Phase Coexistence of Mn Trimer Clusters and Antiferromagnetic Mn Islands on Ir(111).

Clusters supported by solid substrates are prime candidates for heterogeneous catalysis and can be prepared in various ways. While mass-selected soft-landing methods are often used for the generation of monodisperse particles, self-assembly typically leads to a range of different cluster sizes. Here we show by scanning tunneling microscopy measurements that in the initial stages of growth, Mn forms trimers on a close-packed hexagonal Ir surface, providing a route for self-organized monodisperse cluster formation on an isotropic metallic surface. For an increasing amount of Mn, first a phase with reconstructed monolayer islands is formed, until at full coverage a pseudomorphic Mn phase evolves, which is the most densely packed one of the three different observed Mn phases on Ir(111). The magnetic state of both the reconstructed islands and the pseudomorphic film is found to be the prototypical antiferromagnetic Néel state with a 120° spin rotation between all nearest neighbors in the hexagonal layer.

Item response theory in early phase clinical trials: Utilization of a reference model to analyze the Montgomery-Åsberg Depression Rating Scale.

In clinical trials, Montgomery-Åsberg Depression Rating Scale (MADRS) questionnaire data are added up to total scores before analysis, assuming equal contribution of each separate question. Item Response Theory (IRT)-based analysis avoids this by using individual question responses to determine the latent variable (ψ), which represents a measure of depression severity. However, utilization of IRT in early phase trials remains difficult, because large datasets are needed to develop IRT models. Therefore, we aimed to evaluate the application and assumptions of a reference IRT model for analysis of an early phase trial. A cross-over, placebo-controlled study investigating the effect of intravenous racemic ketamine on MADRS scores in patients with treatment-resistant major depressive disorder was used as a case study. One hundred forty-seven MADRS responses were measured in 17 patients at five timepoints (predose to 2 weeks after dosing). Two reference IRT models based on different patient populations were selected from literature and used to determine ψ, while testing multiple approaches regarding assumed data distribution. Use of ψ versus total score to determine treatment effect was compared through linear mixed model analysis. Results showed that determined ψ values did not differ significantly between assumed distributions, but were significantly different when changing reference IRT model. Estimated treatment effect size was not significantly affected by chosen approach nor reference population. Finally, increased precision to determine treatment effect was achieved by using IRT versus total scores. This demonstrates the usefulness of reference IRT model application for analysis of questionnaire data in early phase clinical trials.

Characterization of the Pharmacokinetic and Pharmacodynamic Profile of Apraglutide, a Glucagon-Like Peptide-2 Analog, in Healthy Volunteers.

Apraglutide (FE 203799) is a glucagon-like peptide-2 (GLP-2) analog under development for the treatment of intestinal failure associated with short bowel syndrome (SBS-IF) and graft-versus-host disease (GvHD). Compared with native GLP-2, apraglutide has slower absorption, reduced clearance, and higher protein binding, enabling once-weekly dosing. This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of apraglutide in healthy adults. Healthy volunteers were randomized to receive 6 weekly subcutaneous administrations of 1, 5, or 10 mg apraglutide or placebo. PK and citrulline (an enterocyte mass PD marker) samples were collected at multiple time points. Kinetic parameters of apraglutide and citrulline were calculated using noncompartmental analysis; repeated PD measures were analyzed with a mixed model of covariance. A population PK/PD model was developed that also included data from a previous phase 1 study in healthy volunteers. Twenty-four subjects were randomized; 23 received all study drug administrations. Mean estimated apraglutide clearance was 16.5-20.7 l/day, and mean volume of distribution was 55.4-105.0 liters. A dose-dependent increase in citrulline plasma concentration was observed, with 5-mg and 10-mg doses inducing higher citrulline levels than 1-mg doses and placebo. PK/PD analysis showed that weekly 5-mg apraglutide induced the maximal citrulline response. Increased plasma citrulline levels were sustained for 10-17 days after the final apraglutide administration. Apraglutide displays predictable dose-dependent PK and PD profiles, with a 5-mg dose showing significant PD effects. Results suggest that apraglutide has early and enduring effects on enterocyte mass and supports the continued development of weekly subcutaneous apraglutide for SBS-IF and GvHD patient populations. SIGNIFICANCE STATEMENT: Once-weekly subcutaneous apraglutide results in dose-dependent elevations of plasma citrulline (an enterocyte mass pharmacodynamic marker) with parameters suggesting that apraglutide has lasting effects on enterocyte mass and the potential to provide therapeutic benefits. This is the first report of a model relating glucagon-like peptide-2 (GLP-2) agonism and its effects in intestinal mucosa, affording not only the ability to predict pharmacologic effects of GLP-2 analogs but also the exploration of optimal dosing regimens for this drug class across populations with different body weights.

