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In BCR-ABL1 lymphoblastic leukemia, treatment heterogeneity to tyrosine kinase inhibitors (TKIs), especially in the absence of kinase domain mutations in BCR-ABL1, is poorly understood. Through deep molecular profiling, we uncovered three transcriptomic subtypes of BCR-ABL1 lymphoblastic leukemia, each representing a maturation arrest at a stage of B-cell progenitor differentiation. An earlier arrest was associated with lineage promiscuity, treatment refractoriness and poor patient outcomes. A later arrest was associated with lineage fidelity, durable leukemia remissions and improved patient outcomes. Each maturation arrest was marked by specific genomic events that control different transition points in B-cell development. Interestingly, these events were absent in BCR-ABL1+ preleukemic stem cells isolated from patients regardless of subtype, which supports that transcriptomic phenotypes are determined downstream of the leukemia-initialing event. Overall, our data indicate that treatment response and TKI efficacy are unexpected outcomes of the differentiation stage at which this leukemia transforms.

Pressure injuries pose significant health risks, especially for the elderly, immobile individuals, and those with sensory impairments. These injuries can rapidly become chronic, making initial diagnosis important. Due to the difficulty of transporting patients from local health facilities to higher-level general hospitals for treatment, it is essential to utilize telemedicine tools, such as chatbots, to ensure rapid initial diagnosis. Recent advances in artificial intelligence have demonstrated potential for medical imaging and disease classification. Ongoing research in the field of dermatological diseases focuses on disease classification. However, the assessment accuracy of artificial intelligence is often limited by unequal class distributions and insufficient dataset quantities. In this study, we aim to enhance the accuracy of artificial intelligence models by generating synthetic datasets. Specifically, we focused on training models for Pressure Injury assessment using both real and synthetic datasets. We used PI data at a domestic medical university. As part of our supplementary research, we established a chatbot system to facilitate the assessment of pressure injuries. Using both constructed and synthetic data, we achieved a top-1 accuracy of 92.03%. The experimental results demonstrate that combining real and synthetic data significantly improves model accuracy. These findings suggest that synthetic datasets can be effectively utilized to address the limitations of small-scale datasets in medical applications. Future research should explore the use of diverse synthetic data generation methods and validate model performance on a variety of datasets to enhance the generalization and robustness of AI models for Pressure Injury assessment. [ABSTRACT FROM AUTHOR]

Recently, HfO2‐based ferroelectric thin films have attracted widespread interest in developing next‐generation nonvolatile memories. To form a metastable ferroelectric orthorhombic phase in HfO2, a post‐annealing process is typically necessary. However, the microscopic mechanism underlying the effect of annealing temperature on ferroelectric domain nucleation and growth is still obscure, despite its importance in optimizing the operation speed of HfO2‐based devices. In this study, the ferroelectric properties and polarization switching of Hf0.5Zr0.5O2 thin films annealed at different temperatures (550–700 °C) are systematically investigated. Evidently, the crystal structure, remnant polarization, and dielectric constant monotonically change with annealing temperature. However, microscopic piezoresponse force microscopy images as well as macroscopic switching current measurements reveal non‐monotonic changes in the polarization switching speed with annealing temperature. This intriguing behavior is ascribed to the difference in the ferroelectric‐domain nucleation process induced by the amount of oxygen vacancies in the Hf0.5Zr0.5O2 thin films annealed at different temperatures. This work demonstrates that controlling the defect concentration of ferroelectric HfO2 by tuning the post‐annealing process is critical for optimizing device performance, particularly polarization switching speed. [ABSTRACT FROM AUTHOR]

Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development. The current model of tumorigenesis, based on analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations (KRAS, followed by CDKN2A, then TP53 and SMAD4); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently. A shortcoming of this model is that clonally expanded precursor lesions do not always belong to the tumour lineage, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing model of tumorigenesis has contributed to the clinical notion that pancreatic cancer evolves slowly and presents at a late stage. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes, despite efforts aimed at early detection, suggest that pancreatic cancer progression is not gradual. Here, using newly developed informatics tools, we tracked changes in DNA copy number and their associated rearrangements in tumour-enriched genomes and found that pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory. In a subset of cases, the consequence of such errors is the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that are likely to set-off invasive cancer growth. These findings challenge the current progression model of pancreatic cancer and provide insights into the mutational processes that give rise to these aggressive tumours.

