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.

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.

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.

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.

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}.

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.

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}

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}.

Comparison of column ozone retrievals by use of an UV multifilter rotating shadow-band radiometer with those from Brewer and Dobson spectrophotometers.

The U.S. Department of Agriculture UV-B Monitoring Program measures ultraviolet light at seven wavelengths from 300 to 368 nm with an ultraviolet multifilter rotating shadow-band radiometer (UV-MFRSR) at 25 sites across the United States, including Mauna Loa, Hawaii. Column ozone has been retrieved under all-sky conditions near Boulder, Colorado (40.177 degrees N, 105.276 degrees W), from global irradiances of the UV-MFRSR 332- and 305-nm channels (2 nm FWHM) using lookup tables generated from a multiple-scattering radiative transfer code suitable for solar zenith angles (SZA's) up to 90 degrees. The most significant sources of error for UV-MFRSR column ozone retrievals at SZA's less than 75 degrees are the spectral characterizations of the filters and the absolute calibration uncertainty, which together yield an estimated uncertainty in ozone retrievals of +/-4.0%. Using model sensitivity studies, we determined that the retrieved column ozone is relatively insensitive (<+/-2%) to typical variations in aerosol optical depth, cloud cover, surface pressure, stratospheric temperature, and surface albedo. For 5 months in 1996-1997 the mean ratio of column ozone retrieved by the UV-MFRSR divided by that retrieved by the collocated Brewer was 1.024 and for the UV-MFRSR divided by those from a nearby Dobson was 1.025. The accuracy of the retrieval becomes unreliable at large SZA's of more than 75 degrees as the detection limit of the 305-nm channel is reached and because of overall angular response errors. The UV-MFRSR advantages of relatively low cost, unattended operation, automated calibration stability checks using Langley plots, and minimal maintenance make it a unique instrument for column ozone measurement.

Active vs. passive resistance, dose-response relationships, high dose chemotherapy, and resistance modulation: a hypothesis.

With chemotherapy, the in vitro and clinical dose-response curve is steep in some situations, but is relatively flat in others, possibly due to the mechanism by which tumors are resistant to chemotherapy. For tumors with resistance due to factors that actively decrease chemotherapy efficacy (e.g., p-glycoprotein, glutathione, etc.), one would predict that high dose chemotherapy and therapy with some resistance modulating agents would increase therapeutic efficacy. Such "active" resistance would most likely generally arise from gene amplification or over expression, and would be characterized by a shoulder on the log response vs. dose curve, with eventual saturation of the protective mechanism. On the other hand, one would expect that high dose chemotherapy and most resistance modulating agents would be of little value for tumors with resistance due to defective apoptosis or due to a deficiency in or decreased drug affinity for a drug target, drug activating enzyme, drug active uptake system, or essential cofactor. Such "passive" resistance would most likely generally arise from gene down regulation, deletion, or mutation, and would probably be characterized by a relatively flat log response vs. dose curve, or by a curve in which a steep initial section is followed by a plateau, as target, etc., is saturated. (If response were plotted vs. log dose, then compared to the curve for a sensitive cell line, the curve for active resistance would be analogous to the pharmacodynamic curve seen with competitive antagonism [i.e., a sigmoid curve shifted to the right], and the curve for most types of passive resistance would be analogous to the pharmacodynamic curve seen with noncompetitive antagonism [i.e., a sigmoid curve with reduced maximal efficacy]. As such, one might also refer to active vs. passive resistance as competitive vs. noncompetitive resistance, respectively.) Many tumor types probably possess a combination of active and passive mechanisms of resistance. New in vivo strategies could be helpful in defining dose-response relationships, mechanisms of resistance, and targets for resistance modulation. Such in vivo studies would be conducted initially in animals, but might also be tested clinically if animal studies demonstrated them to be feasible and useful. These in vivo studies would be conducted by randomizing 5-25 subjects to one of 10-20 dose levels over a potentially useful therapeutic range. Nonlinear regression analysis would then be used to define the characteristics of a curve generated by plotting against dose the log percent tumor remaining after the first course of therapy. While this might offer insight into the nature of resistance mechanisms present initially, plotting further tumor shrinkage vs. dose-intensity vs. course number for each later treatment course (or plotting dose-intensity vs. time to tumor progression) might provide information on how tumors become increasingly resistant to drugs following treatment.

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)

Evidence that amikacin ototoxicity is related to total perilymph area under the concentration-time curve regardless of concentration.

Previous studies have failed to fully establish whether ototoxicity is related in any way to the levels of an aminoglycoside antibiotic in the perilymph. To study this we exposed guinea pigs to continuously infused amikacin at four different dosing rates under conditions parallel to those used in our previous study which related ototoxicity to total plasma area under the concentration-time curve regardless of the level in plasma. It was found that at all dosing rates, levels in the perilymph and ratios of levels in perilymph/plasma remained constant as the dosing duration increased from nonototoxic to strongly ototoxic. Plasma and perilymph amikacin levels were found to be linear functions of the dosing rate even at ototoxic dosing exposures, and ratios of levels in perilymph/plasma did not differ between dosing rates. The total perilymph area under the concentration-time curve was not different between dosing rates either for a total dose associated with threshold ototoxicity or for one associated with severe ototoxicity. The results suggest that amikacin ototoxicity is related to the integral of the concentration in the perilymph over the total time of amikacin exposure regardless of the level in the perilymph.

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.

Incidence of amikacin ototoxicity: a sigmoid function of total drug exposure independent of plasma levels.

A sigmoid curve was found to closely describe the relationship between the incidence of amikacin ototoxicity (greater than or equal to 15 dB hearing loss at a given frequency) and either (1) total dose, or (2) the area under the curve (AUC) describing plasma drug concentration v time over the total period of amikacin administration (total AUC) in continuously infused guinea pigs. Total dose or total AUC estimates of the drug exposure required to produce ototoxicity in 50% of the animals (ED50s) were not significantly different over an eight-fold range of dosing rates or plasma concentrations. A theoretical explanation for this result is that ototoxicity occurs only when a critical amount of drug is accumulated at the ototoxic site by an essentially unidirectional process with a rate that is slow and linearly related to the extracellular drug concentration. The sigmoid relationships for pooled data were parallel in slope for all hearing frequencies from 2 to 32 kHz, and the ED50s showed a strong negative linear relationship to the log of the hearing frequency over this range. The magnitude of ototoxicity expressed as the number of octaves (frequency ratios of 2) for which hearing loss damage was continuous from 32 kHz downward, was correlated to both total dose (r = .605) and total AUC (r = 0.703). No relationship between ototoxicity and plasma level or dosing rate was found. The extreme steepness of the dose-effect curve for the incidence of ototoxicity greatly amplified the variability between individuals and offers an explanation for the unpredictability of aminoglycoside ototoxicity in human patients. The results indicate that either total dose or total AUC (in cases of highly unpredictable blood levels), and not peak or trough serum levels, should be used as an index of ototoxic risk and that the safety limits of drug exposure should be set conservatively.

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 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.

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.