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AIMS: Osimertinib is a third-generation, irreversible, central nervous system-active, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with efficacy in EGFR-mutated non-small cell lung cancer (NSCLC). We assessed the relationship between plasma osimertinib levels and its efficacy and safety events. METHODS: Comprehensive pharmacokinetics exposure-response (E-R) modelling was performed utilizing steady state area under the curve (AUCss) data from first-line, ≥second-line and adjuvant studies from the osimertinib clinical development programme (20-240 mg once-daily dosing; N = 1689 patients). Analyses were conducted for survival using a proportional hazard model; for interstitial lung disease (ILD) and left ventricular ejection fraction (LVEF) events using a penalized logistic regression model and graphical analysis of potential confounding factors; and for rash and diarrhoea events using descriptive analysis. RESULTS: E-R modelling analyses indicated no clear trend of increasing efficacy with increasing osimertinib AUCss; efficacy in all exposure quartiles was significantly better than the control arm (comparator EGFR-TKI, chemotherapy or placebo) irrespective of treatment line. Model-based analysis suggested a potential relationship between increased osimertinib exposure and increased probability of ILD events, predominantly in Japanese patients. Additionally, there were increased probabilities of rash or diarrhoea with increasing osimertinib exposure. The probability of LVEF events showed overlapping confidence intervals for osimertinib ≤80 mg and control. CONCLUSIONS: E-R modelling in patients with EGFR-mutated NSCLC demonstrated that increased osimertinib exposure was unlikely to increase efficacy but may increase occurrence of certain adverse events. Hence, long-term treatment with doses ≥80 mg was not expected to provide additional benefit.
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Adavosertib (AZD1775) is a potent small-molecule inhibitor of Wee1 kinase. This analysis utilized pharmacokinetic data from 8 Phase I/II studies of adavosertib to characterize the population pharmacokinetics of adavosertib in patients (n = 538) with solid tumors and evaluate the impact of covariates on exposure. A nonlinear mixed-effects modeling approach was employed to estimate population and individual parameters from the clinical trial data. The model for time dependency of apparent clearance (CL) was developed in a stepwise manner and the final model validated by visual predictive checks (VPCs). Using an adavosertib dose of 300 mg once daily on a 5 days on/2 days off dosing schedule given 2 weeks out of a 3-week cycle, simulation analyses evaluated the impact of covariates on the following exposure metrics at steady state: maximum concentration during a 21-day cycle, area under the curve (AUC) during a 21-day cycle, AUC during the second week of a treatment cycle, and AUC on day 12 of a treatment cycle. The final model was a linear 2-compartment model with lag time into the dosing compartment and first-order absorption into the central compartment, time-varying CL, and random effects on all model parameters. VPCs and steady-state observations confirmed that the final model satisfied all the requirements for reliable simulation of randomly sampled Phase I and II populations with different covariate characteristics. Simulation-based analyses revealed that body weight, renal impairment status, and race were key factors determining the variability of drug-exposure metrics.
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AZD7442 is a combination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing antibodies, tixagevimab and cilgavimab, developed for pre-exposure prophylaxis (PrEP) and treatment of coronavirus disease 2019 (COVID-19). Using data from eight clinical trials, we describe a population pharmacokinetic (popPK) model of AZD7442 and show how modeling of "interim" data accelerated decision-making during the COVID-19 pandemic. The final model was a two-compartmental distribution model with first-order absorption and elimination, including standard allometric exponents for the effect of body weight on clearance and volume. Other covariates included were as follows: sex, age >65 years, body mass index ≥30 kg/m2, and diabetes on absorption rate; diabetes on clearance; Black race on central volume; and intramuscular (IM) injection site on bioavailability. Simulations indicated that IM injection site and body weight had > 20% effects on AZD7442 exposure, but no covariates were considered to have a clinically relevant impact requiring dose adjustment. The pharmacokinetics of AZD7442, cilgavimab, and tixagevimab were comparable and followed linear kinetics with extended half-lives (median 78.6 days for AZD7442), affording prolonged protection against susceptible SARS-CoV-2 variants. Comparison of popPK simulations based on "interim data" with a target concentration based on 80% viral inhibition and assuming 1.81% partitioning into the nasal lining fluid supported a decision to double the PrEP dosage from 300 mg to 600 mg to prolong protection against Omicron variants. Serum AZD7442 concentrations in adolescents weighing 40-95 kg were predicted to be only marginally different from those observed in adults, supporting authorization for use in adolescents before clinical data were available. In these cases, popPK modeling enabled accelerated clinical decision-making.
