BACKGROUND: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation and joint destruction. Iguratimod (IGU) is a novel conventional synthetic disease-modifying antirheumatic drugs (csDMARD) with good efficacy and safety for the treatment of active RA in China and Japan. However, the long-term effects of IGU on the progression of bone destruction or radiographic progression in patients with active RA remain unknown. We aimed to investigate the efficacy and safety of iguratimod (IGU), a combination of methotrexate (MTX) and IGU, and IGU in patients with active rheumatoid arthritis (RA) who were naïve to MTX. METHODS: This multicenter, double-blind, randomized, non-inferiority clinical trial was conducted at 28 centers for over 52 weeks in China. In total, 911 patients were randomized (1:1:1) to receive MTX monotherapy (10-15 mg weekly, n = 293), IGU monotherapy (25 mg twice daily, n = 297), or IGU + MTX (10-15 mg weekly for MTX and 25 mg twice daily for IGU, n = 305) for 52 weeks. The patients' clinical characteristics, Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), disease activity score in 28 joints-C-reactive protein (DAS28-CRP) level, and disease activity score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) were assessed at baseline. The primary endpoints were the proportion of patients with ≥20% improvement according to the American College of Rheumatology (ACR20) response and changes in the van der Heijde-modified total Sharp score (vdH-mTSS) at week 52. RESULTS: The proportions of patients achieving an ACR20 response at week 52 were 77.44%, 77.05 %, and 65.87% for IGU monotherapy, IGU + MTX, and MTX monotherapy, respectively. The non-inferiority of IGU monotherapy to MTX monotherapy was established with the ACR20 (11.57%; 95% confidence interval [CI], 4.35-18.79%; P <0.001) and vdH-mTSS (-0.37; 95% CI, -1.22-0.47; P = 0.022). IGU monotherapy was also superior to MTX monotherapy in terms of ACR20 ( P = 0.002) but not the vdH-mTSS. The superiority of IGU + MTX over MTX monotherapy was confirmed in terms of the ACR20 (11.18%; 95% CI, 3.99-18.37%; P = 0.003), but not in the vdH-mTSS (-0.68; 95% CI, -1.46-0.11; P = 0.091). However, the difference in the incidence rates of adverse events was not statistically significant. CONCLUSIONS: IGU monotherapy/IGU + MTX showed a more favorable clinical response than did MTX monotherapy. IGU may have some clinical benefits over MTX in terms of radiographic progression, implying that IGU may be considered as an initial therapeutic option for patients with active RA. TRIAL REGISTRATION https://classic.clinicaltrials.gov/ , NCT01548001.
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Antirheumatic Agents/therapeutic use* ; Arthritis, Rheumatoid/drug therapy* ; Chromones/adverse effects* ; Double-Blind Method ; Drug Therapy, Combination ; Methotrexate/adverse effects* ; Treatment Outcome ; Sulfonamides

Nanotechnologies seek to overcome inherent deficiencies of conventional diagnosis and treatment, which attracted sustained attention and a limited number of nanomedicines approved by the FDA. However, the critical gaps in clinical translation remain, and nanomedicines that were initially heralded as magic bullets have yet to reach their realistic potential. The major obstacles of fabrication technologies may be overlooked in the nanoparticles' journey. Suboptimal manufacturing strategies partly hampered the inefficient transformation. In this review, we discuss the nanoparticle manufacturing strategies of "Top-Down" and "Bottom-Up" on precise nanoscale fabrication, including artificial intelligence introduced to guided nanomedicine fabrication for accelerating the transformation. Re-engineering existing nanomedicine fabrication, individual manufacturing, and modular technology might highlight the dilemmas of nanomedicines to meet their initial expectations.

