Crossover Phase Research Articles

Dynamics of cosmological phase crossover during Bose–Einstein condensation of dark matter in Tsallis cosmology

AbstractDuring the cosmic evolution process, as the temperature of a cosmological boson gas falls below a certain threshold, a Bose–Einstein condensation process can occur at various points throughout the cosmic history of the Universe. In this model, dark matter, conceptualized as a non-relativistic, Newtonian gravitational condensate is governed by the Gross–Pitaevskii–Poisson system. In our present study, we investigate the Bose–Einstein condensation process of bosonic DM by treating it as an approximate first-order phase transition within a modified cosmological framework, known as Tsallis cosmology. We examine the evolution of relevant physical quantities characterizing the evolution dynamics of the Universe, including energy density, temperature, redshift, scale factor, Hubble parameter, and dimensionless deceleration parameter before, during, and following the Bose–Einstein condensation phase transition takes place. Additionally, we especially investigate the specific era of the evolution of the Universe characterized by a mixture of normal and condensate phases of dark matter. We analyze the behavior of temporal evolution of an important time-dependent parameter, called the condensate dark matter fraction throughout the condensation process and find the time duration of condensation of dark matter in the Tsallis cosmological model. We see that the presence of Bose–Einstein condensate dark matter in the framework of Tsallis-modified cosmology significantly alters the cosmological evolution of the Universe as compared to the standard model of cosmology. We also find for a typical value of Tsallis non-extensive parameter $$\beta =0.35$$ β = 0.35 , the model could explain an accelerated Universe without invoking any additional energy component and solve the age problem of our Universe.

Bioequivalence Analysis of Ondansetron Hydrochloride Tablets in Healthy Chinese Subjects: A Randomized, Open-Label, Two-Period Crossover Phase I Study.

Ondansetron is a highly selective 5-HT3 receptor antagonist that alleviates nausea and vomiting. Bioequivalence evaluation ensures that the efficacy of generic drugs is consistent with that of the original drug. The objective of this study was to evaluate the bioequivalence of ondansetron hydrochloride (HCl) tablets taken in single doses under fasting and postprandial conditions in healthy subjects. In this randomized, open-label, two-cycle, crossover phase I study, liquid chromatography‒tandem mass spectrometry (LC‒MS/MS) was used to determine the ondansetron concentration in dipotassium-ethylenediaminetetraacetate (K2-EDTA) plasma after the subjects received a single 8 mg of ondansetron and reference formulation. Twenty-six healthy subjects received one tablet of ondansetron under fasting conditions and 28 subjects received one under postprandial conditions. Bioequivalence was established if the 90% confidence interval (CI) was 80.00-125.00%. The pharmacokinetic parameters were calculated via WinNonLin 8.1 software and the bioequivalence data were evaluated via Phoenix WinNonlin 8.1 statistics software. The geometric mean ratio (GMR) of the maximum observed concentration (Cmax), the area under the plasma concentration‒time curve (AUC) from time zero to the last sampling time (AUC0-t), and the AUC from time zero to infinity (AUC0-∞) from the test/reference formulation under fasting conditions were 90.50, 90.43, and 90.25, respectively. The 90% CIs were 83.75-97.79, 82.64-98.95, and 82.25-99.03, respectively. The GMRs of Cmax, AUC0-t, and AUC0-∞ after a high-fat meal were 96.85, 93.57, and 93.77, respectively; the 90% CIs were 88.43-106.07, 87.35-100.24, and 87.35-100.68, respectively. The test and reference formulations of ondansetron HCl have bioequivalence for healthy adult subjects under fasting and postprandial conditions.

PPGAF-score: a photoplethysmographic risk prediction tool for developing atrial fibrillation