Antiferromagnetism-driven two-dimensional topological nodal-point superconductivity.

Magnet/superconductor hybrids (MSHs) hold the promise to host emergent topological superconducting phases. Both one-dimensional (1D) and two-dimensional (2D) magnetic systems in proximity to s-wave superconductors have shown evidence of gapped topological superconductivity with zero-energy end states and chiral edge modes. Recently, it was proposed that the bulk transition-metal dichalcogenide 4Hb-TaS2 is a gapless topological nodal-point superconductor (TNPSC). However, there has been no experimental realization of a TNPSC in a MSH system yet. Here we present the discovery of TNPSC in antiferromagnetic (AFM) monolayers on top of an s-wave superconductor. Our calculations show that the topological phase is driven by the AFM order, resulting in the emergence of a gapless time-reversal invariant topological superconducting state. Using low-temperature scanning tunneling microscopy we observe a low-energy edge mode, which separates the topological phase from the trivial one, at the boundaries of antiferromagnetic islands. As predicted by the calculations, we find that the relative spectral weight of the edge mode depends on the edge's atomic configuration. Our results establish the combination of antiferromagnetism and superconductivity as a novel route to design 2D topological quantum phases.

Nano-scale collinear multi-Q states driven by higher-order interactions.

Complex magnetic order arises due to the competition of different interactions between the magnetic moments. Recently, there has been an increased interest in such states not only to unravel the fundamental physics involved, but also with regards to applications exploiting their unique interplay with moving electrons. Whereas it is the Dzyaloshinskii-Moriya interaction (DMI) that has attracted much attention because of its nature to induce non-collinear magnetic order including magnetic-field stabilized skyrmions, it is the frustration of exchange interactions that can drive magnetic order down to the nano-scale. On top of that, interactions between multiple spins can stabilize two-dimensional magnetic textures as zero-field ground states, known as multi-Q states. Here, we introduce a two-dimensional itinerant magnet with various competing atomic-scale magnetic phases. Using spin-polarized scanning tunneling microscopy we observe several zero-field uniaxial or hexagonal nano-scale magnetic states. First-principles calculations together with an atomistic spin model reveal that these states are stabilized by the interplay of frustrated exchange and higher-order interactions while the DMI is weak. Unexpectedly, it is found that not only non-collinear magnetic states arise, but that higher-order interactions can also lead to collinear nano-scale multi-Q states.

OX40L Inhibition Suppresses KLH-driven Immune Responses in Healthy Volunteers: A Randomized Controlled Trial Demonstrating Proof-of-Pharmacology for KY1005.

The safety, tolerability, immunogenicity, and pharmacokinetic (PK) profile of an anti-OX40L monoclonal antibody (KY1005, currently amlitelimab) were evaluated. Pharmacodynamic (PD) effects were explored using keyhole limpet hemocyanin (KLH) and tetanus toxoid (TT) immunizations. Sixty-four healthy male subjects (26.5 ± 6.0 years) were randomized to single doses of 0.006, 0.018, or 0.05 mg/kg, or multiple doses of 0.15, 0.45, 1.35, 4, or 12 mg/kg KY1005, or placebo (6:2). Serum KY1005 concentrations were measured. Antibody responses upon KLH and TT immunizations and skin response upon intradermal KLH administration were performed. PD data were analyzed using repeated measures analysis of covariances (ANCOVAs) and post hoc exposure-response modeling. No serious adverse events occurred and all adverse events were temporary and of mild or moderate severity. A nonlinear increase in mean serum KY1005 concentrations was observed (median time to maximum concentration (Tmax ) ~ 4 hours, geometric mean terminal half-life (t½) ~ 24 days). Cutaneous blood perfusion (estimated difference (ED) -13.4 arbitrary unit (AU), 95% confidence interval (CI) -23.0 AU to -3.8 AU) and erythema quantified as average redness (ED -0.23 AU, 95% CI -0.35 AU to -0.11 AU) decreased after KY1005 treatment at doses of 0.45 mg/kg and above. Exposure-response analysis displayed a statistically significant treatment effect on anti-KLH antibody titers (IgG maximum effect (Emax ) -0.58 AU, 95% CI -1.10 AU to -0.06 AU) and skin response (erythema Emax -0.20 AU, 95% CI -0.29 AU to -0.11 AU). Administration of KY1005 demonstrated an acceptable safety and tolerability profile and PK analyses displayed a nonlinear profile of KY1005. Despite the observed variability, skin challenge response after KY1005 treatment indicated pharmacological activity of KY1005. Therefore, KY1005 shows potential as a novel pharmacological treatment in immune-mediated disorders.

