Objective To evaluate the safety,tolerability and pharmacokinetic profiles of naldemedine in Chinese healthy adult subjects after single and multiple administrations.Methods After single and multiple oral administrations of naldemedine to 10 healthy Chinese subjects,the plasma concentrations of naldemedine and its metabolite(nor-naldemedine)were measured by liquid chromatography-mass spectrometry,and the pharmacokinetic parameters were calculated by Phoenix WinNonlin 8.3.1 software.Results Compared with single administration,naldemedine showed no significant change in the tmax(1.06 h for single and 1.08 h for multiple)and Cmax(4.16 ng·mL-1 for single and 4.11 ng·mL-1 for multiple),higher AUC0-τ than that of single(23.88 ng·h·mL-1 for single and 28.93 ng·h·mL-1 for multiple),slightly prolonged t1/2(9.26 h for single,12.50 h for multiple),there was a slight drug accumulation after multiple doses(accumulation ratio of 0.99 for Cmax and 1.22 for AUC);t1/2(18.10 h for single,29.30 h for multiple),Cmax(0.19 ng·mL-1 for single,0.38 ng·mL-1 for multiple),and AUC0-τ(3.13 ng·h·mL-1 for single,6.02 ng·h·mL-1 for multiple)were all significantly elevated with nor-naldemedine,and the tmax(single was 3.49 h and multiple was 3.56 h)did not change significantly.The Cmax ratio and AUC ratio of metabolites to naldemedine were significantly elevated,and accumulation was present after multiple administrations(accumulation ratio of 2.01 for Cmax and 1.95 for AUC).All adverse events that occurred after treatment were mild.Conclusion After multiple oral administrations of 0.2 mg naldemedine tablets to Chinese healthy subjects(single dose on day 1 and once daily on days 4-13),the drug was eliminated rapidly with mild accumulation,and reached a steady state before the second dose of the multiple-dosing phase,and the product has a favorable safety and tolerability profiles.

Objective To investigate the incidence rate,clinical characteristics,and prognosis of neonatal stroke in Shenzhen,China.Methods Led by Shenzhen Children's Hospital,the Shenzhen Neonatal Data Collaboration Network organized 21 institutions to collect 36 cases of neonatal stroke from January 2020 to December 2022.The incidence,clinical characteristics,treatment,and prognosis of neonatal stroke in Shenzhen were analyzed.Results The incidence rate of neonatal stroke in 21 hospitals from 2020 to 2022 was 1/15 137,1/6 060,and 1/7 704,respectively.Ischemic stroke accounted for 75％(27/36);boys accounted for 64％(23/36).Among the 36 neonates,31(86％)had disease onset within 3 days after birth,and 19(53％)had convulsion as the initial presentation.Cerebral MRI showed that 22 neonates(61％)had left cerebral infarction and 13(36％)had basal ganglia infarction.Magnetic resonance angiography was performed for 12 neonates,among whom 9(75％)had involvement of the middle cerebral artery.Electroencephalography was performed for 29 neonates,with sharp waves in 21 neonates(72％)and seizures in 10 neonates(34％).Symptomatic/supportive treatment varied across different hospitals.Neonatal Behavioral Neurological Assessment was performed for 12 neonates(33％,12/36),with a mean score of(32±4)points.The prognosis of 27 neonates was followed up to around 12 months of age,with 44％(12/27)of the neonates having a good prognosis.Conclusions Ischemic stroke is the main type of neonatal stroke,often with convulsions as the initial presentation,involvement of the middle cerebral artery,sharp waves on electroencephalography,and a relatively low neurodevelopment score.Symptomatic/supportive treatment is the main treatment method,and some neonates tend to have a poor prognosis.