Objective To observe the clinical efficacy and safety of nivolumab combined with anlotinib in the treatment of patients with advanced gastric cancer.Methods The patients with advanced gastric cancer were randomly divided into control group and treatment group.The control group received oral apatinib capsules 12 mg,once a day,and discontinued treatment for 7 days after 14 days of maintenance therapy.On the basis of control group,the treatment group received intravenous infusion of 3 mg·kg-1 nivolumab,once every two weeks.Two groups were treated for four cycles with 21 days per cycle.The clinical efficacy,tissue polypeptide specific antigen(TPS),carbohydrate antigen 125(CA125),carcinoembryonic antigen(CEA)and adverse drug reactions were compared between two groups.Results In the treatment group,80 cases were enrolled,and 4 cases dropped out and 76 cases were included in the statistical analysis;in the control group,80 cases were enrolled,and 8 cases dropped out and 72 cases were included in the statistical analysis.After treatment,the total effective rates in the treatment and control group weres 78.95％(60 cases/76 cases)and 52.78％(38 cases/72 cases),and the difference was statistically significant(P＜0.05).After treatment,the levels of CEA in the treatment and control groups were(5.34±1.12)and(7.01±0.97)U·mL-1;the levels of CA125 were(22.65±4.27)and(27.61±5.09)U·mL-1;the levels of TPS were(69.21±11.64)and(53.06±10.57)U·mL-1;these differences were statistically significant(all P＜0.05).The adverse drug reactions of two groups were nausea/diarrhea,leukopenia,thrombocytopenia,abnormal liver function,and hypothyroidism.The total incidences of adverse drug reactions in the treatment and control groups were 40.79％and 37.50％without statistically significant difference(P＞0.05).Conclusion Ramucirumab injection combined with anlotinib capsules is more effective than single-agent anlotinib in the treatment of advanced gastric cancer,without increasing the incidence of adverse drug reactions.

Objective:To retrieve, evaluate and integrate the relevant evidence of prevention of lower limb ischemic complications in venous-arterial extracorporeal membrane oxygenation (VA-ECMO) patients, and provide reference for the development of scientific and complete prevention and management of lower limb ischemic complications.Methods:According to the evidence-based methodology, clinical decisions, guidelines, expert consensus, evidence summary, systematic review, randomized controlled trials and experimental studies related to lower limb ischemia complications in VA-ECMO patients were searched from CNKI, Wanfang, PubMed, Cochrane Library and other domestic and foreign databases as well as relevant professional websites. The literature search period was from the establishment of the database to August 2023. Two researchers independently evaluated the literature quality, and then extracted and summarized the evidence according to the theme.Results:A total of 27 004 articles were obtained in the preliminary search, and 11 articles were finally included after screening, including 1 guide, 2 expert consensus, 2 systematic reviews and 6 original studies. Through literature reading, evidence extraction and classification, and expert group meetings, a total of 24 best evidences were concluded in four dimensions, including team training and management, VA-ECMO pre-computer evaluation, VA-ECMO catheter selection, and the monitoring and management of lower limb ischemia.Conclusions:This study summarized the best evidence for the prevention of lower limb ischemia complications associated with VA-ECMO patients, and can provide reference for healthcare providers in clinical practice. In order to ensure the safety of VA-ECMO treatment and reduce the incidence of related complications, healthcare professionals should carefully select and apply evidence according to the clinical context and patients′ wishes.

Objective To evaluate the application effect of broth microdilution(BMD)method in susceptibility testing of multidrug-resistant Mycobacterium tuberculosis(MDR-MTB).Methods The Roche's proportion method and BMD method were adopted in drug susceptibility testing on 108 MDR-MTB strains and 11 non-MDR-MTB strains in Hainan Province.Whole genome sequencing(WGS)was performed on strains with inconsistent results by the above two methods.Results The average time to acquire drug susceptibility testing results by Roche's propor-tional method and BMD method were 28.0 and 8.5 days,respectively.Roche's proportional method showed higher resistance rates to isoniazid(INH),rifampicin(RFP),ethambutol(EMB),kanamycin(KM),and capreomycin(CPM)than BMD method(all P＜0.001).BMD method showed higher resistance rates to protionamide(PTO)and para-aminosalicylic acid(PAS)than Roche's proportional method(both P＜0.001).Taking Roche's proportional method as the gold standard,the sensitivity and specificity of BMD method for testing drug resistance were 50.00％-100％and 95.69％-100％,respectively.Except EMB(87.39％)and INH(94.96％),the consistency rates of the BMD method in testing drug resistance of other drugs were all ≥95.00％.The overall consistency rate between Roche's proportional method and WGS was 76.19％(32/42),while the consistency rate between BMD method and WGS was 23.81％(10/42),difference was statistically significant(x2=23.048,P＜0.001).34 MTB strains showed inconsistent results by two drug susceptibility testing methods.Among the 26 MTB strains that were resis-tant in Roche's proportion method but sensitive in BMD method,22 strains(84.62％)had mutations in relevant re-sistance genes.Among the 11 MTB strains that were sensitive in Roche's proportion method but resistant in BMD method,5 strains(45.45％)had mutations in relevant resistance genes.Conclusion BMD method is an accurate and rapid MDR-MTB susceptibility testing method,but further improvement and optimization are still needed.Drug resistance is closely related to mutations in relevant resistance genes.

