Continuous age- and sex-specific reference ranges of liver enzymes in Chinese children and application in pediatric non-alcoholic fatty liver disease.

BACKGROUND: Alanine aminotransferase (ALT) is widely used to screen patients with hepatic diseases. However, the current reference ranges (< 50 U/L) were developed by laboratories and have not been validated in populations with a large number of healthy individuals. METHODS: This study collected venous blood and anthropometric data from a total of 13,287 healthy children aged 3 months to 18 years who underwent routine physical examinations in the Department of Pediatric Healthcare. We applied the least mean square algorithm to establish age- and sex-related reference percentiles of serum levels of transaminases. For validation, we recruited 4276 children and adolescents with obesity/overweight who underwent evaluation and metabolic tests in the hospital. Using receiver operating characteristic curves, we determined age- and sex-specific upper limit percentiles of liver enzymes for fatty liver diseases. RESULTS: This study revealed a significant correlation between serum transaminase levels and age and sex (P < 0.01). These transaminase levels exhibited age- and sex-specific patterns. Among individuals in the non-alcoholic fatty liver disease (NAFLD) cohort, elevated ALT levels displayed a positive association with clinical markers of disease severity, including homeostatic model assessment of insulin resistance, waist-hip ratio, and serum uric acid levels (P < 0.01). According to the receiver operating characteristic curves, ALT levels at the 92.58th percentile for boys and the 92.07th percentile for girls yielded the highest accuracy and specificity. CONCLUSIONS: This study provides age- and sex-specific reference ranges for ALT, aspartate aminotransferase, and γ-glutamyltransferase in Chinese children and adolescents, making it the largest population study to date. Furthermore, the study establishes a precise upper limit for ALT levels, facilitating their use in NAFLD screening. Video Abstract.

Validation of an established TW3 artificial intelligence bone age assessment system: a prospective, multicenter, confirmatory study.

Background: In 2020, our center established a Tanner-Whitehouse 3 (TW3) artificial intelligence (AI) system using a convolutional neural network (CNN), which was built upon 9059 radiographs. However, the system, upon which our study is based, lacked a gold standard for comparison and had not undergone thorough evaluation in different working environments. Methods: To further verify the applicability of the AI system in clinical bone age assessment (BAA) and to enhance the accuracy and homogeneity of BAA, a prospective multi-center validation was conducted. This study utilized 744 left-hand radiographs of patients, ranging from 1 to 20 years of age, with 378 boys and 366 girls. These radiographs were obtained from nine different children's hospitals between August and December 2020. The BAAs were performed using the TW3 AI system and were also reviewed by experienced reviewers. Bone age accuracy within 1 year, root mean square error (RMSE), and mean absolute error (MAE) were statistically calculated to evaluate the accuracy. Kappa test and Bland-Altman (B-A) plot were conducted to measure the diagnostic consistency. Results: The system exhibited a high level of performance, producing results that closely aligned with those of the reviewers. It achieved a RMSE of 0.52 years and an accuracy of 94.55% for the radius, ulna, and short bones series. When assessing the carpal series of bones, the system achieved a RMSE of 0.85 years and an accuracy of 80.38%. Overall, the system displayed satisfactory accuracy and RMSE, particularly in patients over 7 years old. The system excelled in evaluating the carpal bone age of patients aged 1-6. Both the Kappa test and B-A plot demonstrated substantial consistency between the system and the reviewers, although the model encountered challenges in consistently distinguishing specific bones, such as the capitate. Furthermore, the system's performance proved acceptable across different genders and age groups, as well as radiography instruments. Conclusions: In this multi-center validation, the system showcased its potential to enhance the efficiency and consistency of healthy delivery, ultimately resulting in improved patient outcomes and reduced healthcare costs.

New Era of Mapping and Understanding Common Fragile Sites: An Updated Review on Origin of Chromosome Fragility.

Common fragile sites (CFSs) are specific genomic loci prone to forming gaps or breakages upon replication perturbation, which correlate well with chromosomal rearrangement and copy number variation. CFSs have been actively studied due to their important pathophysiological relevance in different diseases such as cancer and neurological disorders. The genetic locations and sequences of CFSs are crucial to understanding the origin of such unstable sites, which require reliable mapping and characterizing approaches. In this review, we will inspect the evolving techniques for CFSs mapping, especially genome-wide mapping and sequencing of CFSs based on current knowledge of CFSs. We will also revisit the well-established hypotheses on the origin of CFSs fragility, incorporating novel findings from the comprehensive analysis of finely mapped CFSs regarding their locations, sequences, and replication/transcription, etc. This review will present the most up-to-date picture of CFSs and, potentially, a new framework for future research of CFSs.

Genome-wide high-resolution mapping of mitotic DNA synthesis sites and common fragile sites by direct sequencing.

Common fragile sites (CFSs) are genomic loci prone to the formation of breaks or gaps on metaphase chromosomes. They are hotspots for chromosome rearrangements and structural variations, which have been extensively implicated in carcinogenesis, aging, and other pathological processes. Although many CFSs were identified decades ago, a consensus is still lacking for why they are particularly unstable and sensitive to replication perturbations. This is in part due to the lack of high-resolution mapping data for the vast majority of the CFSs, which has hindered mechanistic interrogations. Here, we seek to map human CFSs with high resolution on a genome-wide scale by sequencing the sites of mitotic DNA synthesis (MiDASeq) that are specific for CFSs. We generated a nucleotide-resolution atlas of MiDAS sites (MDSs) that covered most of the known CFSs, and comprehensively analyzed their sequence characteristics and genomic features. Our data on MDSs tallied well with long-standing hypotheses to explain CFS fragility while highlighting the contributions of late replication timing and large transcription units. Notably, the MDSs also encompassed most of the recurrent double-strand break clusters previously identified in mouse neural stem/progenitor cells, thus bridging evolutionarily conserved break points across species. Moreover, MiDAseq provides an important resource that can stimulate future research on CFSs to further unravel the mechanisms and biological relevance underlying these labile genomic regions.