OBJECTIVE: Circadian rhythm disruption (CRD) is a risk factor that correlates with poor prognosis across multiple tumor types, including hepatocellular carcinoma (HCC). However, its mechanism remains unclear. This study aimed to define HCC subtypes based on CRD and explore their individual heterogeneity. METHODS: To quantify CRD, the HCC CRD score (HCCcrds) was developed. Using machine learning algorithms, we identified CRD module genes and defined CRD-related HCC subtypes in The Cancer Genome Atlas liver HCC cohort (n = 369), and the robustness of this method was validated. Furthermore, we used bioinformatics tools to investigate the cellular heterogeneity across these CRD subtypes. RESULTS: We defined three distinct HCC subtypes that exhibit significant heterogeneity in prognosis. The CRD-related subtype with high HCCcrds was significantly correlated with worse prognosis, higher pathological grade, and advanced clinical stages, while the CRD-related subtype with low HCCcrds had better clinical outcomes. We also identified novel biomarkers for each subtype, such as nicotinamide n-methyltransferase and myristoylated alanine-rich protein kinase C substrate-like 1. CONCLUSION We classify the HCC patients into three distinct groups based on circadian rhythm and identify their specific biomarkers. Within these groups greater HCCcrds was associated with worse prognosis. This approach has the potential to improve prediction of an individual's prognosis, guide precision treatments, and assist clinical decision making for HCC patients. Please cite this article as: Li XJ, Chang L, Mi Y, Zhang G, Zhu SS, Zhang YX, et al. Integrated-omics analysis defines subtypes of hepatocellular carcinoma based on circadian rhythm. J Integr Med. 2025; 23(4): 445-456.
Humans ; Carcinoma, Hepatocellular/pathology* ; Liver Neoplasms/pathology* ; Circadian Rhythm/genetics* ; Prognosis ; Male ; Female ; Biomarkers, Tumor/genetics* ; Middle Aged ; Machine Learning ; Computational Biology

Objective:To investigate the clinical effects and impact on balance control ability in elderly patients with chronic low back pain using dynamic neuromuscular stabilization(DNS)technique.Method:Forty elderly patients with chronic low back pain were randomly divided into two groups:an experi-mental group and a control group,with 20 participants in each group.The experimental group received DNS training,while the control group received conventional core muscle training.Both groups trained three times a week for four consecutive weeks.Before and after the intervention,visual analogue scale(VAS),Oswestry disability index(ODI),and Roland-Morris disability questionnaire(RMDQ)were used to evaluate the pain and functionality in both groups.The balance control performance of the two groups was evaluated using a bal-ance testing system,assessing parameters such as anterior-posterior movement speed,left-right movement speed,and travel distance during open-eyed double-leg stance,closed-eyed double-leg stance,and open-eyed single-leg stance before and after intervention.Repeated measures analysis of variance was used to assess differ-ences in clinical scales and balance performance before and after intervention in two groups.Result:After 4 weeks of intervention,both groups showed significant reductions in VAS(F=63.386,P<0.001),ODI(F=21.204,P<0.001),and RMDQ(F=38.501,P<0.001)scores compared to pre-intervention(P<0.01).There were no statistically significant differences between two groups(P>0.05).During open-eyed double-leg stance,the experimental group had smaller left-right movement speed than the control group(F=4.228,P=0.047).During closed-eyed double-leg stance,the experimental group had smaller left-right move-ment speed(F=6.560,P=0.015)compared to the control group.During open-eyed single-leg stance,the experi-mental group had smaller anterior-posterior movement speed(F=14.252,P=0.002)and travel distance(F=1.014,P=0.036)compared to the control group.Conclusion:DNS training can relieve pain,improve functionality and balance control ability in elderly pa-tients with chronic low back pain.