Abstract Background Digital screening for AF was recently shown to significantly increased the detection rate of treatment-relevant AF when compared to usual care. In this post-hoc analysis of the eBRAVE-AF trial, we hypothesized that information derived from sequential PPG-measurements in sinus rhythm might be predictive for future AF-development and we aimed to develop a dynamic AF-risk score (PPGAF-score). Methods In eBRAVE-AF, individuals who were free of AF were randomized to digital screening or usual care. For digital screening, participants screened for irregularities by means of PPG and abnormal findings were confirmed by a 14-day Holter-ECG. The primary endpoint was newly diagnosed AF treated with oral anticoagulation (OAC) within 6 months. After 6 months, participants were invited to a second, cross-over study phase. In this sub-study we identified participants who performed PPG-measurements both on day (8 am-6 pm) and at night (10 pm-6 am). PPGAF-score was calculated using the coefficients derived from Cox regression analysis. The multivariable model included age ≥ 65 years, sex and three PPG-derived parameters: (i) mean heart rate (HR) of each single PPG-measurement and (ii) the standard deviation (SD) of the HR between subsequent PPG-measurements, which were both dichotomized at the median value and (iii) the failure to demonstrate nocturnal HR reduction (day HR/night HR < 1). PPGAF-score was dichotomized at the median value. Results Of the 2,436 participants included in this analysis, 1,208 (50%) were ≥ 65 years old and 776 (32%) participants were females. Cumulatively 186,551 PPG measurements were performed, corresponding to a median of 28 (IQR 23) daytime and 3 (IQR 5) nighttime measurements per participant. The median HR per measurement was 69 (IQR 11) bpm, the median SD of the HR was 6 (IQR 2) bpm, and 759 (31%) participants failed to show a nocturnal HR reduction. During a follow-up time of 12 months, 53 subjects reached the primary endpoint. Cox regression analysis showed that age ≥ 65 years (HR 3.6; 95% CI 1.9–7.0; p < 0.001), male sex (2.7; 95% CI 1.2–5.9;p = 0.017), HR < 69bpm (HR 1.9; 95% CI 1.1–3.5;p=0.028), SD of HR ≥ 6bpm (HR 2.2; 95% CI 1.2–4.0;p=0.011) and the failure to show nocturnal HR reduction (HR 3.2; 95% CI 1.9–5.5; p < 0.001) were all independent predictors of the primary endpoint. PPGAF-score was calculated from the multivariable model. The median value was 0.22. PPGAF-score > 0.22 compared to a risk score ≤ 0.22 was associated with a significantly higher risk for developing AF requiring OAC (HR 6.9, 95% CI 3.1–15.4;p < 0.001; Figure 1). Conclusion Combining demographic and PPG-derived parameters, we developed a dynamic prediction tool for assessing the one-year risk of developing AF requiring OAC. A risk score of > 0.22 was associated with a 7-fold increased risk for developing treatment-relevant AF. PPG recordings might provide a valuable tool not only for diagnosing AF, but also for selecting high-risk individuals.

Magnetic properties and linear negative magnetocapacitance in rutile like LiFe2SbO6

Abstract We report the high-temperature magnetic ordering and the observation of linear negative magnetocapacitance mediated by a low-temperature magnetic phase crossover in the compound LiFe2SbO6. The combined observations of the absence of a second harmonic generation (SHG) signal, and Rietveld refinements of X-ray and neutron powder diffraction (NPD) patterns of the sample confirm that LiFe2SbO6 crystalizes in a centrosymmetric Pnnm structure. The DC magnetization measurements reveal that an antiferromagnetic ordering sets in at high temperature (TN= 850). The magnetic anomaly in the DC magnetization at a lower temperature T = 13 K, is corroborated by AC susceptibility and the specific heat measurements. We observe a linear negative magnetocapacitance below T = 13 K, demonstrating an indirect magneto-dielectric coupling. Further, the neutron powder diffraction study reveals a collinear antiferromagnetic ordering with a wavevector k = (0, 0, 0).

Pharmacokinetics and safety of daptomycin administered subcutaneously in healthy volunteers: a single-blinded randomized crossover trial.

Daptomycin stands as a key IV antibiotic in treating MRSA infections. However, patients facing challenges with difficult venous access require alternative administration routes. This study aimed to evaluate the pharmacokinetic (PK) profile and safety of subcutaneous (SC) daptomycin. In a two-period, two-treatment, single-blind crossover Phase I trial (ClinicalTrials.gov NCT04434300), participants with no medical history received daptomycin (10 mg/kg) both IV and SC in a random order, with a minimum 2 week washout period together with matched placebo (NaCl 0.9%). Blood samples collected over 24 h facilitated PK comparison. Monte Carlo simulations assessed the PTA for various dosing regimens. Adverse events were graded according to Common Terminology Criteria for Adverse Events(CTCAE) v5.0. Twelve participants (aged 30.9 ± 24.4 years; 9 male,75%) were included. SC daptomycin exhibited delayed (median Tmax 0.5 h for IV versus 4 h for SC) and lower peak concentration than IV (Cmax = 132.2 ± 16.0 μg/mL for IV versus 57.3 ± 8.6 μg/mL for SC; P < 0.001). SC AUC0-24 (937.3 ± 102.5 μg·h/mL) was significantly lower (P = 0.005) than IV AUC0-24 (1056.3 ± 123.5 μg·h/mL) but was deemed bioequivalent. PTA demonstrated target AUC0-24 attainment for 100% of simulated individuals, for both 8 and 10 mg/kg/24 h SC regimens. Adverse events (AEs) related to SC daptomycin were more frequent than for SC placebo (25 versus 13, P = 0.016). No serious AEs were reported. Single-dose SC daptomycin infusion proved to be safe, exhibiting a bioequivalent AUC0-24 compared with the IV route. The SC route emerges as a potential and effective alternative when IV administration is not possible.

