BACKGROUND: The American Heart Association (AHA) introduced the concept of cardiovascular-kidney-metabolic (CKM) health and stage, reflecting the interaction among metabolism, chronic kidney disease (CKD), and the cardiovascular system. However, the association between CKM stage and the long-term risk of cardiovascular disease (CVD) has not been validated. This study aimed to evaluate the long-term CVD risk associated with CKM health metrics and CKM stage using data from a population-based cohort study. METHODS: In total, 5293 CVD-free participants were followed up to around 13 years in the Chinese Multi-provincial Cohort Study (CMCS). Considering the pathophysiologic progression of CKM health metrics abnormalities (comprising obesity, central adiposity, prediabetes, diabetes, hypertriglyceridemia, CKD, and metabolic syndrome), participants were divided into CKM stages 0, 1, and 2. The time-dependent Cox regression models were used to estimate the cardiovascular risk associated with CKM health metrics and stage. Additionally, broader CVD outcomes were examined, with a specific assessment of the impact of stage 3 in 2581 participants from the CMCS-Beijing subcohort. RESULTS: Among participants, 91.2% (4825/5293) had at least one abnormal CKM health metric, 8.8% (468/5293), 13.3% (704/5293), and 77.9% (4121/5293) were in CKM stages 0, 1, and 2, respectively; and 710 incident CVD cases occurred during a median follow-up time of 13.3 years (interquartile range: 12.1 to 13.6 years). Participants with each poor CKM health metric exhibited significantly higher CVD risk. Compared with stage 0, the hazard ratio (HR) (95% confidence interval [CI]) for CVD incidence was 1.31 (0.84-2.04) in stage 1 and 2.27 (1.57-3.28) in stage 2. Significant interactive impacts existed between CKM stage and age or sex, with higher CVD risk related to increased CKM stages in participants aged <60 years or females. CONCLUSION These findings highlight the contribution of CKM health metrics and CKM stage to the long-term risk of CVD, suggesting the importance of multi-component recognition and management of poor CKM health in CVD prevention.
Humans ; Female ; Male ; Cardiovascular Diseases/etiology* ; Middle Aged ; Adult ; Cohort Studies ; Renal Insufficiency, Chronic/metabolism* ; Aged ; Risk Factors ; Metabolic Syndrome/metabolism* ; China ; East Asian People

Objective:To prepare a 177Lu labeled human epidermal growth factor receptor 2 (HER2) affibody 177Lu-1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid (NOTA)-maleimide (Mal)-cysteine (Cys)-ZHER 2: 342 ( 177Lu-NOTA-MZHER2 for short), and investigate its labeling process and anti-tumor properties. Methods:Two kinds of buffer systems (sodium acetate buffer system and sodium ascorbate buffer system) were investigated. The effects of pH value, precursor mass and reaction temperature on 177Lu labeling NOTA-MZHER2 were compared to obtain optimal labeling conditions. The radiochemical purity of labeled product was determined by instant thin-layer chromatography (ITLC), and its stabilities in PBS and plasma were observed. Human ovarian cancer cell line SKOV-3 was selected for cell internalization and cytotoxicity test to evaluate cell uptake and killing effect of 177Lu-NOTA-MZHER2. SKOV-3 tumor-bearing mice( n=3) were injected with 177Lu-NOTA-MZHER2, and microSPECT/CT imaging was performed. Another 40 tumor-bearing mice were divided into 22.2 MBq group (tail vein injection with probe of 22.2 MBq), control group (tail vein injection with PBS), low-dose group (tumor injection with probe of 3.7 MBq) and high-dose group (tumor injection with probe of 7.4 MBq). Tumor volume and mass of tumor-bearing mice were monitored after injection, and the anti-tumor effect and toxicity of probe were evaluated. Repeated measurement analysis of variance (Bonferroni method) was used to analyze the data. Results:The optimal labeling condition was 70-80 ℃ for 30 min in the system of sodium acetate buffer solution with pH=4 and precursor mass of 50 μg. Under these conditions, the labeling rate of 177Lu-NOTA-MZHER2 was (99.3±0.4)% and radiochemical purity was >99%. After 12 d in PBS and plasma, the radiochemical purities were (95.0±1.5)% and (95.0±2.1)%. Results of cell experiment showed that the internalization of 177Lu-NOTA-MZHER2 accounted for (29.02±3.50)% of the total uptake, and the survival rate of SKOV-3 cells was (48±6)% with the probe concerntration of 6×10 -3 Bq/L. SPECT imaging showed that 177Lu-NOTA-MZHER2 was still concentrated at the tumor site 96 h after injection with a dose of 18.5 MBq. Relative tumor volume (RTV) of tumor-bearing mice in 22.2 MBq group, high-dose group and low-dose group was significantly different from that in control group ( F=21.75, P<0.001). Twenty days after injection, RTV and relative body mass of the tumor-bearing mice in high-dose group were (140±7)% and (80±9)%, respectively. Compared with control group, high-dose group had obvious anti-tumor effect (both P<0.001). Conclusion:177Lu-NOTA-MZHER2 is successfully prepared, which is simple and efficient, and the probe has good anti-tumor effect.