Objective:To explore the association between serum magnesium levels during catheterization in peritoneal dialysis (PD) patients and the failure of PD technology.Methods:It was a retrospective study. The baseline data, laboratory tests and clinical events of inpatients with end-stage renal disease aged ≥18 years who received PD catheterization for the first time from April 1, 2005 to February 29, 2024 were collected, and the follow-up was conducted until June 1, 2024. PD technique failure was defined as extubation for conversion to hemodialysis or patient death. The optimal cut-off value of serum magnesium (0.782 mmol/L) was determined based on the Youden index of the receiver operating characteristic curve for predicting the failure of PD technology. The patients were divided into high serum magnesium group and low serum magnesium group, and differences of baseline clinical data and follow-up outcomes between the two groups were compared. Kaplan-Meier method was used to compare the differences of PD technical survival rates between the two groups. Logistic regression model was used to analyze the related factors of baseline increased serum magnesium levels (0.785 mmol/L) in PD patients. Cox proportional hazards regression model was used to analyze the risk factors for the failure of PD technology.Results:A total of 706 PD patients were included in this study, with age of 43.89 (33.43, 53.70) years. Among them, 339 (48.02%) patients were male. The serum creatinine was (800.45±238.81) μmol/L. The follow-up time was 726.00 (216.00, 1 344.00) days. The incidence of peritonitis was 0.072 times per patient-year, and the failure rate of PD technique was 15.58% (110/706). There were 551 patients (78.05%) in the high serum magnesium group and 155 patients (21.95%) in the low serum magnesium group. Compared with the high serum magnesium group, the low serum magnesium group had significantly lower levels of serum creatinine ( t=-2.743, P=0.006), blood urea nitrogen ( t=-2.428, P=0.004), serum uric acid ( t=-2.346, P=0.005), red blood cell count ( t=-4.100, P<0.001), hemoglobin ( Z=-4.195, P<0.001), serum albumin ( t=-4.400, P<0.001), platelet count ( Z=-2.428, P=0.015), platelet-to-monocyte ratio ( Z=-2.541, P=0.011), serum calcium ( t=-7.463, P<0.001), serum phosphorus ( t=-3.052, P=0.001), prothrombin activity ( t=-3.052, P=0.005) and proportion of hyperphosphatemia ( χ2=6.924, P=0.009), and higher male proportion ( χ2=8.984, P=0.030), proportion of conversion to hemodialysis ( χ2=6.098, P=0.014), neutrophil percentage-to-albumin ratio ( Z=2.875, P=0.004), serum chloride ( Z=4.011, P<0.001), alkaline phosphatase ( Z=2.850, P=0.040), D-dimer ( Z=3.166, P=0.002), proportion of hypoalbuminemia ( χ2=7.543, P=0.006), and proportion of hypocalcemia ( χ2=39.836, P<0.001). Kaplan-Meier survival analysis showed that the PD technical survival rates in the peritonitis group and the low serum magnesium group were significantly lower than those in the control group and the high serum magnesium group, respectively (Log-rank test, χ2=9.332, P=0.002; χ2=7.856, P=0.005). Multivariate logistic regression analysis showed that the serum calcium ( OR=23.237, 95% CI 3.807-141.845) and serum chlorine level ( OR=0.919, 95% CI 0.858-0.985) were independently correlated with the increased serum magnesium. Multivariate Cox regression analysis showed that elevated baseline serum magnesium was an independent protective factor of PD technique failure ( HR=0.351, 95% CI 0.188-0.653). Conclusions:Elevated serum magnesium is an independent protective factor of PD technology failure. Maintaining an appropriate serum magnesium level may improve the prognosis of PD patients.

Objective To establish a scientific and feasible Chinese medicine(CM)comprehensive control and prevention program for elderly hypertension with early renal damage(EH-ERD)patients through high-level evidence-based medicine(EBM)evidence.Methods On the basis of literature research and evidence evaluation,we construct a database of specific prescriptions and implementation methods of CM comprehensive control and prevention program with EH-ERD.40 senior titled-experts were consulted in two rounds of questionnaires based on Delphi methods.We selected,evaluated,and revised specific CM comprehensive control and prevention program of EH-ERD through the analysis of multiple factors,such as expert's positive activity coefficient,authority coefficient,degree of opinion concentration and degree of coordination.Results In view of the CM appropriate intervention techniques with high-grade evidence(level Ⅰ and Ⅱ)and recommendation(level A and B),we have developed the CM comprehensive control and prevention plan items for EH-ERD.The activity coefficients in two-round consultation were 92.5%and 97.14%respectively,the overall authority coefficient(Cr)was exceeded 0.70,and the coordination coefficient was less than 0.25.With a sound activity coefficient,a relatively high Cr and a rather unified degree of opinion concentration and coordination,the CM comprehensive control and prevention program for EH-ERD was established,which included six primary indicators(CM compound preparation,acupuncture and massage,CM health education,medicinal diet therapy,health care exercise and foot bath)and seventeen secondary indicators.Conclusion The CM comprehensive control and prevention program for EH-ERD established in this study can provide a basis for the further formation of expert consensus or guidelines.Moreover,it can supply the strategy and paradigm for standardization of CM-based health management of EH-ERD.