Pharmacokinetics and Bioequivalence of a Generic Ticagrelor 90-mg Formulation Versus the Innovator Product in Healthy White Subjects Under Fasting Conditions.

Ticagrelor is a key antiplatelet agent used to prevent thrombotic events in patients with acute coronary syndrome. This open-label, 2-period, crossover Phase I study assessed the pharmacokinetics and bioequivalence of a generic ticagrelor 90-mg formulation compared to the innovator product under fasting conditions. Twenty-eight healthy White adults participated in the study. Each participant received a single dose of either the test or reference formulation, followed by a 7-day washout period before switching to the alternate formulation. Plasma concentrations of ticagrelor were measured using a validated high-performance liquid chromatography-tandem mass spectrometry method. Statistical analysis of primary pharmacokinetic parameters, including maximum concentration and area under the plasma concentration-time curve from time 0 to the last quantifiable concentration, showed bioequivalence with test/reference ratios of 110.9% and 107.1%, respectively, and 90% confidence intervals within the 80%-125% regulatory range. Treatment-emergent adverse events, such as headache, dysphagia, and dizziness, were moderate and transient and resolved promptly, with no significant difference in incidence between the formulations. These results confirm that the generic ticagrelor formulation is bioequivalent to the innovator product, supporting its use as an interchangeable option in clinical practice.

Impact of the Novel MRI Contrast Agent Gadopiclenol on Radiotherapy Decision Making in Patients With Brain Metastases.

The aim of this study was to assess the effect of gadopiclenol versus gadobenate dimeglumine contrast-enhanced magnetic resonance imaging (MRI) on decision-making between whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) for treatment of brain metastases (BMs). Patients with BMs underwent 2 separate MRI examinations in a double-blind crossover phase IIb comparative study between the MRI contrast agents gadopiclenol and gadobenate dimeglumine, both administered at 0.1 mmol/kg. The imaging data of a single site using identical MRI scanners and protocols were included in this post hoc analysis. Patients with 1 or more BMs in any of both MRIs were subjected to target volume delineation for treatment planning. Two radiation oncologists contoured all visible lesions and decided upon SRS or WBRT, according to the number of metastases. For each patient, SRS or WBRT treatment plans were calculated for both MRIs, considering the gross target volume (GTV) as the contrast-enhancing aspects of the tumor. Mean GTVs and volume of healthy brain exposed to 12 Gy (V12), as well as Dice similarity coefficient scores, were obtained. The Spearman rank (ρ) correlation was additionally calculated for assessing linear differences. Three different expert radiation oncologists blindly rated the contrast enhancement for contouring purposes. Thirteen adult patients were included. Gadopiclenol depicted additional BM as compared with gadobenate dimeglumine in 7 patients (54%). Of a total of 63 identified metastatic lesions in both MRI sets, 3 subgroups could be defined: A, 48 (24 pairs) detected equal GTVs visible in both modalities; B, 13 GTVs only visible in the gadopiclenol set (mean ± SD, 0.16 ± 0.37 cm3); and C, 2 GTVs only visible in the gadobenate dimeglumine set (mean ± SD, 0.01 ± 0.01). Treatment indication was changed for 2 (15%) patients, 1 from no treatment to SRS and for 1 from SRS to WBRT. The mean GTVs and brain V12 were comparable between both agents (P = 0.694, P = 0.974). The mean Dice similarity coefficient was 0.70 ± 0.14 (ρ = 0.82). According to the readers, target volume definition was improved in 63.9% of cases (23 of 36 evaluations) with gadopiclenol and 22.2% with gadobenate dimeglumine (8 of 36), whereas equivalence was obtained in 13.9% (5 of 36). Gadopiclenol-enhanced MRI improved BM detection and characterization, with a direct impact on radiotherapy treatment decision between WBRT and SRS. Additionally, a more exact target delineation and planning could be performed with gadopiclenol. A prospective evaluation in a larger cohort of patients is required to confirm these findings.

