ObjectiveTo investigate the effects of metformin on the immune functions of immature dendritic cells （imDCs） and the underlying mechanisms. MethodsMouse bone marrow-derived imDCs were treated with different concentrations of metformin. The working concentration and treatment time of metformin in this study were determined based on the results of cell apoptosis and cell viability assays. The effects of metformin on the phagocytic capacity of imDCs was evaluated using an antigen endocytosis assay. The expression of cluster of differentiation 205 （CD205）， the polymerization of filamentous actin （F-actin）， and the underlying regulatory mechanisms were investigated through flow cytometry， laser confocal fluorescence microscopy， and Western blot. ResultsThe working concentrations of metformin were 1， 2， 4 mmol/L for 24 h determined by the apoptosis and cell viability assays.Metformin significantly suppressed the phagocytic capacity of imDCs， down-regulated the expression of the mannose receptor CD205 on the cell surface， which was closely associated with phagocytic function； metformin inhibited the RhoA-ROCK1-LIMK1-Cofilin signaling pathway， which inhibited the polymerization of F-actin and disturbed its dynamic remodeling of imDCs. ConclusionMetformin can inhibit the expression of CD205 and disrupt the remodeling of F-actin， thereby suppressing the antigen-capturing capacity of imDCs.

Background: The association of changes in metabolic syndrome (MetS) with cognitive function remains unclear. We explored this association using prospective and Mendelian randomization (MR) studies. Methods: MetS components including high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), waist circumference (WC), fasting plasma glucose (FPG), and triglycerides were measured at baseline and two follow-ups, constructing a MetS index. Immediate, delayed memory recall, and cognitive function along with its dimensions were assessed by immediate 10- word recall test (IWRT) and delayed 10-word recall test (DWRT), and mini-mental state examination (MMSE), respectively, at baseline and follow-ups. Linear mixed-effect model was used. Additionally, the genome-wide association study (GWAS) of MetS was conducted and one-sample MR was performed to assess the causality between MetS and cognitive function. Results: Elevated MetS index was associated with decreasing annual change rates (decrease) in DWRT and MMSE scores, and with decreases in attention, calculation and recall dimensions. HDL-C was positively associated with an increase in DWRT scores, while SBP and FPG were negatively associated. HDL-C showed a positive association, whereas WC was negatively associated with increases in MMSE scores, including attention, calculation and recall dimensions. Interaction analysis indicated that the association of MetS index on cognitive decline was predominantly observed in low family income group. The GWAS of MetS identified some genetic variants. MR results showed a non-significant causality between MetS and decrease in DWRT, IWRT, nor MMSE scores. Conclusion Our study indicated a significant association of MetS and its components with declines in memory and cognitive function, especially in delayed memory recall.

Background: The association of changes in metabolic syndrome (MetS) with cognitive function remains unclear. We explored this association using prospective and Mendelian randomization (MR) studies. Methods: MetS components including high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), waist circumference (WC), fasting plasma glucose (FPG), and triglycerides were measured at baseline and two follow-ups, constructing a MetS index. Immediate, delayed memory recall, and cognitive function along with its dimensions were assessed by immediate 10- word recall test (IWRT) and delayed 10-word recall test (DWRT), and mini-mental state examination (MMSE), respectively, at baseline and follow-ups. Linear mixed-effect model was used. Additionally, the genome-wide association study (GWAS) of MetS was conducted and one-sample MR was performed to assess the causality between MetS and cognitive function. Results: Elevated MetS index was associated with decreasing annual change rates (decrease) in DWRT and MMSE scores, and with decreases in attention, calculation and recall dimensions. HDL-C was positively associated with an increase in DWRT scores, while SBP and FPG were negatively associated. HDL-C showed a positive association, whereas WC was negatively associated with increases in MMSE scores, including attention, calculation and recall dimensions. Interaction analysis indicated that the association of MetS index on cognitive decline was predominantly observed in low family income group. The GWAS of MetS identified some genetic variants. MR results showed a non-significant causality between MetS and decrease in DWRT, IWRT, nor MMSE scores. Conclusion Our study indicated a significant association of MetS and its components with declines in memory and cognitive function, especially in delayed memory recall.

