Development of a SARS-CoV-2 viral dynamic model for patients with COVID-19 based on the amount of viral RNA and viral titer.

The target-cell limited model, which is one of the mathematical modeling approaches providing a quantitative understanding of viral dynamics, has been applied to describe viral RNA profiles of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in previous studies. However, these models have been developed mainly using patient data from the early phase of the pandemic. Furthermore, no reports focused on the profiles of the viral titer. In this study, the dynamics of both viral RNA and viral titer were characterized using data reflecting the current clinical situation in which the Omicron variant has become epidemic and vaccines for SARS-CoV-2 have become available. Consecutive data for 5212 viral RNA levels and 5216 viral titers were obtained from 720 patients with coronavirus disease 2019 (COVID-19) in a phase II/III study for ensitrelvir. Our model assumed that productively infected cells would produce only infectious viruses, which could be transformed into non-infectious viruses, and has been used to describe the dynamics of both viral RNA levels and viral titer. The time from infection to symptom onset (tinf) of unvaccinated patients was estimated to be 3.0 days, which was shorter than that of the vaccinated patients. The immune-related parameter as a power function for the vaccinated patients was 1.1 times stronger than that for the unvaccinated patients. Our model allows the prediction of the viral dynamics in patients with COVID-19 from the time of infection to symptom onset. Vaccination status was identified as a factor influencing tinf and the immune function.

Effect of Renal Impairment on Pharmacokinetics and Safety of Ensitrelvir, a SARS-CoV-2 3CL Protease Inhibitor.

INTRODUCTION: Ensitrelvir, a novel oral inhibitor of 3C-like protease of SARS-CoV-2, shows efficacy and safety in participants with mild to moderate COVID-19. Since urinary recovery of ensitrelvir ranged from 12.9% to 21.8% across dose groups given 20-1000 mg in a single-ascending dose study, renal excretion contributes to the elimination of ensitrelvir. Therefore, the effect of renal impairment on the pharmacokinetics and safety of ensitrelvir needed to be evaluated. METHODS: This study (NCT05363215) was a phase 1, open-label, nonrandomized, parallel-group study. The effect of renal function on the pharmacokinetics of ensitrelvir was investigated. Ensitrelvir was administered as a single dose of 375 mg to participants with normal renal function and those with mild, moderate, and severe renal impairment. The participants with normal renal function were matched to each participant with moderate renal impairment with respect to sex, age, and body mass index. The unbound fractions in plasma after administration of ensitrelvir were also evaluated. For the safety assessment, the nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded. RESULTS: The plasma concentrations of participants with renal impairment were higher than those of participants with normal renal function. The ratios (90% confidence intervals) of the area under the plasma concentration-time curve from 0 to infinity (AUC0-inf) in participants with mild, moderate, and severe renal impairment compared to normal renal function were 1.4374 (1.1716-1.7636), 1.4885 (1.1883-1.8646), and 1.6021 (1.2782-2.0080), respectively. The plasma protein-unbound fraction was similar regardless of the plasma ensitrelvir concentration or renal function. Ensitrelvir was well tolerated in participants with mild to severe renal impairment and normal renal function. CONCLUSION: Ensitrelvir was well tolerated by participants with renal impairment. There was no clinically meaningful increase on exposure to ensitrelvir in participants with renal impairment, indicating that no dose adjustment would be required due to renal function.

Pathway selectivity in time-resolved spectroscopy using two-photon coincidence counting with quantum entangled photons.

Ultrafast optical spectroscopy is a powerful technique for studying the dynamic processes of molecular systems in condensed phases. However, in molecular systems containing many dye molecules, the spectra can become crowded and difficult to interpret owing to the presence of multiple nonlinear optical contributions. In this work, we theoretically propose time-resolved spectroscopy based on the coincidence counting of two entangled photons generated via parametric down-conversion with a monochromatic laser. We demonstrate that the use of two-photon counting detection of entangled photon pairs enables the selective elimination of the excited-state absorption signal. This selective elimination cannot be realized with classical coherent light. We anticipate that the proposed spectroscopy will help simplify the spectral interpretation of complex molecular and material systems comprising multiple molecules.

Utility of Coproporphyrin-I Determination in First-in-Human Study for Early Evaluation of OATP1B Inhibitory Potential Based on Investigation of Ensitrelvir, an Oral SARS-CoV-2 3C-Like Protease Inhibitor.

