First Measurement of R(X_{τ/ℓ}) as an Inclusive Test of the b→cτν Anomaly.

We measure the tau-to-light-lepton ratio of inclusive B-meson branching fractions R(X_{τ/ℓ})≡B(B→Xτν)/B(B→Xℓν), where ℓ indicates an electron or muon, and thereby test the universality of charged-current weak interactions. We select events that have one fully reconstructed B meson and a charged lepton candidate from 189 fb^{-1} of electron-positron collision data collected with the Belle II detector. We find R(X_{τ/ℓ})=0.228±0.016(stat)±0.036(syst), in agreement with standard-model expectations. This is the first direct measurement of R(X_{τ/ℓ}).

Observation of e

We study the processes e^{+}e^{-}→ωχ_{bJ}(1P) (J=0, 1, or 2) using samples at center-of-mass energies sqrt[s]=10.701, 10.745, and 10.805 GeV, corresponding to 1.6, 9.8, and 4.7 fb^{-1} of integrated luminosity, respectively. These data were collected with the Belle II detector during special operations of the SuperKEKB collider above the ϒ(4S) resonance. We report the first observation of ωχ_{bJ}(1P) signals at sqrt[s]=10.745 GeV. By combining Belle II data with Belle results at sqrt[s]=10.867 GeV, we find energy dependencies of the Born cross sections for e^{+}e^{-}→ωχ_{b1,b2}(1P) to be consistent with the shape of the ϒ(10753) state. These data indicate that the internal structures of the ϒ(10753) and ϒ(10860) states may differ. Including data at sqrt[s]=10.653 GeV, we also search for the bottomonium equivalent of the X(3872) state decaying into ωϒ(1S). No significant signal is observed for masses between 10.45 and 10.65 GeV/c^{2}.

Measurement of the Λ_{c}

An absolute measurement of the Λ_{c}^{+} lifetime is reported using Λ_{c}^{+}→pK^{-}π^{+} decays in events reconstructed from data collected by the Belle II experiment at the SuperKEKB asymmetric-energy electron-positron collider. The total integrated luminosity of the data sample, which was collected at center-of-mass energies at or near the ϒ(4S) resonance, is 207.2 fb^{-1}. The result, τ(Λ_{c}^{+})=203.20±0.89±0.77 fs, where the first uncertainty is statistical and the second systematic, is the most precise measurement to date and is consistent with previous determinations.

Search for a Dark Photon and an Invisible Dark Higgs Boson in µ

The dark photon A^{'} and the dark Higgs boson h^{'} are hypothetical particles predicted in many dark sector models. We search for the simultaneous production of A^{'} and h^{'} in the dark Higgsstrahlung process e^{+}e^{-}→A^{'}h^{'} with A^{'}→µ^{+}µ^{-} and h^{'} invisible in electron-positron collisions at a center-of-mass energy of 10.58 GeV in data collected by the Belle II experiment in 2019. With an integrated luminosity of 8.34 fb^{-1}, we observe no evidence for signal. We obtain exclusion limits at 90% Bayesian credibility in the range of 1.7-5.0 fb on the cross section and in the range of 1.7×10^{-8}-200×10^{-8} on the effective coupling ϵ^{2}×α_{D} for the A^{'} mass in the range of 4.0 GeV/c^{2}

Search for Lepton-Flavor-Violating τ Decays to a Lepton and an Invisible Boson at Belle II.

We search for lepton-flavor-violating τ^{-}→e^{-}α and τ^{-}→µ^{-}α decays, where α is an invisible spin-0 boson. The search uses electron-positron collisions at 10.58 GeV center-of-mass energy with an integrated luminosity of 62.8 fb^{-1}, produced by the SuperKEKB collider and collected with the Belle II detector. We search for an excess in the lepton-energy spectrum of the known τ^{-}→e^{-}ν[over ¯]_{e}ν_{τ} and τ^{-}→µ^{-}ν[over ¯]_{µ}ν_{τ} decays. We report 95% confidence-level upper limits on the branching-fraction ratio B(τ^{-}→e^{-}α)/B(τ^{-}→e^{-}ν[over ¯]_{e}ν_{τ}) in the range (1.1-9.7)×10^{-3} and on B(τ^{-}→µ^{-}α)/B(τ^{-}→µ^{-}ν[over ¯]_{µ}ν_{τ}) in the range (0.7-12.2)×10^{-3} for α masses between 0 and 1.6 GeV/c^{2}. These results provide the most stringent bounds on invisible boson production from τ decays.

