir as a treatment option during the pandemic.

Organic Anion Transporting Polypeptide Inhibition Dramatically Increases Plasma Exposure but not Pharmacodynamic Effect nor Inferred Hepatic Intracellular Exposure of Firsocostat.

Firsocostat (FIR: previously GS-0976), a highly sensitive OATP substrate, reduces hepatic de novo lipogenesis (DNL) by inhibiting acetyl-CoA carboxylases (ACC). Measuring the pharmacodynamic (PD) efficacy of FIR on DNL provides a unique opportunity to determine optimal dosing strategies for liver-targeted OATP substrates in settings of altered OATP function. A randomized, four-way crossover drug-drug interaction study was conducted. Hepatic DNL, a marker for ACC activity, was measured in 28 healthy volunteers after reference, single dose FIR 10 mg, FIR 10 mg plus the OATP inhibitor rifampin (RIF) 300 mg i.v., or RIF 300 mg i.v. (control for DNL effect of RIF), each separated by a 7-day washout. Samples were collected for pharmacokinetic (PK) and PD assessments through 24 hours after each treatment. Hepatic DNL and its inhibition by FIR were assessed. Twenty-four subjects completed the study. All adverse events were mild. RIF alone increased hepatic DNL area under the effect curve from time of administration up to the time of the last quantifiable concentration (AUEClast ; 35.7%). Despite a 5.2-fold increase in FIR plasma exposure (area under the concentration-time curve from zero to infinity (AUCinf )) when administered with RIF, FIR alone, and FIR + RIF had the same hepatic PD effect, 37.1% and 34.9% reduction in DNL AUEClast , respectively, compared with their respective controls. These findings indicate that large decreases in OATP activity do not alter hepatic intracellular exposure (as inferred by no change in PD) for drugs that are primarily eliminated hepatically and permeability rate-limited, such as FIR. These results support PK theory that has been difficult to test and provide practical guidance on administration of liver-targeted drugs in settings of reduced OATP function.

Ledipasvir plus sofosbuvir in pregnant women with hepatitis C virus infection: a phase 1 pharmacokinetic study.

BACKGROUND: Hepatitis C virus (HCV) infection is increasing among pregnant women because of the opioid epidemic, yet there are no interventions to reduce perinatal HCV transmission or to treat HCV during pregnancy. Physiological changes in pregnancy alter the pharmacokinetics of some medications; thus, our aim was to compare the pharmacokinetic parameters of ledipasvir 90 mg plus sofosbuvir 400 mg during pregnancy with non-pregnant women. METHODS: This was an open-label, phase 1 study of pregnant women with genotype 1 HCV infection and their infants. A reference group of women who had participated in pharmacokinetic studies of ledipasvir-sofosbuvir during phase 2 and 3 trials was used. Participants were enrolled at Magee-Womens Hospital (Pittsburgh, PA, USA) between 23 and 24 weeks' gestation and had a 12-week course of oral ledipasvir-sofosbuvir (daily 90 mg ledipasvir plus 400 mg sofosbuvir). Three 12-h intensive pharmacokinetic visits were done at 25-26, 29-30, and 33-34 weeks' gestation and individual pharmacokinetics were summarised by geometric mean across the three visits. The primary outcome, analysed in all participants without suspected dosing errors, was the ledipasvir-sofosbuvir area under the concentration-time curve of the dosing interval (AUCtau) during pregnancy compared with the reference group by geometric mean ratio. This study is registered with ClinicalTrials.gov, NCT02683005. FINDINGS: From Oct 1, 2016, to Sept 30, 2018, 29 pregnant women were screened and nine (31%) were enrolled. Eight (89%) women were included in the primary analysis. Ledipasvir and sofosbuvir exposures were similar in the pregnant women versus the non-pregnant reference group (geometric mean ratio of AUCtau ledipasvir 89·3% [90% CI 68·7-116·1]; sofosbuvir 91·1% [78·0-106·3]). INTERPRETATION: Ledipasvir-sofosbuvir was safe and effective without clinically meaningful differences in drug exposure among pregnant versus non-pregnant women. FUNDING: National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health/Office of Research on Women's Health, and Gilead Sciences.

Sofosbuvir plus ribavirin and sofosbuvir plus ledipasvir in patients with genotype 1 or 3 hepatitis C virus and severe renal impairment: a multicentre, phase 2b, non-randomised, open-label study.