Coproporphyrin-I (CP-I) has been investigated as an endogenous biomarker of organic anion transporting polypeptide (OATP) 1B. Here, we determined the CP-I concentrations in a cocktail drug-drug interaction (DDI) study of ensitrelvir to evaluate the OATP1B inhibitory potential because ensitrelvir had increased plasma concentrations of rosuvastatin in this study, raising concerns about breast cancer resistance protein and OATP1B inhibition. Furthermore, CP-I concentrations were compared between active and placebo groups in a first-in-human (FIH) study of ensitrelvir to verify whether the OATP1B inhibitory potential could be estimated at an early drug development stage. In the cocktail DDI study, CP-I did not differ between with/without administration of ensitrelvir, indicating that ensitrelvir has no OATP1B inhibitory effect. Although there were some individual variabilities in CP-I concentrations among the treatment groups in the FIH study, the normalization of CP-I concentrations with pre-dose values minimized these variabilities, suggesting that this normalized method would be helpful for comparing the CP-I from different participants. Finally, we concluded that CP-I concentrations were not affected by ensitrelvir in the FIH study. These results suggested that the CP-I determination in an FIH study and its normalized method can be useful for an early evaluation of the OATP1B-mediated DDI potential in humans.

Comparison of multi-mode Hong-Ou-Mandel interference and multi-slit interference.

Hong-Ou-Mandel (HOM) interference of multi-mode frequency entangled states plays a crucial role in quantum metrology. However, as the number of modes increases, the HOM interference pattern becomes increasingly complex, making it challenging to comprehend intuitively. To overcome this problem, we present the theory and simulation of multi-mode-HOM interference (MM-HOMI) and compare it to multi-slit interference (MSI). We find that these two interferences have a strong mapping relationship and are determined by two factors: the envelope factor and the details factor. The envelope factor is contributed by the single-mode HOM interference (single-slit diffraction) for MM-HOMI (MSI). The details factor is given by sin (Nx)/sin (x) ([sin (Nv)/sin (v)]2) for MM-HOMI (MSI), where N is the mode (slit) number and x (v) is the phase spacing of two adjacent spectral modes (slits). As a potential application, we demonstrate that the square root of the maximal Fisher information in MM-HOMI increases linearly with the number of modes, indicating that MM-HOMI is a powerful tool for enhancing precision in time estimation. We also discuss multi-mode Mach-Zehnder interference, multi-mode NOON-state interference, and the extended Wiener-Khinchin theorem. This work may provide an intuitive understanding of MM-HOMI patterns and promote the application of MM-HOMI in quantum metrology.

A Phase 1 Study of Ensitrelvir Fumaric Acid Tablets Evaluating the Safety, Pharmacokinetics and Food Effect in Healthy Adult Populations.

BACKGROUND: A reported clinical pharmacokinetics and safety study of suspension formulation of ensitrelvir, a therapeutic agent used in severe acute respiratory syndrome coronavirus 2 infection, demonstrated favorable pharmacokinetics and was well tolerated in healthy male Japanese and White participants. Understanding the safety and pharmacokinetic features of ensitrelvir (using the formulation approved for clinical use) in various populations, and the effect of food, is crucial for optimal clinical use. OBJECTIVES: The objectives of this study were to (1) assess the safety, tolerability, and pharmacokinetics of ensitrelvir following multiple-dose administration of ensitrelvir tablets in populations with different races, ages, and sex; and (2) assess the effect of food on the pharmacokinetics of ensitrelvir tablets in the fasted or fed state. METHODS: A phase 1, multicenter, double-blinded, randomized, placebo-controlled study was conducted to evaluate the safety and pharmacokinetics of once-daily ensitrelvir tablets at loading/maintenance doses of 375/125 mg or 750/250 mg for 5 days in healthy Japanese females, Japanese elderly (only 375/125 mg), and White male and female participants. An open-label, two-group, two-period crossover study was also conducted to estimate the effect of food on the pharmacokinetics of ensitrelvir at single dose of 375 mg. The nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded in safety assessments in both studies. RESULTS: The maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were similar within these populations. The geometric mean half-life of ensitrelvir following multiple-dose administration was 48.7-58.9 h across all cohorts. The Cmax and AUC increased in a dose-proportional manner in Japanese female participants, and increased in a less than dose-proportional manner in White participants. Furthermore, there was no clear relationship between the dose and geometric mean half-life of ensitrelvir. The plasma concentration at 24 h (C24) after an initial dose of 375/125 mg exceeded the target plasma concentration (6.09 µg/mL) in all populations. Regarding the effect of food on the pharmacokinetics of ensitrelvir, although time to Cmax in the fed state was delayed, there was no clinically meaningful difference in the exposure levels (Cmax and AUC) of ensitrelvir between the fasted and fed states. Most treatment-emergent adverse events were mild in nature and had resolved. CONCLUSION: Ensitrelvir (375/125 mg and 750/250 mg tablet formulation) was well tolerated, without any major safety concerns. The pharmacokinetics of ensitrelvir between all populations in the study were similar and C24 exceeded the target plasma concentration at 375/125 mg. These results suggest that ensitrelvir can be effectively administered with no necessity for dose adjustment for age, sex, and race without food restriction. CLINICAL TRIAL REGISTRATION: Japan Registry of Clinical Trials identifier: jRCT2031210202, registered on 16 July 2021.