First-in-human trial to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of STR-324, a dual enkephalinase inhibitor for pain management.

AIM: Dual enkephalinase inhibitors (DENKIs) are involved in the regulation of nociception via opioid receptors. The novel compound STR-324 belongs to the DENKI pharmacological class. This first-in-human study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of STR-324 in healthy male participants. METHODS: This was a randomised, double-blind, placebo-controlled ascending dosing study in two parts: in part 1, 30 participants received 0.004-11.475 mg h-1 of STR-324 or placebo (ratio 4:1) by 4 h intravenous infusion in a two-group, partial crossover design with four treatment periods separated by 1 month wash-out, and in part 2, 48 participants divided into three groups received either the active drug (1.25-11.25 mg h-1 ) or placebo (ratio 3:1) by 48 h intravenous infusion. Safety and tolerability parameters, pharmacokinetics and pharmacodynamic effects on neurocognitive and neurophysiological tasks and on a nociceptive test battery were evaluated. RESULTS: No clinically relevant changes in safety parameters were observed. All treatment-emergent adverse events were mild and transient. The pharmacokinetics of STR-324 could not be determined due to most concentrations being below quantifiable limits. STR-324 metabolite concentrations were measurable, showing dose proportionality of Cmax and AUCinf with an estimated t1/2 of 0.2-0.5 h. Significant changes in pharmacodynamic parameters were observed, but these were not consistent or dose-dependent. CONCLUSION: STR-324 displayed favourable safety and tolerability profiles at all doses up to 11.475 mg h-1 . Although pharmacokinetic characterisation of STR-324 was limited, dose proportionality could be assumed based on major metabolite data assayed as proxy. No clear effects on nociceptive thresholds or other pharmacodynamic measures were observed. TRIAL REGISTRY: EudraCT (2014-002402-21) and toetsingonline.nl (63085).

Population pharmacokinetics of clonazepam in saliva and plasma: Steps towards noninvasive pharmacokinetic studies in vulnerable populations.

AIM: Traditional studies focusing on the relationship between pharmacokinetics (PK) and pharmacodynamics necessitate blood draws, which are too invasive for children or other vulnerable populations. A potential solution is to use noninvasive sampling matrices, such as saliva. The aim of this study was to develop a population PK model describing the relationship between plasma and saliva clonazepam kinetics and assess whether the model can be used to determine trough plasma concentrations based on saliva samples. METHODS: Twenty healthy subjects, aged 18-30, were recruited and administered 0.5 or 1 mg of clonazepam solution. Paired plasma and saliva samples were obtained until 48 hours post-dose. A population pharmacokinetic model was developed describing the PK of clonazepam in plasma and the relationship between plasma and saliva concentrations. Bayesian maximum a posteriori optimization was applied to estimate the predictive accuracy of the model. RESULTS: A two-compartment distribution model best characterized clonazepam plasma kinetics with a mixture component on the absorption rate constants. Oral administration of the clonazepam solution caused contamination of the saliva compartment during the first 4 hours post-dose, after which the concentrations were driven by the plasma concentrations. Simulations demonstrated that the lower and upper limits of agreements between true and predicted plasma concentrations were -28% to 36% with one saliva sample. Increasing the number of saliva samples improved these limits to -18% to 17%. CONCLUSION: The developed model described the salivary and plasma kinetics of clonazepam, and could predict steady-state trough plasma concentrations based on saliva concentrations with acceptable accuracy.

Theoretical Performance of Nonlinear Mixed-Effect Models Incorporating Saliva as an Alternative Sampling Matrix for Therapeutic Drug Monitoring in Pediatrics: A Simulation Study.

