BACKGROUND: Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. METHODS: This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. RESULTS: Eighty-two patients were assigned to variant ( n  = 42) and wild type groups ( n  = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUC tau ) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. CONCLUSION: ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. REGISTRATION NCT04410965, https://clinicaltrials.gov .
Humans ; Crotonates/adverse effects* ; Toluidines/adverse effects* ; Nitriles ; Hydroxybutyrates ; Female ; Male ; Adult ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics* ; Middle Aged ; Multiple Sclerosis, Relapsing-Remitting/genetics* ; Prospective Studies ; Young Adult ; Neoplasm Proteins/genetics* ; East Asian People

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Objective To observe the abnormal brain activity in patients with migraine without aura(MwoA)with MRI.Methods Fifty MwoA patients(MwoA group)and 46 healthy volunteers(control group)were prospectively enrolled.Functional MRI(fMRI)was performed to observe the dynamic regional homogeneity(dReHo)of brain regions,then brain regions with differences of dReHo value between groups were extracted,and correlations with clinical scales were analyzed.Results Compared with control group,dReHo values of surrounding cortex of bilateral calcarine fissure and right middle occipital gyrus increased,of right middle temporal gyrus,right middle frontal gyrus and left cuneus decreased in MwoA group(GRF correction,voxel level all P＜0.005,cluster level all P＜0.05).The weight analysis showed that brain regions with top 3 absolute weight values were surrounding cortex of right calcarine fissure,left cuneus and right middle occipital gyrus.dReHo value of surrounding cortex of left calcarine fissure in MwoA patients was negative correlated with self-rating depression scale(SDS)(r=-0.28,P=0.04).Conclusion Abnormalities in the upward transmission pathway of visual information existed in MwoA patient,especially in surrounding cortex of right calcarine fissure,left cuneus and right middle occipital gyrus.

Objective To investigate the correlation between red blood cell distribution width(RDW),systemic immune-inflammation index(SII)and major depressive disorder(MDD).Methods The clinical data of 176 MDD patients hospitalized in the clinical psychology department of our hospital from 2020 to 2022 and 209 non-MDD comparators who were routinely examined in Hebei General Hospital were retrospectively analyzed.Blood analysis was conducted to obtain values of RDW,SII,and red blood cell distribution width/platelet ratio(RPR).The data was used to plot the receiver operator characteristic(ROC)curve to determine the optimal threshold and the area under the curve(AUC)for RDW to discriminate between patients and controls.Result Patients in the MDD group had significantly higher RDW[median and quartiles:13.20(12.70,13.98)vs.12.80(12.40,13.35)],and SII levels[median and quartiles 510.87(350.95,878.12)vs.405.33(313.74,539.92)]compared with those in non-MDD group(P<0.05).There was no significant difference in RPR between the two groups(P>0.05).Multifactorial logistic regression analysis showed that RDW was positively correlated with MDD after adjusting for confounders(OR=3.086,95% CI:1.926-4.944).ROC curve showed that the optimal threshold for RDW to differentiate the risk of developing MDD was 12.85,with an AUC of 0.647(95% CI:0.592-0.702;P<0.001).Conclusion Present study shows that high RDW is a risk factor for the occurrence of MDD and an important parameter for the risk of developing depression.

Objective:To explore the application value of real-time shear wave elastography(SWE)and ultrafast pulse wave velocity(UFPWV)techniques in assessing carotid artery stiffness of patients with gouty arthritis(GA).Methods:A total of 80 GA patients admitted to the First People's Hospital of Yibin from August 2022 to July 2023 were selected as GA group.Among of them,24 cases combined with bone erosion who were confirmed by imaging examination,and 56 cases did not combine with bone erosion.In addition,a total of 40 healthy individuals,who underwent physical examinations in our hospital during the same period,were selected as the healthy control group.SWE and UFPWV were used to detect the maximum,minimum and mean values of Young's modulus values of the vessel wall of common carotid artery,and the pulse wave velocity at the beginning of systole(PWVBS)and pulse wave velocity at the end of systole(PWVES)of the vessel wall of common carotid artery of all subjects,and to assess the hardness of circumferential and longitudinal vessel wall of common carotid artery of them.The differences in Young's modulus values,PWVBS and PWVES between two groups were compared.And then,the correlations between bone erosion and Young's modulus values,PWVBS,PWVES of GA patients were further analyzed.Results:The maximum,minimum,mean values,PWVBS and PWVES in the GA group were respectively(78.80±12.38)kPa,(57.83±7.42)kPa,(67.67±8.38)kPa,(7.06±0.59)m/s and(9.50±0.63)m/s,which were significantly higher than those in the healthy control group(t=11.066,8.216,11.751,14.159,19.118,P＜0.05).The maximum,minimum,mean values,PWVBS and PWVES of GA patients with bone erosion were respectively(82.95±6.37)kPa,(59.59±5.29)kPa,(72.18±7.62)kPa,(7.37±0.43)m/s,(10.43±0.47)m/s,which were significantly higher than those[(77.01±5.32)kPa,(57.08±4.73)kPa,(65.73±4.54)kPa,(6.92±0.39)m/s and(9.10±0.41)m/s]of GA patients without bone erosion,the differences were significant(t=4.309,2.099,4.699,4.586,12.720,P＜0.05).Spearman correlation analysis showed that there was significant correlations between maximum,minimum,mean values,PWVBS,PWVES and the combined bone erosion in GA patients(r=0.602,0.421,0.682,0.647,0.732,P＜0.05).Conclusion:SWE and UFPEV techniques can evaluate the hardness of vascular wall of GA patients,and the hardness of circumferential and longitudinal vessel wall of common carotid artery of GA patient is higher than that of healthy person,and the hardness of circumferential and longitudinal vessel wall of common carotid artery of GA patient with bone erosion is higher.

