OBJECTIVE: 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.

Metal halide perovskites are crystalline materials with a sharp increase in popularity and rapidly becoming a major contender for optoelectronic device applications. In this work, we provide the optoelectronic features of a possible novel candidate, ZSnCl3 (Z = Na/K) Sn-based on a detailed numerical simulation. The output of the current computations is compared to the results that are currently available, and a respectable agreement is noted. The studied compounds were cubic in nature and structurally stabe. The mechanical properties reflect the mechanical stability and ductility of the proposed materials. The Sn-based single perovskite compounds proposed in this study are mechanically stable and ductile. The narrow direct band gap for NaSnCl3 and KSnCl3 are 1.36 eV and 1.47 eV, respectively, using the HSE06 hybrid function with the Boltztrp2 integrated in Quantum ESPRESSO (QE) software. The effective use of these compounds in perovskite solar cells and other optoelectronic applications was confirmed by optical absorption spectral measurements conducted in the photon energy range of 0-20 eV.

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Linking sensory input and its consequences is a fundamental brain operation. During behavior, the neural activity of neocortical and limbic systems often reflects dynamic combinations of sensory and task-dependent variables, and these \"mixed representations\" are suggested to be important for perception, learning, and plasticity. However, the extent to which such integrative computations might occur outside of the forebrain is less clear. Here, we conduct cellular-resolution two-photon Ca2+ imaging in the superficial \"shell\" layers of the inferior colliculus (IC), as head-fixed mice of either sex perform a reward-based psychometric auditory task. We find that the activity of individual shell IC neurons jointly reflects auditory cues, mice\'s actions, and behavioral trial outcomes, such that trajectories of neural population activity diverge depending on mice\'s behavioral choice. Consequently, simple classifier models trained on shell IC neuron activity can predict trial-by-trial outcomes, even when training data are restricted to neural activity occurring prior to mice\'s instrumental actions. Thus, in behaving mice, auditory midbrain neurons transmit a population code that reflects a joint representation of sound, actions, and task-dependent variables.

BACKGROUND: Many theories referring to the conception of a beautiful buttock have been put forward, but little has been proved, especially in the Asian group.
OBJECTIVE: To analyse the aesthetic preference for aesthetically pleasing characteristics in the Chinese population.
METHODS: In the survey, we computerized the buttock image of a Chinese female through the Photoshop software (Adobe Photoshop CS5; Adobe Systems, Inc., San Jose, Calif), and buttocks with and without four features were attained. An online questionnaire was made to rank the most aesthetic buttocks. The data for the various demographic groups were compared using the Pearson Chi-square test. A value of p < 0.05 was used for statistical significance.
RESULTS: In total, 2348 responses were collected. Over half of the respondents prefer without supragluteal fossettes (56.9%), V-shaped crease (60.4%) and lateral depression (90.1%). The most attractive infragluteal fold option was short type (34.9%), followed by median infragluteal fold (32.7%) and long infragluteal fold (32.4%). Supragluteal fossettes, median or long infragluteal fold and V-shaped crease were more preferred among young people.
CONCLUSIONS: Supragluteal fossettes, V-shaped crease and lateral depressions were not preferred in over half of the respondents. The aesthetic preference was influenced by the gender and age. The plastic surgeons should consider the variabilities above when establishing aesthetic aim for beautiful buttocks in gluteoplasty.
METHODS: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Mangroves are an important part of coastal and estuarine ecosystems where they serve as nurseries for marine species and prevent coastal erosion. Here we report the genome of Sonneratia ovata, which is a true mangrove that grows in estuarine environments and can tolerate moderate salt exposure. We sequenced the S. ovata genome and assembled it into chromosome-level scaffolds through the use of Hi-C. The genome is 212.3 Mb and contains 12 chromosomes that range in size from 12.2 to 23.2 Mb. Annotation identified 29,829 genes with a BUSCO completeness of 95.9%. We identified salt genes and found copy number expansion of salt genes such as ADP-ribosylation factor 1, and elongation factor 1-alpha. Population analysis identified a low level of genetic variation and a lack of population structure within S. ovata.