A free-standing lithium phosphorus oxynitride thin film electrolyte promotes uniformly dense lithium metal deposition with no external pressure.

Lithium phosphorus oxynitride (LiPON) is an amorphous solid electrolyte that has been extensively studied over the last three decades. Despite the promise of pairing it with various electrode materials, LiPON's rigidity and air sensitivity set limitations to understanding its intrinsic properties. Here we report a methodology to synthesize LiPON in a free-standing form that manifests remarkable flexibility and a Young's modulus of ∼33 GPa. We use solid-state nuclear magnetic resonance and differential scanning calorimetry to quantitatively reveal the chemistry of the Li/LiPON interface and the presence of a well-defined LiPON glass-transition temperature of 207 °C. Combining interfacial stress and a gold seeding layer, our free-standing LiPON shows a uniformly dense deposition of lithium metal without the aid of external pressure. This free-standing LiPON film offers opportunities to study fundamental properties of LiPON for interface engineering for solid-state batteries.

Pharmacokinetics, safety, and tolerability of single and multiple doses of zuranolone in Japanese and White healthy subjects: A phase 1 clinical trial.

AIM: This phase 1 study assessed the pharmacokinetics, safety, and tolerability of zuranolone in Japanese and White healthy adults, and Japanese healthy elderly subjects. METHODS: This single-center study consisted of three parts. In Part A (randomized, double-blind), the safety, tolerability, and pharmacokinetics of single dose and 7-day consecutive multiple doses of zuranolone 10, 20, and 30 mg and placebo were assessed in 36 Japanese adults, 24 White adults, and 12 Japanese elderly (aged 65-75 years) subjects. In Part B (randomized, open-label, crossover), the effect of food intake on the pharmacokinetics and safety of single-dose zuranolone 30 mg was evaluated in 12 Japanese adults. In Part C (randomized, double-blind, crossover), the effects of single-dose zuranolone 10 and 30 mg and placebo on electroencephalography parameters were evaluated in eight Japanese adults. RESULTS: Single and multiple doses of zuranolone were safe and well tolerated in all subjects. Linear pharmacokinetics were observed in the studied dose range. Time to steady-state plasma concentration was within 72 h for Japanese and White adults. Pharmacokinetic profiles were comparable between Japanese and White adults and between Japanese adults and Japanese elderly subjects. Plasma exposures of zuranolone were greater in the fed versus fasted state. Single-dose zuranolone 30 mg increased low-beta electroencephalography power. CONCLUSION: In healthy Japanese subjects, zuranolone was well tolerated; pharmacokinetic profile was unaffected by ethnicity or age; plasma exposures were greater in the fed state. The increased low-beta electroencephalography power with the 30-mg dose is consistent with γ-aminobutyric acid receptor type A activation by zuranolone.

Efficacy of Integrated Online Mindfulness and Self-compassion Training for Adults With Atopic Dermatitis: A Randomized Clinical Trial.