Search for an Invisible Z

The L_{µ}-L_{τ} extension of the standard model predicts the existence of a lepton-flavor-universality-violating Z^{'} boson that couples only to the heavier lepton families. We search for such a Z^{'} through its invisible decay in the process e^{+}e^{-}→µ^{+}µ^{-}Z^{'}. We use a sample of electron-positron collisions at a center-of-mass energy of 10.58 GeV collected by the Belle II experiment in 2019-2020, corresponding to an integrated luminosity of 79.7 fb^{-1}. We find no excess over the expected standard-model background. We set 90%-confidence-level upper limits on the cross section for this process as well as on the coupling of the model, which ranges from 3×10^{-3} at low Z^{'} masses to 1 at Z^{'} masses of 8 GeV/c^{2}.

Measurement of CP Violation in B

We report a measurement of the CP-violating parameters C and S in B^{0}→K_{S}^{0}π^{0} decays at Belle II using a sample of 387×10^{6} BB[over ¯] events recorded in e^{+}e^{-} collisions at a center-of-mass energy corresponding to the ϒ(4S) resonance. These parameters are determined by fitting the proper decay-time distribution of a sample of 415 signal events. We obtain C=-0.04_{-0.15}^{+0.14}±0.05 and S=0.75_{-0.23}^{+0.20}±0.04, where the first uncertainties are statistical and the second are systematic.

Search for a τ

We report the first search for a nonstandard-model resonance decaying into τ pairs in e^{+}e^{-}→µ^{+}µ^{-}τ^{+}τ^{-} events in the 3.6-10 GeV/c^{2} mass range. We use a 62.8 fb^{-1} sample of e^{+}e^{-} collisions collected at a center-of-mass energy of 10.58 GeV by the Belle II experiment at the SuperKEKB collider. The analysis probes three different models predicting a spin-1 particle coupling only to the heavier lepton families, a Higgs-like spin-0 particle that couples preferentially to charged leptons (leptophilic scalar), and an axionlike particle, respectively. We observe no evidence for a signal and set exclusion limits at 90% confidence level on the product of cross section and branching fraction into τ pairs, ranging from 0.7 to 24 fb, and on the couplings of these processes. We obtain world-leading constraints on the couplings for the leptophilic scalar model for masses above 6.5 GeV/c^{2} and for the axionlike particle model over the entire mass range.

Precise Measurement of the D_{s}

We measure the lifetime of the D_{s}^{+} meson using a data sample of 207 fb^{-1} collected by the Belle II experiment running at the SuperKEKB asymmetric-energy e^{+}e^{-} collider. The lifetime is determined by fitting the decay-time distribution of a sample of 116×10^{3} D_{s}^{+}→ϕπ^{+} decays. Our result is τ_{D_{s}^{+}}=(499.5±1.7±0.9) fs, where the first uncertainty is statistical and the second is systematic. This result is significantly more precise than previous measurements.

Tests of Light-Lepton Universality in Angular Asymmetries of B

We present the first comprehensive tests of the universality of the light leptons in the angular distributions of semileptonic B^{0}-meson decays to charged spin-1 charmed mesons. We measure five angular-asymmetry observables as functions of the decay recoil that are sensitive to lepton-universality-violating contributions. We use events where one neutral B is fully reconstructed in ϒ(4S)→BB[over ¯] decays in data corresponding to 189 fb^{-1} integrated luminosity from electron-positron collisions collected with the Belle II detector. We find no significant deviation from the standard model expectations.

Test of Light-Lepton Universality in the Rates of Inclusive Semileptonic B-Meson Decays at Belle II.

We present the first measurement of the ratio of branching fractions of inclusive semileptonic B-meson decays, R(X_{e/µ})=B(B→Xeν)/B(B→Xµν), a precision test of electron-muon universality, using data corresponding to 189 fb^{-1} from electron-positron collisions collected with the Belle II detector. In events where the partner B meson is fully reconstructed, we use fits to the lepton momentum spectra above 1.3 GeV/c to obtain R(X_{e/µ})=1.007±0.009(stat)±0.019(syst), which is the most precise lepton-universality test of its kind and agrees with the standard-model expectation.

Toxicodynamics and toxicokinetics of amikacin in the guinea pig cochlea.