Effect of charm quark on chiral phase transition in Nf=2+1+1 holographic QCD

We investigate the effect of the charm quark on the chiral phase transition of light quarks at finite temperature based on the four-flavor soft-wall holographic QCD model. In the massless limit, we find that the thermal chiral phase transition is of the second order in the four-quark-flavor system. In the case with the massive charm quark and the massless light and strange quarks, the order of the phase transition changes to the first order. This is due to the quark-flavor symmetry breaking which is associated with the violation of the U(1) axial symmetry. Once the light and strange quarks get massive, the explicit chiral symmetry breaking becomes eminent, and then the crossover phase transition is realized at the physical quark masses. We also map the order of the phase transition on a phase diagram in the quark-mass plane where the light- and strange-quark masses are degenerate but differ from the value of the charm-quark mass. This phase diagram is an extension of the conventional Columbia plot to the four-quark-flavor system. The critical exponents related to the chiral phase transition are also addressed. Published by the American Physical Society 2024

A compensator design and stability margin monitor for digitally controlled DC-DC converters

ABSTRACT In this paper, an automatic direct digital design approach for compensators is presented to achieve a lookup table proportional – integral – derivative controller. Additionally, a correlation-based stability margin monitor with adaptive sliding window smoothing is proposed to increase the identifiable range for bandwidth detection. The proposed automatic compensator design approach meets the expected phase margin and crossover frequency and considers limit-cycle oscillation conditions throughout the design process. The digital controller with the direct digital design was implemented on a field programmable gate array to validate the approach and alternative design capabilities. Experimental results show that the direct digital design yields a higher crossover frequency than digital redesign. The best transient response performance can be obtained if a proper integral gain is designed. The digital controller with ASWS was fabricated using the TSMC 1P6M 0.18-μm standard CMOS process. Further experimental results show that the proposed ASWS provides a significantly more accurate identified frequency response by using narrow windows at low frequencies and expansive windows at high frequencies.

No Consistent Antidepressant Effects of Deep Brain Stimulation of the Bed Nucleus of the Stria Terminalis.

Applying deep brain stimulation (DBS) to several brain regions has been investigated in attempts to treat highly treatment-resistant depression, with variable results. Our initial pilot data suggested that the bed nucleus of the stria terminalis (BNST) could be a promising therapeutic target. The aim of this study was to gather blinded data exploring the efficacy of applying DBS to the BNST in patients with highly refractory depression. Eight patients with chronic severe treatment-resistant depression underwent DBS to the BNST. A randomised, double-blind crossover study design with fixed stimulation parameters was followed and followed by a period of open-label stimulation. During the double-blind crossover phase, no consistent antidepressant effects were seen with any of the four stimulation parameters applied, and no patients achieved response or remission criteria during the blinded crossover phase or during a subsequent period of three months of blinded stimulation. Stimulation-related side effects, especially agitation, were reported by a number of patients and were reversible with adjustment of the stimulation parameters. The results of this study do not support the application of DBS to the BNST in patients with highly resistant depression or ongoing research utilising stimulation at this brain site. The blocked randomised study design utilising fixed stimulation parameters was poorly tolerated by the participants and does not appear suitable for assessing the efficacy of DBS at this location.

Research on Multi-Objective Process Parameter Optimization Method in Hard Turning Based on an Improved NSGA-II Algorithm

To address the issue of local optima encountered during the multi-objective optimization process with the Non-dominated Sorting Genetic Algorithm II (NSGA-II) algorithm, this paper introduces an enhanced version of the NSGA-II. This improved NSGA-II incorporates polynomial and simulated binary crossover operators into the genetic algorithm’s crossover phase to refine its performance. For evaluation purposes, the classic ZDT benchmark functions are employed. The findings reveal that the enhanced NSGA-II algorithm achieves higher convergence accuracy and surpasses the performance of the original NSGA-II algorithm. When applied to the machining of the high-hardness material 20MnCrTi, four algorithms were utilized: the improved NSGA-II, the conventional NSGA-II, NSGA-III, and MOEA/D. The experimental outcomes show that the improved NSGA-II algorithm delivers a more optimal combination of process parameters, effectively enhancing the workpiece’s surface roughness and material removal rate. This leads to a significant improvement in the machining quality of the workpiece surface, demonstrating the superiority of the improved algorithm in optimizing machining processes.