Purpose To investigate the protective effect and mechanism of A-485 on renal tubular injury in diabetic mice.Methods Eighteen male C57BL/6J mice were randomly divided into three groups:Control group,diabetic kidney dis-ease(DKD)group and A-485 treatment group.The DKD mice model was established by feeding high-fat diet for 8 weeks and intraperitoneal injection of streptozotocin for 5 days.Subsequent-ly,the A-485 treatment group was given A-485(10 mg/kg/day)by intraperitoneal injection every other day for 4 weeks.After treatment,the renal function,P300 enzyme activity and lipid deposition in renal tissue were measured.Western blot a-nalysis was performed to detect SREBP-1,FASN,ACC,ChREBP,P300,CBP,H3K18ac and H3K27ac protein levels.Results Compared with control mice,the levels of FBG,BUN,Scr and UAE were significantly increased in diabetic mice(FBG:2.52 times,BUN:2.89 times,Scr:2.13 times,UAE:4.21 times),while diabetic mice treatment with A-485 exhibi-ted a remarkable decrease on BUN,Scr and UAE(BUN:0.511 times,Scr:0.636 times,UAE:0.574 times,P＜0.01).The results of the transmission electron microscopy and oil red O stai-ning showed that A-485 treatment prevents lipid droplets forma-tion and up-regulation of SREBP-1,FASN,ACC and ChREBP in renal tubular cells of diabetic mice(SREBP-1:0.544 times,FASN:0.449 times,ACC:0.306 times,ChREBP:0.317 times,P＜0.01).Furthermore,A-485 intervention downregu-lated the enzyme activity of P300(0.546 times)and suppressed the expression of H3K18ac(0.337 times)and H3K27ac(0.308 times,P＜0.01).Conclusion A-485 can significant-ly improve renal lipid metabolic disorder in diabetic mice,which may be achieved by inhibiting p300-induced H3K18ac and H3K27ac.

Osteosarcoma (OS) is the most common primary malignant bone tumor that more commonly occurs in children and adolescents. The most commonly used treatment for OS is surgery combined with chemotherapy, but the treatment outcomes are typically unsatisfactory. High rates of metastasis and post-treatment recurrence rates are major challenges in the treatment of OS. This underlines the need for studying the in-depth characterization of the pathogenetic mechanisms of OS and development of more effective therapeutic modalities. Previous studies have demonstrated the important role of the bone microenvironment and the regulation of signaling pathways in the occurrence and development of OS. In this review, we discussed the available evidence pertaining to the mechanisms of OS development and identified therapeutic targets for OS. We also summarized the available treatment modalities for OS and identified future priorities for therapeutics research.
Child ; Adolescent ; Humans ; Bone Neoplasms/drug therapy* ; Signal Transduction ; Bone and Bones/metabolism* ; Treatment Outcome ; Osteosarcoma/drug therapy* ; Tumor Microenvironment