Cerebroprotein hydrolysate oral liquid (COL) is a neuroprotective preparation composed of various amino acids and peptides, which has beneficial effects on diverse central system diseases. However, the therapeutic effect and potential mechanism of oral COL on ischemic stroke (IS) still need to be explored. This study aims to investigate the therapeutic effects and underlying mechanisms of COL on IS in vivo and in vitro. An IS rat model was established through middle cerebral artery occlusion (MCAO) surgery, and triphenyltetrazolium chloride (TTC) staining, behavioral scoring, Evans blue leakage, enzyme-linked immunosorbent assay (ELISA) and immunofluorescence staining were performed to investigate the effects of COL on cerebral infarct size, neurological function, blood-brain barrier (BBB) and neuroinflammation in IS rats. An in vitro model of IS was established on hCMEC/D3 cells through oxygen-glucose deprivation/reperfusion (OGD/R), and cell counting kit-8 assay, reactive oxygen species (ROS) detection, scratch test and Transwell test were conducted to examine the influence of COL on cell viability, oxidative stress and migration ability. Lipidomics technology, real-time quantitative PCR and Western blot experiments were used to investigate the regulation and mechanism of COL on lipid metabolism in the brain of IS rats. All the animal experiments were approved by Ethical Committee of Animal Experiments of China Pharmaceutical University (No.2022-02-23). Our results showed that intragastric administration of COL could significantly reduce the area of cerebral infarction, improve neurological deficits, lower the levels of inflammatory factors, and protect against the blood-brain barrier damage of rats with IS. OGD/R modeling resulted in a significant decrease in the viability, an elevation in intracellular ROS levels, and a weakened cell migration ability of hCMEC/D3 cells. COL treatment could effectively protect hCMEC/D3 cells from damage caused by OGD/R. More importantly, cerebral ischemia led to significant lipid metabolism disorders in the brain of rats, and significant accumulation of intracerebral triglycerides (TAG) and ceramides (Cer) was observed in IS rats. COL was proved to significantly reverse lipid metabolism disorders in the brain of IS rats and reduce the content of cytotoxic lipid Cer by upregulating the intracerebral levels of an acid ceramidase called N-acylsphingosine amidehydrolase 1 (ASAH1). In summary, COL was proved to be a promising and effective candidate for IS treatment, which could alleviate cerebral ischemic injury by regulating abnormal lipid metabolism.

