BACKGROUND: Alpha-glucosidase inhibitors or dipeptidyl peptidase-4 inhibitors are both hypoglycemia agents that specifically impact on postprandial hyperglycemia. We compared the effects of acarbose and sitagliptin add on to metformin on time in range (TIR) and glycemic variability (GV) in Chinese patients with type 2 diabetes mellitus through continuous glucose monitoring (CGM). METHODS: This study was a randomized, open-label, active-con-trolled, parallel-group trial conducted at 15 centers in China from January 2020 to August 2022. We recruited patients with type 2 diabetes aged 18-65 years with body mass index (BMI) within 19-40 kg/m 2 and hemoglobin A1c (HbA1c) between 6.5% and 9.0%. Eligible patients were randomized to receive either metformin combined with acarbose 100 mg three times daily or metformin combined with sitagliptin 100 mg once daily for 28 days. After the first 14-day treatment period, patients wore CGM and entered another 14-day treatment period. The primary outcome was the level of TIR after treatment between groups. We also performed time series decomposition, dimensionality reduction, and clustering using the CGM data. RESULTS: A total of 701 participants received either acarbose or sitagliptin treatment in combination with metformin. There was no statistically significant difference in TIR between the two groups. Time below range (TBR) and coefficient of variation (CV) levels in acarbose users were significantly lower than those in sitagliptin users. Median (25th percentile, 75th percentile) of TBR below target level <3.9 mmol/L (TBR 3.9 ): Acarbose: 0.45% (0, 2.13%) vs . Sitagliptin: 0.78% (0, 3.12%), P = 0.042; Median (25th percentile, 75th percentile) of TBR below target level <3.0 mmol/L (TBR 3.0 ): Acarbose: 0 (0, 0.22%) vs . Sitagliptin: 0 (0, 0.63%), P = 0.033; CV: Acarbose: 22.44 ± 5.08% vs . Sitagliptin: 23.96 ± 5.19%, P <0.001. By using time series analysis and clustering, we distinguished three groups of patients with representative metabolism characteristics, especially in GV (group with small wave, moderate wave and big wave). No significant difference was found in the complexity of glucose time series index (CGI) between acarbose users and sitagliptin users. By using time series analysis and clustering, we distinguished three groups of patients with representative metabolism characteristics, especially in GV. CONCLUSIONS: Acarbose had slight advantages over sitagliptin in improving GV and reducing the risk of hypoglycemia. Time series analysis of CGM data may predict GV and the risk of hypoglycemia. TRIAL REGISTRATION Chinese Clinical Trial Registry: ChiCTR2000039424.
Humans ; Metformin/therapeutic use* ; Sitagliptin Phosphate/therapeutic use* ; Acarbose/therapeutic use* ; Diabetes Mellitus, Type 2/blood* ; Middle Aged ; Male ; Female ; Adult ; Blood Glucose/drug effects* ; Hypoglycemic Agents/therapeutic use* ; Aged ; Glycated Hemoglobin/metabolism* ; Adolescent ; Young Adult ; China ; East Asian People

Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for clinical use in pre and early symptomatic children with MLD to increase ARSA activity. Unfortunately, this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis. Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system, whereas those with early onset infantile MLD die within a few years of symptom onset. We conducted a pilot study to determine the safety and benefit of HSCGT in patients with postsymptomatic juvenile MLD and report preliminary results. The safety profile of HSCGT was favorable in this long-term follow-up over 9 years. The most common adverse events (AEs) within 2 months of HSCGT were related to busulfan conditioning, and all AEs resolved. No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years. Importantly, to date, patients have maintained remarkably improved ARSA activity with a stable disease state, including increased Functional Independence Measure (FIM) score and decreased magnetic resonance imaging (MRI) lesion score. This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with postsymptomatic juvenile MLD.
Humans ; Leukodystrophy, Metachromatic/genetics* ; Pilot Projects ; Genetic Therapy/methods* ; Hematopoietic Stem Cell Transplantation ; Male ; Follow-Up Studies ; Female ; Lentivirus/genetics* ; Child ; Child, Preschool ; Hematopoietic Stem Cells/metabolism* ; Cerebroside-Sulfatase/metabolism* ; Adolescent