Chromosomal rearrangements are a hallmark of acute lymphoblastic leukemia (ALL) and are important ALL initiating events. We describe four different rearrangements of the erythropoietin receptor gene EPOR in Philadelphia chromosome-like (Ph-like) ALL. All of these rearrangements result in truncation of the cytoplasmic tail of EPOR at residues similar to those mutated in primary familial congenital polycythemia, with preservation of the proximal tyrosine essential for receptor activation and loss of distal regulatory residues. This resulted in deregulated EPOR expression, hypersensitivity to erythropoietin stimulation, and heightened JAK-STAT activation. Expression of truncated EPOR in mouse B cell progenitors induced ALL in vivo. Human leukemic cells with EPOR rearrangements were sensitive to JAK-STAT inhibition, suggesting a therapeutic option in high-risk ALL.

An excessive amount of differential settlement was observed during the construction of taxiways at Changi Airport in Singapore. The pavement exhibited severe settlement (up to 200 mm). The first cracks appeared in April 2018, 11 months after the pavement construction was completed. The cracks stayed in the asphalt concrete layer, but 15 months after the emergence of the first cracks, they extended downward and propagated beyond a subgrade layer. From the analyses performed on the pavement structure using the finite element method, it was found that tensile strain occurred at the surface of the pavement. The amount of tensile strain was higher at the joint between the main pavement and the shoulder pavement than in any other location on the pavement. Fracture analyses were conducted and indicated that cracks would propagate from the top of the pavement due to the tensile strain and move to its bottom. To identify an indication of settlement, heavy weight deflect (HWD) tests were conducted over three pavements experiencing three levels of settlement—severe, moderate, and no settlement. Backcalculation analysis was done for the three pavements using backcalculation programs BAKFAA and BAKSIMPLEX, and the closed-form solution. It was observed that the backcalcuated asphalt modulus was highly affected by root mean square (RMS) %. It is hence less reliable when the asphalt concrete modulus was determined at a higher RMS %, whereas the correlation became stronger when it was determined at an RMS % lower than four. Meanwhile, subgrade modulus backcalculated even at higher RMS % values was less affected by the error because most errors occurred and accumulated near the loading area of HWD. From the statistical analysis (t-test) performed on subgrade moduli backcalculated, it was concluded that the means of subgrade moduli obtained from the three different pavements differed from the hypothetical means of interest at a 95% level of confidence. This indicates that if a pavement undergoes settlement, the indication of settlement could be captured from HWD tests and the backcalculation of subgrade moduli. [ABSTRACT FROM AUTHOR]

Greater access to flexible work arrangements is considered a solution to many working parents' challenges balancing the demands of work and family, yet it remains unclear whether such arrangements are associated with parents' time in the active caregiving activities linked to children's development and parents' notions of quality time. We examine this question using data from the American Time Use Survey and Leave and Job Flexibilities Module (2017–2018) (n = 1,874 mothers, n = 1,756 fathers) and linear regression and inverse probability weighting techniques. Results indicate that access to flextime is associated with more active caregiving time for mothers but not fathers. They also provide suggestive evidence that flexplace is associated with more active caregiving time for mothers and fathers and strong evidence that it is associated with more passive caregiving time for both parents. The findings highlight the importance of expanding parents' access to flexible work options, and the limits of doing so. [ABSTRACT FROM AUTHOR]

Loaded tooth contact analysis (LTCA) adopted to obtain the static transmission error for the gear optimization affects significantly the computation time and results. This paper is to study an efficient process of macro geometry optimization of helical gear pairs with LTCA. An analytical LTCA model was proposed and verified with the measured transmission error. To find an efficient LTCA method, the proposed model was divided into three types (based on whether the slice stiffness and extended contact were included) by adjusting the fidelity. When extended contact was included in LTCA, the increased computation time was very short, but the accuracy of the results improved significantly. Optimization processes were designed based on the analysis results, and it was most efficient when starting with the model considering only the extended contact and ending 5%−10% of the entire generation with the highest fidelity model. In the process, the computational effort was significantly reduced compared to when the optimization process was configured with only the highest fidelity model, and the level of optimization was almost equal. [ABSTRACT FROM AUTHOR]