AIM:To evaluate the safety and toler-ability of single dose oral BTK inhibitor YZJ-3058 tablets under fasting conditions in healthy adults,as well as the pharmacokinetic and pharmacologi-cal characteristics of YZJ-3058 and its metabolites.METHODS:A total of 22 healthy subjects were en-rolled in this experiment and administered a single dose orally.They were divided into three groups:50 mg,100 mg,and 200 mg.Among them,2 sub-jects were enrolled in the 50 mg dose group,and 10 subjects were enrolled in the 100 mg and 200 mg dose groups,respectively.RESULTS:In healthy subjects,YZJ-3058 tablets were administered orally on an empty stomach at doses of 50,100,and 200 mg,with a median Tmax of 1.25 to 2.00 hours and an average Cmax of 62.85,89.44,and 99.20 ng/mL,re-spectively.The average AUC0-t was 183.87,297.72,and 453.98 h·ng-1·mL,respectively.The average AUC0-∞ was 189.30,321.33,and 551.44 h·ng-1·mL,and the median t1/2 was 1.16,5.06,and 7.97 hours,respectively.After a single oral administration of 50,100,and 200 mg YZJ-3058 tablets,the highest target occupancy rate was achieved at 4 hours.The average BTK occupancy rates at 24 hours after ad-ministration were 88.95％,96.73％,and 99.24％,re-spectively.The average BTK occupancy rates at 48 hours after administration were 75.65％,89.80％,and 96.68％,respectively.No serious adverse events or adverse events leading to withdrawal oc-curred,and all subjects had good tolerability.CON-CLUSION:YZJ-3058 tablets have good safety and tolerability for single oral administration on an empty stomach in healthy subjects within the dose range of 50-200 mg.Cmax and AUC increase with dose,with fast absorption and saturation.The ter-minal elimination rate gradually slows down with dose increase,and it has a significant and sus-tained occupying effect on BTK targets.

Objective:To analyze the association between physical activity levels and all-cause mortality risk in patients with diabetic kidney disease (DKD) and to investigate the mediating effect of inflammation.Methods:Based on National Health and Nutrition Examination Survey of America data matched with the National Death Index of America, a prospective cohort was formed, including 59 482 participants from six cycles between 2007 and 2018. After applying inclusion and exclusion criteria, 2 214 DKD patients were selected for the study. Cox proportional hazard regression models were used to analyze the impact of physical activity levels on all-cause mortality risk. The mediating effect of inflammatory markers in the association between physical activity and all-cause mortality risk was explored.Results:There were statistically significant differences in survival curves among different physical activity level groups ( P<0.001). As physical activity levels increased, the risk of mortality decreased. Patients in the high physical activity group had a lower mortality risk compared to those in the inactive group ( HR=0.64, 95% CI: 0.53-0.78), with a statistically significant difference ( P<0.001). Patients with higher physical activity levels had lower levels of inflammation (white blood cell, neutrophil, and C-reactive protein) ( P<0.001). White blood cell, neutrophil, C-reactive protein, the neutrophil-to-lymphocyte ratio (NLR), and the systemic inflammation index (SII) were independent risk factors for mortality in DKD patients ( HR>1.00), with higher risk effects observed for the combined indicator lgNLR ( HR=2.06, 95% CI: 1.76-2.41) and lgSII ( HR=1.44, 95% CI: 1.26-1.64). Mediation analysis showed that physical activity had an indirect effect on all-cause mortality risk through neutrophil, with an effect size of -0.033 (95% CI: -0.052 - -0.002), which was statistically significant ( P<0.05), with a mediation effect proportion of 9.75%. Conclusion:Physical activity is a protective factor against all-cause mortality risk in DKD patients, partly through reducing neutrophil levels.

