Objective:Exploring the association between Life's Crucial 9 (LC9) and the risk of thyroid dysfunction (TD), as well as its potential predictive capacity.Methods:A total of 247 600 TD-free participants from the UK Biobank were enrolled in the study. The LC9 score was divided into three CVH groups: low (0-), medium (50-), and high (80-100). Cox proportional hazards regression models were used to calculate the HRs and 95% CIs of the risk of TD with LC9 CVH status. Calculate Harrell's concordance index ( C-index), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) to evaluate the predictive ability of the LC9 score and Life's Essential 8 (LE8) score. Results:During a median follow-up of 12.3 years, 5 515, 911, and 4 869 new cases of TD, hyperthyroidism, and hypothyroidism were documented, respectively. Participants with a high LE8 CVH group had 57.00% ( HR=0.43, 95% CI: 0.38-0.49), 55.00% ( HR=0.45, 95% CI: 0.34-0.60), and 58.00% ( HR=0.42, 95% CI: 0.37-0.47) lower risk of TD, hyperthyroidism, and hypothyroidism, respectively, than those with low CVH group. Compared with the LE8 score, the improvement in C-index for the LC9 score predicted TD risk was 0.004 (95% CI: 0.001-0.007), the NRI was 0.101 (95% CI: 0.021-0.103), and the IDI was 0.001 (95% CI: 0.000-0.001). Conclusions:The better CVH status, defined by LC9, was associated with a lower risk of TD. Compared to the LE8 score, the LC9 score demonstrated a significant enhancement in both risk discrimination and reclassification capability for TD risk.

Objective To investigate the expression of T cell subsets in the spleen of BTBR T+Itpr3tf autistic mouse at 4,8,and 12 weeks of age,and to determine the optimal age for studying the relationship between immune abnormalities and autism in BTBR autistic mice.Methods It randomly selected 5～6 male BTBR mouse at 4 weeks,8 weeks,and 12 weeks of age and C57BL/6J mouse of the same gender at corresponding ages for the three-box social interaction test,the self-grooming test,and the marble-burying test;Single cell suspensions were prepared from the spleens of mouse at 8 and 12 weeks of age,and flow cytometry was used to detect 8 subsets of T cells(TH 1,TH2,TH17,TC1,TC2,TC17,TFH,and Treg).Results Compared with C57BL/6J mouse of the same age,BTBR mouse at 4 weeks,8 weeks,and 12 weeks of age showed a decrease in social time(P＜0.001),an increase in grooming time(P＜0.01,P＜0.001),and an increase in the number of marbles buried(P＜0.01,P＜0.001)in BTBR mouse at 8 weeks and 12 weeks of age.As well,the expression of TH 1(P＜0.001),TH2(P＜0.01),TC 1(P＜0.05),TC2(P＜0.001),and TFH(P＜0.01)cells in 8-week-old BTBR mouse were significantly increased,while the expression of Treg(P＜0.001)cells were significantly decreased;The expression of TH 1(P＜0.01),TH2(P＜0.01),TH 17(P＜0.05),TC1(P＜0.01),TC2(P＜0.001),TC 17(P＜0.01),and TFH(P＜0.001)increased in 12-week-old BTBR mouse,while the expression of Treg(P＜0.05)cells decreased.At different age stages(P＜0.050)the ratio of TH 1/Treg and TC 1/Treg in 8-week-old BTBR mouse were significantly higher than those in 12 week old mouse,while the TC 17/Treg ratio decreased.Conclusions BTBR mouse at different developmental stages exhibit varying degrees of abnormal increase in Teff/Treg ratio.Based on result of behavioral test,it is recommended to use 8-week-old BTBR mice for research on autism and immune abnormalities.