BACKGROUND: Historically, pharmacokinetic (PK) studies and therapeutic drug monitoring (TDM) have relied on plasma as a sampling matrix. Noninvasive sampling matrices, such as saliva, can reduce the burden on pediatric patients. The variable plasma-saliva relationship can be quantified using population PK models (nonlinear mixed-effect models). However, criteria regarding acceptable levels of variability in such models remain unclear. In this simulation study, the authors aimed to propose a saliva TDM evaluation framework and evaluate model requirements in the context of TDM, with gentamicin and lamotrigine as model compounds. METHODS: Two population pharmacokinetic models for gentamicin in neonates and lamotrigine in pediatrics were extended with a saliva compartment including a delay constant (kSALIVA), a saliva:plasma ratio, and between-subject variability (BSV) on both parameters. Subjects were simulated using a realistic covariate distribution. Bayesian maximum a posteriori TDM was applied to assess the performance of an increasing number of TDM saliva samples and varying levels of BSV and residual variability. Saliva TDM performance was compared with plasma TDM performance. The framework was applied to a known voriconazole saliva model as a case study. RESULTS: TDM performed using saliva resulted in higher target attainment than no TDM, and a residual proportional error <25% on saliva observations led to saliva TDM performance comparable with plasma TDM. BSV on kSALIVA did not affect performance, whereas increasing BSV on saliva:plasma ratios by >25% for gentamicin and >50% for lamotrigine reduced performance. The simulated target attainment for voriconazole saliva TDM was >90%. CONCLUSIONS: Saliva as an alternative matrix for noninvasive TDM is possible using nonlinear mixed-effect models combined with Bayesian optimization. This article provides a workflow to explore TDM performance for compounds measured in saliva and can be used for evaluation during model building.

Discovery and characterization of a new type of domain wall in a row-wise antiferromagnet.

Antiferromagnets have recently moved into the focus of application-related research, with the perspective to use them in future spintronics devices. At the same time the experimental determination of the detailed spin texture remains challenging. Here we use spin-polarized scanning tunneling microscopy to investigate the spin structure of antiferromagnetic domain walls. Comparison with spin dynamics simulations allows the identification of a new type of domain wall, which is a superposition state of the adjacent domains. We determine the relevant magnetic interactions and derive analytical formulas. Our experiments show a pathway to control the number of domain walls by boundary effects, and demonstrate the possibility to change the position of domain walls by interaction with movable adsorbed atoms. The knowledge about the exact spin structure of the domain walls is crucial for an understanding and theoretical modelling of their properties regarding, for instance, dynamics, response in transport experiments, and manipulation.

A novel sustained-release cysteamine bitartrate formulation for the treatment of cystinosis: Pharmacokinetics and safety in healthy male volunteers.

The strict intake regimen of cysteamine bitartrate formulations, associated with side effects, is a concern for the treatment compliance in cystinosis therapy. Therefore, there is a need for a cysteamine formulation with an improved pharmacokinetic profile. This study investigated the pharmacokinetics, safety and tolerability of a new sustained-release cysteamine dosage form, PO-001, in healthy volunteers. This was a randomized, investigator-blinded, three-way cross-over study to compare single doses (600 mg) of PO-001 with Cystagon® (immediate-release) and Procysbi® (delayed-release). Collected blood samples were analyzed for plasma cysteamine concentrations and pharmacokinetic parameters were estimated by noncompartmental analysis. In addition, plasma cysteamine concentrations were analyzed using a population pharmacokinetic approach using NONMEM® . Pharmacokinetics showed clear sustained-release characteristics of PO-001 over time with a lower Cmax and longer Tmax compared to Cystagon® and Procysbi® . All treatment-emergent adverse events were of mild severity, with the exception of two subjects who reported moderate severity gastrointestinal problems including vomiting and diarrhea, which were related to Cystagon® intake. Population PK simulations showed a favourable PK profile based on Cmax and Ctrough concentrations at steady state. In conclusion, a single dose of 600 mg PO-001 was well tolerated with no findings of clinical concern. This new cysteamine bitartrate formulation showed pharmacokinetics of a sustained-release formulation, which may be beneficial for the treatment of cystinosis patients. This study supports advancing this type of sustained-release formulation into a subsequent study to confirm reduced dosing frequency with efficient control of white blood cells (WBCs) cystine levels. Netherlands Trial Registry (NTR) (NL67638.056.18).

Mechanism-based modeling of the effect of a novel inhibitor of vascular adhesion protein-1 on albuminuria and renal function markers in patients with diabetic kidney disease.