Objective To explore the causal relationship between rheumatoid arthritis(RA)and iron deficiency a-nemia(IDA)in European population by two-sample Mendelian randomization analysis.Methods The single nu-cleotide polymorphisms(SNPs)of RA and IDA were analyzed using public genome-wide association studies(GWAS).The inverse variance weighting method(IVW)was used as the main analysis method to evaluate the causal effect of RA on IDA.MR-Egger method,weighted median method(WM),weighted model method and simple model method were used as regression supplements to evaluate the robustness of sensitivity analysis results.The het-erogeneity function was used to calculate the P-value to test the heterogeneity,and the intercept term intercept was used to test the level pleiotropy.Results In the FINNGEN database at the genome-wide level,strong-related SNPs that removed linkage disequilibrium and met the P＜5.0 × 10-8 by Mendelian randomization analysis were select-ed.After integrating exposure and outcome data,31 SNPs were obtained as the final effective instrumental variables.IVW showed that RA was a risk factor for IDA(the risk of IDA in RA patients was 1.064 times higher than that in non-RA patients,OR=1.064,95％CI:1.028-1.103).The weighted median method and MR-Egger method re-sults supported the positive correlation between RA and IDA.The intercept value was close to 0,indicating that there was no horizontal pleiotropy between exposure and outcome.The heterogeneity function's P＜0.05 indicated that there was heterogeneity between exposure and outcome,but the random effect model test showed P＜0.05,indi-cating that even if there was heterogeneity in causality,the overall trend was stable.Conclusion RA is a risk factor for IDA,and there is a positive correlation between RA and IDA.

Objective:To evaluate the efficacy and safety of CD30 antibody-drug conjugates (ADC) brentuximab vedotin (BV) combined with chemotherapy in children with refractory or relapsed classic Hodgkin′s lymphoma (R/R cHL).Methods:Clinical data (including age, gender, B symptoms, clinical stage, previous treatment, etc.) of the 10 R/R cHL children diagnosed and treated at Beijing Children′s Hospital Affiliated to Capital Medical University from October 2021 to August 2023 were analyzed retrospectively. According to the different intensity of chemotherapy drugs, the dose of BV applied in the same course of treatment was 1.8 mg/kg for BV applied once every 3 weeks, and 1.2 mg/kg for BV applied once every 2 weeks. All 10 patients received at least 2 cycles of BV combined with chemotherapy and were evaluated every 2 cycles. The patients were followed up until May 31, 2024. The infusion reactions and adverse reactions after treatment were recorded.Results:In all 10 patients, there were 7 males and 3 females, the age ranged from 5.3-16.9 years, and there were 6 cases of refractory and 4 cases of relapsed. There were 6 cases of nodular sclerosis type, 2 cases of mixed cell type, 1 case of lymphocyte-rich type, and 1 case of lymphodepletion type. There were 5 cases of stage Ⅳ and 5 cases of stage Ⅲ. Previous treatment was mainly chemotherapy, 4 cases received radiotherapy and 1 case received programmed cell death protein 1 (PD-1) antibody therapy. The follow-up time ranged from 9 to 27 months. A total of 43 courses with 49 doses of BV alone or combined with chemotherapy were recorded, and the number of courses was 2 to 10 times. All 10 children responded to the treatment, and 9 achieved complete remission. BV infusion was successfully completed in all cases. A total of 28 cases of grade 3 or above adverse events were recorded, mainly myelosuppression, all of which were related to chemotherapy and did not affect sequential treatment.Conclusion:Brentuximab vedotin has demonstrated efficacy and a tolerable safety profile in the treatment of refractory and relapsed CD30-positive Hodgkin′s lymphoma in children.