Temperature-scan-rate dependent SCO hysteresis found in a tetramethylphosphonium tripodal ferrate(II) salt

A new compound (Me4P)[Fe(py3COH)(NCS)3]•MeOH was prepared and structurally characterized, where py3COH stands for tris(2-pyridyl)methanol. After annealed at 400 K, desolvated (Me4P)[Fe(py3COH)(NCS)3] displayed an abrupt spin-crossover (SCO) at T1/2↑ = 255 K and T1/2↓ = 234 K. Namely, 21 K-wide hysteresis was recorded at a temperature scan rate of 5 K min−1. The χmT vs T profile was temperature-scan rate dependent; the wider hysteresis with the slower scan. The secondary SCO with T1/2↑ = 275 K emerged, and a new concomitant hysteresis loop overlapped the primary one. The total hysteresis width became 39 K at a slow scan with 0.1 K min−1. A mechanism of interplaying spin crossover and structural phase transition is described. Combining a similar result on the corresponding Me4N+ analog, we supposed that the tripod py3COH ligand would have an advantage for hysteretic SCO and possibly for double SCO behavior.

Strategies for knee stabilising and pivot-shift avoidance in a step-down and cross-over task observed sub-acutely after anterior cruciate ligament reconstruction

BackgroundIndividuals with a recent anterior cruciate ligament reconstruction may demonstrate an altered movement strategy for protecting the knee and maintaining stability. Altered knee movement might lead to abnormal intra-articular load, potentially contributing to early knee osteoarthritis onset. A protective strategy may be particularly evident during active tasks that induce a pivot-shift manoeuvre, such as a step-down and cross-over task. In this study, we investigated whether knee joint mechanics and muscle activity differed between participants early (∼3 months) following reconstruction (n = 35) to uninjured controls (n = 35) during a step-down and cross-over task with a 45° change-of-direction. MethodsWe used motion capture, force plates and surface electromyography to compare time-normalised curves of sagittal and transverse-plane knee mechanics and muscle activity during the cross-over phase between groups using functional t-tests. We also compared knee mechanics between sides within the injured group and compared discrete outcomes describing the cross-over phase between groups. FindingsCompared to controls, the injured participants had greater knee flexion angle and moment, lower internal rotation moment, more preparatory foot rotation of the pivoting leg, a smaller cross-over angle, and a longer cross-over phase for both the injured and uninjured sides. The injured leg also had greater biceps femoris and vastus medialis muscle activity compared to controls and different knee mechanics than the uninjured leg. InterpretationIndividuals with anterior cruciate ligament reconstruction showed a knee-stabilising and pivot-shift avoidance strategy for both legs early in rehabilitation. These results may reflect an altered motor representation and motivate considerations early in rehabilitation.

Neutral pion masses within a hot and magnetized medium in a lattice-improved soft-wall AdS/QCD model

We investigate chiral phase transitions and the screening masses, pole masses, and thermal widths of neutral pion mesons with finite temperature T and magnetic field B in a lattice-improved AdS/QCD model, which is constructed by fitting the lattice results of the pseudocritical temperatures Tpc(B). Specifically, we find that the chiral condensate σ undergoes a crossover phase transition demonstrating distinct magnetic catalysis and inverse magnetic catalysis effects in very low- and high-temperature regions with fixed finite B, respectively. For the screening masses, we find that the longitudinal component decreases with B at very low and high temperatures and increases with B near Tpc. The transverse component always increases with B at fixed T. However, both the longitudinal and transverse screening masses increase with T at fixed B. Furthermore, we find that the pole mass decreases with the increase of B or T. It is interesting to note that the thermal width shows similar behavior to the longitudinal screening masses in the very-high-temperature region. Published by the American Physical Society 2024

Extensive phase transformation in an equiatomic CrCoNi medium entropy alloy under extreme uniaxial tension

The dynamic tension behavior of an equiatomic CrCoNi medium entropy alloy (MEA) has been studied at both room temperature (RT, 298 K) and liquid nitrogen temperature (LNT, 77 K). Microstructural observations show that extensive phase transformations were activated in this alloy under dynamic tension at LNT instead of the activation of the deformation twins under high strain rate only or quasi-static loading at LNT. The appearance of massive nanoscale phase transformation bands along multiple slip directions even created a network structure of HCP lamellae in the FCC grains. This leads to defect accumulation at the intersection regions and results in the formation of new HCP variants, inverse phase transformations to FCC structure and even amorphous domains. Such transformation induced plasticity (TRIP) effects including the mutual interactions of crossover phase transformation bands on the plasticity and tension fracture of the MEA under extreme loading conditions were further discussed. These findings provide a deeper understanding of the deformation mechanisms in the equiatomic MEA under extreme loads.