Importance: Quality of life (QOL) of patients with atopic dermatitis (AD) is reported to be the lowest among skin diseases. To our knowledge, mindfulness and self-compassion training has not been evaluated for adults with AD. Objective: To evaluate the efficacy of mindfulness and self-compassion training in improving the QOL for adults with AD. Design, Setting, and Participants: This randomized clinical trial conducted from March 2019 through October 2022 included adults with AD whose Dermatology Life Quality Index (DLQI) score, a skin disease-specific QOL measure, was greater than 6 (corresponding to moderate or greater impairment). Participants were recruited from multiple outpatient institutes in Japan and through the study's social media outlets and website. Interventions: Participants were randomized 1:1 to receive eight 90-minute weekly group sessions of online mindfulness and self-compassion training or to a waiting list. Both groups were allowed to receive any dermatologic treatment except dupilumab. Main Outcomes and Measures: The primary outcome was the change in the DLQI score from baseline to week 13. Secondary outcomes included eczema severity, itch- and scratching-related visual analog scales, self-compassion and all of its subscales, mindfulness, psychological symptoms, and participants' adherence to dermatologist-advised treatments. Results: The study randomized 107 adults to the intervention group (n = 56) or the waiting list (n = 51). The overall participant mean (SD) age was 36.3 (10.5) years, 85 (79.4%) were women, and the mean (SD) AD duration was 26.6 (11.7) years. Among participants from the intervention group, 55 (98.2%) attended 6 or more of the 8 sessions, and 105 of all participants (98.1%) completed the assessment at 13 weeks. The intervention group demonstrated greater improvement in the DLQI score at 13 weeks (between-group difference estimate, -6.34; 95% CI, -8.27 to -4.41; P < .001). The standardized effect size (Cohen d) at 13 weeks was -1.06 (95% CI, -1.39 to -0.74). All secondary outcomes showed greater improvements in the intervention group than in the waiting list group. Conclusions and Relevance: In this randomized clinical trial of adults with AD, integrated online mindfulness and self-compassion training in addition to usual care resulted in greater improvement in skin disease-specific QOL and other patient-reported outcomes, including eczema severity. These findings suggest that mindfulness and self-compassion training is an effective treatment option for adults with AD. Trial Registration: https://umin.ac.jp/ctr Identifier: UMIN000036277.

Evaluation of the Drug-Drug Interaction Potential of Ensitrelvir Fumaric Acid with Cytochrome P450 3A Substrates in Healthy Japanese Adults.

BACKGROUND: Management of drug-drug interactions (DDIs) for ensitrelvir, a novel 3-chymotrypsin-like protease inhibitor of SARS-CoV-2 infection is crucial. A previous clinical DDI study of ensitrelvir with midazolam, a clinical index cytochrome P450 (CYP) 3A substrate, demonstrated that ensitrelvir given for 5 days orally with a loading/maintenance dose of 750/250 mg acted as a strong CYP3A inhibitor. OBJECTIVES: The objectives of this study were to investigate the effect of ensitrelvir on the pharmacokinetics of CYP3A substrates, dexamethasone, prednisolone and midazolam, and to assess the pharmacokinetics, safety, and tolerability of ensitrelvir following multiple-dose administration of ensitrelvir. METHODS: This was a Phase 1, multicenter, single-arm, open-label study in healthy Japanese adult participants. The effects of multiple doses of ensitrelvir in the fasted state on the pharmacokinetics of dexamethasone, prednisolone, and midazolam were investigated. Ensitrelvir was administered from Day 1 through Day 5, with a loading/maintenance dose of 750/250 mg for the dexamethasone and prednisolone cohorts whereas 375/125 mg for the midazolam cohort. Either dexamethasone, prednisolone, or midazolam was administered alone (Day - 2) or in combination with ensitrelvir (Day 5) in each of the cohorts. Additionally, dexamethasone or prednisolone was administered on Days 9 and 14. The pharmacokinetic parameters of ensitrelvir, dexamethasone, prednisolone, and midazolam were calculated based on their plasma concentration data with non-compartmental analysis. In safety assessments, the nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded. RESULTS: The area under the concentration-time curve (AUC) ratio of dexamethasone on Day 5 was 3.47-fold compared with the corresponding values for dexamethasone alone on Day - 2 and the effect diminished over time after the last dose of ensitrelvir. No clinically meaningful effect was observed for prednisolone. The AUC ratio of midazolam was 6.77-fold with ensitrelvir 375/125 mg suggesting ensitrelvir at 375/125 mg strongly inhibits CYP3A similar to that at 750/250 mg. No new safety signals with ensitrelvir were reported during the study. CONCLUSION: The inhibitory effect for CYP3A was confirmed after the last dose of ensitrelvir, and the effect diminished over time. In addition, ensitrelvir at 375/125 mg showed CYP3A inhibitory potential similar to that at 750/250 mg. These findings can be used as a clinical recommendation for prescribing ensitrelvir with regard to concomitant medications. CLINICAL TRIAL REGISTRATION: Japan Registry of Clinical Trials identifier: jRCT2031210202.