Objective:To evaluate the efficacy and safety of brentuximab vedotin (BV) combined with rituximab and attenuated chemotherapy in the treatment of children with classic Hodgkin lymphoma (cHL).Methods:A prospective, non-randomized, risk-assigned study. Clinical data (including age, gender, B symptoms, bulky disease, CD30 and Epstein-Barr virus-encoded RNA(EBER) expression, clinical stage, risk stratification, etc.) of 28 intermediate to high-risk cHL children diagnosed and treated at Beijing Children′s Hospital Affiliated to Capital Medical University from October 2022 to May 2024 were collected. Immuno-targeted combined with attenuated chemotherapy was administered based on risk stratification and early treatment response. The patients were followed up until May 1st, 2024. The infusion reactions and adverse reactions after treatment were recorded.Results:In all 28 patients, there were 22 males and 6 females, the age was 12 (5,16) years, 16 cases (57%) presented with bulky disease and 10 cases (36%) with B symptoms. The most common pathological type was nodular sclerosis (14 cases, 50%). There were 7 cases of stage Ⅱ, 14 cases of stage Ⅲ and 7 cases of stage Ⅳ according to the Ann Arbor staging system. There were 5 cases in the intermediate-risk group and 23 cases in the high-risk group. EBER was positive in 20 cases (71%) and negative in 6 cases (21%), and CD30 antigen was expressed in tumor cells of all enrolled children. Treatment duration: 5 cases (18%) received 4 courses of treatment, 21 cases (75%) received 6 courses of treatment, and 2 cases (7%) received 8 courses of treatment, 25 cases (89%) achieved complete metabolism response (CMR) through early assessment after 2 courses of chemotherapy. The CMR rates were 100% in intermediate-risk group and 87% (20/23) in high-risk group, respectively. Four patients (14%) finally received residual field radiotherapy. Toxicities included grade Ⅰ-Ⅱ myelosuppression, early infusion reaction and mild peripheral neuropathy, only one case of grade 3 adverse events was recorded and did not affect sequential treatment. At the end of treatment and 3 months of follow-up, the levels of IgA, IgG and IgM were all decreased compared with the baseline before chemotherapy, and the total B cell count began to be lower than the level before chemotherapy at the early stage of treatment (after 2 courses). The total B cell count monitored during treatment was 50 (0, 101)×10 6/L and was 12 (0, 25)×10 6/L at the end of treatment. The follow-up time was 6 (3, 13) months, all 28 children had event-free survival and all achieved complete remission. At 6 and 9 months of follow-up, IgA, IgG, IgM and total B cell counts returned to pre-chemotherapy baseline levels, respectively. Conclusion:BV combined with rituximab attenuated chemotherapy has demonstrated efficacy and a tolerable safety profile in the treatment of cHL in children, and significantly reduce radiation rate.

Objective To investigate the causal relationship between rheumatoid arthritis (RA) and pulmonary hypertension (PH) by the Mendelian randomization design method.Methods The data on single nucleotide polymorphisms (SNPs) of exposure and outcome were obtained by using publicly available ge-nome-wide association studies and the summary analysis was conducted;the inverse variance-weighted (IVW) method as the primary analysis method was used to assess the causal effect of exposure factors (RA) on the outcomes (PH);the MR-Egger regression method,weighted median method (WM),weighted model and sim-ple model were used as supplementary regression explanations to conduct the sensitivity analysis for evalua-ting the robustness of results;the "heterogeneity" function was used to calculate the "P value" for testing the heterogeneity,and the "horizontal pleiotropy" function was used to calculate the "P value" to test the level pleiotropy.Results In the "FINNGEN data" included in the GWAS database,the SNPs had the strong corre-lation after removing the linkage imbalance by Mendelian random analysis and satisfying "P<5×10-8" were selected,the effective instrumental variables were obtained by integrating the exposure and outcome.The IVW results showed that RA was a risk factor for PH (OR=1.295,95％CI:1.053-1.593,P=0.014)."heteroge-neity" function test showed that the results had no heterogeneity (P=0.221);" horizontal pleiotropy" func-tion test showed that the results had no horizontal pleiotropy (P=0.877),and the total results were steady and reliable.Conclusion RA is a risk factor for PH,and RA is positively associated with PH.