Objective:To explore the associated factors for membranous nephropathy (MN) patients with IgM deposition, and to construct a prediction model.Methods:This study was a retrospective cohort study. Patients diagnosed with MN with IgM deposition by renal biopsy in the Fourth Hospital of Hebei Medical University from February 2017 to December 2023 were retrospectively included. Clinical and pathological data were collected. The study population was randomized into a training set and a validation set at a 7:3 ratio. The endpoint event was defined as the remission of MN, and the patients were divided into remission group and non-remission group to compare the clinical and pathological examination results. Least absolute shrinkage and selection operator regression analysis and Cox regression analysis were used to explore the associated factors of poor prognosis of MN patients with IgM deposition. Internal validation was conducted using the validation set data. The clinical efficacy of the predictive model was evaluated by calculating the area under the receiver operating characteristic (ROC) curve and generating calibration curves. The total nomogram score for each patient was calculated based on the training set data, and the predictive performance was assessed by plotting the ROC curve. Patients were then stratified into low-risk and high-risk groups according to the optimal cut-off value derived from the ROC analysis of the total nomogram score. Kaplan-Meier survival analysis was performed to compare the remission rate between the two groups. Model performance was evaluated using the validation set.Results:A total of 200 MN patients with IgM deposition were included, and 49.0% of them achieved clinical remission. In the training set, statistically significant differences were observed in 24-hour urine protein quantification ( Z=-2.638, P=0.008), renal arteriolar wall thickening ( χ2=6.891, P=0.009), the proportion of patients receiving immunosuppressive therapy ( χ2=21.381, P<0.001), and the proportion of patients treated with corticosteroids combined with cyclophosphamide ( χ2=10.107, P=0.001). Through least absolute shrinkage and selection operator regression and Cox regression, 2 factors associated with clinical remission in MN patients with IgM deposition were simultaneously identified from 16 potential associated factors, including the use of immunosuppressants ( HR=3.823, 95% CI 2.055-7.113, P<0.001), and renal arteriolar wall thickening ( HR=0.428, 95% CI 0.221-0.831, P=0.012). Incorporating the clinical measurement of phospholipase A2 receptor (PLA2R) antibodies, a predictive model was established. The performance of the model was evaluated using the training dataset, yielding an area under the ROC curve of 0.731 (95% CI 0.648-0.814), with a sensitivity of 88.7% and a specificity of 55.1%. The optimal cut-off value was a total nomogram score of 41.7 points. The Kaplan-Meier survival analysis showed that the remission rate was significantly higher in the low-risk group than that of the high-risk group (Log-rank test, χ2=33.525, P<0.001). Model validation was performed using the validation dataset, which showed an AUC of 0.715 (95% CI 0.591-0.839), sensitivity of 70.4%, and specificity of 63.6%. Similarly, the Kaplan-Meier survival analysis demonstrated a significantly higher remission rate in the low-risk group than in the high-risk group (Log-rank test, χ2=8.467, P=0.004). Conclusion:A nomogram predictive model for remission of MN patients with IgM deposition, based on serum PLA2R antibody levels, the use of immunosuppressive therapy, and renal arteriolar wall thickening is developed. The model demonstrates a moderate clinical applicability.