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Anticuerpos Monoclonales Humanizados , Tratamiento Farmacológico de COVID-19 , COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/efectos de los fármacos , Femenino , Masculino , Persona de Mediana Edad , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anciano , Adulto , COVID-19/prevención & control , Antivirales/farmacocinética , Antivirales/uso terapéutico , Adulto Joven , Adolescente , Anticuerpos Neutralizantes/sangreRESUMEN
We have studied the mutual neutralization reaction of vibronically cold NO^{+} with O^{-} at a collision energy of ≈0.1 eV and under single-collision conditions. The reaction is completely dominated by production of three ground-state atomic fragments. We employ product-momentum analysis in the framework of a simple model, which assumes the anion acts only as an electron donor and the product neutral molecule acts as a free rotor, to conclude that the process occurs in a two-step mechanism via an intermediate Rydberg state of NO which subsequently fragments.
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Mutual neutralization of hydronium (H3O+) and hydroxide (OH-) ions is a very fundamental chemical reaction. Yet, there is only limited experimental evidence about the underlying reaction mechanisms. Here, we report three-dimensional imaging of coincident neutral products of mutual-neutralization reactions at low collision energies of cold and isolated ions in the cryogenic double electrostatic ion-beam storage ring (DESIREE). We identified predominant H2O + OH + H and 2OH + H2 product channels and attributed them to an electron-transfer mechanism, whereas a minor contribution of H2O + H2O with high internal excitation was attributed to proton transfer. The reported mechanism-resolved internal product excitation, as well as collision-energy and initial ion-temperature dependence, provide a benchmark for modeling charge-transfer mechanisms.
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Several small Polycyclic Aromatic Hydrocarbons (PAHs) have been identified recently in the Taurus Molecular Cloud (TMC-1) using radio telescope observations. Reproducing the observed abundances of these molecules has been a challenge for astrochemical models. Rapid radiative cooling of PAHs by Recurrent Fluorescence (RF), the emission of optical photons from thermally populated electronically excited states, has been shown to efficiently stabilize small PAHs following ionization, augmenting their resilience in astronomical environments and helping to rationalize their observed high abundances. Here, we use a novel method to experimentally determine the radiative cooling rate of the cation of 1-cyanonaphthalene (C10H7CN, 1-CNN), the neutral species of which has been identified in TMC-1. Laser-induced dissociation rates and kinetic energy release distributions of 1-CNN cations isolated in a cryogenic electrostatic ion-beam storage ring are analysed to track the time evolution of the vibrational energy distribution of the initially hot ion ensemble as it cools. The measured cooling rate is in good agreement with the previously calculated RF rate coefficient. Improved measurements and models of the RF mechanism are needed to interpret astronomical observations and refine predictions of the stabilities of interstellar PAHs.
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Naphthalene and azulene are isomeric polycyclic aromatic hydrocarbons (PAHs) and are topical in the context of astrochemistry due to the recent discovery of substituted naphthalenes in the Taurus Molecular Cloud-1 (TMC-1). Here, the thermal- and photo-induced isomerization, dissociation, and radiative cooling dynamics of energized (vibrationally hot) naphthalene (Np+) and azulene (Az+) radical cations, occurring over the microsecond to seconds timescale, are investigated using a cryogenic electrostatic ion storage ring, affording "molecular cloud in a box" conditions. Measurement of the cooling dynamics and kinetic energy release distributions for neutrals formed through dissociation, until several seconds after hot ion formation, are consistent with the establishment of a rapid (sub-microsecond) Np+ â Az+ quasi-equilibrium. Consequently, dissociation by C2H2-elimination proceeds predominantly through common Az+ decomposition pathways. Simulation of the isomerization, dissociation, recurrent fluorescence, and infrared cooling dynamics using a coupled master equation combined with high-level potential energy surface calculations [CCSD(T)/cc-pVTZ], reproduce the trends in the measurements. The data show that radiative cooling via recurrent fluorescence, predominately through the Np+ D0 â D2 transition, efficiently quenches dissociation for vibrational energies up to ≈1 eV above dissociation thresholds. Our measurements support the suggestion that small cations, such as naphthalene, may be more abundant in space than previously thought. The strategy presented in this work could be extended to fingerprint the cooling dynamics of other PAH ions for which isomerization is predicted to precede dissociation.