BACKGROUND: There is a medical need for highly effective, safe, and well tolerated treatments for patients infected with hepatitis C virus (HCV) with severe renal impairment. We investigated the safety and efficacy of sofosbuvir with ribavirin or ledipasvir combined with sofosbuvir in a prospective study of patients with genotype 1 or 3 HCV infection and stage 4-5 chronic kidney disease (creatinine clearance by Cockcroft-Gault ≤30 mL/min) who were not on dialysis. METHODS: This phase 2b, open-label, non-randomised, multicentre study in the USA and New Zealand investigated three sequentially enrolled cohorts of patients. Patients were recruited from ten hospitals and clinical research centres and were included if they had genotype 1 or 3 HCV infection, a creatinine clearance less than or equal to 30 mL/min, and were not on dialysis. In cohorts 1 and 2, patients received sofosbuvir (200 mg in cohort 1 and 400 mg in cohort 2) plus ribavirin 200 mg once per day for 24 weeks. In cohort 3, 18 patients received ledipasvir combined with sofosbuvir (90 mg ledipasvir and 400 mg sofosbuvir) once per day for 12 weeks. The primary efficacy endpoint was the proportion of patients achieving sustained virological response 12 weeks after the end of treatment (SVR12). Safety and pharmacokinetic data were also collected. The trial is registered with ClinicalTrials.gov, number NCT01958281, and is completed. FINDINGS: This study was done between Oct 7, 2013, and Oct 29, 2017. In the sofosbuvir plus ribavirin cohorts, 32 patients were screened, of whom 20 were enrolled and assessed for efficacy and safety (ten patients in each cohort). In the ledipasvir plus sofosbuvir cohort, 33 patients were screened, of whom 18 were enrolled and assessed for treatment efficacy and safety. Four (40%, 95% CI 12-74) of ten patients in cohort 1 and six (60%, 26-88) of ten patients in cohort 2 achieved SVR12. All 18 (100%, 82-100) patients in cohort 3 achieved SVR12. Adverse events were mostly mild or moderate in severity. The most commonly reported adverse events overall were headache (eight [21%] of 38 patients), anaemia (seven [18%] of 38 patients), and fatigue (six [16%] of 38 patients). Eight patients had serious adverse events, none of which were treatment related. There were no treatment-related cardiac events or clinically significant changes in echocardiographic parameters or creatinine clearance by Cockcroft-Gault. INTERPRETATION: In this phase 2b study, ledipasvir combined with sofosbuvir for 12 weeks was safe and effective in patients with genotype 1 HCV infection and stage 4-5 chronic kidney disease who were not on dialysis. FUNDING: Gilead Sciences.

Rational design protocols for size-based particle sorting microdevices using symmetry-induced cyclical dynamics.

In this paper, we describe the unification and extension of multiple kinematic theories on the advection of colloidal particles through periodic obstacle lattices of arbitrary geometry and infinitesimally small obstacle size. We focus specifically on the particle displacement lateral to the flow direction (termed "deterministic lateral displacement") and the particle-obstacle interaction frequency, and develop methods for describing these as a function of particle size and lattice parameters for arbitrary lattice geometries. We then demonstrate design algorithms for microfluidic devices consisting of chained obstacle lattices of this type that approximate any lateral displacement function of size to arbitrary accuracy with respect to multiple optimization metrics, prove their validity mathematically, and compare the generated results favorably to designs in the literature with respect to metrics such as accuracy, device size, and complexity.

Correlation-driven eightfold magnetic anisotropy in a two-dimensional oxide monolayer.

Engineering magnetic anisotropy in two-dimensional systems has enormous scientific and technological implications. The uniaxial anisotropy universally exhibited by two-dimensional magnets has only two stable spin directions, demanding 180° spin switching between states. We demonstrate a previously unobserved eightfold anisotropy in magnetic SrRuO3 monolayers by inducing a spin reorientation in (SrRuO3)1/(SrTiO3) N superlattices, in which the magnetic easy axis of Ru spins is transformed from uniaxial 〈001〉 direction (N < 3) to eightfold 〈111〉 directions (N ≥ 3). This eightfold anisotropy enables 71° and 109° spin switching in SrRuO3 monolayers, analogous to 71° and 109° polarization switching in ferroelectric BiFeO3. First-principle calculations reveal that increasing the SrTiO3 layer thickness induces an emergent correlation-driven orbital ordering, tuning spin-orbit interactions and reorienting the SrRuO3 monolayer easy axis. Our work demonstrates that correlation effects can be exploited to substantially change spin-orbit interactions, stabilizing unprecedented properties in two-dimensional magnets and opening rich opportunities for low-power, multistate device applications.