Background::Ainuovirine (ANV) is a new generation of non-nucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus (HIV) type 1 infection. This study aimed to evaluate the population pharmacokinetic (PopPK) profile and exposure-response relationship of ANV among people living with HIV.Methods::Plasma concentration-time data from phase 1 and phase 3 clinical trials of ANV were pooled for developing the PopPK model. Exposure estimates obtained from the final model were used in exposure-response analysis for virologic responses and safety responses.Results::ANV exhibited a nonlinear pharmacokinetic profile, which was best described by a two-compartment model with first-order elimination. There were no significant covariates correlated to the pharmacokinetic parameters of ANV. The PopPK parameter estimate (relative standard error [%]) for clearance adjusted for bioavailability (CL/F) was 6.46 (15.00) L/h, and the clearance of ANV increased after multiple doses. The exposure-response model revealed no significant correlation between the virologic response (HIV-RNA <50 copies/mL) at 48 weeks and the exposure, but the incidence of adverse events increased with the increasing exposure ( P value of steady-state trough concentration and area under the steady-state curve were 0.0177 and 0.0141, respectively). Conclusions::Our PopPK model supported ANV 150 mg once daily as the recommended dose for people living with HIV, requiring no dose adjustment for the studied factors. Optimization of ANV dose may be warranted in clinical practice due to an increasing trend in adverse reactions with increasing exposure.Trial registration::Chinese Clinical Trial Registry https://www.chictr.org.cn (Nos. ChiCTR1800018022 and ChiCTR1800019041).

Aim To investigate the effect of Toddalia asiatica(TA)on bone destruction in rheumatoid ar-thritis(RA)and its possible mechanism by network pharmacology and in vitro experiments.Methods The active components and targets of TA against RA bone damage were analyzed by network pharmacology.Mo-lecular docking was performed by using AutoDock and PyMOL software pairs.MC3T3-e1 cells were cultured in vitro,and the effect of Toddalia asiatica alcohol ex-tract(TAAE)on cell viability was detected by CCK-8,and appropriate drug concentration and intervention time were screened.The osteoblast model was induced by osteogenic induction medium,and the osteogenic differentiation was detected by ALP staining,activity detection and alizarin red staining.The expression of pathway-related proteins Wnt3a and β-catenin was de-tected by Western blot,and the pathway inhibitor DKK-1 was used to further verify whether TAAE regulated osteoblast differentiation through the Wnt/β-catenin signaling pathway.Results A total of 158 anti-RA bone destruction targets and 56 core targets were se-lected.The enrichment of KEGG signaling pathway mainly included cancer pathway,phosphatidylinositol 3-kinase/protein kinase B signaling pathway and cAMP signaling pathway.The results of CCK-8 showed that 1 g·L-1 TAAE could significantly improve cell survival rate.The results of ALP staining and ALP activity de-tection showed that TAAE could significantly increase the staining positive rate and ALP activity of cells in-duced by osteogenic induction medium.Western blot showed that TAAE could increase the expression of Wnt3a and β-catenin.The expression of these proteins decreased after DKK-1 inhibitors were used.Conclu-sion TAAE can regulate osteoblast differentiation through Wnt/β-catenin signaling pathway to treat os-teodestruction in rheumatoid arthritis.

Objective To investigate the risk factors for bronchopulmonary dysplasia(BPD)in twin preterm infants with a gestational age of<34 weeks,and to provide a basis for early identification of BPD in twin preterm infants in clinical practice.Methods A retrospective analysis was performed for the twin preterm infants with a gestational age of<34 weeks who were admitted to 22 hospitals nationwide from January 2018 to December 2020.According to their conditions,they were divided into group A(both twins had BPD),group B(only one twin had BPD),and group C(neither twin had BPD).The risk factors for BPD in twin preterm infants were analyzed.Further analysis was conducted on group B to investigate the postnatal risk factors for BPD within twins.Results A total of 904 pairs of twins with a gestational age of<34 weeks were included in this study.The multivariate logistic regression analysis showed that compared with group C,birth weight discordance of>25%between the twins was an independent risk factor for BPD in one of the twins(OR=3.370,95%CI:1.500-7.568,P<0.05),and high gestational age at birth was a protective factor against BPD(P<0.05).The conditional logistic regression analysis of group B showed that small-for-gestational-age(SGA)birth was an independent risk factor for BPD in individual twins(OR=5.017,95%CI:1.040-24.190,P<0.05).Conclusions The development of BPD in twin preterm infants is associated with gestational age,birth weight discordance between the twins,and SGA birth.