Objective : To explore whether chrysophanol(CHR) affects macrophage polarization by promoting mitochondrial biosynthesis through AMPK/PGC-1α pathway. Methods : The molecular docking and binding ability of CHR with AMPK and PGC-1α were predicted by Autodock vina software. Human monocytes(THP-1) were induced to M0 macrophages by phorbol myristate acetate(PMA), and to M1 macrophages by lipopolysaccharide(LPS) combined with interferon-γ(IFN-γ), which were set as Control group. M1 macrophages treated with CHR were set as CHR group. M1 macrophages treated with CHR combined with AMPK inhibitor(Compound C) were set as CHR+Compound C group. The mRNA expression levels of M1 macrophage markers(iNOS, CD86) and mitochondrial biosynthesis related genes(PGC-1α, NFR-1, TFAM) were detected by Quantitative real time polymerase chain reaction(qRT-PCR). The expression level of M1 macrophage marker iNOS was detected by immunofluorescence. The protein expression levels of AMPK, p-AMPK and PGC-1α were detected by Western blot. Results : The docking results showed that the binding energies of CHR with AMPK and PGC-1α were-8.4 kcal/mol and-7.4 kcal/mol, respectively. qRT-PCR results showed that the in vitro model of M1 macrophages was successfully established. Compared with the Control group, CHR treatment significantly increased the mRNA expression of mitochondrial biosynthesis-related genes PGC-1α, NFR-1, and TFAM(P<0.001). Compared with CHR treatment group, CHR combined with Compound C treatment significantly decreased the mRNA expression levels of mitochondrial biosynthesis-related genes PGC-1α, NFR-1, and TFAM(P<0.05). Immunofluorescence results showed that CHR treatment inhibited the protein expression of iNOS compared with the Control group(P<0.001). Compared with CHR treatment group,CHR combined with Compound C treatment reversed the inhibitory effect of CHR on i NOS protein expression(P<0.05). Western blot results showed that compared with the Control group,the CHR treatment group had significant increase in the protein expression levels of p-AMPK and PGC-1α(P<0.001).Compared with CHR treatment group,CHR combined with Compound C treatment significantly decreased the protein expression levels of p-AMPK and PGC-1α(P<0.05). Conclusion Chrysophanol may inhibit macrophage polarization to M1 by activating AMPK/PGC-1α signaling pathway to promote mitochondrial biosynthesis.

Objective:To investigate the clinical effects and impact on balance control ability in elderly patients with chronic low back pain using dynamic neuromuscular stabilization(DNS)technique.Method:Forty elderly patients with chronic low back pain were randomly divided into two groups:an experi-mental group and a control group,with 20 participants in each group.The experimental group received DNS training,while the control group received conventional core muscle training.Both groups trained three times a week for four consecutive weeks.Before and after the intervention,visual analogue scale(VAS),Oswestry disability index(ODI),and Roland-Morris disability questionnaire(RMDQ)were used to evaluate the pain and functionality in both groups.The balance control performance of the two groups was evaluated using a bal-ance testing system,assessing parameters such as anterior-posterior movement speed,left-right movement speed,and travel distance during open-eyed double-leg stance,closed-eyed double-leg stance,and open-eyed single-leg stance before and after intervention.Repeated measures analysis of variance was used to assess differ-ences in clinical scales and balance performance before and after intervention in two groups.Result:After 4 weeks of intervention,both groups showed significant reductions in VAS(F=63.386,P<0.001),ODI(F=21.204,P<0.001),and RMDQ(F=38.501,P<0.001)scores compared to pre-intervention(P<0.01).There were no statistically significant differences between two groups(P>0.05).During open-eyed double-leg stance,the experimental group had smaller left-right movement speed than the control group(F=4.228,P=0.047).During closed-eyed double-leg stance,the experimental group had smaller left-right move-ment speed(F=6.560,P=0.015)compared to the control group.During open-eyed single-leg stance,the experi-mental group had smaller anterior-posterior movement speed(F=14.252,P=0.002)and travel distance(F=1.014,P=0.036)compared to the control group.Conclusion:DNS training can relieve pain,improve functionality and balance control ability in elderly pa-tients with chronic low back pain.