Objective:To radiolabel hyperbranched polymer (HG)-modified liquid metal nanodroplet (LMND)@HG with 177Lu, and explore the radiotherapy sensitization effect on anti-breast cancer therapy. Methods:The ultrasonication method was used to prepare LMND@HG, and then 177LuCl 3 was mixed with LMND@HG to label 177Lu by alloying reactions. The labeling rate, plasma stability and cytotoxicity of 177Lu-LMND@HG were detected. Xenograft mouse model of breast cancer was constructed, and the tumor inhibition test was performed by an intratumoral injection. The tumor progression was monitored by in vivo imaging system. The mechanism of tumor inhibition was verified by immunohistochemistry and immunofluorescence assays. One-way analysis of variance, repeated measures analysis of variance, and the least significant difference t test were used to analyze the data. Results:177Lu was successfully labeled to LMND@HG with a high labeling efficiency >95%. The product did not require further purification and the plasma radiochemical purity was still higher than 95% after 5 d. The cytotoxicity test showed that a dose of 888 kBq (40 mg/L) 177Lu-LMND@HG had obvious toxicity to 4T1 cells, which was significantly lower than 177LuCl 3 (cell viabilities: (16.48±7.81)% vs (85.77±8.87)%; F=77.81, t=11.73, P<0.001) and LMND@HG ((46.53±5.75)%; t=6.20, P<0.001). The biological distribution results showed that 177Lu-LMND@HG was mainly distributed in tumor tissue 5 d after intratumoral injection. The results of the tumor inhibition experiment showed that 1.48 MBq 177Lu-LMND@HG could significantly inhibit the tumor growth compared with the 177LuCl 3 (tumor volume: (222.66±97.70) vs (789.13±245.04) mm 3;F=18.55, t=4.29, P=0.005). In vivo optical imaging of small animals showed that 1.48 MBq and 3.70 MBq 177Lu-LMND@HG both significantly inhibited the tumor growth. Immunofluorescence and immunohistochemical results showed that 177Lu-LMND@HG caused double-stranded DNA break, and suppressed the tumor growth by inhibiting cell proliferation and angiogenesis. Conclusions:A novel 177Lu-liquid metal-based reactive oxygen species (ROS) radiation sensitizer is successfully prepared in this study. The preparation method is efficient and convenient, and the product has high stability. 177Lu-LMND@HG shows an obvious radiotherapy sensitization effect on breast tumor-bearing mice.