Simultaneously enhanced of energy storage and energy harvesting performances of [(Bi0.5Na0.5)TiO3–BaTiO3] ceramics by addition of SrTiO3

As is well known, relaxor dielectrics are characterized by high energy storage efficiency (η), while high recoverable energy storage density (Wrec) can be achieved by anti-ferroelectric ceramics. Herein, our approach is to find relaxor- anti-ferroelectric coexistence phases of (Bi0.5Na0.5)TiO3- BaTiO3 ceramics for achieving high performance in energy storage and energy harvesting as well. Therefore, [(0.9-x) ( Bi0.5Na0.5)TiO3-xSrTiO3-0.1BaTiO3] (abbreviation (0.9-x) NBT-0.1BT-xST) (0.0 ≤ x ≤ 0.4) were synthesized via the solid-state reaction route in air. The tolerance factor (τ) increased from 0.9901 to 0.9998 when ST-content increased from 0.0 to 0.4, indicating an increase in crystal lattice symmetry. The FT-IR de-convolution vibration modes shown in the TiO6 octahedra exhibit two peaks at ∼550 and 650 cm−1, which indicate present coexistence phases of the crystal structure. Ferroelectric to relaxor phase crossover has been detected by the addition of ST with the present anti-ferroelectric phase in particular dopant ST = 0.2. The increasing into the diffused phase transition (γ) is signified by enhancement of the relaxor degree of NBT-BT at high content of ST. The rapidly suppressed remnant polarization (Pr) at high content of ST is due to substitute iso-valence (Sr2+) by tri-valence (Bi3+) and mono-valence (Na1+). Ultrahigh Wrec = 1.13 J/ cm3 with excellent η = 92.62% were obtained at ST = 0.3 at low electric field (E = 110 kV cm−1). A remarkable response of the strain with a high converse piezoelectric coefficient ( d33* = 390.47 pm V−1) at ST = 0.2 was obtained due to decreasing the non-revisable 180° domain switching. Based on the obtained results, the addition of ST to NBT-BT ceramics can provide a head start in the implementation of ceramic capacitors for potential effective into energy harvesting and energy storage applications.

Phase diagram and crossover phases of topologically ordered graphene zigzag nanoribbons: role of localization effects

We computed the phase diagram of zigzag graphene nanoribbons as a function of on-site repulsion, doping, and disorder strength. The topologically ordered phase undergoes topological phase transitions into crossover phases, which are new disordered phases with non-universal topological entanglement entropy that exhibits significant variance. We explored the nature of non-local correlations in both the topologically ordered and crossover phases. In the presence of localization effects, strong on-site repulsion and/or doping weaken non-local correlations between the opposite zigzag edges of the topologically ordered phase. In one of the crossover phases, both e−/2 solitonic fractional charges and spin-charge separation were absent; however, charge-transfer correlations between the zigzag edges were possible. Another crossover phase contains solitonic e−/2 fractional charges but lacks charge transfer correlations. We also observed properties of non-topological, strongly disordered, and strongly repulsive phases. Each phase on the phase diagram exhibits a different zigzag-edge structure. Additionally, we investigated the tunneling of solitonic fractional charges under an applied voltage between the zigzag edges of undoped topologically ordered zigzag ribbons, and found that it may lead to a zero-bias tunneling anomaly.

Abstract CT131: Effect of rivoceranib administered as 200 mg once daily on the pharmacokinetics of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 substrates

