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BackgroundThe incidence of early-onset colorectal cancer (EOCRC) is increasing globally. This study aims to describe the temporal trends of incidence and explore related risk exposures in early-life at the country level based on the GBD 2019.MethodsData on the incidence and attributable risk factors of EOCRC were obtained from the GBD 2019. Temporal trends of age-standardized incidence were evaluated by average annual percentage change (AAPC). Early-life exposures were indicated as summary exposure values (SEV) of selected factors, SDI and GDP per capita in previous decades and at ages 0–4, 5–9, 10–14 and 15–19 years. Weighted linear or non-linear regressions were applied to evaluate the ecological aggregate associations of the exposures with incidences of EOCRC.ResultsThe global age-standardized incidence of EOCRC increased from 3.05 (3.03, 3.07) to 3.85 (3.83, 3.86) per 100,000 during 1990 and 2019. The incidence was higher in countries with high socioeconomic levels, and increased drastically in countries in East Asia and Caribbean, particularly Jamaica, Saudi Arabia and Vietnam. The GDP per capita, SDI, and SEVs of iron deficiency, alcohol use, high body-mass index, and child growth failure in earlier years were more closely related with the incidences of EOCRC in 2019. Exposures at ages 0–4, 5–9, 10–14 and 15–19 years were also associated with the incidences, particularly for the exposures at ages 15–19 years.ConclusionThe global incidence of EOCRC increased during past three decades. The large variations at regional and national level may be related with the distribution of risk exposures in early life.

BackgroundThe effectiveness of triage screening for colorectal cancer (CRC) is not fully achieved in Chinese populations, mainly due to low compliance to colonoscopy follow-up. This study aimed to collect viewpoints of experts in China on ongoing screening programs and emerging screening tests for CRC, which may help to improve effectiveness of CRC screening in the country.MethodsWe conducted 15 semi-structured interviews with experts involving CRC screening in China during October to November of 2020. Interview topics included personal characteristics, work context, opinions on ongoing screening programs, challenges and opportunities in optimization of screening strategies, and prospects for CRC screening in near future. To analyze the data, we used a generic qualitative research approach inspired by grounded theory, including open, axial, and selective coding.ResultsThis analysis revealed a total of 83 initial categories, 37 subcategories and 10 main categories, which included 4 core categories of current modality for CRC screening, factors influencing screening effectiveness, optimization of CRC screening modality, and prospects for development of CRC screening. The results provide insight into the factors underlying the challenges of the ongoing CRC screening programs in China: the most important concern is the low compliance to colonoscopy, followed by the low specificity of the currently-used initial tests. The experts proposed to use quantitative instead of qualitative fecal immunochemical test (FIT), and optimize risk assessment tools to improve specificity of initial tests. Regarding the emerging screening tests, 9 of 15 experts did not think that the novel techniques are good enough to replace the current tests, but can be used complementarily in opportunistic screening for CRC.ConclusionThe viewpoints of Chinese experts suggested that use quantitative FIT or optimize risk assessment tools may help to identify high-risk individuals of CRC more accurately, improve adherence to colonoscopy, and thus fully achieve the effectiveness of screening.

Abstract Background Fecal immunochemical test (FIT) is a commonly used initial test for colorectal cancer (CRC) screening. Parallel use of FIT with risk assessment (RA) could improve the detection of non‐bleeding lesions, but at the expense of compromising sensitivity. In this study, we evaluated the accuracy of FIT and/or RA in the Shanghai CRC screening program, and systematically reviewed the relevant evaluations worldwide. Methods RA and 2‐specimen FIT were used in parallel in the Shanghai screening program, followed by a colonoscopy among those with positive results. Sensitivity, specificity, detection rate of CRC, positive predictive value (PPV), and other measures with their 95% confident intervals were calculated for each type of tests and several assumed combined tests. We further searched PubMed, Embase, Web of Science, and Cochrane Library for relevant studies published in English up to January 5, 2022. Results By the end of 2019, a total of 1,901,360 participants of the screening program completed 3,045,108 tests, with 1,901,360 first‐time tests and 1,143,748 subsequent tests. Parallel use of RA and 2‐specimen FIT achieved a sensitivity of 0.78 (0.77–0.80), a specificity of 0.78 (0.78–0.78), PPV of 0.89% (0.86–0.92), and a detection rate of 1.99 (1.93–2.05) for CRC per 1000 among participants enrolled in the first screening round, and performed similarly among those who participated for several times. A meta‐analysis of 103 published observational studies demonstrated a higher sensitivity [0.76 (0.36, 0.94)] but a much lower specificity [0.59 (0.28, 0.85)] of parallel use of RA and FIT for detecting CRC in average‐risk populations than in our subjects. One‐specimen FIT, the most commonly used initial test, had a pooled specificity comparable to the Shanghai screening program (0.92 vs. 0.91), but a much higher pooled sensitivity (0.76 vs. 0.57). Conclusion Our results indicate the limitation of FIT only as an initial screening test for CRC in Chinese populations, and highlight the higher sensitivity of parallel use of RA and FIT. Attempts should be made to optimize RA to improve effectiveness of screening in the populations.