Objective:To evaluate the clinical significance of morular metaplasia (MM) in fertility-preserving treatment for young patients with endometrial hyperplasia and grade 1 endometrial endometrioid carcinoma.Methods:Clinical data was retrospectively collected from patients diagnosed with endometrial hyperplasia or grade 1 endometrial endometrioid carcinoma under 40 years old who underwent progestin-based fertility-sparing treatmentat in Tianjin Medical University General Hospital between January 2018 and November 2022.Patients were divided into the MM group (37 cases) and the non-MM group (63 cases) based on pathological findings. Clinical characteristics, hysteroscopic features, treatment efficacy and fertility outcomes were compared between the two groups. The MM group was further stratified into three subgroups based on the timing of MM occurrence:(1) MM-Bef group ( n=10): MM was present in the initial endometrial curettage or hysteroscopic biopsy pathology before fertility-sparing treatment and disappeared after treatment; (2) MM-Sus group ( n=14): MM persisted consistently before and after therapy;(3) MM-Aft group ( n=13): MM was absent before therapy but appeared after treatment. The risk factors which had impact on the treatment outcomes of the patients were analyzed using univariate and multivariate Cox regression analysis. Results:The rate of polycystic ovary syndrome were higher in the MM group than the non-MM group [51% (19/37) vs 27% (17/63), P=0.014]. The complete response (CR) rate was significantly lower in the MM group than in the non-MM group [73% (27/37) vs 95% (60/63), P=0.006], and the median time to CR was significantly longer in the MM group (6.0 vs 5.0 months, P=0.005).Multivariate analysis identified that MM-Sus ( HR=0.355, 95% CI:0.174-0.723; P=0.004) and MM-Aft ( HR=0.314, 95% CI:0.145-0.681; P=0.003) were independent risk factors for delayed CR in fertility-sparing treatment. The patients in the MM group and non-MM group underwent hysteroscopic biopsy for 76 and 131 times. "Gravel-like change" was a more frequent hysteroscopic manifestation in the MM group than that in the non-MM group [18% (14/76) vs 2% (2/131), P<0.001]. Conclusions:Patients in the MM group have poorer treatment outcomes than patients in the non-MM group. MM-Sus and MM-Aft are risk factors for fertility-preserving treatment in young patients with endometrial hyperplasia or grade 1 endometrial endometrioid carcinoma. "Gravel-like change" is the characteristic hysteroscopic manifestations of MM.

Objective:To evaluate the clinical significance of morular metaplasia (MM) in fertility-preserving treatment for young patients with endometrial hyperplasia and grade 1 endometrial endometrioid carcinoma.Methods:Clinical data was retrospectively collected from patients diagnosed with endometrial hyperplasia or grade 1 endometrial endometrioid carcinoma under 40 years old who underwent progestin-based fertility-sparing treatmentat in Tianjin Medical University General Hospital between January 2018 and November 2022.Patients were divided into the MM group (37 cases) and the non-MM group (63 cases) based on pathological findings. Clinical characteristics, hysteroscopic features, treatment efficacy and fertility outcomes were compared between the two groups. The MM group was further stratified into three subgroups based on the timing of MM occurrence:(1) MM-Bef group ( n=10): MM was present in the initial endometrial curettage or hysteroscopic biopsy pathology before fertility-sparing treatment and disappeared after treatment; (2) MM-Sus group ( n=14): MM persisted consistently before and after therapy;(3) MM-Aft group ( n=13): MM was absent before therapy but appeared after treatment. The risk factors which had impact on the treatment outcomes of the patients were analyzed using univariate and multivariate Cox regression analysis. Results:The rate of polycystic ovary syndrome were higher in the MM group than the non-MM group [51% (19/37) vs 27% (17/63), P=0.014]. The complete response (CR) rate was significantly lower in the MM group than in the non-MM group [73% (27/37) vs 95% (60/63), P=0.006], and the median time to CR was significantly longer in the MM group (6.0 vs 5.0 months, P=0.005).Multivariate analysis identified that MM-Sus ( HR=0.355, 95% CI:0.174-0.723; P=0.004) and MM-Aft ( HR=0.314, 95% CI:0.145-0.681; P=0.003) were independent risk factors for delayed CR in fertility-sparing treatment. The patients in the MM group and non-MM group underwent hysteroscopic biopsy for 76 and 131 times. "Gravel-like change" was a more frequent hysteroscopic manifestation in the MM group than that in the non-MM group [18% (14/76) vs 2% (2/131), P<0.001]. Conclusions:Patients in the MM group have poorer treatment outcomes than patients in the non-MM group. MM-Sus and MM-Aft are risk factors for fertility-preserving treatment in young patients with endometrial hyperplasia or grade 1 endometrial endometrioid carcinoma. "Gravel-like change" is the characteristic hysteroscopic manifestations of MM.