Objective To explore the correlations of lumbar bone mineral density(BMD)and metabolic syndrome(MS)in adult males.Methods Data of low dose chest CT and quantitative CT of 13 490 adult males were retrospectively analyzed,and lumbar BMD were measured to judge whether MS existed and the degree of MS,and the correlations of lumbar BMD with MS or not and the degree of MS,as well as of lumbar BMD value and the related indicators of MS were assessed.Taken lumbar BMD as the dependent variable,the age,low density lipoprotein cholesterol(LDL-C),blood uric acid(BUA),hemoglobin(Hb)and MS or not were included in multiple linear regression analysis to observe the impact of MS and related indicators on lumbar BMD.Results Among 13 490 adult males,3 900 were found with MS(MS group),while 9 590 were found without MS(non-MS group).Significant difference of lumbar BMD was detected between groups(P=0.001).Lumbar BMD values were negatively correlated with MS(rs=-0.025,P=0.004)and the degree of MS(rs=-0.038,P＜0.001),whereas positively correlated with abdominal obesity,high triglyceride and low HDL-C or not(rs=0.024,0.061,0.036,all P＜0.001)but negatively correlated with hypertension and hyperglycemia or not(rs=-0.135,-0.104,both P＜0.05).After adjustment of age,lumbar BMD of adult males was negatively correlated with MS or not as well as LDL-C(both P＜0.05),but positively correlated with BUA and Hb(both P＜0.001).Conclusion Lumbar BMD was associated with MS in adult males.

Objective:To analyze the clinical characteristics and influencing factors of vascular involvement in Beh?et′s Disease (BD) to improve and provideunderstanding of insights for clinicians to better understand this condition.Methods:Clinical data from 220 BD patients admitted to the First Affiliated Hospital of Guangxi Medical University from January 2012 to May 2022 were collected. Clinical manifestations and laboratory findings were compared between BD patients with and without vascular involvement, as well as between those with improved conditions and those with progressive conditions. Binary logistic regression was used to analyze the influencing factors.Results:①The average age of the 220 BD patients was 36.5±15.3 years. Among them, 23 patients (10.5%) had vascular involvement, including 20 males (87.0%).②Compared to BD patients without vascular involvement, those with vascular involvement had significantly higher rates of smoking [6.1%(12/197) vs.34.8%(8/23), χ2=17.19, P<0.001], cardiac involvement [1.5%(3/197) vs. 13.0%(9/23), χ2=6.42, P=0.011], and elevated C-reactive protein(CRP) levels (78.3% vs. 56.3%, χ2=4.08, P=0.043).③ Among BD patients with vascular involvement, 11 cases (47.8%) had venous lesions, and 20 cases (87.0%) had arterial lesions, with 8 cases (34.8%) having both venous and arterial involvement. The most common type of vascular involvement was arterial dilatation (11 cases), mainly aneurysms (10 cases), and deep venous thrombosis of the lower extremities (7 cases).④The 23 BD patients with vascular involvement were followed up for an average of 18.3 months. Among them, 16 patients (69.6%) showed stable improvement, while 7 patients (30.4%) experienced disease progression, including 4 deaths (1 male and 3 females). A total of 91.3% (21/23) of the patients received glucocorticoid therapy. Immunosuppressive therapy was administered to 82.6% (19/23) of the patients, with 65.2% (10/23) receiving with cyclophosphamide and 43.5% receiving with thalidomide. Additionally, 13% (3/23) of the patients were treated with cyclosporine and methotrexate, respectively, and 8.7% (2/23) were treated with received mycophenolate mofetil. Anticoagulant therapy was given to 21.7% (5/23) of the patients, using either warfarin or low molecular weight heparin. Biologic therapy was administered to 17.4% (4/23) of the patients, and surgical intervention was performed in 43.5% (10/23) of the patients. ⑤Binary logistic regression analysis identified male gender [ OR(95% CI)=5.70(1.60, 20.90), P=0.009] as an indepe-ndent risk factor for vascular involvement in BD. Conclusion:The incidence of vascular involvement in BD is 10.5%, with a higher prevalence in males. Arterial involvement is more common than venous involvement, with arterial aneurysms being the most common manifestation. Clinicians should pay attention to CRP and total cholesterol levels in BD patients.