Objective:To explore the efficacy and its related factors of rituximab (RTX) in the treatment of children with frequently relapsing nephrotic syndrome/steroid-dependent nephrotic syndrome (FRNS/SDNS).Methods:It was a single-center retrospective study. The clinical data of FRNS/SDNS children first treated with RTX in the First Affiliated Hospital of Sun Yat-sen University from November 1, 2016 to September 1, 2023 were collected. The number of relapse within 1 year before and after RTX treatment, the time to first relapse after RTX treatment, and the time to B-cell reconstitution were analyzed. At the first treatment, a single dose of RTX was given at 375 mg/m 2, with a maximum dose of 500 mg, once a week, for 1 to 4 doses. The count of CD19 + lymphocytes in the peripheral blood of the children was continuously monitored. If B-cell reconstruction was performed, the decision on whether to proceed to the next course of RTX treatment was made based on clinical manifestations. Kaplan-Meier method was used to analyze relapse-free survival rate after receiving RTX. Cox proportional hazards regression model was used to analyze the related factors of relapse after RTX treatment. Results:A total of 98 FRNS/SDNS children receiving RTX treatment were enrolled, including 75 males (76.5%). The age at onset was 4.0 (1.9, 7.1) years and age of receiving RTX was 11.3 (8.5, 13.5) years. There were 90 children (91.8%) achieving complete remission, while 8 patients (8.2%) did not respond to RTX treatment, and 3 patients (3.1%) progressed to end-stage kidney disease after receiving RTX. The relapse-free survival rates at 6 months and 1 year after RTX treatment were 83.3% (75/90) and 57.9% (22/38), respectively. The frequency of relapse 1 year after RTX treatment decreased compared to 1 year before RTX treatment ( Z=-7.398, P<0.001). Compared with children without relapse during the period of B-cell depletion, relapsed children had a higher number of relapse within one year after RTX treatment ( Z=5.246, P<0.001). The time to first relapse after RTX treatment was 8.3 (4.6, 13.9) months in 51 relapse patients. Compared with children receiving 1 dose of RTX in the first course, those receiving 2 or more doses had a longer time to the first relapse ( Z=2.983, P=0.003). There was no statistically significant difference in time to the first relapse between children who received mycophenolate mofetil therapy after RTX treatment and those who didn't ( P>0.05). The reconstruction time of B cells after the first course of RTX was 6.9 (5.3, 9.0) months. Compared to children receiving one dose of RTX in the first course, those receiving two or more doses had a longer B-cell reconstitution time ( Z=2.739, P=0.006). There was no statistically significant difference in B-cell reconstitution time between children who received mycophenolate mofetil therapy after RTX treatment and those who didn't ( P>0.05). Univariate Cox regression analysis showed that recurrence after calcineurin inhibitor (CNI) treatment before RTX treatment and the number of recurrence in one year before RTX treatment were correlated factors of recurrence after RTX treatment (both P<0.05). Multivariate Cox regression analysis showed that recurrence after CNI treatment before RTX treatment was an independent correlated factor of relapse after RTX therapy ( HR=3.496, 95% CI 1.245-9.818, P=0.018). Infusion reactions occurred in 10 patients (10.2%) and infections were observed in 24 patients (24.5%) during B cell depletion. No serious adverse events occurred. Conclusions:RTX is well tolerated and effective in treating FRNS/SDNS. Recurrence after CNI treatment before RTX treatment may be an independent related factor of relapse after RTX treatment.

Objective To comparatively analyze the clinical characteristics of primary bilateral macronodular adrenal hyperplasia(PBMAH)and adrenal cortisol-producing Adenoma(CPA),and enhance the understanding of two diseases.Methods The clinical data of 85 PBMAH patients(PBMAH group)and 195 CPA patients(CPA group)diagnosed at Department of Endocrinology,the First Medical Center of Chinese PLA General Hospital,from September 2014 to August 2024 were retrospectively analyzed.The demographic characteristics,comorbidities,biochemical indicators,adrenocorticotropic hormone-cortisol(ACTH-F)levels,and adrenal imaging features and treatment conditions were compared between the two groups.Results(1)General characteristics:Compared with CPA group,PBMAH group had older age at diagnosis and a higher proportion of male patients.(2)Clinical characteristics:Compared with CPA group,PBMAH group had a longer disease duration,a higher proportion of subclinical Cushing's syndrome(CS),and a higher proportion of hypertension,impaired glucose tolerance/diabetes,bone mass reduction or osteoporosis,with higher serum potassium levels,and the differences were statistically significant(P<0.01).(3)Hormone levels:Both PBMAH and CPA groups showed ACTH-F rhythm disorder,significantly increased cortisol levels and suppressed ACTH.Compared with PBMAH group,CPA group had stronger autonomous cortisol secretion ability,manifested by increased midnight serum cortisol(F0:00),16:00 serum cortisol(F16:00),24-hour urinary free cortisol(24 h UFC)levels and lower 8:00 serum ACTH(ACTH8:00)and 16:00 serum ACTH(ACTH16:00)(P<0.01).After low-dose dexamethasone suppression test(LDDST),CPA group showed lower suppression rates of ACTH and cortisol,and higher proportions of paradoxical elevation in serum cortisol and 24 h UFC compared with PBMAH(P<0.01).Conclusions PBMAH has a longer disease course and higher proportions of comorbid metabolic disorders than CPA,mostly manifested as subclinical Cushing's syndrome.CPA has stronger autonomous cortisol secretion ability,with cortisol less likely to be suppressed after LDDST and more obvious paradoxical elevation of cortisol and 24 h UFC.