An extensive overview of the relationship between cochlear toxicity and amikacin blood concentrations in the guinea pig is provided which should assist in the clinical application of this class of antibiotic. A data set previously used to relate the incidence of amikacin ototoxicity to dosing rates and blood concentrations was re-examined to assess the toxicodynamics of amikacin in terms of decibels of hearing loss across dosing rate, hearing frequency and time following drug exposure. Animals in this data set had received continuously i.v. infused amikacin over an 8-fold range of dosing rates. Preliminary analysis indicated that the data were consistent with a sigmoid relationship between hearing loss (decibels) and area under the amikacin plasma concentration vs time curve cumulated over the entire course of drug administration (cAUC). The sigmoid model was therefore used as the backbone of a far more comprehensive toxicodynamic model which described all the data with a single equation. Testing with this model showed that the cAUC required to produce half-maximum hearing loss (cAUC-1/2) was related to dosing rate (P < 0.01), to hearing frequency (P < 0.00001), and to post-drug interval (P < 0.00001). Maximum hearing loss (difference between upper and lower sigmoid asymptotes) was less than total and was significantly related to frequency (P < 0.00001). No effects could be detected on the sigmoid slope. Further modelling of the significant effects detected by the comprehensive toxicodynamic model was done to determine if they could be described by simple relationships or by biologically relevant sub-models. Modelling of maximum hearing loss (postulated to represent loss of mainly outer hair cell function) indicated that this parameter was constant at about 61 decibels for 2-12 kHz and linearly decreased with log frequency for frequencies > 12 kHz. Modelling of cAUC-1/2 on frequency indicated that there was a strong inverse linear relationship to log frequency. Modelling of cAUC-1/2 on post-drug interval indicated that delayed ototoxicity continued at progressively slower rates for at least 56 days after drug administration had ceased. Modelling of cAUC-1/2 on dosing rate showed an increased requirement for drug as the dosing rate decreased. However, cAUC-1/2 changed no more than 20% across the range of dosing rates compared to the 8-fold difference in mean steady-state plasma concentrations, suggesting that plasma concentration is not a primary determinant of ototoxicity. A toxicokinetic model was developed which explained the dosing rate effect on cAUC-1/2 very successfully.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of thioridazine and diazepam on the pharmacokinetics of [14C]imipramine in rat: acute study.

The pharmacokinetics of [14C]imipramine (10 mg kg minus 1) were tested in male Wistar rats for interaction with thioridazine (16 mg kg minus 1) or diazepam (10 mg kg- minus 1). All drugs were administered orally with the test substances being given 40 min before [14C]imipramine dosing. Bile and urine were collected for 90 min after the radioactive drug was given. The animals were then killed and the tissues removed. Thioridazine reduced the excretion of radioactivity into the bile and urine, and increased the weight of the contents within the gastrointestinal tract. These effects were interpreted as being mainly due to a reduction in gastrointestinal motility resulting in a slower stomach emptying of [14C]imipramine. No effect on metabolism was detected. Diazepam pretreatment reduced the concentration ratio of radioactivity in the small intestinal contents to that of plasma, but did not alter the tissue distribution, metabolism or excretion of [14C]imipramine.

Delay in hearing loss following drug administration. A consistent feature of amikacin ototoxicity.

The time course of threshold increase in the VIII nerve compound action potential was studied in guinea pigs following amikacin administration at four different constant infusion rates. Despite the wide range of dosing durations required to achieve drug ototoxicity (2-24 days), the full development of both high and low frequency hearing loss was invariably found to be delayed with respect to the time of drug removal. The greatest degree of delayed hearing loss generally occurred within the first 7 days after drug removal, with smaller losses occurring during later time intervals. The delay showed a tendency to decrease as the ototoxic dose was increased. Using the data from the two highest dosing rates, it was estimated that a minimum of 4 days had to elapse before any hearing loss could be detected, once an ototoxic amount of drug had been administered. These data suggest that hearing loss is always substantially delayed with respect to the receipt of an ototoxic dose of amikacin, and that this must be taken into account when conducting animal experiments and when monitoring hearing in patients for the early detection of ototoxicity.

Flow microcalorimetry investigation of the influence of surfactants on a heterogeneous aerobic culture.

The influence of various surfactants on the biological activity of a mixed aerobic culture has been investigated by using flow microcalorimetry. The response of the culture to the addition of homologous n-alkylcarboxylates (C2 to C16) and n-alkylpyridinium bromides (C11 to C14) has been examined under endogenous and substrate saturation conditions, and inhibitory concentrations (MIC or the concentration which decreased the initial activity (heat flux) of the culture by 50%) were determined for each state. Under both conditions, the n-alkylpyridinium bromides were found to be more toxic than the n-alkylcarboxylates of identical chain length, thus confirming that the head group of the amphiphiles plays an important role in the microbial toxicity of surfactants. The relationship observed between the concentration at which 50% of the activity is lost and the chain length of the surfactant further confirms that cellular toxicity is also dependent on surfactant hydrophobicity. In relation to the biodegradability of surfactants in mixed aerobic cultures, the low concentration effects of n-alkylcarboxylates on endogenous culture were investigated in some detail. There appear to be compounded indications that these surfactants are rapidly metabolized by the microorganisms of the mixed culture, at least for homologs lower than C10.