AIM:To evaluate the safety and toler-ability of single dose oral BTK inhibitor YZJ-3058 tablets under fasting conditions in healthy adults,as well as the pharmacokinetic and pharmacologi-cal characteristics of YZJ-3058 and its metabolites.METHODS:A total of 22 healthy subjects were en-rolled in this experiment and administered a single dose orally.They were divided into three groups:50 mg,100 mg,and 200 mg.Among them,2 sub-jects were enrolled in the 50 mg dose group,and 10 subjects were enrolled in the 100 mg and 200 mg dose groups,respectively.RESULTS:In healthy subjects,YZJ-3058 tablets were administered orally on an empty stomach at doses of 50,100,and 200 mg,with a median Tmax of 1.25 to 2.00 hours and an average Cmax of 62.85,89.44,and 99.20 ng/mL,re-spectively.The average AUC0-t was 183.87,297.72,and 453.98 h·ng-1·mL,respectively.The average AUC0-∞ was 189.30,321.33,and 551.44 h·ng-1·mL,and the median t1/2 was 1.16,5.06,and 7.97 hours,respectively.After a single oral administration of 50,100,and 200 mg YZJ-3058 tablets,the highest target occupancy rate was achieved at 4 hours.The average BTK occupancy rates at 24 hours after ad-ministration were 88.95％,96.73％,and 99.24％,re-spectively.The average BTK occupancy rates at 48 hours after administration were 75.65％,89.80％,and 96.68％,respectively.No serious adverse events or adverse events leading to withdrawal oc-curred,and all subjects had good tolerability.CON-CLUSION:YZJ-3058 tablets have good safety and tolerability for single oral administration on an empty stomach in healthy subjects within the dose range of 50-200 mg.Cmax and AUC increase with dose,with fast absorption and saturation.The ter-minal elimination rate gradually slows down with dose increase,and it has a significant and sus-tained occupying effect on BTK targets.

Objective:To analyze the association between physical activity levels and all-cause mortality risk in patients with diabetic kidney disease (DKD) and to investigate the mediating effect of inflammation.Methods:Based on National Health and Nutrition Examination Survey of America data matched with the National Death Index of America, a prospective cohort was formed, including 59 482 participants from six cycles between 2007 and 2018. After applying inclusion and exclusion criteria, 2 214 DKD patients were selected for the study. Cox proportional hazard regression models were used to analyze the impact of physical activity levels on all-cause mortality risk. The mediating effect of inflammatory markers in the association between physical activity and all-cause mortality risk was explored.Results:There were statistically significant differences in survival curves among different physical activity level groups ( P<0.001). As physical activity levels increased, the risk of mortality decreased. Patients in the high physical activity group had a lower mortality risk compared to those in the inactive group ( HR=0.64, 95% CI: 0.53-0.78), with a statistically significant difference ( P<0.001). Patients with higher physical activity levels had lower levels of inflammation (white blood cell, neutrophil, and C-reactive protein) ( P<0.001). White blood cell, neutrophil, C-reactive protein, the neutrophil-to-lymphocyte ratio (NLR), and the systemic inflammation index (SII) were independent risk factors for mortality in DKD patients ( HR>1.00), with higher risk effects observed for the combined indicator lgNLR ( HR=2.06, 95% CI: 1.76-2.41) and lgSII ( HR=1.44, 95% CI: 1.26-1.64). Mediation analysis showed that physical activity had an indirect effect on all-cause mortality risk through neutrophil, with an effect size of -0.033 (95% CI: -0.052 - -0.002), which was statistically significant ( P<0.05), with a mediation effect proportion of 9.75%. Conclusion:Physical activity is a protective factor against all-cause mortality risk in DKD patients, partly through reducing neutrophil levels.