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We have measured recurrent fluorescence (RF) cooling rates of internally hot tetracene cations, C18H12+, as functions of their storage times and internal energies in two different electrostatic ion-beam storage rings - the cryogenic ring DESIREE with a circumference of 8.6 meters in Stockholm and the much smaller room temperature ring Mini-Ring in Lyon, which has a circumference of 0.71 meters. The RF rates were measured to be as high as 150 to 1000 s-1 for internal energies in the 7 to 9.4 eV energy range, where we have probed the time evolution of the internal energy distribution with nanosecond laser pulses with a 1 kHz repetition rate. These RF rates are found to be significantly higher than those of previously investigated smaller PAHs such as e.g. anthracene and naphthalene, for which the lowest non-forbidden electronic excited state, the D2 state, is populated with a smaller probability by inverse internal conversion. Furthermore, the D2-D0 transition rate is smaller for these smaller molecules than for tetracene. The complementary features of the two storage rings allow for RF rate measurements in a broader internal energy range than has been possible before. The smaller sampling period of about 6 µs in Mini-Ring is ideal to study the cooling dynamics of the hotter ions that decay fast, whereas DESIREE with a sampling period of about 60 µs is better suited to study the colder ions that decay on longer timescales ranging up to hundreds of milliseconds. The excellent agreement between the two series of measurements in the region where they overlap demonstrates the complementarity of the two electrostatic ion-beam storage rings.
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After decades of searching, astronomers have recently identified specific Polycyclic Aromatic Hydrocarbons (PAHs) in space. Remarkably, the observed abundance of cyanonaphthalene (CNN, C10H7CN) in the Taurus Molecular Cloud (TMC-1) is six orders of magnitude higher than expected from astrophysical modeling. Here, we report unimolecular dissociation and radiative cooling rate coefficients of the 1-CNN isomer in its cationic form. These results are based on measurements of the time-dependent neutral product emission rate and kinetic energy release distributions produced from an ensemble of internally excited 1-CNN+ studied in an environment similar to that in interstellar clouds. We find that Recurrent Fluorescence - radiative relaxation via thermally populated electronic excited states - efficiently stabilizes 1-CNN+, owing to a large enhancement of the electronic transition probability by vibronic coupling. Our results help explain the anomalous abundance of CNN in TMC-1 and challenge the widely accepted picture of rapid destruction of small PAHs in space.
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This corrects the article DOI: 10.1103/PhysRevLett.128.033401.
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Time-dependent photodetachment action spectra for the linear hydrocarbon anions C4H- and C6H- are investigated using the cryogenic Double ElectroStatic Ion Ring ExpEriment. The radiative cooling characteristics of these ions on the millisecond to seconds timescale are characterized by monitoring changes in their spectra as the ions cool by spontaneous infrared (IR) emission. The average cooling rates, extracted using Non-negative Matrix Factorization, are fit with 1/e lifetimes of 19 ± 2 and 3.0 ± 0.2 s for C4H- and C6H-, respectively. The cooling rates are successfully reproduced using a simple harmonic cascade model of IR emission. The ultraslow radiative cooling dynamics determined in this work provide important data for understanding the thermal cooling properties of linear hydrocarbon anions and for refining models of the formation and destruction mechanisms of these anions in astrochemical environments.
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Negative ions are important in many areas of science and technology, e.g., in interstellar chemistry, for accelerator-based radionuclide dating, and in anti-matter research. They are unique quantum systems where electron-correlation effects govern their properties. Atomic anions are loosely bound systems, which with very few exceptions lack optically allowed transitions. This limits prospects for high-resolution spectroscopy, and related negative-ion detection methods. Here, we present a method to measure negative ion binding energies with an order of magnitude higher precision than what has been possible before. By laser-manipulation of quantum-state populations, we are able to strongly reduce the background from photodetachment of excited states using a cryogenic electrostatic ion-beam storage ring where keV ion beams can circulate for up to hours. The method is applicable to negative ions in general and here we report an electron affinity of 1.461 112 972(87) eV for 16O.