Objective:Exploring the association between Life's Crucial 9 (LC9) and the risk of thyroid dysfunction (TD), as well as its potential predictive capacity.Methods:A total of 247 600 TD-free participants from the UK Biobank were enrolled in the study. The LC9 score was divided into three CVH groups: low (0-), medium (50-), and high (80-100). Cox proportional hazards regression models were used to calculate the HRs and 95% CIs of the risk of TD with LC9 CVH status. Calculate Harrell's concordance index ( C-index), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) to evaluate the predictive ability of the LC9 score and Life's Essential 8 (LE8) score. Results:During a median follow-up of 12.3 years, 5 515, 911, and 4 869 new cases of TD, hyperthyroidism, and hypothyroidism were documented, respectively. Participants with a high LE8 CVH group had 57.00% ( HR=0.43, 95% CI: 0.38-0.49), 55.00% ( HR=0.45, 95% CI: 0.34-0.60), and 58.00% ( HR=0.42, 95% CI: 0.37-0.47) lower risk of TD, hyperthyroidism, and hypothyroidism, respectively, than those with low CVH group. Compared with the LE8 score, the improvement in C-index for the LC9 score predicted TD risk was 0.004 (95% CI: 0.001-0.007), the NRI was 0.101 (95% CI: 0.021-0.103), and the IDI was 0.001 (95% CI: 0.000-0.001). Conclusions:The better CVH status, defined by LC9, was associated with a lower risk of TD. Compared to the LE8 score, the LC9 score demonstrated a significant enhancement in both risk discrimination and reclassification capability for TD risk.

Objective To investigate the expression of T cell subsets in the spleen of BTBR T+Itpr3tf autistic mouse at 4,8,and 12 weeks of age,and to determine the optimal age for studying the relationship between immune abnormalities and autism in BTBR autistic mice.Methods It randomly selected 5～6 male BTBR mouse at 4 weeks,8 weeks,and 12 weeks of age and C57BL/6J mouse of the same gender at corresponding ages for the three-box social interaction test,the self-grooming test,and the marble-burying test;Single cell suspensions were prepared from the spleens of mouse at 8 and 12 weeks of age,and flow cytometry was used to detect 8 subsets of T cells(TH 1,TH2,TH17,TC1,TC2,TC17,TFH,and Treg).Results Compared with C57BL/6J mouse of the same age,BTBR mouse at 4 weeks,8 weeks,and 12 weeks of age showed a decrease in social time(P＜0.001),an increase in grooming time(P＜0.01,P＜0.001),and an increase in the number of marbles buried(P＜0.01,P＜0.001)in BTBR mouse at 8 weeks and 12 weeks of age.As well,the expression of TH 1(P＜0.001),TH2(P＜0.01),TC 1(P＜0.05),TC2(P＜0.001),and TFH(P＜0.01)cells in 8-week-old BTBR mouse were significantly increased,while the expression of Treg(P＜0.001)cells were significantly decreased;The expression of TH 1(P＜0.01),TH2(P＜0.01),TH 17(P＜0.05),TC1(P＜0.01),TC2(P＜0.001),TC 17(P＜0.01),and TFH(P＜0.001)increased in 12-week-old BTBR mouse,while the expression of Treg(P＜0.05)cells decreased.At different age stages(P＜0.050)the ratio of TH 1/Treg and TC 1/Treg in 8-week-old BTBR mouse were significantly higher than those in 12 week old mouse,while the TC 17/Treg ratio decreased.Conclusions BTBR mouse at different developmental stages exhibit varying degrees of abnormal increase in Teff/Treg ratio.Based on result of behavioral test,it is recommended to use 8-week-old BTBR mice for research on autism and immune abnormalities.