Objective:To investigate the differences in acoustic characteristics between older patients with dysarthria resulting from anterior and posterior circulation cerebral infarctions.Methods:A case-control study was conducted.Sixty hospitalized older patients with dysarthria were selected and divided into two groups: the anterior circulation cerebral infarction group and the posterior circulation cerebral infarction group, each comprising 30 cases.Additionally, thirty healthy individuals aged 65 and above were included as a control group.The subjective evaluation of the patients' overall phonetic function was conducted using the GRBAS scale.Objective parameters, including fundamental frequency(F0), Jitter, Shimmer, maximum phonation time(MPT), maximum sound pressure level(SPLmax), minimum sound pressure level(SPLmin), and the dysphonia severity index(DSI), were collected using the DIVAS2.5 voice analysis system.We analyzed the acoustic characteristics across the three groups: patients with dysarthria and healthy subjects.Results:The grade(G), roughness(R), breathiness(B), asthenia(A), and strain(S)scores of patients in both the anterior and posterior circulation cerebral infarction groups were significantly higher than those of the healthy control group( F=16.574, 39.793, 46.309, 52.154, 25.603; all P<0.001).Furthermore, the roughness(R)and strain(S)of the voice in the anterior circulation cerebral infarction group were significantly elevated compared to the posterior circulation cerebral infarction group, whereas the breathiness(B), asthenia(A), and grade(G)scores in the posterior circulation cerebral infarction group were significantly higher than those in the anterior circulation cerebral infarction group(all P<0.001).The fundamental frequency value(F0)of the voice in patients with anterior circulation cerebral infarction was significantly greater than that of both the posterior circulation cerebral infarction group and the healthy control group( F=39.050, P<0.001).In contrast, the fundamental frequency value(F0)of patients with posterior circulation cerebral infarction was lower than that of the healthy control group( P=0.003).Additionally, the Jitter value in the anterior circulation cerebral infarction group was higher than in both the posterior circulation cerebral infarction group and the healthy control group( F=64.976, P<0.001).The Shimmer value in the anterior circulation cerebral infarction group was lower than that in the posterior circulation cerebral infarction group but higher than that in the healthy control group(both P<0.001).Finally, the values of MPT, SPLmin and SPL max, DSI in the anterior circulation cerebral infarction group were higher than those in the posterior circulation cerebral infarction group and lower than those in the healthy control group( F=90.406, 24.003, 16.164; all P<0.001); the value of DSI in the anterior circulation cerebral infarction group was lower than in both the posterior circulation cerebral infarction group and the healthy control group( F=87.921, P<0.001). Conclusions:There are notable differences in the acoustic characteristic parameters of dysarthria resulting from injuries at various anatomical sites in older patients with cerebral infarction.In practical clinical settings, a comprehensive evaluation of dysarthria in these patients should integrate the anatomical location of the injury, subjective symptom assessment, and objective analysis of acoustic characteristics to inform precise and personalized rehabilitation strategies.