The vascular adhesion protein-1 (VAP-1) inhibitor ASP8232 reduces albuminuria in patients with type 2 diabetes and chronic kidney disease. A mechanism-based model was developed to quantify the effects of ASP8232 on renal markers from a placebo-controlled Phase 2 study in diabetic kidney disease with 12 weeks of ASP8232 treatment. The model incorporated the available pharmacokinetic, pharmacodynamic (plasma VAP-1 concentration and activity), serum and urine creatinine, serum cystatin C, albumin excretion rate, urinary albumin-to-creatinine ratio, and urine volume information in an integrated manner. Drug-independent time-varying changes and different drug effects could be quantified for these markers using the model. Through simulations, this model provided the opportunity to dissect the relationship and longitudinal association between the estimated glomerular filtration rate and albuminuria and to quantify the pharmacological effects of ASP8232. The developed drug-independent model may be useful as a starting point for other compounds affecting the same biomarkers in a similar time scale.

Population pharmacokinetics and pharmacodynamics of a novel vascular adhesion protein-1 inhibitor using a multiple-target mediated drug disposition model.

ASP8232 is a novel inhibitor of vascular adhesion protein-1 that was under evaluation for reducing residual albuminuria in patients with diabetic kidney disease. To characterize the pharmacokinetics (PK) of ASP8232 and its effect on vascular adhesion protein 1 (VAP-1) plasma activity and VAP-1 concentrations (pharmacodynamics, PD) in an integrated and quantitative manner, a target mediated drug disposition model was developed based on pooled data from four completed clinical trials with ASP8232 in healthy volunteers, and in patients with diabetic kidney disease and diabetic macular edema, respectively. In this model, the binding of ASP8232 to its soluble and membrane-bound target in the central and peripheral compartments were included. The model was able to adequately describe the non-linear PK and PD of ASP8232. The observed difference in PK between healthy volunteers and renally impaired patients could be explained by an effect of baseline estimated glomerular filtration rate on ASP8232 clearance and relative bioavailability. The relationship between ASP8232 concentration and VAP-1 inhibition was successfully established and can be applied to simulate drug exposure and degree of VAP-1 inhibition for any given dose of ASP8232 across the spectrum of renal function.

Non-verbal Enrichment in Vocabulary Learning With a Virtual Pedagogical Agent.

Non-verbal enrichment in the form of pictures or gesture can support word learning in first and foreign languages. The present study seeks to compare the effects of viewing pictures vs. imitating iconic gestures on learning second language (L2) vocabulary. In our study participants learned L2 words (nouns, verbs, and adjectives) together with a virtual, pedagogical agent. The to-be-learned items were either (i) enriched with pictures, or (ii) with gestures that had to be imitated, or (iii) without any non-verbal enrichment as control. Results showed that gesture imitation was particularly supportive for learning nouns, whereas pictures showed to be most beneficial for memorizing verbs. These findings, suggesting that the type of vocabulary learning strategy has to match with the type of linguistic material to be learned, have important educational implications for L2 classrooms and technology-enhanced tutoring systems.

Safety, pharmacokinetics, and pharmacodynamics of Gln-1062, a prodrug of galantamine.

INTRODUCTION: Gln-1062 (MEMOGAIN) is an intranasally administered lipophilic prodrug of galantamine. Based on high brain-to-blood concentrations observed in pre-clinical studies, Gln-1062 is expected to have superior cognitive efficacy compared to oral galantamine. METHODS: Forty-eight healthy elderly subjects were randomized 12:4 to Gln-1062 (5.5, 11, or 22 mg, b.i.d., for 7 days) or placebo. Safety, tolerability, pharmacokinetics, and pharmacodynamics were assessed repeatedly. Pharmacokinetics were compared with 16 mg oral galantamine. RESULTS: Gln-1062 up to 22 mg, b.i.d., was well tolerated. Gln-1062 plasma concentrations increased immediately following dosing (median Tmax of 0.5 hour [range 0.5-1.0]). Cmax and AUC0-last increased in a dose-linear manner over all three dose levels. Gln-1062 was rapidly cleaved into galantamine. Gln-1062 significantly improved adaptive tracking (sustained attention) with 1.95% (95% confidence interval [CI] 0.630-3.279, P = 0.0055) compared to placebo after correction for individual baseline performance. DISCUSSION: Gln-1062 was considered to be safe and caused fewer gastrointestinal side effects than oral galantamine. Gln-1062 behaved pharmacokinetically as expected and improved performance on cognitive tests.

First Clinical Study with AP30663 - a KCa 2 Channel Inhibitor in Development for Conversion of Atrial Fibrillation.