Efficacy and safety of zuranolone in Japanese adults with major depressive disorder: A double-blind, randomized, placebo-controlled, phase 2 clinical trial.

AIM: To evaluate the efficacy and safety of an oral, once-daily, 14-day treatment course of zuranolone in Japanese patients with major depressive disorder (MDD). METHODS: This multicenter, randomized, double-blind, placebo-controlled study randomized eligible patients (1:1:1) to receive oral zuranolone 20 mg, zuranolone 30 mg, or placebo once daily for 14 days (treatment-period), followed by two 6-week follow-up periods. The primary endpoint was change from baseline in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score on Day 15. RESULTS: Overall, 250 patients (enrolled: 07/07/2020-05/26/2021) were randomized to receive placebo (n = 83), zuranolone 20 mg (n = 85), or zuranolone 30 mg (n = 82). The demographic and baseline characteristics were balanced between groups. The adjusted mean (standard error) change from baseline in the HAMD-17 total score on Day 15 was -6.22 (0.62), -8.14 (0.62), and - 8.31 (0.63) in the placebo, zuranolone 20-mg, and zuranolone 30-mg groups, respectively. Significant differences in the adjusted mean (95% confidence interval [CI]) for zuranolone 20 mg versus placebo (-1.92; [-3.65, -0.19]; P = 0.0296) and zuranolone 30 mg versus placebo (-2.09; [-3.83, -0.35]; P = 0.0190) groups were observed on Day 15, and also as early as Day 3. A nonsignificant yet distinct drug-placebo separation was observed during follow-up. Somnolence (placebo [3.7%], zuranolone 20 mg [10.6%], and zuranolone 30 mg [20.7%]) and dizziness (3.7%, 9.4%, and 9.8%, respectively) were more common with zuranolone. CONCLUSION: Oral zuranolone was safe and demonstrated significant improvements in depressive symptoms, as assessed by HAMD-17 total score change from baseline over 14 days in Japanese patients with MDD.

Spatial-spectral mapping to prepare frequency entangled qudits.

Entangled qudits, the high-dimensional entangled states, play an important role in the study of quantum information. How to prepare entangled qudits in an efficient and easy-to-operate manner is still a challenge in quantum technology. Here, we demonstrate a method to engineer frequency entangled qudits in a spontaneous parametric downconversion process. The proposal employs an angle-dependent phase-matching condition in a nonlinear crystal, which forms a classical-quantum mapping between the spatial (pump) and spectral (biphotons) degrees of freedom. In particular, the pump profile is separated into several bins in the spatial domain, and thus shapes the down-converted biphotons into discrete frequency modes in the joint spectral space. Our approach provides a feasible and efficient method to prepare a high-dimensional frequency entangled state. As an experimental demonstration, we generate a three-dimensional entangled state by using a homemade variable slit mask.

Evaluation of Drug-Drug Interactions of Ensitrelvir, a SARS-CoV-2 3CL Protease Inhibitor, With Transporter Substrates Based on In Vitro and Clinical Studies.

Drug-drug interaction potentials of ensitrelvir, a novel oral inhibitor of 3C-like protease of severe acute respiratory syndrome coronavirus 2, for drug transporters were evaluated by in vitro and clinical studies. The target drug transporters assessed were P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, and multidrug and toxin extrusion 1 and 2K. In vitro study revealed that ensitrelvir is a substrate for P-gp and BCRP and inhibits P-gp, BCRP, OATP1B1, OATP1B3, OCT1, and OAT3. Based on these results, a clinical drug-drug interaction study to evaluate the effect of ensitrelvir on the pharmacokinetics of P-gp, BCRP, OATP1B1, OATP1B3, and OCT1 substrates was conducted with a cocktail approach using digoxin (P-gp substrate), rosuvastatin (BCRP, OATP1B1, and OATP1B3 substrate), and metformin (OCT1 substrate). The cocktail was administered first, and after the washout period, the cocktail was coadministered with 500 mg of ensitrelvir. No treatment-emergent adverse events were observed. Pharmacokinetic analyses demonstrated that the ratios (90% confidence intervals) of "cocktail with ensitrelvir" to "cocktail without ensitrelvir" for maximum plasma concentration and area under the plasma concentration-time curve were, respectively, 2.17 (1.72-2.73) and 1.31 (1.13-1.52) for digoxin, 1.97 (1.73-2.25) and 1.65 (1.47-1.84) for rosuvastatin, and 1.03 (0.91-1.16) and 1.02 (0.94-1.11) for metformin. The results indicate that the exposure levels of digoxin and rosuvastatin increased when coadministered with ensitrelvir, but those of metformin were not changed. In conclusion, ensitrelvir has an impact on the exposure levels of P-gp, BCRP, OATP1B1, and OATP1B3 substrates.