Objective:To investigate the association of serum uric acid (SUA) with the outcome in patients with acute ischemic stroke (AIS) at one year after onset.Methods:Patients with AIS admitted to the Department of Neurology, Dagang Hospital, Tianjin Binhai New Area were included retrospectively. According to the modified Rankin Scale (mRS) score at 1 year after onset, patients were divided into a good outcome group (0-2) and a poor outcome group (>2). They were also divided into a survival group and a death group based on their survival status at 1 year after onset. The clinical baseline data and laboratory tests were compared. Multivariate logistic regression analysis was used to determine the associations of SUA with poor outcome and death in patients with AIS. Results:A total of 651 patients were enrolled, including 430 males (66.1%) aged 67.5±11.7 years. Four hundred and fourteen patients (63.6%) were in the good outcome group, and 237 (36.4%) were in the poor outcome group. There were 568 patients (87.3%) in the survival group and 43 (16.7%) in the death group. Univariate analysis showed that there were differences in age, atrial fibrillation, history of stroke or transient ischemic attack, baseline National Institutes of Health Stroke Scale (NIHSS) score, and pre-admission mRS score between the poor outcome group and the good outcome group. The homocysteine, SUA, white blood cell count, and creatinine in the poor outcome group were higher than those in the good outcome group, while the red blood cell count and hemoglobin were lower than those in the good outcome group (all P<0.05). There were differences in age, history of ischemic heart disease, atrial fibrillation, history of stroke or transient ischemic attack, baseline NIHSS score, pre-admission mRS score, and stroke etiology classification between the survival group and the death group. Hemoglobin and triglycerides in the survival group were higher than those in the death group, while the white blood cell count and creatinine were lower than those in the death group (all P<0.05). Multivariate logistic regression analysis showed that SUA was an independent risk factor for poor outcome in patients with AIS (odds ratio 1.004, 95% confidence interval 1.001-1.006; P<0.01), but there was no independent correlation with death. Conclusion:Higher SUA is an independent risk factor for poor outcome at one year after onset in patients with AIS.

Objective This study aims to analyze the medication patterns of traditional Chinese medicine(TCM)for the treatment of chronic arrhythmia and provide reference for its clinical management.Methods Relevant clinical research literature on TCM treatment for chronic arrhythmia was retrieved from databases including China National Knowledge Infrastructure,Wanfang Data Knowledge Service Platform,China Science and Technology Journal Database and PubMed.Software such as Excel 2019,SPSS Modeler 18.0,and SPSS 25.0 were utilized for statistical analysis of TCM formulas used in the treatment of chronic arrhythmia,including association rule analysis,factor analysis,and cluster analysis.Results A total of 77 prescriptions were included,involving 138 traditional Chinese medicines.The top 5 ranked medicines were Astragali Radix,Cinnamomi Ramulus,Glycyrrhizae Radix et Rhizoma,Salviae Miltiorrhizae Radix et Rhizoma,and Aconitum carmichaeli Debx.The highest support is for the combination of Astragali Radix and Aconitum carmichaeli Debx.Cluster analysis yielded 7 different combinations of medicines.Conclusion In the clinical treatment of chronic arrhythmia,the main therapeutic approach emphasizes tonifying Qi,warming Yang,nourishing Yin,and promoting blood circulation,with a greater emphasis on tonifying Qi.In TCM clinical practice,Shengmai San and modified Guizhi Gancao Tang are commonly used.

Objective To investigate the application value of tenofovir alafenamide fumarate(TAF)in patients with first-time hepatitis B virus-related decompensated cirrhosis(HBV-DC)and its impact on renal function and lipid metabolism.Methods A total of 57 patients with first-time HBV-DC who were hospitalized and received TAF antiviral therapy in The Affiliated Hospital of Xuzhou Medical University from January 1,2020 to December 31,2022 were enrolled,and all of them received TAF antiviral therapy.Related data were collected at baseline and at weeks 12,24,and 48 of treatment,including virological and serological indicators,liver and renal function,serum phosphorus,and blood lipids.The paired t-test or single group repeated measures ANOVA were used for comparison of normally distributed continuous data,the Friedman test was used for comparison of non-normally distributed continuous data,and the chi-square test or the Fisher's exact test were used for categorical data.Results A total of 52 patients completed the 48 weeks of follow-up.After 12,24,and 48 weeks of treatment,the patients achieving HBV DNA seroconversion accounted for 38.5%,63.5%,and 84.6%,respectively;the alanine aminotransferase normalization rate were 71.2%,82.7%,and 82.7%,respectively;the proportion of the patients with Child-Pugh class A disease increased to 55.8%,73.1%,and 92.3%,respectively.Within the 48 weeks of treatment,there were significant increases in the levels of cystatin C(χ2=35.163,P＜0.001)and serum phosphorus(F=8.600,P＜0.001)and low-density lipoprotein cholesterol(χ2=10.064,P=0.018).The ratio of total cholesterol/high-density lipoprotein cholesterol decreased continuously from 3.61(2.61～5.84)to 3.27(2.70～4.36)(χ2=5.000,P=0.172).Conclusion TAF can rapidly inhibit HBV replication and significantly improve liver function in HBV-DC patients,with no significant impact on renal function.However,blood lipid should be closely monitored.