Objective:To investigate the relationship between IGF2BP3 gene expression and prognosis in patients with acute myeloid leukemia(AML).Methods:High throughput transcriptome sequencing was performed on bone marrow primary leukemia cells from 27 patients with AML in our center,the relationship between IGF2BP3 expression levels and clinical characteristics were analyzed and verify the samples from patients with newly treated AML and refractory AML.The expression level of IGF2BP3 gene were analyzed in 20 healthy subjects and 26 patients with AML.The expression of IGF2BP3 in two anthracycline-resistant cell lines(HL60/ADR,K562/ADR)was detected by RT-qPCR and Western blot,and the expression difference of IGF2BP3 was compared with that in sensitive cells(HL60,K562).The relationship between the expression level of IGF2BP3 in patients with AML and prognostic were analyzed through data analysis of 746 patients with AML,and the prognostic value of IGF2BP3 in AML was analyzed by multivariate Cox regression analysis.Results:In the bone marrow primary leukemia cells of 27 AML patients in our center,the expression level of IGF2BP3 in patients with refractory AML was significantly higher than that in chemotherapy sensitive patients(P=0.0343).The expression of IGF2BP3 in leukemia patients with extramedullary infiltration(EMI)was significantly higher than that in AML patients without extramedullary infiltration(P=0.0049).Compared with healthy subjects(n=20),IGF2BP3 expression in AML patients(n=26)was higher(P=0.0009).The expression of IGF2BP3 mRNA in the anthracycline resistant cell lines(HL60/ADR,K562/ADR)was significantly higher than that in the sensitive cell lines(K562/ADR vs K562,P=0.0430;HL60/ADR vs HL60,P=0.7369).Western blot results showed that the expression of IGF2BP3 protein in mycin resistant cells was significantly higher than that in sensitive cells(P＜0.001).qPCR results showed that the expression level of IGF2BP3 mRNA in refractory AML patients was significantly higher than that in patients with chemotherapy sensitive(P=0.002).High expression of IGF2BP3 was associated with poor prognosis in AML(P＜0.05)in 3 large sample cohorts of AML patients.Univariate and multivariate prognostic analyses demonstrated that high expression of IGF2BP3 was significantly associated with shorter event-free survival(EFS,HR=1.887,P=0.024)and overall survival(OS,HR=1.619,P=0.016).Conclusion:The high expression of IGF2BP3 gene may be an important factor in the poor prognosis of AML,suggesting that IGF2BP3 gene may be a new molecular marker for the clinical prognosis evaluation and treatment strategy of AML.

OBJECTIVE: To retrospectively analyze efficacy of single structure internal fixation and double structure internal fixation in the treatment of ipsilateral femoral shaft and neck fracture, and analyze their indications. METHODS: From June 2015 to December 2020, 21 patients with ipsilateral femoral shaft and femoral neck fracture were treated, including 14 males and 7 females, aged 23 to 69 years old with an average of(38.1±12.9) years old. According to different femoral shaft fracture sites, some patients were fixed with cephalomedullary implant for both femoral neck and the femoral shaft(single structure, InterTan or PFNA Ⅱ), some patients were fixed with cannulated screws for the femoral neck and a retrograde locking nail for the femoral shaft (dual structure), and postoperative function and complications were recorded during follow-up. In 10 cases of single-structure fixation, the femoral necks were all basicervical fractures, and the femoral shaft fractures were located in the proximal isthmus;11 cases were double-structure fixation, 9 cases in 11 were basal type of femoral neck, 2 cases in 11 were neck type, and the femoral shaft fractures were located in the isthmus and the distal isthmus. RESULTS: All patients were followed up for 12 to 27 months. No femoral head necrosis, deformity, delay or nonunion occurred in the patients with single-structure fixation, and no delayed union or nonunion occurred in femoral shaft fractures;At the final follow-up, Harris score of patients with single-structure fixation was 91.8±4.1, with 8 cases were excellent and 2 cases were good. The fractures of patients with dual-structure fixation achieved good union without femoral head necrosis, except 1 case of femoral shaft fracture had delayed union;At the final follow-up, Harris score of patients with dual-structure fixation was 92.4±5.9, 7 cases were excellent, 3 cases were good, and 1 case was fair. CONCLUSION Good reduction and fixation is the key to the treatment of such fractures. Both the single-structure fixation and the dual-structure fixation are good methods, and it should be selected according to the locations of femoral shaft and femoral neck fractures. Single-structure fixation is a good choice for femoral shaft fractures located at the proximal isthmus and basal femoral neck fractures. For isthmus and distal femoral shaft fractures combined with ipsilateral femoral neck fractures, dual-structure fixation is recommended.
Male ; Female ; Humans ; Young Adult ; Adult ; Middle Aged ; Aged ; Femur Neck ; Retrospective Studies ; Femoral Neck Fractures/complications* ; Femoral Fractures/complications* ; Fracture Fixation, Internal/methods* ; Femoral Fractures, Distal ; Treatment Outcome ; Fracture Fixation, Intramedullary/methods*