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Spontaneous and photo-induced decay processes of HfF5 - and WF5 - molecular anions were investigated in the Double ElectroStatic Ion Ring ExpEriment (DESIREE). The observation of these reactions over long time scales (several tens of ms) was possible due to the cryogenic temperatures (13 K) and the extremely low residual gas pressure (â¼10-14 mbar) of DESIREE. For photo-induced reactions, laser wavelengths in the range 240 to 450 nm were employed. Both anion species were found to undergo spontaneous decay via electron detachment or fragmentation. After some ms, radiative cooling processes were observed to lower the probability for further decay through these processes. Photo-induced reactions indicate the existence of an energy threshold for WF5 - anions at about 3.5 eV, above which the neutralization yield increases strongly. By contrast, HfF5 - ions exhibit essentially no enhanced production of neutrals upon photon interaction, even for the highest photon energy used in this experiment (â¼5.2 eV). This suppression will be highly beneficial for the efficient detection, in accelerator mass spectrometry, of the extremely rare isotope 182Hf using the 182HfF5 - anion while effectively reducing the interfering stable isobar 182W in the analyte ion 182WF5 -. The radionuclide 182Hf is of great relevance in astrophysical environments as it constitutes a potential candidate to study the events of nucleosynthesis that may have taken place in the vicinity of the solar system several million years ago.
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We report measurements of the statistical vibrational autodetachment (VAD, also called thermionic emission) and radiative cooling rates of isolated para-benzoquinone (pBQ, C6H4O2) radical anions using the cryogenic electrostatic ion storage ring facility DESIREE. The results are interpreted using master equation simulations with rate coefficients calculated using statistical detailed balance theory. The VAD rate is determined by measuring the time-dependent yield of neutral pBQ due to spontaneous electron emission from a highly-excited ensemble of anions formed in an electron-attachment ion source. Competition with radiative cooling quenches the VAD rate after a critical time of τc = 11.00(5) ms. Master equation simulations which reproduce the VAD yield provide an estimate of the initial effective vibrational temperature of the ions of 1100(20) K, and provide insight into the anion formation scenario. A second measurement of the radiative cooling rate of pBQ- stored for up to 0.5 s was achieved using time-dependent photodetachment action spectroscopy across the 2Au â 2B2g and 2B2u â 2B2g transitions. The rate at which hot-band contributions fade from the action spectrum is quantified by non-negative matrix factorisation. This is found to be commensurate with the average vibrational energy extracted from the simulations, with 1/e lifetimes of 0.16(3) s and 0.1602(7) s, respectively. Implications for astrochemistry are discussed.
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The concepts of executive function (EF) and effortful control (EC) are strikingly similar. EF originate from neurocognitive research and are described as an accumulation of cognitive processes that serve the goal-oriented self-regulation (SR) of an individual. EC originates from temperament research and is defined as the efficiency of executive attention, including the ability to inhibit a dominant response, to activate a subdominant response, to proceed in a planned manner and to recognize conflicts or errors. The aim of this article was to examine the association between the constructs of EF and EC at the preschool-age. Eighty-eight children (49 female; M-age = 3.93 years, SD = .78) were tested with a computerized battery designed to assess EF at 3-6 years of age (EF Touch). Children's parents completed questionnaires assessing EF impairments (BRIEF-P) and EC (CBQ). Associations between the constructs and their conceptual overlap were analyzed using correlations and confirmatory factor analyses. We found significant correlations between EF and EC measures. A one-factor confirmatory model fitted the data very well and indicated that EF and EC are indeed overlapping and highly similar constructs. Therefore, our results show that measures of EC and EF have substantial overlap in preschoolers and suggest an integrated model of self-regulation.
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Función Ejecutiva , Autocontrol , Niño , Preescolar , Femenino , Humanos , Función Ejecutiva/fisiología , Temperamento , Atención , EscolaridadRESUMEN
We present experimental final-state distributions for Mg atoms formed in Mg^{+}+D^{-} mutual neutralization reactions at center-of-mass collision energies of 59±12 meV by using the merged-beams method. Comparisons with available full-quantum results reveal large discrepancies and a previously underestimated total rate coefficient by up to a factor of 2 in the 0-1 eV (<10^{4} K) regime. Asymptotic model calculations are shown to describe the process much better and we recommend applying this method to more complex iron group systems; data that is of urgent need in stellar spectral modeling.