Pharmacological cardioversion of atrial fibrillation (AF) is frequently inefficacious. AP30663, a small conductance Ca2+ activated K+ (KCa 2) channel blocker, prolonged the atrial effective refractory period in preclinical studies and subsequently converted AF into normal sinus rhythm. This first-in-human study evaluated the safety and tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) effects were explored. Forty-seven healthy male volunteers (23.7 ± 3.0 years) received AP30663 intravenously in ascending doses. Due to infusion site reactions, changes to the formulation and administration were implemented in the latter 24 volunteers. Extractions from a 24-hour continuous electrocardiogram were used to evaluate the PD effect of AP30663. Data were analyzed with a repeated measure analysis of covariance, noncompartmental analysis, and concentration-effect analysis. In total, 33 of 34 adverse events considered related to AP30663 exposure were related to the infusion site, mild in severity, and temporary in nature, although full recovery took up to 110 days. After formulation and administration changes, the local infusion site reaction remained, but the median duration was shorter despite higher dose levels. AP30663 displayed a less than dose proportional increase in peak plasma concentration (Cmax ) and a terminal half-life of around 5 hours. In healthy volunteers, no effect of AP30663 was observed on electrocardiographic parameters, other than a concentration-dependent effect on the corrected QT Fridericia's formula interval (+18.8 ± 4.3 ms for the highest dose level compared with time matched placebo). In conclusion, administration of AP30663, a novel KCa 2 channel inhibitor, was safe and well-tolerated systemically in humans, supporting further development in patients with AF undergoing cardioversion.

Discovery of Magnetic Single- and Triple-q States in Mn/Re(0001).

We experimentally verify the existence of two model-type magnetic ground states that were previously predicted but so far unobserved. We find them in Mn monolayers on the Re(0001) surface using spin-polarized scanning tunneling microscopy. For fcc stacking of Mn the collinear row-wise antiferromagnetic state occurs, whereas for hcp Mn a three-dimensional spin structure appears, which is a superposition of three row-wise antiferromagnetic states known as the triple-q state. Density-functional theory calculations elucidate the subtle interplay of different magnetic interactions to form these spin structures and provide insight into the role played by relativistic effects.

Plumbene on a Magnetic Substrate: A Combined Scanning Tunneling Microscopy and Density Functional Theory Study.

As a heavy analog of graphene, plumbene is a two-dimensional material with strong spin-orbit coupling effects. Using scanning tunneling microscopy, we observe that Pb forms a flat honeycomb lattice on an Fe monolayer on Ir(111). In contrast, without the Fe layer, a c(2×4) structure of Pb on Ir(111) is found. We use density-functional theory calculations to rationalize these findings and analyze the impact of the hybridization on the plumbene band structure. In the unoccupied states the splitting of the Dirac cone by spin-orbit interaction is clearly observed, while the occupied Pb states are strongly hybridized with the substrate. In a freestanding plumbene we find a band inversion below the Fermi level that leads to the formation of a topologically nontrivial gap. Exchange splitting as mediated by the strong hybridization with the Fe layer drives a quantum spin Hall to quantum anomalous Hall state transition.

Clinical trial simulations of the interaction between cannabidiol and clobazam and effect on drop-seizure frequency.

With this study, we aim to test the hypothesis that the effect of cannabidiol on drop-seizure frequency in patients with Lennox-Gastaut syndrome and Dravet syndrome could be attributed to a drug-drug interaction with clobazam. We performed clinical trial simulations for the effect of 20 mg/kg/day cannabidiol on drop-seizure frequency in patients with Lennox-Gastaut syndrome. We assumed that patients taking 10 or 20 mg clobazam would have a 2- to 7-fold increase in N-desmethylclobazam exposure, whereas patients not taking clobazam would have a median reduction in drop-seizure frequency and a variability in the percent reduction similar to the placebo group. The results show that the effect of cannabidiol on the median reduction in drop-seizure frequency in patients with Lennox-Gastaut syndrome may be explained by a drug-drug interaction with clobazam. This may have important implications for the use of cannabidiol and its Food and Drug Administration registration.

Electrical Detection of Domain Walls and Skyrmions in Co Films Using Noncollinear Magnetoresistance.

A large noncollinear magnetoresistance (NCMR) is observed for Rh/Co atomic bilayers on Ir(111) using scanning tunneling microscopy and spectroscopy. The effect is 20% at the Fermi energy and large in a broad energy range. The NCMR can be used to electrically detect nanometer-scale domain walls and skyrmions directly in the tunnel current without the need for a differential measurement. The NCMR results from changes in the density of states of noncollinear spin textures with respect to the ferromagnetic state. Density functional theory calculations reveal that they originate from spin mixing between majority d_{xz} and minority p_{z} states.