Electrochemical Epoxidation Catalyzed by Manganese Salen Complex and Carbonate with Boron-Doped Diamond Electrode.

Epoxides are essential precursors for epoxy resins and other chemical products. In this study, we investigated whether electrochemically oxidizing carbonate ions could produce percarbonate to promote an epoxidation reaction in the presence of appropriate metal catalysts, although Tanaka and co-workers had already completed a separate study in which the electrochemical oxidation of chloride ions was used to produce hypochlorite ions for electrochemical epoxidation. We found that epoxides could be obtained from styrene derivatives in the presence of metal complexes, including manganese(III) and oxidovanadium(IV) porphyrin complexes and manganese salen complexes, using a boron-doped diamond as the anode. After considering various complexes as potential catalysts, we found that manganese salen complexes showed better performance in terms of epoxide yield. Furthermore, the substituent effect of the manganese salen complex was also investigated, and it was found that the highest epoxide yields were obtained when Jacobsen's catalyst was used. Although there is still room for improving the yields, this study has shown that the in situ electrochemical generation of percarbonate ions is a promising method for the electrochemical epoxidation of alkenes.

Safety, Tolerability, and Pharmacokinetics of the Novel Antiviral Agent Ensitrelvir Fumaric Acid, a SARS-CoV-2 3CL Protease Inhibitor, in Healthy Adults.

Ensitrelvir is a novel selective inhibitor of the 3C-like protease of SARS-CoV-2, which is essential for viral replication. This phase 1 study of ensitrelvir assessed its safety, tolerability, and pharmacokinetics of single (part 1, n = 50) and multiple (part 2, n = 33) ascending oral doses. Effect of food on the pharmacokinetics of ensitrelvir, differences in pharmacokinetics of ensitrelvir between Japanese and white participants, and effect of ensitrelvir on the pharmacokinetics of midazolam (a cytochrome P450 3A [CYP3A] substrate) were also assessed. In part 1, Japanese participants were randomized to placebo or ensitrelvir at doses of 20, 70, 250, 500, 1,000, or 2,000 mg. In part 2, Japanese and white participants were randomized to placebo or once-daily ensitrelvir at loading/maintenance dose 375/125 mg or 750/250 mg for 5 days. Most treatment-related adverse events observed were mild in severity and were resolved without treatment. Plasma exposures showed almost dose proportionality, and geometric mean half-life of ensitrelvir following the single dose was 42.2 to 48.1 h. Food intake reduced Cmax and delayed Tmax of ensitrelvir but did not impact the area under the curve (AUC), suggesting suitability for administration without food restriction. Compared with Japanese participants, plasma exposures were slightly lower for white participants. Ensitrelvir affected the pharmacokinetics of CYP3A substrates because of increase in AUC of midazolam coadministered with ensitrelvir 750/250 mg on day 6. In conclusion, ensitrelvir was well-tolerated and demonstrated favorable pharmacokinetics, including a long half-life, supporting once-daily oral dosing. These results validate further assessments of ensitrelvir in participants with SARS-CoV-2 infection.

Ultrafast measurement of a single-photon wave packet using an optical Kerr gate.

Ultrafast quantum optics with time-frequency entangled photons is at the forefront of progress towards future quantum technologies. However, to unravel the time domain structure of entangled photons and exploit fully their rich dimensionality, a single-photon detector with sub-picosecond temporal resolution is required. Here, we present ultrafast single-photon detection using an optical Kerr gate composed of a photonic crystal fiber (PCF) placed inside a Sagnac interferometer. A near-rectangle temporal waveform of a heralded single-photon generated via spontaneous parametric down-conversion is measured with temporal resolution as high as 224 ± 9 fs. The large nonlinearity and long effective interaction length of the PCF enables maximum detection efficiency to be achieved with only 30.5 mW gating pulse average power, demonstrating an order-of-magnitude improvement compared to optical gating with sum-frequency generation. Also, we discuss the trade-off relationship between detection efficiency and temporal resolution.