Objective Studies on the relationship between iodine,vitamin A(VA),and vitamin D(VD)and thyroid function are limited.This study aimed to analyze iodine and thyroid-stimulating hormone(TSH)status and their possible relationships with VA,VD,and other factors in postpartum women. Methods A total of 1,311 mothers(896 lactating and 415 non-lactating)from Hebei,Zhejiang,and Guangxi provinces were included in this study.The urinary iodine concentration(UIC),TSH,VA,and VD were measured. Results The median UIC of total and lactating participants were 142.00 μg/L and 139.95 μg/L,respectively.The median TSH,VA,and VD levels in all the participants were 1.89 mIU/L,0.44 μg/mL,and 24.04 ng/mL,respectively.No differences in the UIC were found between lactating and non-lactating mothers.UIC and TSH levels were significantly different among the three provinces.The rural UIC was higher than the urban UIC.Obese mothers had a higher UIC and a higher prevalence of excessive TSH.Higher UICs and TSHs levels were observed in both the VD deficiency and insufficiency groups than in the VD-sufficient group.After adjustment,no linear correlation was observed between UIC and VA/VD.No interaction was found between vitamins A/D and UIC on TSH levels. Conclusion The mothers in the present study had no iodine deficiency.Region,area type,BMI,and VD may be related to the iodine status or TSH levels.

Objective To discuss the effect of PI3K-AKT signaling pathway regulated by microRNA-155(miRNA-155)targeted protein tyrosine phosphatase non-receptor type 21(PTPN21)on the proliferation,migration and invasion of hepatocellular carcinoma(HCC)cells.Methods Lentivirus transfection was used to silence the expression of miRNA-155 in human Huh7 HCC cells,and real-time fluorescent quantitative polymerase chain reaction(RT-qPCR)was used to detect the silencing effect of miR-155.After obtaining stable cell lines,the cell lines were randomly divided into Blank group(normal Huh7 cells),shNC group(Huh7 cells+empty miR-155 vector),sh-miR-155(Huh7 cells+miR-155 silencing),sh-miR-155+Recilisib group(Huh7 cells+miR-155 silencing+PI3K-AKT agonist),shNC+Recilisib group(Huh7 cells+empty miR-155 vector+PI3K-AKT agonist).Dual luciferase assay was used to determine whether PTPN21 was the downstream of miR-155.The cell proliferation ability of cells in each group was detected by MTT assay.The apoptosis level of each group was tested by flow cytometry.The invasion and migration ability of cells was assessed by Transwell assay.Western blot analysis was used to observe the differences in protein expression of PTPN21,PI3K,P-PI3K,AKT,P-AKT,and apoptosis-related proteins including BAX,BCL-2 and caspase-3 in all groups.Results The expression level of miR-155 in sh-miR-155 group was lower than that in Blank group and shNC group(P＜0.000 1),and the difference in miR-155 expression level between Blank group and shNC group was not statistically significant(P＞0.05).MTT results showed that A values of Huh7 cells at 2,3,4 and 5 day in sh-miR-155 group were lower than those in Blank group and shNC group(P＜0.000 1),while these differences between Blank group and shNC group were not statistically significant(P＞0.05).In sh-miR-155 group the A values at 2,3,4 and 5 day were lower than those in sh-miR-155+Recilisib group and shNC+Recilisib group(P=0.0052 and P＜0.0001,respectively),while the A values at 2,3,4 and 5 day in sh-miR-155+Recilisib were lower than those in shNC+Recilisib group(P＜0.000 1).There was no significant differences in cell migration and number of invasion cells between the Blank group and shNC group(P＞0.05).After activation of PI3K-AKT signaling pathway,the migration and invasion capacity of HCC cells in the shNC+Recilisib group were significantly enhanced when compared with the Blank group(P＜0.000 1).In contrast,the number of migrated and invaded Huh7 cells after miR-155 silencing was significantly lower than that in the Blank group and shNC group(P＜0.000 1)and this phenomenon became reversed by PI3K agonist.Compared with the sh-miR-155 group,in the sh-miR-155+Recilisib group the migration and invasion ability of HCC cells was enhanced(P=0.000 2).Lentiviral transfection of Huh7 human HCC cells to silence miR-155 and downregulate miR-155 inhibiting PTPN21 regulation of the PI3K-AKT signaling pathway,thus inhibiting the invasion,migration and proliferation ability of HCC cells and promoting the apoptosis of HCC cells.Conclusion miR-155 inhibits the migration,invasion and proliferation of HCC cells through targeting PTPN21 regulation of PI3K-AKT signaling pathway.The miR-155 may be a potential therapeutic target for HCC in the future.(J Intervent Radiol,2024,32:44-51)