Objective:To prepare a novel 68Ga-labeled bicyclic peptide targeting poliovirus receptor related protein 4 (PVRL4, Nectin-4), and evaluate its feasibility for breast cancer imaging via in vitro and in vivo experiments. Methods:A Biotin-modified bicyclic peptide targeting Nectin-4, Biotin-BMIC, was synthesized, and its targeting properties were preliminarily evaluated by in vitro cell staining experiments. BMIC was modified by 1, 4, 7-triazonane-1, 4-diacetic acid (NODA) and the labeling precursor NODA-BMIC was prepared. A potential PET probe targeting Nectin-4, 68Ga-NODA-BMIC was prepared by one-step labeling strategy. The imaging properties of the probe were investigated by in vivo microPET imaging and in vitro experiments in mice bearing breast tumors. Data were analyzed by independent-sample t test and repeated measures analysis of variance. Results:Fluorescence staining of the cells showed that the fluorescently labeled bicyclic peptide, Biotin-BMIC, was highly aggregated in Nectin-4 positive BT474 breast cancer cells compared to those in Nectin-4 negative MDA-MB-231 cells. The uncorrected yield of 68Ga-NODA-BMIC was (71.5±2.2)% and the radiochemical purity was greater than 95%. The specific activity was greater than 3 GBq/μmol. After incubation 10, 30, 60 and 120 min, higher radioactivity uptakes were found in BT474 breast cancer cells compared to those in MDA-MB-231 breast cancer cells respectively ( F=1 302.00, P<0.001). MicroPET imaging showed that the BT474 xenograft tumors were clearly visible with favorable contrast. A significant statistical difference in uptakes between BT474 and MDA-MB-231 xenograft tumor uptake at 10, 30, 60, and 120 min after probe injection respectively was existed ( F=1 826.00, P<0.001). At 60 min postinjection, the uptake value of BT474 tumors was (5.03±0.14) percentage activity of injection dose per gram of tissue (%ID/g), which was significantly higher than that of MDA-MB-231 tumors ((0.19±0.04) %ID/g; t=79.40, P<0.001). Meanwhile, the tumor-to-muscle ratios in the former were also greater than those in the latter ( F=222.00, P<0.001). At 60 min postinjection, the tumor-to-muscle ratio in the former was significantly higher than that in the latter (24.75±3.10 vs 1.30±0.15; t=14.31, P=0.002). The results were consistent with the immunohistochemistry staining. Conclusions:A novel bicyclic peptide PET probe targeting Nectin-4, 68Ga-NODA-BMIC, is easy to be synthesized and owns satisfactory labeling yield and radiological purity. The imaging performance is good and the target tissues could be visualized. It may play a unique role in the diagnosis and treatment of breast cancer.

Objective:To explore the etiological rules of multifactorial refractory infertility patients by association analysis.Methods:A total of 283 patients with refractory infertility met the inclusion criteria from January 2019 to December 2021 in Nanping People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine,were analyzed retrospectively.Using the Apriori algorithm,association rule analysis was performed on 7 etiological fac-tors:fallopian tube obstruction(FTO),intrauterine adhesions(IUA),ovarian dysfunction[diminished ovarian re-serve(DOR),premature ovarian insufficiency(POI)],polycystic ovary syndrome(PCOS),endometriosis(EMT),adenomyosis(AM)and thin endometrium(TE).Further stratified analysis was performed to assess the combina-tions of causes based on the severity of 4 major factors(EMT,FTO,IUA and DOR/POI).Results:①Among 283 patients,EMT(59.0%)and FTO(50.5%)were identified as the most frequent etiological factors,significantly more prevalent than the other causes(P=0.0000,P＜α').②The 5 most common etiological combinations were:FTO with EMT,PCOS with EMT,AM with FTO,DOR/POI with EMT,and AM with EMT.③After stratified analysis,it was found that the following combination of causes was ranked in the top three:with EMT stages I-IV being highly associated with FTO;the degree of merger between low stage with PCOS is high,while the degree of merger be-tween high stage with AM and DOR/POI is high.Different degrees of IUA are highly associated with EMT,FTO and DOR/POI,while severe IUA also being highly associated with TE.Both unilateral and bilateral FTO have a high degree of merger with EMT and AM.DOR and POI have a high degree of merger with EMT,FTO and AM.Conclusions:EMT and FTO are the main causes of refractory infertility.There are correlations among the causes combinations.The etiological factors combined with different stages of endometriosis are also different.These findings underscore the importance of a comprehensive diagnostic framework to address multifactorial etiologies and reduce missed diagnoses.