Abstract Title: Effect of Rivoceranib Administered as 200 mg Once Daily on the Pharmacokinetics of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 Substrates Background: Rivoceranib is a selective vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor with potent antitumor activity. The purpose of this study is to evaluate the effect of rivoceranib on the pharmacokinetics of various CYP substrates in healthy subjects following administration of rivoceranib 200 mg once daily (QD), which is similar to the proposed rivoceranib dosing regimen (250 mg QD) in combination with camrelizumab for the treatment of hepatocellular carcinoma. Methods: This open-label, fixed-sequence, crossover drug-drug interaction phase 1 study evaluated the impact of multiple oral doses of rivoceranib at 200 mg QD on the pharmacokinetics of single oral doses of CYP enzyme substrates included in the Cooperstown 5+1 cocktail (midazolam 2 mg [CYP3A4/5 substrate], warfarin 10 mg [CYP2C9 substrate]/vitamin K 10 mg, dextromethorphan 30 mg [CYP2D6 substrate], omeprazole 40 mg [CYP2C19 substrate], and caffeine 200 mg [CYP1A2 substrate]). On Day 1, subjects received a single oral dose of the Cooperstown cocktail. Blood samples were collected predose on Day 1 and up to 120 hours post-dose for pharmacokinetic analyses. On Days 6-15, subjects received rivoceranib at 200 mg QD. On Day 11, a single dose of the Cooperstown Cocktail was co-administered with rivoceranib at 200 mg. Each dose was administered under postprandial conditions except for Day 11 when subjects fasted. Blood samples were collected predose on Day 11 and up to 120 hours post cocktail dosing for pharmacokinetic analyses. Subjects returned on any day between Days 21-25 for safety follow-up. Results: Rivoceranib 200 mg QD increased dextromethorphan AUC0-inf by 144% and Cmax by 70%, increased midazolam AUC0-inf by 65% and Cmax by 16%, increased the warfarin AUC0-inf by 28% and Cmax by 5%, increased omeprazole AUC0-inf by 77% and Cmax by 62%, and decreased caffeine AUC0-inf by 20% and Cmax by 7%. Cooperstown Cocktail alone or coadministration of Cooperstown Cocktail and rivoceranib was generally well tolerated. Conclusions:Rivoceranib at 200 mg QD does not substantially affect the exposure of the substrates of CYP3A4/5, CYP2C9, CYP2C19, and CYP1A2. Recommendation of dose adjustment of these CYP substrates is not needed when administered with rivoceranib at 200 mg QD. Rivoceranib may increase the exposure of the substrate of CYP2D6 by approximately 100%, indicating that a dose adjustment of CYP2D6 substrates and/or close monitoring patients should be considered when administered with rivoceranib 200 mg QD. Citation Format: Seong Jang, Xiaohui (Tracey) Wei, Xianzhang Meng, Joseph Reitano, Vinoo Urity, Cheol Hee Park, Bill Strickland, Grace Lee, David Nguyen. Effect of rivoceranib administered as 200 mg once daily on the pharmacokinetics of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 substrates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT131.

Abstract CT280: FURVENT, Phase 3 trial testing furmonertinib vs chemotherapy as first-line treatment for advanced NSCLC with EGFR exon 20 insertions (FURMO-004)

Abstract Introduction: EGFR exon 20 insertion mutations occur in approximately 2% of non-small cell lung cancer (NSCLC) and overall account for approximately 9% of all the EGFR mutations in NSCLC (Robichaux et al., 2021). Current first-line standard of care for NSCLC patients with these mutations is platinum-based chemotherapy (NCCN NSCLC, 2023). Furmonertinib is an oral, highly brain penetrant, broadly active mutant-selective EGFR inhibitor that targets EGFR exon 20 insertions and other EGFR mutations (Musib et al., NACLC 2022). Furmonertinib recently obtained FDA Breakthrough Therapy Designation for the first line treatment of patients with advanced NSCLC with EGFR ex20ins based on the data from the FAVOUR study. Promising preliminary clinical activity was observed in the FAVOUR study testing furmonertinib (240 mg daily [QD]) in patients with treatment naïve locally advanced or metastatic NSCLC, with EGFR exon 20 insertion (ex20ins) mutations showing confirmed overall response rate (ORR) of 78.6% (n=28) by blinded independent central review (BICR) with a preliminary median DOR of 15.2 months (Han et al., WCLC 2023). In previously treated patients both the 240 mg and 160 mg QD dose levels were active with confirmed ORR of 46.2% (n=26) and 38.5% (n=26) respectively, and included patients harboring near and far loop mutations.Furmonertinib showed a generally well-tolerated safety profile with expected EGFR-TKI class toxicities. Additional furmonertinib preclinical data in uncommon EGFR mutations, including P-loop and αC-helix Compressing (PACC) and ex20ins mutations will be presented at the AACR 2024 Annual Meeting (Nilsson et al., AACR 2024 Abstract #4174). Methods: The FURVENT (FURMO-004) study is a registrational global, phase 3, randomized, multicenter, open-label study. Eligible patients havetreatment-naïve, locally advanced or metastatic non-squamous NSCLC with EGFR exon 20 insertion mutations. Key inclusion criteria include documented EGFR exon 20 insertion mutation and measurable disease per RECIST 1.1. Key exclusion criteria include prior systemic anticancer therapy in the locally advanced or metastases setting or any prior EGFR TKI therapy. Approximately 375 patients will be randomized 1:1:1 to receive furmonertinib 160 mg QD, furmonertinib 240 mg QD, or platinum-based chemotherapy (cisplatin or carboplatin plus pemetrexed for 4 cycles followed by pemetrexed maintenance therapy). Stratification factors include the history or presence of central nervous system metastases at baseline, geographic region, and sex at birth. Patients from the platinum-based chemotherapy arm with documented disease progression are eligible to participate in the crossover phase of this trial to furmonertinib therapy. The primary endpoint is progression-free survival comparing between the treatment arms (furmonertinib 160 mg or 240 mg vs chemotherapy) based on BICR assessment. The key secondary endpoint is overall survival. Study enrollment is ongoing. Clinical trial information: NCT05607550. Citation Format: Alexander Spira, Byoung Chul Cho, Enriqueta Felip, Edward Garon, Koichi Goto, Melissa Lynne Johnson, Natasha B. Leighl, Antonio Passaro, David Planchard, Sanjay Popat, James Yang, Xiaoqian Lu, Yong Jiang, Jack Huang, Morgan Lam, Marcin Kowanetz, Shirley Wang, John Le, Jerry Hsu, Caicun Zhou. FURVENT, Phase 3 trial testing furmonertinib vs chemotherapy as first-line treatment for advanced NSCLC with EGFR exon 20 insertions (FURMO-004) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT280.

