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Additional file 2: Figure S1. [Kaplan-Meier curves of overall survival for the preoperative groups of CEA (a), CA19-9 (b), and CA125 (c) in colorectal cancer patients]. Figure S2. [Kaplan-Meier curves of overall survival for the first postoperative groups of CEA (a), CA1 -9 (b), and CA125 (c) in colorectal cancer patients]. Figure S3. [Longitudinal trajectories of CEA (a), CA19-9 (b) and CA125 (c) of survived and died patients]. Figure S4. [The eigenfunctions of FPCA for CEA (a), CA19-9 (b), and CA125 (c)]. Figure S5. [The first five eigenfunctions for CEA (a), CA19-9 (b), and CA125 (c) based on MFPCA of the three markers]. Figure S6. [Variable importance of preoperative CEA&CA19-9&CA125 model (a) and longitudinal CEA&CA19-9&CA125 model (b)]. Figure S7. [ROC curves of the preoperative, postoperative and longitudinal CEA&CA19-9&CA125 models at 60 months after surgery for internal validation (a) and external validation (b)]. Figure S8. [Personalized dynamic prediction for the survival probability of patient A (a), patient B (b) and patient C (c) based on longitudinal CEA&CA19-9&CA125 model]. Figure S9. [AUC (a) and BS (b) of the prediction models with MSI status at 24 to 60 months after surgery for external validation].

Additional file 1. Characteristics of the included and excluded patients in YNCH and SYSU6.

Context Current medicine for Alzheimer's disease (AD) cannot effectively reverse or block nerve injury. Traditional Chinese Medicine practice and research imply Aconiti lateralis Radix Praeparata (Fuzi) may meet this goal. Objective Analysing the anti-AD effect of Fuzi and its potential molecular mechanism. Materials and methods AD model cells were treated with Fuzi in 0-300 mg/mL for 24 h in 37 °C. The cell viability (CV) and length of cell projections (LCP) for each group were observed, analysed, and standardised using control as a baseline (CVs and LCPs). The Fuzi and AD relevant genes were identified basing on databases, and the molecular mechanism of Fuzi anti-AD was predicted by network analysis. Results Experiment results showed that Fuzi in 0.4 mg/mL boosted LCP (LCPs = 1.2533, p ≤ 0.05), and in 1.6-100 mg/mL increased CV (CVs from 1.1673 to 1.3321, p ≤ 0.05). Bioinformatics analysis found 17 Fuzi target genes (relevant scores ≥ 20), showing strong AD relevant signals (RMS_p ≤ 0.05, related scores ≥ 5), enriched in the pathways regulating axon growth, synaptic plasticity, cell survival, proliferation, apoptosis, and death (p ≤ 0.05). Especially, GRIN1 and MAPK1 interacted with APP protein and located in the key point of the "Alzheimer's disease" pathway. Discussion and conclusions These results suggest that Fuzi may have therapeutic and prevention potential in AD, and GRIN1 and MAPK1 may be the core of the pathways of the Fuzi anti-AD process. Fuzi should be studied more extensively, especially for the prevention of AD.

Additional file 1: FigureS1. Association between preoperative CA19-9 status and overall survival. (a) overall population. (b) patients with normal preoperative CEA. (c) patientswith elevated preoperative CEA. Solid yellow lines are unadjustedhazard ratios, with dashed yellow lines showing 95% confidence intervalsderived from restricted cubic spline regressions. Reference lines for noassociation are indicated by the solid bold lines at a hazard ratio (HR) of 1.0. Dashed blue curves show the fraction of the population with different levels of preoperative CA19-9. Arrows indicate the concentration of preoperative CA19-9 with HR of 1.0. CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; CI, confidence interval; E, number of events; HR, hazard ratio; N, number of patients. FigureS2. Kaplan‐Meier curves for overall survival according to the preoperative CA19-9 group. (a) overall population. (b) patients with normal preoperative CEA. (c) patientswith elevated preoperative CEA. CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen. FigureS3. Kaplan‐Meier curves according to the joint group of preoperative CEA and CA19-9 in colorectal cancer patients. (a) recurrence-free survival. (b) overall survival. CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; OS, overall survival; RFS, recurrence-free survival. FigureS4. Forest plot for recurrence-free survival of preoperative CA 19-9 groups stratified by clinicopathological features based on the Cox models. P values for interaction were calculated using Cox regression model. HR and 95%CIs were given and visually represented by the squares and error bars. CA 19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; CI, confidence interval; HR, hazard ratio. FigureS5. Forest plot for performance overallsurvival of preoperative CA19-9 groups stratified by clinicopathological features based on the Cox models. P values for interaction were calculated using Cox regression model. HR and 95%CIs were given and visually represented by the squares and error bars. CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; CI, confidenceinterval; HR, hazard ratio. FigureS6. Kaplan‐Meier curves according to the joint group of preoperative CEA and CA19-9 in patients with stage II colorectal cancer. (a) recurrence-free survival.(b) overall survival. CA 19-9, carbohydrate antigen 19-9;CEA, carcinoembryonic antigen; OS, overall survival; RFS, recurrence-freesurvival.

Additional file 1.

Additional file 2: Table S1.Baseline characteristics by participant site. Table S2.Multivariate analyses of recurrence-free survival in total population (Cox model). Table S3.Multivariate analyses of overall survival in total population (Cox model). Table S4.Interaction between preoperative CEA and CA19-9 with risk of outcomes. Table S5.Multivariate analyses of recurrence-free survival in colorectal cancer subgroup with CEA < 5 ng/ml (Cox model). Table S6.Multivariate analyses of recurrence-free survival in colorectal cancer subgroup with CEA ≥ 5 ng/ml (Cox model). Table S7. Multivariate analyses of overall survival in colorectal cancer subgroup with CEA < 5 ng/ml (Cox model). Table S8.Multivariate analyses of overall survival in colorectal cancer subgroup with CEA ≥ 5 ng/ml (Cox model). Table S9.A frailty model analysis of preoperative CA19-9 (cutoff: 37 U/ml) on colorectal cancer outcomes in total population. TableS10.Cox proportional hazard regression analysis of preoperative CA19-9 (cutoff:74 U/ml) on colorectal cancer outcomes in total population. Table S11.Relationship between preoperative CA19-9 and benefit from adjuvant chemotherapyin patients with stage II colorectal cancer.

Additional file 1: Supplementary 1. Secular trends in AAM among other ethnic minorities*.

Additional file 1. Table S1. Classification criteria of depression level and anxiety level.