Objective The dense fibrous connective tissue that connects sub-occipital muscles which consist of the rectus capitis posterior minor muscle (RCPmi), rectus capitis posterior major muscle (RCPma), obliquus capitis inferior muscle (OCI) and nuchal ligament (NL) to the spinal dura mater (SDM), is described as the myodural bridge (MDB) in humans. The MDB is perceived as an essential anatomical structure and has been a subject of interest for clinicians. Studies have revealed that MDB may be related to the dynamic circulation of the cerebrospinal fluid (CSF) and a chronic cervicogenic headache. To date, the MDB is identified as a universal, existing structure in mammals and it exists in other vertebrates as well, such as Gallus domesticus and Rock pigeons in Avifauna, Siamese crocodile and Trachemys scripta elegans in Reptile. The current study is to further analyze different structures features of the MDB in sundry classes and provide the anatomical basis for functional studies. The JapaLura Splendida is the most common species in Lacertiformes, Reptilia. So we chose it as the experimental object to supply the morphological study of the MDB in Reptilia. Methods The study was based on gross anatomical dissection, thick sheet section, histological staining to observe the structural characteristics of the post-occipital area of twenty JapaLura Splendidas and the existence of the MDB. Results The deep post-occipital muscles were composed of the rectus capitis dorsal muscle (RCD) and the obliquus capital posterior (OCP) muscle. The RCD was merged by the rectus capitis dorsal major muscle (RCDma), the rectus capitis dorsal minor muscle (RCDmi) and the obliquus capitis anterior muscle (OCA). In the atlanto-occipital space, the dense fibrous bundles were found to originate from the ventral aspect of the RCD and run ventral, closely inserting into the SDM. In the atlanto-axial space, the dense fibrous bundles were found to originate from the ventral aspect of the OCP and run ventral, closely contacted with the SDM. These dense fibrous bundles were the collagen type I fibers with strong double refraction. Conclusion The result of this study indicates that the MDB is located between the post-occipital muscles and the SDM in JapaLura Splendida. The MDB of Japalura splendida may be related to the activities of the head and neck, and exert a physiological function similar to the MDB in humans.

Neonatal seizures are the most common clinical manifestations of critically ill neonates and often suggest serious diseases and complicated etiologies. The precise diagnosis of this disease can optimize the use of anti-seizure medication, reduce hospital costs, and improve the long-term neurodevelopmental outcomes. Currently, a few artificial intelligence-assisted diagnosis and treatment systems have been developed for neonatal seizures, but there is still a lack of high-level evidence for the diagnosis and treatment value in the real world. Based on an artificial intelligence-assisted diagnosis and treatment systems that has been developed for neonatal seizures, this study plans to recruit 370 neonates at a high risk of seizures from 6 neonatal intensive care units (NICUs) in China, in order to evaluate the effect of the system on the diagnosis, treatment, and prognosis of neonatal seizures in neonates with different gestational ages in the NICU. In this study, a diagnostic study protocol is used to evaluate the diagnostic value of the system, and a randomized parallel-controlled trial is designed to evaluate the effect of the system on the treatment and prognosis of neonates at a high risk of seizures. This multicenter prospective study will provide high-level evidence for the clinical application of artificial intelligence-assisted diagnosis and treatment systems for neonatal seizures in the real world.
Artificial Intelligence ; Electroencephalography/methods* ; Epilepsy/diagnosis* ; Humans ; Infant, Newborn ; Infant, Newborn, Diseases/diagnosis* ; Intensive Care Units, Neonatal ; Multicenter Studies as Topic ; Prospective Studies ; Randomized Controlled Trials as Topic ; Seizures/drug therapy*