Objective:To investigate the efficacy and safety of tocilizumab in the treatment of critically ill children with acute necrotizing encephalopathy (ANE).Methods:It is a retrospective cohort study. The children with ANE admitted to the pediatric intensive care unit of 4 Chinese tertiary hospitals from December 2022 to November 2023 were divided into conventional treatment group and tocilizumab group, and the comparison between groups was performed by using Mann ‐ Whitney U test or Chi-square test. Results:Among 21 cases of severe ANE, there were 11 males with the onset age of 65 (27, 113) months. The duration from onset to PICU admission was 2 (1, 2) days. There were 13 cases of ultra-high fever (greater than 40 ℃), including 18 cases of convulsions, and 19 cases with a GCS score of less than 8 points. The causative agent was novel coronavirus Omicron in 7 cases and influenza A in 14 cases. All cases had central respiratory failure requiring mechanical ventilation. Of the 21 cases, 18 were shock, 15 were coagulopathy, 10 were kidney injury and 13 were liver dysfunction. Of these hospitalized patients, 8 children with ANE were treated with tocilizumab. Eight cases received continuous blood purification (CBP) treatment, 5 of them were combined with plasmapheresis. Serum cytokine levels were elevated in 21 children with ANE, including (interleukin, IL)-6 and IL-8 (61 (22, 1 513) and 68 (5, 296) ng/L). There were 14 cases (67%) deaths, including 11 cases in the conventional treatment group and 3 cases in the tocilizumab group. There was no significant difference in the mortality rate between the two groups ( P=0.056). Tocilizumab-related rash or other adverse events were not observed. Conclusions:The motality of critically ill ANE patients was high. The combination of Tocilizumab with conventional treatment did not reduce the motality of severe ANE patients, and no adverse reactions of tocilizumab were observed.

Objective Neuromuscular electrical stimulation(NMES)-evoked kinesthetic information in muscle spindle can be purely extracted from the mixed motor and sensory afferents using Ischemic nerve block(INB).This study aims to investigate the somatosensory cortical response evoked by NMES activating muscle spindle afferents in forearm.Methods All subjects performed four experimental tasks designed according to a 2×2 factors,including one factor of the INB state(without INB and within INB)and the other of the stimulation intensity(above and below motor threshold).During the experiment,we recorded EEG data with 64 channels and then beta event-related desynchronization(Beta ERD)were utilized quantize somatosensory cortical excitability evoked by the tasks.The subjective perception about the sensation and movement of the right hand were evaluated by a psychophysical test after the right wrist was performed by INB.Results INB significantly reduced beta ERD on the contralateral somatosensory cortex evoked by NMES above the motor threshold,and there was significant difference of NMES-evoked beta ERD values on the contralateral somatosensory cortex between above and below motor threshold.Meanwhile,contralateral dominance of NMES-evoked beta ERD on the somatosensory cortex was transferred to ipsilateral hemisphere under INB.Conclusion INB can significantly reduce NMES-evoked somatosensory cortical response above motor threshold and decrease cortical perception on the stimulus intensity,which may be due to INB resulting in rapid functional reorganization of somatosensory cortex.