Objective:To explore the association between serum magnesium levels during catheterization in peritoneal dialysis (PD) patients and the failure of PD technology.Methods:It was a retrospective study. The baseline data, laboratory tests and clinical events of inpatients with end-stage renal disease aged ≥18 years who received PD catheterization for the first time from April 1, 2005 to February 29, 2024 were collected, and the follow-up was conducted until June 1, 2024. PD technique failure was defined as extubation for conversion to hemodialysis or patient death. The optimal cut-off value of serum magnesium (0.782 mmol/L) was determined based on the Youden index of the receiver operating characteristic curve for predicting the failure of PD technology. The patients were divided into high serum magnesium group and low serum magnesium group, and differences of baseline clinical data and follow-up outcomes between the two groups were compared. Kaplan-Meier method was used to compare the differences of PD technical survival rates between the two groups. Logistic regression model was used to analyze the related factors of baseline increased serum magnesium levels (0.785 mmol/L) in PD patients. Cox proportional hazards regression model was used to analyze the risk factors for the failure of PD technology.Results:A total of 706 PD patients were included in this study, with age of 43.89 (33.43, 53.70) years. Among them, 339 (48.02%) patients were male. The serum creatinine was (800.45±238.81) μmol/L. The follow-up time was 726.00 (216.00, 1 344.00) days. The incidence of peritonitis was 0.072 times per patient-year, and the failure rate of PD technique was 15.58% (110/706). There were 551 patients (78.05%) in the high serum magnesium group and 155 patients (21.95%) in the low serum magnesium group. Compared with the high serum magnesium group, the low serum magnesium group had significantly lower levels of serum creatinine ( t=-2.743, P=0.006), blood urea nitrogen ( t=-2.428, P=0.004), serum uric acid ( t=-2.346, P=0.005), red blood cell count ( t=-4.100, P<0.001), hemoglobin ( Z=-4.195, P<0.001), serum albumin ( t=-4.400, P<0.001), platelet count ( Z=-2.428, P=0.015), platelet-to-monocyte ratio ( Z=-2.541, P=0.011), serum calcium ( t=-7.463, P<0.001), serum phosphorus ( t=-3.052, P=0.001), prothrombin activity ( t=-3.052, P=0.005) and proportion of hyperphosphatemia ( χ2=6.924, P=0.009), and higher male proportion ( χ2=8.984, P=0.030), proportion of conversion to hemodialysis ( χ2=6.098, P=0.014), neutrophil percentage-to-albumin ratio ( Z=2.875, P=0.004), serum chloride ( Z=4.011, P<0.001), alkaline phosphatase ( Z=2.850, P=0.040), D-dimer ( Z=3.166, P=0.002), proportion of hypoalbuminemia ( χ2=7.543, P=0.006), and proportion of hypocalcemia ( χ2=39.836, P<0.001). Kaplan-Meier survival analysis showed that the PD technical survival rates in the peritonitis group and the low serum magnesium group were significantly lower than those in the control group and the high serum magnesium group, respectively (Log-rank test, χ2=9.332, P=0.002; χ2=7.856, P=0.005). Multivariate logistic regression analysis showed that the serum calcium ( OR=23.237, 95% CI 3.807-141.845) and serum chlorine level ( OR=0.919, 95% CI 0.858-0.985) were independently correlated with the increased serum magnesium. Multivariate Cox regression analysis showed that elevated baseline serum magnesium was an independent protective factor of PD technique failure ( HR=0.351, 95% CI 0.188-0.653). Conclusions:Elevated serum magnesium is an independent protective factor of PD technology failure. Maintaining an appropriate serum magnesium level may improve the prognosis of PD patients.