Objective:To compare the aneuploidy rate of embryos between poor ovarian response (POR) patients and women with normal ovarian reserve stratified by age, and to eliminate the influence of ovarian reserve on embryo quality.Methods:This was a retrospective case-control study of patients who underwent preimplantation genetic testing for aneuploidies (PGT-A) at the Department of Reproduction and Genetics in Hospital for Reproductive Medicine, Shandong University from January 2017 to December 2020. According to the POSEIDON criteria, POR patients were divided into group 1 [age<35 years, anti-Müllerian hormone (AMH)≥1.2 μg/L, number of oocytes retrieved≤9, 258 cycles], group 2 (age≥35 years, AMH≥1.2 μg/L, number of oocytes retrieved≤9, 397 cycles), group 3 (age<35 years, AMH<1.2 μg/L, number of oocytes retrieved≤9, 99 cycles) and group 4 (age≥35 years, AMH<1.2 μg/L, number of oocytes retrieved≤9, 377 cycles). The aneuploidy rate of the blastocysts in each group was compared with age-matched control women with normal ovarian reserve and normal ovarian response (non-POR 1 group, non-POR 2 group, non-POR 3 group and non-POR 4 group, AMH≥1.2 μg/L, number of oocytes retrieved>9). Based on the difference in sample size of POR groups and control groups, a 1∶2 propensity score matching (PSM) analysis was performed between the <35 years old POR groups and age-matched control groups (POR 1 group vs. non-POR 1 group, POR 3 group vs. non-POR 3 group) and a 1∶1 PSM analysis was performed between the ≥35 years old POR groups and age-matched control groups (POR 2 group vs. non-POR 2 group, POR 4 group vs. non-POR 4 group). The main outcomes were the rates of euploid and aneuploid embryo, the secondary outcomes were the numbers of oocytes retrieved, metaphaseⅡ oocytes, two pronuclei, embryos biopsied, euploid embryos, aneuploid embryos and mosaic embryos per cycle. Results:The number of oocytes retrieved and embryos biopsied embryos in POR 1-4 groups was significantly decreased compared with non-POR 1-4 groups [No. of oocytes retrieved: 7.0 (6.0, 9.0) vs. 16.0 (13.0, 20.0), 7.0 (5.0, 8.0) vs. 14.0 (11.0, 17.0), 6.0 (4.0, 9.0) vs. 16.0 (13.0, 20.0), 5.0 (3.0, 7.0) vs. 13.0 (11.0, 17.0), all P<0.001; No. of embryos biopsied: 3.0 (2.0, 4.0) vs. 4.0 (3.0, 6.0), 2.0 (1.0,3.0) vs. 3.0 (2.0, 5), 3.0 (2.0, 4.0) vs. 4.0 (3.0, 6.0), 2.0 (1.0, 3.0) vs. 3.0 (2.0, 5.0), all P<0.001]. After adjusting for repeated egg retrieval, PGT-A indications, ovarian stimulation protocol and total dosage of gonadotrophin, the embryo aneuploidy rate in group 4 POR patients was significantly higher than controls ( OR=1.252, 95% CI:1.053-1.488, P=0.011). However, no differences were identified in embryo aneuploidy rate between POR patients in groups 1, 2, 3 and corresponding controls, respectively (all P>0.05). Conclusion:The ovarian reserve adversely affects the quantity and quality of oocytes in advanced age POR women (≥35 years old). Decreased ovarian reserve in young women (<35 years old) mainly affects the number of oocytes retrieved.