Rapid reduction of depressive symptoms with minimal dissociation: results from the KET01-02 and KET01-03 trials with oral prolonged-release (PR) ketamine KET01

IntroductionCurrent ketamine-based therapies for treatment-resistant depression (TRD) often induce dissociative effects. A novel oral PR ketamine formulation (KET01) results in a low and delayed peak concentration of ketamine, high hydroxynorketamine concentration, and is associated with limited dissociative properties.ObjectivesTo investigate efficacy, safety, and pharmacokinetics of KET01 in TRD.MethodsKET01-02 was a randomized, double-blind phase 2 trial in outpatients with TRD comparing adjunct 120 mg (n=42) or 240 mg (n=40) oral KET01 once-daily for 3 weeks to placebo (PBO, n=40). The primary endpoint was change from baseline in the MADRS mean score on Day 21. KET01-03 was a randomized, double-blind, cross-over phase I trial in 26 healthy volunteers comparing single doses of 240 mg oral KET01 and 84 mg an approved intranasal formulation of eketamine. The primary endpoint was maximum change of Clinician-Administered Dissociative States Scale (CADSS) score from baseline.ResultsKET01-03 trial; the mean (±SD) maximum change of CADSS score within 24 hours after dosing was 29.6±12.5 for intranasal eketamine and 0.7±1.7 for KET01 (p&lt;0.00000000001). KET01-02 trial; no differences in CADSS score (range: 0.2 to 1.3), and heart rate and blood pressure were observed between the groups on Day 1 and beyond. 10%, 12%, and 15% of patients in the PBO, 120 mg/day, and 240 mg/day KET01 groups, respectively had CADSS score &gt;4 and increase from baseline. At 7 hours post first KET01 dose (240 mg), plasma concentration of ketamine (38.7±27.0 ng/ml) was lower than its metabolites norketamine (267.5±81.6 ng/ml) and hydroxynorketamine (190.2±85.5 ng/ml). 240 mg/day KET01 induced clinically relevant reduction from baseline in MADRS score already within the first 7 hours of treatment (-7.65; Δ vs PBO: -2.22, n.s.), with a statistically significant separation on Day 4 (-10.02; Δ vs PBO: -3.66, p=0.020) and Day 7 (-12.21; Δ vs PBO: -3.95, p=0.042). MADRS score decrease was sustained throughout Day 21 (-13.15; Δ vs PBO: -1.82, n.s.), and during 4-week follow-up (-12.51; Δ vs PBO: -3.35, n.s.). Treatment-emergent adverse events occurred in 47.5%, 50.0%, and 62.5% of patients in the PBO, 120 mg/day, and 240 mg/day KET01 group, respectively.ConclusionsOral 240 mg/day KET01 induces a rapid, and clinically relevant reduction of depressive symptoms with only minimal signs of dissociation, potentially due to lower ketamine levels and increased norketamine and hydroxynorketamine levels compared to intravenous administration. Our results suggest that KET01 may be an efficacious and safe take-at-home adjunct treatment for TRD.Disclosure of InterestC. zu Eulenburg Employee of: HMNC Brain Health, E. Papanastasiou Employee of: HMNC Brain Health, K. Schmid Employee of: Develco Pharma, A. Damyanova Employee of: HMNC Brain Health, A. Glas Employee of: HMNC Brain Health, C. Strote Employee of: HMNC Brain Health, L. Arvastson Employee of: HMNC Brain Health, H. Eriksson Employee of: HMNC Brain Health