Multireference Perturbation Theory Combined with PCM and RISM Solvation Models: A Benchmark Study for Chemical Energetics.

The polarizable continuum model (PCM) has been one of the most widely used approaches to take into account the solvation effect in quantum chemical calculations. In this paper, we performed a series of benchmark calculations to assess the accuracy of the PCM scheme combined with the second-order complete-active-space perturbation theory (CASPT2) for molecular systems in polar solvents. For solute molecules with extensive conjugated π orbitals, exemplified by elongated conjugated arylcarbenes, we have incorporated the ab initio density matrix renormalization group algorithm into the PCM-CASPT2 method. In the previous work, we presented a combination of the DMRG-CASPT2 method with the reference interaction site model (RISM) theory for describing the solvation effect using the radial distribution function and compared its performance to the widely used density-functional approaches (PCM-TD-DFT). The work here allows us to further show a more thorough assessment of the RISM model compared to the PCM with an equal level of the wave function treatment, the (DMRG-)CASPT2 theory, toward a high-accuracy electronic structure calculations for solvated chemical systems. With the exception that the PCM models are not capable of properly describing the hydrogen bondings, accuracy of the PCM-CASPT2 model is in most cases quite comparable to the RISM counterpart.

Quantitative systems pharmacology model of thrombopoiesis and platelet life-cycle, and its application to thrombocytopenia based on chronic liver disease.

Platelets are produced by hematopoietic stem cells via megakaryocytes in the bone marrow and play a critical role in hemostasis. The aim of this study was to develop a new platelet model based on the thrombopoiesis and platelet life-cycle by a quantitative systems pharmacology modeling approach, which could describe changes in platelet count profiles in platelet-related diseases and drug intervention. The proposed platelet model consists of 44 components. The model was applied to thrombopoiesis of a thrombopoietin receptor agonist, lusutrombopag. It could well describe the observed platelet count profiles after administration of lusutrombopag for both healthy subjects and patients with chronic liver disease and thrombocytopenia. This model should be useful for understanding the disease progression of platelet-related conditions, such as thrombocytopenia and for predicting platelet count profiles in various disease situations related to platelets and drug administration in drug development.

Mid-infrared spectrally-uncorrelated biphotons generation from doped PPLN: a theoretical investigation.

We theoretically investigate the preparation of mid-infrared (MIR) spectrally-uncorrelated biphotons from a spontaneous parametric down-conversion process using doped LN crystals, including MgO doped LN, ZnO doped LN, and In2O3 doped ZnLN with doping ratio from 0 to 7 mol%. The tilt angle of the phase-matching function and the corresponding poling period are calculated under type-II, type-I, and type-0 phase-matching conditions. We also calculate the thermal properties of the doped LN crystals and their performance in Hong-Ou-Mandel interference. It is found that the doping ratio has a substantial impact on the group-velocity-matching (GVM) wavelengths. Especially, the GVM2 wavelength of co-doped InZnLN crystal has a tunable range of 678.7 nm, which is much broader than the tunable range of less than 100 nm achieved by the conventional method of adjusting the temperature. It can be concluded that the doping ratio can be utilized as a degree of freedom to manipulate the biphoton state. The spectrally uncorrelated biphotons can be used to prepare pure single-photon source and entangled photon source, which may have promising applications for quantum-enhanced sensing, imaging, and communications at the MIR range.

Local Structure of Glassy Lithium Phosphorus Oxynitride Thin Films: A Combined Experimental and Ab†Initio Approach.

Lithium phosphorus oxynitride (LiPON) is an amorphous solid-state lithium ion conductor displaying exemplary cyclability against lithium metal anodes. There is no definitive explanation for this stability due to the limited understanding of the structure of LiPON. Herein, we provide a structural model of RF-sputtered LiPON. Information about the short-range structure results from 1D and 2D solid-state NMR experiments. These results are compared with first principles chemical shielding calculations of Li-P-O/N crystals and ab initio molecular dynamics-generated amorphous LiPON models to unequivocally identify the glassy structure as primarily isolated phosphate monomers with N incorporated in both apical and as bridging sites in phosphate dimers. Structural results suggest LiPON's stability is a result of its glassy character. Free-standing LiPON films are produced that exhibit a high degree of flexibility, highlighting the unique mechanical properties of glassy materials.