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Simulation of combination therapies is challenging due to computational complexity. Either a simple model is used to simulate the response for many combinations of concentration to generate a response surface but parameter variability and uncertainty are neglected and the concentrations are constant-the link to the doses to be administered is difficult to make-or a population pharmacokinetic/pharmacodynamic model is used to predict the response to combination therapy in a clinical trial taking into account the time-varying concentration profile, interindividual variability (IIV), and parameter uncertainty but simulations are limited to only a few selected doses. We devised new algorithms to efficiently search for the combination doses that achieve a predefined efficacy target while taking into account the IIV and parameter uncertainty. The result of this method is a response surface of confidence levels, indicating for all dose combinations the likelihood of reaching the specified efficacy target. We highlight the importance to simulate across a population rather than focus on an individual. Finally, we provide examples of potential applications, such as informing experimental design.
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Algoritmos , Proyectos de Investigación , Simulación por Computador , Humanos , Modelos Biológicos , Probabilidad , IncertidumbreRESUMEN
The maternal death rate remains unacceptably high worldwide, predominantly in areas of poor access to quality health services. According to the WHO, in 2017, 810 women died from preventable causes related to pregnancy and childbirth. Causes of maternal death are plenty, including previous morbidity and unexpected causes. Among the latter are infectious disease-related deaths. Herein, we describe a case of a 29-year-old woman at 37 weeks' gestation who presented with right upper quadrant pain, which was initially considered to be pregnancy-related. However, she collapsed shortly after the hospital admission. The physical examination revealed severe hypovolemic shock due to a large amount of intraperitoneal free fluid. The patient was immediately rushed into an emergency cesarean section followed by exploratory laparotomy, which demonstrated a large intra-abdominal hemorrhage. The patient and her fetus died in the operating room. An autopsy revealed acute gangrenous cholecystitis along with abundant rod-shaped bacteria within the mucosa and vessels of the gallbladder, gas gangrene and rupture of the spleen, and signs of shock. Clostridium perfringens (CP) was isolated in the culture of a splenic sample. Although CP is a well-known and dreadful infectious etiological agent, catastrophic cases still happen. The acquaintance of this infection by the caregivers is crucial for the early diagnosis and treatment. This is a quite unique way to provide a dismal chance of survival in sepsis cases by this agent.
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The mutual neutralisation of O+ with O- has been studied in a double ion-beam storage ring with combined merged-beams, imaging and timing techniques. Branching ratios were measured at the collision energies of 55, 75 and 170 (± 15) meV, and found to be in good agreement with previous single-pass merged-beams experimental results at 7 meV collision energy. Several previously unidentified spectral features were found to correspond to mutual neutralisation channels of the first metastable state of the cation (O+(2Do), τ ≈ 3.6 hours), while no contributions from the second metastable state (O+(2Po), τ ≈ 5 seconds) were observed. Theoretical calculations were performed using the multi-channel Landau-Zener model combined with the anion centered asymptotic method, and gave good agreement with several experimentally observed channels, but could not describe well observed contributions from the O+(2Do) metastable state as well as channels involving the O(3s 5So) state.
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Laboratory studies play a crucial role in understanding the chemical nature of the interstellar medium (ISM), but the disconnect between experimental timescales and the timescales of reactions in space can make a direct comparison between observations, laboratory, and model results difficult. Here we study the survival of reactive fragments of the polycyclic aromatic hydrocarbon (PAH) coronene, where individual C atoms have been knocked out of the molecules in hard collisions with He atoms at stellar wind and supernova shockwave velocities. Ionic fragments are stored in the DESIREE cryogenic ion-beam storage ring where we investigate their decay for up to one second. After 10 ms the initially hot stored ions have cooled enough so that spontaneous dissociation no longer takes place at a measurable rate; a majority of the fragments remain intact and will continue to do so indefinitely in isolation. Our findings show that defective PAHs formed in energetic collisions with heavy particles may survive at thermal equilibrium in the interstellar medium indefinitely, and could play an important role in the chemistry in there, due to their increased reactivity compared to intact or photo-fragmented PAHs.