Following the principles of evidence-based medicine,in accordance with the structure and drafting rules of standardized documents,based on literature research,according to the characteristics of chronic cough in children and issues that need to form a consensus,the TCM Guidelines for Diagnosis and Treatment of Chronic Cough in Children was formulated based on the Delphi method,expert discussion meetings,and public solicitation of opinions.The guideline includes scope of application,terms and definitions,eti-ology and diagnosis,auxiliary examination,treatment,prevention and care.The aim is to clarify the optimal treatment plan of Chinese medicine in the diagnosis and treatment of this disease,and to provide guidance for improving the clinical diagnosis and treatment of chronic cough in children with Chinese medicine.

Objective: To analyze the clinical features, efficacy and prognosis factors of core binding factor (CBF) acute myeloid leukemia (AML) children in South China. Methods: This was a retrospective cohort study. Clinical data of 584 AML patients from 9 hospitals between January 2015 to December 2020 was collected. According to fusion gene results, all patients were divided into two groups: CBF-AML group (189 cases) and non-CBF-AML group (395 cases). CBF-AML group were divided into AML1-ETO subgroup (154 cases) and CBFβ-MYH11 subgroup (35 cases). Patients in CBF-AML group chosen different induction scheme were divided into group A (fludarabine, cytarabine, granulocyte colony stimulating factor and idarubicin (FLAG-IDA) scheme, 134 cases) and group B (daunorubicin, cytarabine and etoposide (DAE) scheme, 55 cases). Age, gender, response rate, recurrence rate, mortality, molecular genetic characteristics and other clinical data were compared between groups. Kaplan-Meier method was used for survival analysis and survival curve was drawn. Cox regression model was used to analyze prognostic factors. Results: A total of 584 AML children were diagnosed, including 346 males and 238 females. And a total of 189 children with CBF-AML were included, including 117 males and 72 females. The age of diagnosis was 7.3 (4.5,10.0)years, and the white blood cell count at initial diagnosis was 21.4 (9.7, 47.7)×10⁹/L.The complete remission rate of the first course (CR1) of induction therapy, relapse rate, and mortality of children with CBF-AML were significantly different from those in the non-CBF-AML group (91.0% (172/189) vs. 78.0% (308/395); 10.1% (19/189) vs. 18.7% (74/395); 13.2% (25/189) vs. 25.6% (101/395), all P<0.05). In children with CBF-AML, the CBFβ-MYH11 subgroup had higher initial white blood cells and lower proportion of extramedullary invasion than the AML1-ETO subgroup, with statistical significance (65.7% (23/35) vs. 14.9% (23/154), 2.9% (1/35) vs. 16.9% (26/154), both P<0.05). AML1-ETO subgroup had more additional chromosome abnormalities (75/154), especially sex chromosome loss (53/154). Compared with group B, group A had more additional chromosome abnormalities and a higher proportion of tumor reduction regimen, with statistical significance (50.0% (67/134) vs. 29.1% (16/55), 34.3% (46/134) vs. 18.2% (10/55), both P<0.05). Significant differences were found in 5-years event free survival (EFS) rate and 5-year overall survival (OS) rate between CBF-AML group and non-CBF-AML group ((77.0±6.4)%vs. (61.9±6.7)%,(83.7±9.0)%vs. (67.3±7.2)%, both P<0.05).EFS and OS rates of AML1-ETO subgroup and CBFβ-MYH11 subgroup in children with CBF-AML were not significantly different (both P>0.05). Multivariate analysis showed in the AML1-ETO subgroup, CR1 rate and high white blood cell count (≥50×10⁹/L) were independent risk factors for EFS (HR=0.24, 95%CI 0.07-0.85,HR=1.01, 95%CI 1.00-1.02, both P<0.05) and OS (HR=0.24, 95%CI 0.06-0.87; HR=1.01, 95%CI 1.00-1.02; both P<0.05). Conclusions: In CBF-AML, AML1-ETO is more common which has a higher extramedullary involvement and additional chromosome abnormalities, especially sex chromosome loss. The prognosis of AML1-ETO was similar to that of CBFβ-MYH11. The selection of induction regimen group FLAG-IDA for high white blood cell count and additional chromosome abnormality can improve the prognosis.
Male ; Female ; Humans ; Child ; Retrospective Studies ; RUNX1 Translocation Partner 1 Protein/genetics* ; Core Binding Factor Alpha 2 Subunit/therapeutic use* ; Prognosis ; Leukemia, Myeloid, Acute/genetics* ; Cytarabine/therapeutic use* ; Oncogene Proteins, Fusion/genetics* ; Chromosome Aberrations