Objective:To explore the value of the imaging nomogram model based on preoperative CT features of patients with small intestinal stromal tumor (SIST) in predicting pathological risk classification.Methods:This was a cohort study. The patients who were diagnosed as primary SIST by postoperative pathology in Cancer Hospital, Chinese Academy of Medical Sciences from January 2014 to October 2023 were retrospectively included. According to the modified 2008 National Institutes of Health classification criteria, the patients were divided into a pathological intermediate/high-risk group (86 cases) and a very low/low-risk group (56 cases). The features of preoperative enhanced CT images of SIST were analyzed, including tumor boundary, necrosis, intra-tumoral hemorrhage, intra-tumoral calcification, growth pattern, enhancement pattern, enhancement degree, enlarged vessels feeding or draining the mass (EVFDM), and tumor location. Patients were followed up to determine the recurrence-free survival (RFS). Univariate and multivariate logistic regression were used to screen the independent predictors of SIST with pathological medium/high-risk group. The independent predictors were combined to construct an imaging prediction model, and a nomogram was drawn. The receiver operating characteristic curve was used to evaluate the predictive efficacy of the model. The Kaplan-Meier method was used to draw the survival curve, and the log-rank test was used to compare the differences in RFS.Results:Univariate logistic regression results showed that tumor shape, necrosis, intra-tumoral hemorrhage, EVFDM, and tumor location were potentially related to medium/high-risk SIST. Multivariate logistic regression results showed that tumor shape ( OR=3.92, 95% CI 1.58-9.71, P=0.003), necrosis ( OR=4.60, 95% CI 1.91-11.09, P<0.001), and EVFDM ( OR=6.25,95% CI 1.74-22.47, P=0.005) were independent predictors of pathological intermediate/high-risk SIST. The area under the curve of the imaging predictive model combining the three predictors to predict the intermediate/high-risk SIST was 0.835 (95% CI 0.769-0.901), the sensitivity was 0.810, the specificity was 0.839, and the accuracy was 0.789. Taking the cut-off value (0.810) as the boundary value, the patients were divided into the high-risk group (74 cases) and the low-risk group (68 cases) according to the prediction results. The median RFS of the predicted high-risk group was poorer than that of the predicted low-risk group, and the difference was statistically significant ( χ2=5.20, P=0.023). Conclusions:The imaging nomogram model based on preoperative CT image features shape, necrosis, and EVFDM can effectively predict the pathological intermediate/high-risk SIST before surgery and has important predictive value for postoperative recurrence.

Objective To observe and compare the concentrations of tryptophan-kynurenine pathway metabolites in serum and urine of adolescents with depression individuals using liquid chromatography-tandem mass spectrometry(LC-MS/MS).Methods The major metabolites in this pathway,such as tryptophan(TRP),kynurenine(KYN),kynurenic acid(KYNA),and 3-hydroxykynurenine(3-HK)were quantitatively analyzed using isotope-labeled internal standards.The separation was achieved using a Shimadzu C18 col-umn with gradient elution of 0.2％aqueous acid and acetonitrile.The detection was performed within 7 minutes using positive ion mode and multiple reaction monitoring(MRM).The parameters,such as linear range and precision were evaluated to assess reliability of the method.Subsequently,this method was applied to detect and compare the results in the samples of serum and urine from 143 adoles-cents with depression and 110 healthy controls.Results Taking TRP as the example,the linear ranges for serum and urine were 0.54 to 107.84 μmol/L and 0.74 to 147.06 μmol/L,respectively.The intra-batch coefficient of variation(CV)was ≤6.3％,the inter-batch CV was ≤3.22％,and the total laboratory CV was ≤6.5％.The results showed the KYNA,KYN and TRP levels were lower in the de-pression group compared to the control group,while 3-HK levels were higher in the depression group with statistical significance(P＜0.01).Apart from TRP,the levels of other metabolites were significantly higher in urine than those in serum,with statistical signifi-cance(P＜0.01).Conclusion Compared to the results of serum,the concentrations of TRP metabolites,including KYN,KYNA and 3-HK were higher than those in urine.The concentrations of TRP-KP metabolites in urine,i.e.,KYN,KYNA and 3-HK were higher than those in serum,and the detection of TRP-KP metabolites in urine may offer a greater advantage because the urine collection process is non-invasive.