Objective:To investigate the differences in acoustic characteristics between older patients with dysarthria resulting from anterior and posterior circulation cerebral infarctions.Methods:A case-control study was conducted.Sixty hospitalized older patients with dysarthria were selected and divided into two groups: the anterior circulation cerebral infarction group and the posterior circulation cerebral infarction group, each comprising 30 cases.Additionally, thirty healthy individuals aged 65 and above were included as a control group.The subjective evaluation of the patients' overall phonetic function was conducted using the GRBAS scale.Objective parameters, including fundamental frequency(F0), Jitter, Shimmer, maximum phonation time(MPT), maximum sound pressure level(SPLmax), minimum sound pressure level(SPLmin), and the dysphonia severity index(DSI), were collected using the DIVAS2.5 voice analysis system.We analyzed the acoustic characteristics across the three groups: patients with dysarthria and healthy subjects.Results:The grade(G), roughness(R), breathiness(B), asthenia(A), and strain(S)scores of patients in both the anterior and posterior circulation cerebral infarction groups were significantly higher than those of the healthy control group( F=16.574, 39.793, 46.309, 52.154, 25.603; all P<0.001).Furthermore, the roughness(R)and strain(S)of the voice in the anterior circulation cerebral infarction group were significantly elevated compared to the posterior circulation cerebral infarction group, whereas the breathiness(B), asthenia(A), and grade(G)scores in the posterior circulation cerebral infarction group were significantly higher than those in the anterior circulation cerebral infarction group(all P<0.001).The fundamental frequency value(F0)of the voice in patients with anterior circulation cerebral infarction was significantly greater than that of both the posterior circulation cerebral infarction group and the healthy control group( F=39.050, P<0.001).In contrast, the fundamental frequency value(F0)of patients with posterior circulation cerebral infarction was lower than that of the healthy control group( P=0.003).Additionally, the Jitter value in the anterior circulation cerebral infarction group was higher than in both the posterior circulation cerebral infarction group and the healthy control group( F=64.976, P<0.001).The Shimmer value in the anterior circulation cerebral infarction group was lower than that in the posterior circulation cerebral infarction group but higher than that in the healthy control group(both P<0.001).Finally, the values of MPT, SPLmin and SPL max, DSI in the anterior circulation cerebral infarction group were higher than those in the posterior circulation cerebral infarction group and lower than those in the healthy control group( F=90.406, 24.003, 16.164; all P<0.001); the value of DSI in the anterior circulation cerebral infarction group was lower than in both the posterior circulation cerebral infarction group and the healthy control group( F=87.921, P<0.001). Conclusions:There are notable differences in the acoustic characteristic parameters of dysarthria resulting from injuries at various anatomical sites in older patients with cerebral infarction.In practical clinical settings, a comprehensive evaluation of dysarthria in these patients should integrate the anatomical location of the injury, subjective symptom assessment, and objective analysis of acoustic characteristics to inform precise and personalized rehabilitation strategies.

Objective:To evaluate the clinical efficacy and safety of a skin care ointment containing oligomeric maltose X in the adjuvant treatment of eczema-related pruritus.Methods:A multicenter, randomized, double-blind, vehicle-controlled clinical study was conducted. From March to September 2021, outpatients with mild to moderate eczema were collected from departments of dermatology of 4 hospitals, including Beijing Friendship Hospital, Hebei Traditional Chinese Medical Hospital, the Third People′s Hospital of Hubei Province, and Taizhou Central Hospital in Zhejiang Province. The patients were randomly divided into two groups by using a random number table: observation group topically treated with a skin care ointment containing oligomeric maltose X, and vehicle control group topically treated with an ointment vehicle. The ointments were applied during the attacks of itching for 14 consecutive days. Visits were scheduled before, 7, and 14 days after the start of the adjuvant treatment. The efficacy was evaluated according to the eczema area and severity index (EASI) and visual analog scale (VAS) , and adverse events were recorded. The efficacy and safety analyses were conducted by using chi-square test and t test. Results:Totally, 232 patients with eczema were enrolled, including 90 males and 142 females, with the age being 40.13 ± 13.36 years; 156 patients were in the observation group, and 76 in the vehicle control group. Before the adjuvant treatment, there were no significant differences in EASI (2.07 ± 2.24 points vs. 2.29 ± 2.28 points) or VAS (6.22 ± 1.78 points vs. 6.20 ± 1.79 points) scores between the observation group and vehicle control group ( t = -0.70, 0.06, P = 0.486, 0.955, respectively) . After one-day treatment, the VAS scores significantly decreased compared with the baseline scores in the two groups ( P < 0.001, P = 0.003, respectively) . After 14-day treatment, the VAS score was significantly lower in the observation group (2.67 points) than in the vehicle control group (3.35 points; t = -2.28, P = 0.024) . After 7- and 14-day treatment, the EASI scores significantly decreased compared with the baseline scores in both the two groups (all P < 0.001) , but there were no significant differences between the two groups ( P = 0.853, 0.731) . No adjuvant treatment-related adverse events were recorded in either of the two groups. Conclusion:The skin care ointment containing oligomeric maltose X is safe and effective in the adjuvant treatment of eczema-related pruritus, and can be applied to clinical practice.