OBJECTIVE To identify the role of mixed lineage kinase domain like protein(MLKL)in cerebral small vessel disease(CSVD)and explore the underlying mechanism.METHODS Transient bilateral common carotid artery occlusion(tBCCAO)was used to establish a mouse model of CSVD.Immunofluorescence staining and Western blotting were used to observe the expres-sions of RIPK3/MLKL signaling molecules in brain tissues at 7,14 and 28 d after tBCCAO.Open field test,rotarod test,Y-maze and novel object recognition test were used to observe the effect of MLKL knockout on cognitive func-tion after tBCCAO.Blood-brain barrier(BBB)disruption was observed by sodium fluorescein permeability test and the expressions of tight junction proteins.Immunoflu-orescence staining and Western blotting were used to detect the expression of microglia marker Iba-1,astro-cyte marker GFAP,and NLRP3/Caspase-1 signaling mol-ecules in the hippocampus of CSVD mice.ELISA was used to detect the level of inflammatory factors(TNF-α,IL-1β,IL-18)in hippocampus.RESULTS The expres-sions of RIPK3/MLKL signaling molecules increased in cortex and hippocampus after tBCCAO,especially on day 14.The expression of pMLKL mainly increased in neurons,glia cells and endothelial cells in CSVD mice.MLKL knockout improved the cognitive functions such as motor learning,spatial learning and working memory,and object recognition ability in CSVD mice.MLKL knock-out alleviated the leakage of sodium fluorescein and attenuated the down-regulation of tight junction proteins at 1 d and 14 d after tBCCAO.At 14 d after tBCCAO,MLKL knock out inhibited the activations of microglia and astrocytes,attenuated the expressions of NLRP3/cas-pase-1 molecules,and decreased the levels of inflamma-tory factors in the hippocampus of mice.CONCLUSION Genetic inhibition of MLKL exerts protective effects against cognitive impairment by ameliorating BBB dam-age and neuroinflammation in a mouse cerebral small vessel disease model.

Objective:To analyze the treatment effect and drug resistance mutation of HIV-1 infected patients who changed to the second-line antiretroviral treatment regimen after they had developed drug-resistance with first-line antiretroviral treatment regimen in some areas of Sichuan Province.Methods:Using the cohort study method, the patients who had developed drug resistance with the first-line regimen were followed up for two years from 1 January 2019 to 31 December 2021.The changes of CD4 +T lymphocytes (CD4) counts and viral load (VL) at the endline and the detection of drug-resistant mutation sites were analyzed using the chi-square test. Multivariate logistic regression model was used to analyze the influencing factors of antiretroviral treatment effect in patients who had good compliance after switching to the second-line regimen. Results:A total of 737 patients were recruited. Among the cases with continuous good compliance, those who timely changed to the second-line regimen had higher proportion of maintaining continuous CD4 >200 cells/μl and sustained virus inhibition ( P<0.05). Among the patients with different levels of drug resistance at baseline, there was no significant difference in continuous CD4 >200 cells/μl and sustained VL <200 copies/ml ( P>0.05). After changing to the second-line regimen, the drug-resistant mutation sites of some protease inhibitors showed an upward trend, while those of the non-nucleoside reverse transcriptase inhibitors showed a downward trend ( P<0.05). Multivariate logistic regression analysis showed that, among patients who had good compliance and who had switched to the second-line regimen, mother-to-child-transmitted patients had 3.01 times higher risk than heterosexual sexually transmitted infection (95% CI:1.29-7.00), failure to change the second-line protocol in time brought 2.55 times higher risk than that of timely changing to the second-line regimen (95% CI:1.41-4.62) and patients who infected with CRF85_BC subtype had 3.32 times higher risk than those infected with CRF01_AE subtype (95% CI:1.49-7.42). Conclusions:Difference in the drug resistance levels with the first-line regimen does not affect patients' antiretroviral treatment effect after changing to the second-line regimen in Sichuan Province. Changing to the second-line regimen in time and maintaining good compliance are beneficial to higher immune levels and lower VLs in drug-resistant patients. Among patients who changed to the second-line regimen, mother-to-child transmission, failure to change the second-line program in time, and infection with CRF85_BC virus are risk factors endangering antiretroviral treatment success after changing to the second-line regimen.