Objective To establish a scientific and feasible Chinese medicine(CM)comprehensive control and prevention program for elderly hypertension with early renal damage(EH-ERD)patients through high-level evidence-based medicine(EBM)evidence.Methods On the basis of literature research and evidence evaluation,we construct a database of specific prescriptions and implementation methods of CM comprehensive control and prevention program with EH-ERD.40 senior titled-experts were consulted in two rounds of questionnaires based on Delphi methods.We selected,evaluated,and revised specific CM comprehensive control and prevention program of EH-ERD through the analysis of multiple factors,such as expert's positive activity coefficient,authority coefficient,degree of opinion concentration and degree of coordination.Results In view of the CM appropriate intervention techniques with high-grade evidence(level Ⅰ and Ⅱ)and recommendation(level A and B),we have developed the CM comprehensive control and prevention plan items for EH-ERD.The activity coefficients in two-round consultation were 92.5%and 97.14%respectively,the overall authority coefficient(Cr)was exceeded 0.70,and the coordination coefficient was less than 0.25.With a sound activity coefficient,a relatively high Cr and a rather unified degree of opinion concentration and coordination,the CM comprehensive control and prevention program for EH-ERD was established,which included six primary indicators(CM compound preparation,acupuncture and massage,CM health education,medicinal diet therapy,health care exercise and foot bath)and seventeen secondary indicators.Conclusion The CM comprehensive control and prevention program for EH-ERD established in this study can provide a basis for the further formation of expert consensus or guidelines.Moreover,it can supply the strategy and paradigm for standardization of CM-based health management of EH-ERD.

Cervical spine health issues not only seriously affect patients' quality of life but also impose a heavy burden on the social healthcare system. Existing guidelines lack sufficient clinical guidance on lifestyle and work habits, such as exercise, posture, daily routine, and diet, making it difficult to meet practical needs. To address this, relying on the China Association of Chinese Medicine, Wangjing Hospital of China Academy of Chinese Medical Sciences took the lead and joined hands with more than ten institutions to form a multidisciplinary guideline development group. For the first time, the group developed the Guidelines for Cervical Spine Health Intervention based on evidence-based medicine methods, strictly following the standardized procedures outlined in the World Health Organization Handbook for Guideline Development and the Guiding Principles for the Formulation/Revision of Clinical Practice Guidelines in China (2022 Edition). This proposal systematically explains the methods and steps for developing the guideline, aiming to make the guideline development process scientific, standardized, and transparent.
Humans ; Practice Guidelines as Topic/standards* ; Cervical Vertebrae ; China

Objective:To investigate the characteristics of spatiotemporal heterogeneity in pathological grading during the latent and invas-ive growth phases of non-metastatic renal cell carcinoma(RCC)and its correlation with clinical outcomes.Methods:A retrospective analysis was conducted on the case data of 316 RCC patients with local recurrence(LR)and 429 RCC patients with venous tumor thrombus(VTT)who underwent surgical treatment at 13 medical centers in China from January 2003 to December 2023.Pathological grade differences between primary tumor(PT)and LR,and between PT and VTT were selected as scenarios for the application of spatiotemporal heterogen-eity in the dynamic progression of RCC.Pathological grading changes were defined according to a new four-tier scheme(upgrading,down-grading,stable low-grade,and stable high-grade).Stable low-or high-grade was defined as low-grade(WHO/ISUP grade Ⅰ or Ⅱ)or high-grade(WHO/ISUP grade Ⅲ or Ⅳ)in both PT and LR/VTT.Upgrading was defined as low-grade in the PT and high-grade in the LR/VTT;con-versely,downgrading was defined as high-grade in the PT and low-grade in the LR/VTT.The potential influencing factors of pathological grading changes and their impact on patient prognosis were analyzed.Results:The median cancer-specific survival(CSS)for RCC patients with VTT and RCC patients with LR was 83 months and 76 months,respectively.The 5-year CSS rates were 65.6%and 60.6%,respectively.Pathological grading changes were observed in 38.0%of patients with PT and VTT and in 43.6%of patients with PT and LR.Lasso-Logistic re-gression analysis revealed a close correlation between primary tumor necrosis and pathological grading changes.Kaplan-Meier survival curves indicated a significant correlation between pathological grading changes and prognosis.Replacing the pathological grading in Leibovich,UISS,and GRANT scores with pathological grading changes significantly improved the predictive performance of the models(P<0.05).Conclusions:Spatiotemporal heterogeneity in pathological grading exists during the dynamic progression of non-metastatic RCC.Compared to the pathological grading of isolated events,the spatiotemporal variation in pathological grading serves as a more accurate in-dependent prognostic factor for RCC patients with VTT and RCC patients with LR.Incorporating pathological grading changes can signific-antly improve the predictive performance of existing prognostic models.