Abstract Background Single-cell RNA sequencing (scRNA-seq) technology has enabled assessment of transcriptome-wide changes at single-cell resolution. Due to the heterogeneity in environmental exposure and genetic background across subjects, subject effect contributes to the major source of variation in scRNA-seq data with multiple subjects, which severely confounds cell type specific differential expression (DE) analysis. Moreover, dropout events are prevalent in scRNA-seq data, leading to excessive number of zeroes in the data, which further aggravates the challenge in DE analysis. Results We developed iDESC to detect cell type specific DE genes between two groups of subjects in scRNA-seq data. iDESC uses a zero-inflated negative binomial mixed model to consider both subject effect and dropouts. The prevalence of dropout events (dropout rate) was demonstrated to be dependent on gene expression level, which is modeled by pooling information across genes. Subject effect is modeled as a random effect in the log-mean of the negative binomial component. We evaluated and compared the performance of iDESC with eleven existing DE analysis methods. Using simulated data, we demonstrated that iDESC had well-controlled type I error and higher power compared to the existing methods. Applications of those methods with well-controlled type I error to three real scRNA-seq datasets from the same tissue and disease showed that the results of iDESC achieved the best consistency between datasets and the best disease relevance. Conclusions iDESC was able to achieve more accurate and robust DE analysis results by separating subject effect from disease effect with consideration of dropouts to identify DE genes, suggesting the importance of considering subject effect and dropouts in the DE analysis of scRNA-seq data with multiple subjects.

Summary: Here, we present Brain Registration and Evaluation for Zebrafish (BREEZE)-mapping, a user-friendly pipeline for the registration and analysis of whole-brain images in larval zebrafish. We describe steps for pre-processing, registration, quantification, and visualization of whole-brain phenotypes in zebrafish mutants of genes associated with neurodevelopmental and neuropsychiatric disorders. By utilizing BioImage Suite Web, an open-source software package originally developed for processing human brain imaging data, we provide a highly accessible whole-brain mapping protocol developed for users with general computational proficiency.For complete details on the use and execution of this protocol, please refer to Weinschutz Mendes et al. (2023).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Summary: Advancing from gene discovery in autism spectrum disorders (ASDs) to the identification of biologically relevant mechanisms remains a central challenge. Here, we perform parallel in vivo functional analysis of 10 ASD genes at the behavioral, structural, and circuit levels in zebrafish mutants, revealing both unique and overlapping effects of gene loss of function. Whole-brain mapping identifies the forebrain and cerebellum as the most significant contributors to brain size differences, while regions involved in sensory-motor control, particularly dopaminergic regions, are associated with altered baseline brain activity. Finally, we show a global increase in microglia resulting from ASD gene loss of function in select mutants, implicating neuroimmune dysfunction as a key pathway relevant to ASD biology.

A central challenge in the genetics of autism spectrum disorders (ASDs) is advancing from gene discovery to the identification of actionable biological mechanisms. To investigate the function of ten genes that are strongly associated with ASD in the developing vertebrate brain, we performed behavioral, whole-brain structural, circuit, cellular and molecular analyses in zebrafish mutants of ASD genes. First, we identified both unique and overlapping effects of gene loss of function on basic sensory processing and arousal behaviors. Next, we identified the forebrain as the most significant contributor to brain size differences, while brain regions involved in sensory motor control, particularly dopaminergic regions, are associated with altered baseline brain activity. Third, using whole-brain RNA sequencing in zebrafish mutants of SCN2A and DYRK1A, we identified conservation of dysregulated pathways associated with ASD gene loss of function in zebrafish and mammals. Using hypothesis-driven gene set enrichment analysis, we found that dopaminergic genes are significantly enriched among downregulated genes in both mutants, while microglial genes are significantly enriched among upregulated genes. Finally, we show that both mutants display a significant increase in microglia throughout the brain, with DYRK1A mutants exhibiting a nearly two-fold increase in microglia. Therefore, our study implicates neuroimmune dysfunction as an important pathway downstream of select ASD genes. As a next step, we are using pharmaco-behavioral profiling to identify pharmacological suppressors of mutant behavioral phenotypes. Together, this study demonstrates the power of in vivo functional analyses in zebrafish to identify biologically relevant pathways downstream of ASD genes. [ABSTRACT FROM AUTHOR]