Objective: To explore the influencing covariates of severe neutrophils and/or thrombocytopenia and their effect on treatment response and outcome in patients with chronic-phase chronic myeloid leukemia (CP-CML) receiving initial second-generation tyrosine kinase inhibitors (2G-TKI) . Methods: Data from consecutive patients aged ≥18 years with newly diagnosed CP-CML who received initial 2G-TKI at Peking University People's Hospital from September 2008 to November 2021 were interrogated. Binary logistic regression models and Fine-Gray and Cox regression models were applied. Results: Data from 267 patients who received initial 2G-TKI, including nilotinib (n=239, 89.5% ) and dasatinib (n=28, 10.5% ) , were interrogated. The median age was 36 (range, 18-73) years, and 156 (58.4% ) patients were male. At a median treatment period of 1.0 (0.1-3.0) month, 43 (16.1% ) patients developed grade ≥3 neutrophils and/or thrombocytopenia and recovered within 1.0 (0.1-24.6) month. Male (OR=2.9, 95% CI 1.2-6.8; P=0.018) , age of ≥36 years (OR=3.2, 95% CI 1.4-7.2, P=0.005) , a spleen below a costal margin of ≥7 cm (OR=2.8, 95% CI 1.2-6.6, P=0.020) , and a hemoglobin (HGB) level of <100 g/L (OR=2.9, 95% CI 1.3-6.8, P=0.012) at diagnosis were significantly associated with grade ≥ 3 neutrophils and/or thrombocytopenia. Based on their regression coefficients, male, age of ≥36 years, a spleen below a costal margin of ≥7 cm, and an HGB level of <100 g/L were given 1 point to form a predictive system. All patients were divided into three risk subgroups, and the incidence of severe cytopenia significantly differed among the three groups (P < 0.001) . Grade ≥3 neutrophils and/or thrombocytopenia for >2 weeks was significantly associated with lower cumulative incidences of complete cytogenetic response (CCyR, HR=0.5, 95% CI 0.3-0.7, P<0.001) and major molecular response (MMR, HR=0.4, 95% CI 0.3-0.8, P=0.004) and was not significantly associated with failure, progression, and survival. Conclusion: Male, advanced age, a large spleen, and a low HGB level were significantly associated with severe cytopenia. The four covariates were used to establish a prediction model, in which the incidence of severe cytopenia among different risk groups was significantly different. Severe cytopenia for >2 weeks was a negative factor for responses but not for outcomes.
Humans ; Male ; Adolescent ; Adult ; Female ; Protein Kinase Inhibitors/therapeutic use* ; Tyrosine Protein Kinase Inhibitors ; Treatment Outcome ; Retrospective Studies ; Dasatinib/therapeutic use* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Leukemia, Myeloid, Chronic-Phase/drug therapy* ; Thrombocytopenia