Objective:To investigate the risk factors of acute symptomatic seizures (ASS) and epilepsy in children with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD).Methods:A ambispective cohort study was used including 74 children with MOGAD who were admitted to the Department of Pediatrics of Peking University First Hospital from January 2013 to June 2023 and were followed up. Demographic information, clinical information, treatment status, ASS and epilepsy status were collected. The clinical phenotypes were classified. According to the presence or absence of ASS in the course of disease, the children and the course of disease were divided into groups with and without ASS. Chi-square test, Fisher exact test and Mann Whitney U test were used to analyze the correlation between symptoms and auxiliary examination characteristics and the occurrence of ASS in the two groups of children. Multivariate Logistic regression analysis was used for multivariate analysis. Results:The onset age of the 74 children with MOGAD was 6.58 (3.80, 9.67) years, including 38 females (51.4%) and 36 males (48.6%). The duration of the final follow-up was 2.67 (1.10, 4.12) years, with a total of 239 times acute clinical episodes. ASS occurred in 39.2% (29/74) children during the course of disease and in 29.3% (70/239) of attacks. The common phenotypes were ADEM (67 times (28.0%)), optic neuritis (37 times (15.4%)) and cerebral cortical encephalitis (31 times (13.0%)) in 239 times acute clinical episodes. The incidence of ASS in ADEM and cerebral cortical encephalitis phenotype was 28.4%(19/67) and 100.0% (31/31), respectively. Multivariate analysis showed that cortical involvement on magnetic resonance imaging during clinical attacks was an independent risk factor for ASS ( β=-1.49, OR=0.23) after excluding attacks involving only optic nerve or spinal cord (49 episodes). During the follow-up, 5 children (6.8%) had epilepsy, and all children with epilepsy had multiple clinical attacks of MOGAD and previous ASS. Conclusions:Cortical involvement on magnetic resonance imaging during clinical episodes is an independent risk factor for ASS in children with MOGAD. All MOGAD children with epilepsy had ASS and multiple MOGAD clinical episodes in the past.

BACKGROUND:Adjustable piezoelectric effect can promote tissue regeneration and repair.Piezoelectric materials are widely used in weight-bearing tissue engineering. OBJECTIVE:To prepare a piezoelectric film material that can promote bone regeneration,and to explore its structural characterization,electrical output performance,biocompatibility,and effect of electrical output on osteogenic differentiation of rabbit bone marrow mesenchymal stem cells. METHODS:Using poly-3-hydroxybutyrateco/4-hydroxybutyrate(P34HB)as raw material,barium calcium stannate titanate powder(Ba0.94Ca0.06Sn0.08Ti0.92O3,BCST)was added according to mass ratios of 0%,5%,10%,15%,and 20%.Dichloromethane was added to solve P34HB,and the thickness of 150-200 μm BCST/P34HB piezoelectric film was prepared by vacuum drying method.After polarization in the oil bath,the surface morphology,crystal phase composition,piezoelectric coefficient and open circuit voltage were tested.The effect of BCST/P34HB electrical output at 110 Hz and 0.25 N force on the proliferation and osteogenic differentiation of rabbit bone marrow mesenchymal stem cells was tested. RESULTS AND CONCLUSION:(1)Scanning electron microscopy,X-ray diffraction,water contact angle,piezoelectric coefficient and electrical output performance tests showed that when the mass ratio of BCST increased to 20%,the BCST/P34HB piezoelectric film had good piezoelectric properties(d33=5.9 pC/N)and electrical output performance(180 mV),which was closer to the suitable range of 500 mV for electrical stimulation.(2)Live and dead staining showed that on the first day of co-culture,15%group and 20%group showed less red fluorescence.On the 5th day of culture,the number of green fluorescence in each group was significantly higher than that on the first day,and the red fluorescence was not observed in the 10%,15%and 20%groups,and only a small amount of red fluorescence was observed in the 0%and 5%groups.(3)On the 1st,3rd and 5th days of co-culture with rabbit bone marrow mesenchymal stem cells,Almar blue staining exhibited that the number of cells in each group showed an increasing trend with the increase of time.On the 5th day of culture,the number of cells in the 20%group was significantly more than that in the 0%group(P<0.05).(4)On day 10 of osteogenic induction,alkaline phosphatase staining results showed that the positive rate of the 20%group was significantly higher than that of the 0%group(P=0.000 1).On day 21,alizarin red staining and quantitative analysis of calcium nodules showed a similar trend to alkaline phosphatase staining.Compared with the 0%group,the 15%group and 20%group showed significant differences(P<0.01,P<0.000 1).(5)The results showed that 20%BCST/P34HB films had good piezoelectric properties,electrical output properties,biocompatibility and the ability of promoting osteogenic differentiation of bone marrow mesenchymal stem cells.