Objective To characterize multimodal metabolic disorders in subclinical Cushing's syndrome(SCS)patients with different cortisol levels,providing a reference for clinical diagnosis and treatment.Methods A retrospective analysis was conducted on the clinical data of 165 SCS patients diagnosed at the First Medical Center of Chinese PLA General Hospital due to adrenal masses from January 2014 to October 2024.Using the serum cortisol levels after the midnight 1 mg dexamethasone suppression test(1 mg DST)as the cut-off point,SCS patients were divided into high-level group(1 mg DST-F>138 nmol/L,n=96)and low-level group(50 nmol/L<1 mg DST-F≤138 nmol/L,n=69).The differences in age,gender,body mass index(BMI),blood pressure,glucolipid metabolism indices,electrolytes,hormone levels,and imaging features of adrenal adenoma(such as CT values)were compared between the two groups.Multivariate linear regression was used to analyze the correlation between CT values and metabolic indices.Results Compared with low-level group,patients in high-level group were younger(54.0±11.3 vs.57.7±10.3,P=0.034),while there were no statistically significant differences in gender ratio or BMI between the two groups(P>0.05).Both groups exhibited decreased adrenocorticotropic hormone(ACTH)levels and disrupted circadian rhythm.Compared with low-level group,high-level group showed significantly higher F0:00 levels[250.00(170.07,422.53)nmol/L vs.110.00(82.74,133.90)nmol/L]and 24-hour urinary free cortisol(24 h UFC)[568.40(377.80,875.45)nmol/24 h vs.369.40(265.40,494.69)nmol/24 h](P<0.001),with no significant differences in serum F8:00,or 1 mg DST ACTH0:00 levels(P>0.05).Except for the fasting C-peptide level in the high-level group being higher than that in low-level group[(2.88±1.01)ng/ml vs.(2.46±0.78)ng/ml,P=0.024],there were no significant differences in blood pressure,blood lipids,glycated hemoglobin(HbA1c),fasting blood glucose,fasting insulin,serum electrolytes,uric acid,and other indices between the two groups(P>0.05).The CT value of adrenal adenoma during contrast-enhanced scanning was higher in high-level group[80.00(17.80,93.00)Hu vs.52.00(35.50,75.00)Hu,P=0.006]compared with low-level group.Multivariate linear regression analysis revealed that diastolic blood pressure was positively correlated with CT values of adrenal adenomas in both plain scanning(β=0.49,95%CI 0.09-0.90)and contrast-enhanced scanning(β=2.08,95%CI 0.76-3.39),while triglyceride levels were negatively correlated with plain scanning CT values(β=-5.77,95%CI-10.88--0.66).Conclusion Patients with SCS at different cortisol levels differ in age,fasting C-peptide levels,and CT values.CT values may serve as potential imaging markers to assess metabolic risk in SCS patients.

Objective To investigate the clinical characteristics of patients with clinical and subclinical Cushing's syndrome caused by primary bilateral macronodular adrenal hyperplasia(PBMAH).Methods A retrospective analysis was performed on the clinical data of 198 patients with Cushing's syndrome caused by PBMAH diagnosed in the First Medical Center of Chinese PLA General Hospital from January 2004 to October 2024.According to clinical manifestations,the patients were classified into clinical type Cushing's syndrome(n=61)and subclinical type Cushing's syndrome(n=137),and the clinical characteristics of the two types were compared.Results The mean age at diagnosis of patients with PBMAH-induced Cushing's syndrome was(53.5±10.4)years,including 118 males and 80 females,with a male-to-female ratio of 1.475:1.Compared with the subclinical type,the clinical type had a higher proportion of females,higher levels of serum cortisol,24-hour urine free cortisol(24 h UFC),and inhibited serum cortisol after low-dose dexamethasone suppression.Additionally,the clinical type had lower plasma ACTH,larger adrenal nodules and a higher risk of surgery(P<0.05)compared with those in subclinical type.The incidences of hypertension,dyslipidemia,obesity,diabetes mellitus,hypokalemia,vitamin D deficiency,osteoporosis,coronary heart disease,and cerebrovascular disease in patients with Cushing's syndrome caused by PBMAH were 87.9%,50.5%,37.1%,36.9%,27.8%,25.9%,18.7%,18.7%and 12.1%,respectively.Among them,compared with subclinical type patients,clinical type patients had higher incidence of hypokalaemia,vitamin D deficiency and osteoporosis(P<0.05),while there were no statistically significant differences in the incidences of other comorbidities between the two types(P>0.05).The results of postoperative follow-up for PBMAH patients showed that the short-term biochemical remission rate of unilateral total adrenalectomy was 41.5%(22/53)and the long-term biochemical remission rate was 32.0%(8/25).The short-term biochemical remission rate of unilateral partial(or nodular)adrenalectomy was 52.9%(9/17),and the long-term biochemical remission rate was 14.3%(1/7).All patients who underwent unilateral total adrenalectomy plus contralateral partial resection developed adrenal insufficiency(3/3),and 1 patient(1/3)relapsed 3.4 years after surgery.Conclusion Clinical and subclinical types of Cushing's syndrome caused by PBMAH have their distinct clinical characteristics.Surgery is an effective treatment for PBMAH,but a certain proportion of patients fail to achieve biochemical remission after non-bilateral total adrenalectomy.