Objective:To explore the etiological rules of multifactorial refractory infertility patients by association analysis.Methods:A total of 283 patients with refractory infertility met the inclusion criteria from January 2019 to December 2021 in Nanping People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine,were analyzed retrospectively.Using the Apriori algorithm,association rule analysis was performed on 7 etiological fac-tors:fallopian tube obstruction(FTO),intrauterine adhesions(IUA),ovarian dysfunction[diminished ovarian re-serve(DOR),premature ovarian insufficiency(POI)],polycystic ovary syndrome(PCOS),endometriosis(EMT),adenomyosis(AM)and thin endometrium(TE).Further stratified analysis was performed to assess the combina-tions of causes based on the severity of 4 major factors(EMT,FTO,IUA and DOR/POI).Results:①Among 283 patients,EMT(59.0%)and FTO(50.5%)were identified as the most frequent etiological factors,significantly more prevalent than the other causes(P=0.0000,P＜α').②The 5 most common etiological combinations were:FTO with EMT,PCOS with EMT,AM with FTO,DOR/POI with EMT,and AM with EMT.③After stratified analysis,it was found that the following combination of causes was ranked in the top three:with EMT stages I-IV being highly associated with FTO;the degree of merger between low stage with PCOS is high,while the degree of merger be-tween high stage with AM and DOR/POI is high.Different degrees of IUA are highly associated with EMT,FTO and DOR/POI,while severe IUA also being highly associated with TE.Both unilateral and bilateral FTO have a high degree of merger with EMT and AM.DOR and POI have a high degree of merger with EMT,FTO and AM.Conclusions:EMT and FTO are the main causes of refractory infertility.There are correlations among the causes combinations.The etiological factors combined with different stages of endometriosis are also different.These findings underscore the importance of a comprehensive diagnostic framework to address multifactorial etiologies and reduce missed diagnoses.

Objective:To explore the etiological rules of multifactorial refractory infertility patients by association analysis.Methods:A total of 283 patients with refractory infertility met the inclusion criteria from January 2019 to December 2021 in Nanping People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine,were analyzed retrospectively.Using the Apriori algorithm,association rule analysis was performed on 7 etiological fac-tors:fallopian tube obstruction(FTO),intrauterine adhesions(IUA),ovarian dysfunction[diminished ovarian re-serve(DOR),premature ovarian insufficiency(POI)],polycystic ovary syndrome(PCOS),endometriosis(EMT),adenomyosis(AM)and thin endometrium(TE).Further stratified analysis was performed to assess the combina-tions of causes based on the severity of 4 major factors(EMT,FTO,IUA and DOR/POI).Results:①Among 283 patients,EMT(59.0%)and FTO(50.5%)were identified as the most frequent etiological factors,significantly more prevalent than the other causes(P=0.0000,P＜α').②The 5 most common etiological combinations were:FTO with EMT,PCOS with EMT,AM with FTO,DOR/POI with EMT,and AM with EMT.③After stratified analysis,it was found that the following combination of causes was ranked in the top three:with EMT stages I-IV being highly associated with FTO;the degree of merger between low stage with PCOS is high,while the degree of merger be-tween high stage with AM and DOR/POI is high.Different degrees of IUA are highly associated with EMT,FTO and DOR/POI,while severe IUA also being highly associated with TE.Both unilateral and bilateral FTO have a high degree of merger with EMT and AM.DOR and POI have a high degree of merger with EMT,FTO and AM.Conclusions:EMT and FTO are the main causes of refractory infertility.There are correlations among the causes combinations.The etiological factors combined with different stages of endometriosis are also different.These findings underscore the importance of a comprehensive diagnostic framework to address multifactorial etiologies and reduce missed diagnoses.

Objective:To explore the etiological rules of multifactorial refractory infertility patients by association analysis.Methods:A total of 283 patients with refractory infertility met the inclusion criteria from January 2019 to December 2021 in Nanping People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine,were analyzed retrospectively.Using the Apriori algorithm,association rule analysis was performed on 7 etiological fac-tors:fallopian tube obstruction(FTO),intrauterine adhesions(IUA),ovarian dysfunction[diminished ovarian re-serve(DOR),premature ovarian insufficiency(POI)],polycystic ovary syndrome(PCOS),endometriosis(EMT),adenomyosis(AM)and thin endometrium(TE).Further stratified analysis was performed to assess the combina-tions of causes based on the severity of 4 major factors(EMT,FTO,IUA and DOR/POI).Results:①Among 283 patients,EMT(59.0%)and FTO(50.5%)were identified as the most frequent etiological factors,significantly more prevalent than the other causes(P=0.0000,P＜α').②The 5 most common etiological combinations were:FTO with EMT,PCOS with EMT,AM with FTO,DOR/POI with EMT,and AM with EMT.③After stratified analysis,it was found that the following combination of causes was ranked in the top three:with EMT stages I-IV being highly associated with FTO;the degree of merger between low stage with PCOS is high,while the degree of merger be-tween high stage with AM and DOR/POI is high.Different degrees of IUA are highly associated with EMT,FTO and DOR/POI,while severe IUA also being highly associated with TE.Both unilateral and bilateral FTO have a high degree of merger with EMT and AM.DOR and POI have a high degree of merger with EMT,FTO and AM.Conclusions:EMT and FTO are the main causes of refractory infertility.There are correlations among the causes combinations.The etiological factors combined with different stages of endometriosis are also different.These findings underscore the importance of a comprehensive diagnostic framework to address multifactorial etiologies and reduce missed diagnoses.