Polymyxin B and polymyxin E (colistin) are presently considered the last line of defense against human infections caused by multidrug-resistant Gram-negative organisms such as carbapenemase-producer Enterobacterales, Acinetobacter baumannii, and Klebsiella pneumoniae. Yet resistance to this last-line drugs is a major public health threat and is rapidly increasing. Polymyxin S₂ (S₂) is a polymyxin B analogue previously synthesized in our institute with obviously high antibacterial activity and lower toxicity than polymyxin B and colistin. To predict the possible resistant mechanism of S₂ for wide clinical application, we experimentally induced bacterial resistant mutants and studied the preliminary resistance mechanisms. Mut-S, a resistant mutant of K. pneumoniae ATCC BAA-2146 (Kpn2146) induced by S₂, was analyzed by whole genome sequencing, transcriptomics, mass spectrometry and complementation experiment. Surprisingly, large-scale genomic inversion (LSGI) of approximately 1.1 Mbp in the chromosome caused by IS26 mediated intramolecular transposition was found in Mut-S, which led to mgrB truncation, lipid A modification and hence S₂ resistance. The resistance can be complemented by plasmid carrying intact mgrB. The same mechanism was also found in polymyxin B and colistin induced drug-resistant mutants of Kpn2146 (Mut-B and Mut-E, respectively). This is the first report of polymyxin resistance caused by IS26 intramolecular transposition mediated mgrB truncation in chromosome in K. pneumoniae. The findings broaden our scope of knowledge for polymyxin resistance and enriched our understanding of how bacteria can manage to survive in the presence of antibiotics.

Objective:To characterize the injury to the ipsilateral ankle joint after low energy spiral fracture of the distal tibia.Methods:A retrospective study was conducted to analyze the 80 patients with distal tibial spiral fracture who had been treated at Department of Traumatic Orthopedics, Affiliated Hospital of Jining Medical University from March 2010 to March 2021. There were 61 males and 19 females with an age of (43.5±12.5) years. Their mean follow-up time was 67.0 (38.5, 90.0) months. All patients underwent preoperative X-ray examination, 64 ones preoperative CT examination, and 30 ones preoperative MRI examination. Of the 80 patients, 3 received conservative treatment with plaster external fixation, 3 closed reduction and intramedullary nail fixation, and 74 plate fixation. Statistically analyzed were incidence of posterior malleolus fracture, characteristics of posterior malleolus fracture lines, normal matching rate of the ipsilateral ankle joint, positive rate of intraoperative Cotton test or stress external rotation test of ipsilateral ankle joint, positive rates of passive pronation-external rotation and supination-external rotation stress tests during follow-up, incidences of short-term ankle pain (≤2 years) and medium-long term pain (>2 years) after operation, injuries to the anterior inferior tibiofibular ligament, the deep medial malleolus deltoid ligament and the posterior malleolus, and incidence of ankle injury.Results:The diagnostic rate for posterior malleolus fracture was 16.3% (13/80) on X-ray film, 60.9% (39/64) on CT and 76.7% (23/30) on MRI. 74.5% (35/47) of the posterior malleolus fracture lines opened on the lateral side. The normal matching rate of the ipsilateral ankle joint was 96.3% (77/80). The positive rates of intraoperative Cotton test and stress external rotation test were 34.8% (8/23) and 7.1% (1/14), respectively. The positive rates of passive pronation-external rotation and supination-external rotation stress tests during follow-up were 46.2% (12/26) and 34.6% (9/26). The incidences of postoperative short term (≤2 years) and medium-long term (>2 years) ankle pain were 37.7% (29/77) and 20.8% (16/77). MRI examination showed that the rates of injury to the anterior inferior tibiofibular ligament, deep medial malleolus deltoid ligament and posterior malleolus were 80.0% (24/30), 80.0% (24/30) and 76.7% (23/30). The incidence of ankle injury was 88.8% (71/80).Conclusions:It is highly probable that spiral fracture of the distal tibia is complicated with ipsilateral ankle injury. The medial malleolus, lateral malleolus, and posterior malleolus are prone to the following hidden injuries while the ankle joint is normally matched in the most cases: injury to the deep deltoid ligament in different degrees, rupture of the inferior tibiofibular anterior ligament and posterior malleolus fracture. Therefore, the ankle injury is likely to be missed in diagnosis. The secondary torsion injuries to the pronation-external rotation and supination-external rotation at the leg are likely to cause ipsilateral ankle injury.

Objective:To investigate the radiotherapy discipline construction and existing problems in non-public hospitals in Zhejiang province and put forward suggestions for improvement.Methods:In 2022, on-site inspection and investigation were carried out in 14 non-public hospitals in Zhejiang province, including equipment configuration and source, discipline setting, personnel qualification and professional experience, academic leaders and admission of patients, etc. Results:For 14 non-public hospitals in Zhejiang province, 19 treatment equipment, 15 positioning equipment and 77 quality control equipment were equipped, and a total of 249 radiotherapy practitioners were employed. A total of 4 224 patients were admitted throught 2022.Conclusion:Multiple problems exist in non-public radiotherapy hospitals in Zhejiang province, such as unscientific discipline setting, fewer professionals, lack of personnel training, unclear management mode, unqualified qualification of partial radiotherapy doctors, and insufficient refinement of clinical quality management, which need to be further improved.