BackgroundDepression in mid-to-late pregnancy has significant negative effects on pregnant women and their offspring. Previous studies have shown that pregnant women with depression in mid-to-late pregnancy exhibit lower frontal lobe activation levels， but the activation phase and its impact on depression require further investigation. ObjectiveTo analyze the functional near-infrared spectroscopy （fNIRS） features of depressed pregnant women in mid-to-late pregnancy， and to provide references for assisting in the clinical screening of depression in them. MethodsA total of 40 pregnant women in mid to late pregnancy with Edinburgh Postnatal Depression Scale （EPDS） score above 11 who underwent prenatal examination at the department of obstetrics of the Third Hospital of Mianyang from September 2023 to July 2024 were included as the study group. During the same period， 40 pregnant women in mid-to-late pregnancy with EPDS score below 11 who were matched with the age， family history， and past history of the study group were recruited as the control group. A self-designed questionnaire was used to collect basic information of the pregnant women. The fNIRS technique was used to measure the prefrontal and temporal lobe integral values and center of gravity values during the verbal fluency task （VFT） pregnant women in mid-to-late pregnancy. Spearman correlation analysis was conducted to examine the correlation between EPDS scores and fNIRS imaging features， as well as demographic characteristics， in mid-to-late pregnant women with depression. Multiple linear regression was used to analyze the influencing factors of depression symptoms in this population. ResultsStatistically significant differences were observed between the study group and the control group in terms of educational level and body mass index （BMI） （χ²/t=4.528， 2.292， P<0.05）. The study group demonstrated a lower prefrontal integral value and a higher prefrontal center of gravity value compared with the control group （t=-7.601， 5.641， P<0.05）. EPDS scores of depressed pregnant women in mid-to-late pregnancy were negatively correlated with prefrontal lobe integral value （r=-0.680， P<0.01）， while positively correlated with prefrontal lobe center of gravity value and BMI （r=0.737， 0.604， P<0.01）. Multiple linear regression analysis showed that age （β=-0.214， P<0.01）， BMI （β=0.340， P<0.01）， prefrontal integral value （β=-0.351， P<0.01）， and prefrontal center of gravity value （β=0.347， P<0.01） were influencing factors of depressive symptoms in pregnant women in mid-to-late pregnancy. ConclusionThe prefrontal lobe activation degree of depressed pregnant women in mid-to-late pregnancy is lower than that of non-depressed pregnant women， and the activation phase is delayed. Age， prefrontal lobe integral value， prefrontal center of gravity value and BMI may be the influencing factors of depressive symptoms in pregnant women in the middle and late pregnancy.

Debates persist regarding the efficacy and safety of azvudine, particularly its real-world outcomes. This study involved patients aged ≥60 years who were admitted to 25 hospitals in mainland China with confirmed SARS-CoV-2 infection between December 1, 2022, and February 28, 2023. Efficacy outcomes were all-cause mortality during hospitalization, the proportion of patients discharged with recovery, time to nucleic acid-negative conversion (T _NANC), time to symptom improvement (T _SI), and time of hospital stay (T _HS). Safety was also assessed. Among the 5884 participants identified, 1999 received azvudine, and 1999 matched controls were included after exclusion and propensity score matching. Azvudine recipients exhibited lower all-cause mortality compared with controls in the overall population (13.3% vs. 17.1%, RR, 0.78; 95% CI, 0.67-0.90; P = 0.001) and in the severe subgroup (25.7% vs. 33.7%; RR, 0.76; 95% CI, 0.66-0.88; P < 0.001). A higher proportion of patients discharged with recovery, and a shorter T _NANC were associated with azvudine recipients, especially in the severe subgroup. The incidence of adverse events in azvudine recipients was comparable to that in the control group (2.3% vs. 1.7%, P = 0.170). In conclusion, azvudine showed efficacy and safety in older patients hospitalized with COVID-19 during the SARS-CoV-2 omicron wave in China.