Objective:To compare the aneuploidy rate of embryos between poor ovarian response (POR) patients and women with normal ovarian reserve stratified by age, and to eliminate the influence of ovarian reserve on embryo quality.Methods:This was a retrospective case-control study of patients who underwent preimplantation genetic testing for aneuploidies (PGT-A) at the Department of Reproduction and Genetics in Hospital for Reproductive Medicine, Shandong University from January 2017 to December 2020. According to the POSEIDON criteria, POR patients were divided into group 1 [age<35 years, anti-Müllerian hormone (AMH)≥1.2 μg/L, number of oocytes retrieved≤9, 258 cycles], group 2 (age≥35 years, AMH≥1.2 μg/L, number of oocytes retrieved≤9, 397 cycles), group 3 (age<35 years, AMH<1.2 μg/L, number of oocytes retrieved≤9, 99 cycles) and group 4 (age≥35 years, AMH<1.2 μg/L, number of oocytes retrieved≤9, 377 cycles). The aneuploidy rate of the blastocysts in each group was compared with age-matched control women with normal ovarian reserve and normal ovarian response (non-POR 1 group, non-POR 2 group, non-POR 3 group and non-POR 4 group, AMH≥1.2 μg/L, number of oocytes retrieved>9). Based on the difference in sample size of POR groups and control groups, a 1∶2 propensity score matching (PSM) analysis was performed between the <35 years old POR groups and age-matched control groups (POR 1 group vs. non-POR 1 group, POR 3 group vs. non-POR 3 group) and a 1∶1 PSM analysis was performed between the ≥35 years old POR groups and age-matched control groups (POR 2 group vs. non-POR 2 group, POR 4 group vs. non-POR 4 group). The main outcomes were the rates of euploid and aneuploid embryo, the secondary outcomes were the numbers of oocytes retrieved, metaphaseⅡ oocytes, two pronuclei, embryos biopsied, euploid embryos, aneuploid embryos and mosaic embryos per cycle. Results:The number of oocytes retrieved and embryos biopsied embryos in POR 1-4 groups was significantly decreased compared with non-POR 1-4 groups [No. of oocytes retrieved: 7.0 (6.0, 9.0) vs. 16.0 (13.0, 20.0), 7.0 (5.0, 8.0) vs. 14.0 (11.0, 17.0), 6.0 (4.0, 9.0) vs. 16.0 (13.0, 20.0), 5.0 (3.0, 7.0) vs. 13.0 (11.0, 17.0), all P<0.001; No. of embryos biopsied: 3.0 (2.0, 4.0) vs. 4.0 (3.0, 6.0), 2.0 (1.0,3.0) vs. 3.0 (2.0, 5), 3.0 (2.0, 4.0) vs. 4.0 (3.0, 6.0), 2.0 (1.0, 3.0) vs. 3.0 (2.0, 5.0), all P<0.001]. After adjusting for repeated egg retrieval, PGT-A indications, ovarian stimulation protocol and total dosage of gonadotrophin, the embryo aneuploidy rate in group 4 POR patients was significantly higher than controls ( OR=1.252, 95% CI:1.053-1.488, P=0.011). However, no differences were identified in embryo aneuploidy rate between POR patients in groups 1, 2, 3 and corresponding controls, respectively (all P>0.05). Conclusion:The ovarian reserve adversely affects the quantity and quality of oocytes in advanced age POR women (≥35 years old). Decreased ovarian reserve in young women (<35 years old) mainly affects the number of oocytes retrieved.

MEK is a canonical effector of mutant KRAS; however, MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers. Here, we identified mitochondrial oxidative phosphorylation (OXPHOS) induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer (NSCLC) resistance to the clinical MEK inhibitor trametinib. Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment, satisfying their energy demand and protecting them from apoptosis. As molecular events in this process, the pyruvate dehydrogenase complex (PDHc) and carnitine palmitoyl transferase IA (CPTIA), two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation. Importantly, the co-administration of trametinib and IACS-010759, a clinical mitochondrial complex I inhibitor that blocks OXPHOS, significantly impeded tumor growth and prolonged mouse survival. Overall, our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.