简介：AbstractBackground:Globally, colorectal cancer (CRC) imposes a substantial burden on healthcare systems and confers considerable medical expenditures. We aimed to evaluate the global and regional burden in epidemiological trends and factors associated with the incidence and mortality of CRC.Methods:We used data from the GLOBOCAN database to estimate CRC incidence and mortality worldwide in 2020 and their association with the human development index (HDI). Trends of age-standardized rates of incidence and mortality in 60 countries (2000-2019) were evaluated by Joinpoint regression analysis using data of Global Burden of Disease 2019. The association between exposure to country-level lifestyle, metabolic and socioeconomic factors obtained from the World Health Organization Global Health Observatory and World Bank DataBank data and CRC incidence and mortality was determined by multivariable linear regression.Results:CRC incidence and mortality varied greatly in the 60 selected countries, and much higher incidence and mortality were observed in countries with higher HDIs, and vice versa. From 2000 to 2019, significant increases of incidence and mortality were observed for 33 countries (average annual percent changes [AAPCs], 0.24-3.82) and 18 countries (AAPCs, 0.41-2.22), respectively. A stronger increase in incidence was observed among males (AAPCs, 0.36-4.54) and individuals <50 years (AAPCs, 0.56-3.86). Notably, 15 countries showed significant decreases in both incidence (AAPCs, -0.24 to -2.19) and mortality (AAPCs, -0.84 to -2.74). A significant increase of incidence among individuals <50 years was observed in 30 countries (AAPCs, 0.28-3.62). Countries with higher incidence were more likely to have a higher prevalence of alcohol drinking, higher level of cholesterol level, higher level of unemployment, and a poorer healthcare system.Conclusions:Some high-HDI countries showed decreasing trends in CRC incidence and mortality, whereas developing countries that previously had low disease burden showed significantly increased incidence and mortality trends, especially in males and populations ≥50 years, which require targeted preventive health programs.

简介：AbstractBackground:Fecal immunochemical tests (FITs) are the most widely used non-invasive tests in colorectal cancer (CRC) screening. However, evidence about the direct comparison of the test performance of the self-administered qualitative a laboratory-based quantitative FITs in a CRC screening setting is sparse.Methods:Based on a CRC screening trial (TARGET-C), we included 3144 pre-colonoscopy fecal samples, including 24 CRCs, 230 advanced adenomas, 622 non-advanced adenomas, and 2268 participants without significant findings at colonoscopy. Three self-administered qualitative FITs (Pupu tube) with positivity thresholds of 8.0, 14.4, or 20.8 μg hemoglobin (Hb)/g preset by the manufacturer and one laboratory-based quantitative FIT (OC-Sensor) with a positivity threshold of 20 μg Hb/g recommended by the manufacturer were tested by trained staff in the central laboratory. The diagnostic performance of the FITs for detecting colorectal neoplasms was compared in the different scenarios using the preset and adjusted thresholds (for the quantitative FIT).Results:At the thresholds preset by the manufacturers, apart from the qualitative FIT-3, significantly higher sensitivities for detecting advanced adenoma were observed for the qualitative FIT-1 (33.9% [95% CI: 28.7-39.4%]) and qualitative FIT-2 (22.2% [95% CI: 17.7-27.2%]) compared to the quantitative FIT (11.7% [95% CI: 8.4-15.8%]), while at a cost of significantly lower specificities. However, such difference was not observed for detecting CRC. For scenarios of adjusting the positivity thresholds of the quantitative FIT to yield comparable specificity or comparable positivity rate to the three qualitative FITs accordingly, there were no significant differences in terms of sensitivity, specificity, positive/negative predictive values and positive/negative likelihood ratios for detecting CRC or advanced adenoma between the two types of FITs, which was further evidenced in ROC analysis.Conclusions:Although the self-administered qualitative and the laboratory-based quantitative FITs had varied test performance at the positivity thresholds preset by the manufacturer, such heterogeneity could be overcome by adjusting thresholds to yield comparable specificities or positivity rates. Future CRC screening programs should select appropriate types of FITs and define the thresholds based on the targeted specificities and manageable positivity rates.

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简介：AbstractObjective:In contrast to the most commonly reported forms of maturity-onset diabetes of the young (MODY), including MODY2, MODY3 and MODY5, MODY6 is a relatively rare subtype. To investigate whether NEUROD1 is responsible for MODY in Chinese individuals, we screened its mutations in MODY pedigrees and explored the potential pathogenic mechanisms.Methods:Polymerase chain reaction direct sequencing was performed to screen NEUROD1 mutations in 32 Chinese MODY probands who were negative for the GCK/MODY2, HNF1A/MODY3 and HNF1B/MODY5 genes in this observational study. In addition, we enrolled 201 unrelated, non-diabetic control subjects of Han Chinese descent. The functional significance of newly identified mutations was analyzed using clinical phenotype, pathophysiology and three-dimensional structure studies. This study was approved by the Institutional Review Board of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, China (approval No. YS-2017-83) on March 3, 2017.Results:E59Q (c.175 G>C, p.Glu59Gln), a heterozygous missense mutation in the NEUROD1 gene, was identified in one family with MODY. The Glu59 residue in NeuroD1 is highly conserved across mammalian species. Four diabetic patients carrying the mutation (a proband and her son, brother and sister) were lean, with a body mass index of 20.9 (20.3-21.2) kg/m2. Compared with their unaffected relatives (n= 4), E59Q carriers (n= 4) had significantly decreased ratios of fasting and 2-hour insulin to plasma glucose (both fasting plasma insulin/fasting plasma glucose and 2-hour postprandial plasma insulin/2-hour postprandial plasma glucose, P < 0.005). The proband’s father had an E59Q mutation and normal glucose tolerance, which suggested non-penetrance. The E59Q mutation was not detected in other probands or in the 201 control subjects with normal glucose tolerance. Two salt-bridge bonds of Glu59 were disrupted at the Q59 mutation site.Conclusion:The NEUROD1-E59Q mutation changed the molecular conformation of the N-terminal in NeuroD1, which may decrease binding of the E59Q mutant to the insulin promoter and insulin gene transcription activity, therefore causing the MODY6 subtype with defective insulin secretion.