OBJECTIVE: The aim of this study was to characterize the population pharmacokinetics of AZD8233, an antisense oligonucleotide (ASO) that targets the PCSK9 transcript to reduce hepatocyte PCSK9 protein production and plasma levels. AZD8233 utilizes generation 2.5 S-constrained ethyl motif (cET) chemistry and is conjugated to a triantennary N-acetylgalactosamine (GalNAc3) ligand for targeted hepatocyte uptake.
METHODS: A non-linear mixed-effect modelling approach utilizing NONMEM software was applied to AZD8233 concentration-time data from 3416 samples in 219 participants from four phase 1-2 studies, one in healthy volunteers (NCT03593785) and three in patients with dyslipidaemia (NCT04155645, NCT04641299 and NCT04823611).
RESULTS: The final model described the AZD8233 plasma concentration-time profile from four phase 1-2 studies in healthy volunteers or participants with dyslipidaemia, covering a dose range of 4 to 120 mg. The pharmacokinetics of AZD8233 were adequately described by a two-compartment model with first-order absorption. The supra-proportional increase in maximum plasma concentration (Cmax) across the observed dose range was described by non-linear Michaelis-Menten elimination (maximum elimination rate, 9.9 mg/h [12% relative standard error]; concentration yielding half-maximal elimination rate, 4.8 mg/L [18% relative standard error]). Body weight, sex, estimated glomerular filtration rate and disease status (healthy participant vs. patient with dyslipidaemia) were identified as factors affecting exposure to AZD8233.
CONCLUSIONS: Covariate analysis showed body weight to be the main factor affecting exposure to AZD8233, which largely explained the higher Cmax observed in the Asian population relative to non-Asians.

The bearded vulture (Gypaetus barbatus) is an endangered species with a specialist osteophagous (bone) diet. We estimated the survival and productivity of this vulture in the Aragonese Pyrenees, where the main population of the species in Europe is found. We used a database covering a period of 33 years (1987-2020). To estimate the probability of survival, we used Cormack-Jolly-Seber models with a Bayesian approach. Our models estimated a survival rate of 0.90 ± 0.08 in juveniles, 0.95 ± 0.04 in subadults and 0.92 ± 0.05 in adults. The survival probability increased over the study period in adults and subadults but not in juveniles. By contrast, productivity decreased over the same period. Our study provides updated information on the status of two demographic parameters of great importance to the species and allows us to identify the most vulnerable age classes and to plan conservation actions to improve the situation of the species in a territory that is a donor of specimens for reintroduction projects. The estimated survival values suggest that more caution should be exercised when planning these feeding points according to the use the species makes of them.

\"Epilepsy is a chronic brain disorder that affects people of all ages. The cause of epilepsy is often unknown and its effect in different age groups is not yet investigated. The main objective of this study is to introduce a novel approach that successfully detects epilepsy even from noisy EEG signals. In addition, this study also investigates population specific epilepsy detection for providing novel insights. Correspondingly, we utilized the TUH EEG corpus database, publicly available challenging multi-channel EEG database containing detailed patient information. We applied a band-pass filter and manual noise rejection to remove noise and artifacts from EEG signals. We then utilized statistical features and correlation to select channels, and applied different transform analysis methods such as continuous wavelet transform, spectrogram, and Wigner-Ville distribution, with and without ensemble averaging, to construct an image dataset. Afterwards, we used various deep-learning models for general analysis. Our findings suggest that different models such as DenseNet201, DenseNet169, DenseNet121, VGG16, VGG19, Xception, InceptionV3, and MobileNetV2 performed better while using images generated from different approaches in general analysis. Furthermore, we split the dataset into two sections according to age for population analysis. All the models that performed well in the general analysis were used for population analysis, which provided novel insights in epilepsy detection from EEG. Our proposed framework for epilepsy detection achieved 100% accuracy, which outperforms other concurrent methods.\"

UNASSIGNED: Quetiapine exhibits notable pharmacokinetic and pharmacodynamic (PK/PD) variability, the origins of which are poorly understood. This systematic review summarizes published population PK/PD studies and identifies significant covariates accounting for this variability to inform precision dosing.
UNASSIGNED: We systematically searched the PubMed, Web of Science, and Embase databases and compared study characteristics, model parameters, and covariate effects. Visual predictive distributions were used to compare different models. Forest plots and Monte Carlo simulations were used to assess the influence of covariates.
UNASSIGNED: Six population PK and three population PK/PD studies were included. The median apparent clearance in adults was 87.7 L/h. Strong and moderate cytochrome P450 3A4 inducers increased the apparent clearance approximately fourfold, while strong cytochrome P450 3A4 inhibitors reduced it by 93%. The half-maximum effect concentrations were 82.8 ng/mL for the Brief Psychiatric Rating Scale and 583 ng/mL for dopamine D2 receptor occupancy. Both treatment duration and quetiapine exposure were associated with weight gain.
UNASSIGNED: Concurrent administration of potent or moderate CYP3A4 inducers and inhibitors need to be avoided in quetiapine-treated patients. When co-medication is required, it is recommended to adjust the dosage based on therapeutic drug monitoring. Additional research is warranted to delineate the dose-exposure-response relationships of quetiapine and active metabolite norquetiapine in pediatrics, geriatrics, hepatically-impaired patients, and women using contraceptives or are pregnant or menopausal.
UNASSIGNED: CRD42023446654.