Objective:To explore the etiological rules of multifactorial refractory infertility patients by association analysis.Methods:A total of 283 patients with refractory infertility met the inclusion criteria from January 2019 to December 2021 in Nanping People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine,were analyzed retrospectively.Using the Apriori algorithm,association rule analysis was performed on 7 etiological fac-tors:fallopian tube obstruction(FTO),intrauterine adhesions(IUA),ovarian dysfunction[diminished ovarian re-serve(DOR),premature ovarian insufficiency(POI)],polycystic ovary syndrome(PCOS),endometriosis(EMT),adenomyosis(AM)and thin endometrium(TE).Further stratified analysis was performed to assess the combina-tions of causes based on the severity of 4 major factors(EMT,FTO,IUA and DOR/POI).Results:①Among 283 patients,EMT(59.0%)and FTO(50.5%)were identified as the most frequent etiological factors,significantly more prevalent than the other causes(P=0.0000,P＜α').②The 5 most common etiological combinations were:FTO with EMT,PCOS with EMT,AM with FTO,DOR/POI with EMT,and AM with EMT.③After stratified analysis,it was found that the following combination of causes was ranked in the top three:with EMT stages I-IV being highly associated with FTO;the degree of merger between low stage with PCOS is high,while the degree of merger be-tween high stage with AM and DOR/POI is high.Different degrees of IUA are highly associated with EMT,FTO and DOR/POI,while severe IUA also being highly associated with TE.Both unilateral and bilateral FTO have a high degree of merger with EMT and AM.DOR and POI have a high degree of merger with EMT,FTO and AM.Conclusions:EMT and FTO are the main causes of refractory infertility.There are correlations among the causes combinations.The etiological factors combined with different stages of endometriosis are also different.These findings underscore the importance of a comprehensive diagnostic framework to address multifactorial etiologies and reduce missed diagnoses.

Objective:To explore the etiological rules of multifactorial refractory infertility patients by association analysis.Methods:A total of 283 patients with refractory infertility met the inclusion criteria from January 2019 to December 2021 in Nanping People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine,were analyzed retrospectively.Using the Apriori algorithm,association rule analysis was performed on 7 etiological fac-tors:fallopian tube obstruction(FTO),intrauterine adhesions(IUA),ovarian dysfunction[diminished ovarian re-serve(DOR),premature ovarian insufficiency(POI)],polycystic ovary syndrome(PCOS),endometriosis(EMT),adenomyosis(AM)and thin endometrium(TE).Further stratified analysis was performed to assess the combina-tions of causes based on the severity of 4 major factors(EMT,FTO,IUA and DOR/POI).Results:①Among 283 patients,EMT(59.0%)and FTO(50.5%)were identified as the most frequent etiological factors,significantly more prevalent than the other causes(P=0.0000,P＜α').②The 5 most common etiological combinations were:FTO with EMT,PCOS with EMT,AM with FTO,DOR/POI with EMT,and AM with EMT.③After stratified analysis,it was found that the following combination of causes was ranked in the top three:with EMT stages I-IV being highly associated with FTO;the degree of merger between low stage with PCOS is high,while the degree of merger be-tween high stage with AM and DOR/POI is high.Different degrees of IUA are highly associated with EMT,FTO and DOR/POI,while severe IUA also being highly associated with TE.Both unilateral and bilateral FTO have a high degree of merger with EMT and AM.DOR and POI have a high degree of merger with EMT,FTO and AM.Conclusions:EMT and FTO are the main causes of refractory infertility.There are correlations among the causes combinations.The etiological factors combined with different stages of endometriosis are also different.These findings underscore the importance of a comprehensive diagnostic framework to address multifactorial etiologies and reduce missed diagnoses.