Effect of thioridazine on the first-pass kinetics of [14C]imipramine in perfused rat liver: interaction at hepatic binding sites.

1. The effect of thioridazine on the first-pass removal and hepatic metabolism of [14C]imipramine was examined in a single-pass rat liver perfusion system using a perfusate free of drug-binding components. Drug exposure continued for 45 min, and bile was collected and analysed during the final 15 min when approx. steady-state conditions were attained. 2. Thioridazine decreased the hepatic extraction ratio for imipramine, lowered the hepatic concentration (P < 0.1) and increased the effluent perfusate-to-liver ratios of imipramine. It is suggested that the increased imipramine in the effluent perfusate was due to competition of thioridazine for non-metabolizing binding sites in the liver rather than to inhibition of drug metabolism. 3. Thioridazine markedly increased desipramine concentrations in both liver and effluent perfusate. This may have resulted from decreased hepatic binding of imipramine, which made more free drug available for demthylation. Competition with thioridazine for hepatic binding sites also explains the increased diffusion of desipramine into the effluent perfusate. 4. Lower concentrations of 2-hydroxylated metabolites, especially 2-hydroxyimipramine, were found in bile when thioridazine was administered with imipramine. There was no evidence of inhibition of imipramine 2-hydroxylation. From bile-to-liver ratios, it is suggested that thioridazine and/or its metabolites inhibits glucuronylation of 2-hydroxyimipramine but not of 2-hydroxydesipramine.

Correlation of amikacin concentrations in perilymph and plasma of continuously infused guinea pigs.

A commercially available radioimmunoassay kit was modified to enable us to measure, in triplicate, the amikacin concentration in 1 microliter of perilymph fluid. Amikacin levels in plasma and perilymph were measured in guinea pigs after continuous intravenous infusion at four different dosing rates. After a 4-h infusion, a good linear correlation was found between the amikacin concentration in plasma and the dosing rate. Likewise, a significant linear relationship was found between concentrations of amikacin in perilymph and plasma (y = 0.21x + 2.56; r = 0.67; n = 45) after 6 h of infusion. These results suggest nonsaturation kinetics at the concentrations used.

Effect of pentobarbital anesthesia on amikacin concentrations in plasma and perilymph and evaluation of multiple sampling in perilymph of guinea pigs.

The purpose of this study was to determine whether a multiple-sampling procedure could be used in guinea pigs to study the kinetics of amikacin in perilymph. Amikacin was infused intravenously for 6 h into conscious anesthetized guinea pigs, and the concentrations of the drug in plasma and perilymph were measured. From each anesthetized guinea pig, five to six perilymph samples were collected from one ear, and one sample was collected from the other ear at 6 h. The concentrations of amikacin in perilymph were dose proportional and increased slowly during the 6-h infusion. However, after 6 h of intravenous infusion, the concentrations of amikacin in perilymph of the multiply sampled ears were significantly higher than those of the singly sampled ears, indicating that the multiple-sampling procedure should not be used as is to study the kinetics of amikacin in perilymph. Amikacin concentrations in perilymph were linearly related to amikacin concentrations in plasma in pentobarbital-anesthetized animals, as had previously been observed for conscious guinea pigs. However, the slope of the regression line was only 0.09 for anesthetized animals compared with 0.24 for conscious animals. Drug concentrations in plasma were found to be threefold higher in anesthetized animals, whereas drug levels in perilymph were the same in both groups at similar dosing rates. These results indicate that the amikacin concentration in perilymph is not solely dependent upon its concentration in plasma and that other factor(s) can affect the entry of amikacin into the inner ear.

Imipramine enhancement of pentobarbital toxicity in rats.

The toxicity of pentobarbital was examined in male Wistar rats pretreated with a non-toxic dose of imipramine (10 mg/kg, po). Pentobarbital (70 mg/kg, ip) lethality was enhanced up to 6 hr after imipramine administration, and pentobarbital (45 mg/kg, ip) sleeping time was prolonged up to 12 hr after imipramine. Physiological measurements showed that imipramine pretreatment 2 hr prior to pentobarbital (70 mg/kg, ip) enhanced barbiturate depression in mean blood pressure, oxygen consumption and respiration rate, but not in heart rate or back skin temperature. Analysis of brain radioactivity after [14C] pentobarbital indicated that these effects of imipramine were not solely the result of inhibition of liver metabolism.