OBJECTIVE: To analyze the kinetic characteristics of lymphocyte subsets and myeloid-derived suppressor cell (MDSC) in patients who newly diagnosed intermediate- to high-risk aGVHD and treated with steroids-ruxolitinib as the first line therapy from a single-arm, open clinical trial (NCT04061876). METHODS: We prospectively observed the efficacy of 23 patients having intermediate- to high-risk aGVHD and treated with steroids-ruxolitinib as the first line therapy. The kinetic characteristics of lymphocyte subsets and MDSC were monitored, and then we compared them in steroids-ruxolitinib group (n=23), free-aGVHD group (n=20) and steroids group (n=23). RESULTS: Of the 23 patients, the CR rate was 78.26% (18/23) on day 28 after first-line treatment with steroids-ruxolitinib. On day 28 after treatment, patients had lower level of CD4⁺CD29⁺ T cells (P=0.08) than that of pre-treatment, whereas levels of other lymphocyte subsets in this study were higher than that of pre-treatment; CD4⁺CD29⁺ T cells in CR patients decreased, compared with refractory aGVHD patients. On day 28 of treatment, CD8⁺CD28^- T cells (P=0.03) significantly increased in patients with aGVHD than that in patients without aGVHD, so did CD8⁺CD28^- T / CD8⁺CD28⁺ T cell ratio (P=0.03). Compared with patients without aGVHD, patients with aGVHD had lower level of G-MDSC, especially on day 14 after allo-HSCT (P=0.04). Compared with pre-treatment, M-MDSC was higher in CR patients on day 3 and 7 post-treatment (P₃=0.01, P₇=0.03), e-MDSC was higher on day 28 post-treatment (P=0.01). Moreover, compared with CR patients, M-MDSC was lower in refractory aGVHD patients on day 3 post-treatment (P=0.01) and e-MDSC was lower on day 28 post-treatment (P=0.01). Compared with steroids group, MDSC in steroids-ruxolitinib group was higher, with the most significant difference in M-MDSC (P₃=0.0351; P₇=0.0142; P₁₄=0.0369). CONCLUSION We found that patients newly diagnosed intermediate- to high-risk aGVHD receiving first-line therapy with steroids-ruxolitinib achieved high response rate. Moreover, the novel first-line therapy has a small impact on the immune reconstitution of patients after allo-HSCT. Elevated MDSC might predict a better response in aGVHD patients receiving this novel first-line therapy. M-MDSC responded earlier to steroids-ruxolitinib than e-MDSC, G-MDSC.
Graft vs Host Disease ; Hematopoietic Stem Cell Transplantation ; Humans ; Kinetics ; Myeloid-Derived Suppressor Cells ; Nitriles ; Pyrazoles ; Pyrimidines ; Retrospective Studies ; Steroids

OBJECTIVE: To investigate the relationship between AML1-ETO (AE) fusion gene and intracellular N6-methyladenosine (m6A) modification pattern in t(8;21) acute myeloid leukemia (AML). METHODS: RNA m6A sequencing was performed in SKNO-1 and AE knockdown SKNO-1 (SKNO-1 siAE) cells using RNA-protein co-immunoprecipitation and high-throughput sequencing (methylated RNA immunoprecipitation sequencing, MeRIP-Seq) to analyze the changes in m6A modification of the entire transcriptome. Transcriptome sequencing (RNA-seq) was performed using high-throughput sequencing. The differentially modified mRNAs were further functionally annotated by Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The changes in m6A-related enzyme expressions were detected using real-time PCR. RESULTS: A total of 26 441 genes were identified in AE knockdown AML cells and AE-expressing cells, containing 72 036 m6A peaks. AE knockdown caused a reduction of the number of intracellular m6A peaks from 37 042 to 34 994, among which 1278 m6A peaks were significantly elevated and 1225 were significantly decreased; 1316 genes with newly emerged m6A modification were detected and 1830 genes lost m6A modification after AE knockdown. The differential peaks were mainly enriched in pathways involving cancer and human T-lymphocytic leukemia virus I. RNA-seq results showed that 2483 genes were up-regulated and 3913 genes were down-regulated after AE knockdown. The combined analysis of MeRIP-Seq and RNA-Seq results revealed relatively high expression levels of m6A-modified genes as compared with the genes without m6A modification (SKNO-1: 0.6116±1.263 vs 2.010±1.655, P < 0.0001; SKNO-1 siAE: 0.5528±1.257 vs 2.067±1.686, P < 0.0001). The m6A modified genes located in the 3'UTR or 5 'UTR had significantly higher expression levels than those located in exonic regions (SKNO-1: 2.177± 1.633 vs 1.333 ± 1.470 vs 2.449 ± 1.651, P < 0.0001; SKNO-1 siAE: 2.304 ± 1.671 vs 1.336 ± 1.522 vs 2.394 ± 1.649, P < 0.05). Analysis of RNA-seq data identified 3 m6A-related enzymes that showed significantly elevated mRNA expression after AE knockdown, namely WTAP, METTL14, and ALKBH5 (P < 0.05), but the results of real-time PCR showed that the expressions of WTAP and ALKBH5 were significantly increased while the expression of METTL14 was lowered after AE knockdown (P < 0.05). CONCLUSION AE knockdown results in differential expressions of m6A-associated enzymes, suggesting that the AE fusion gene regulates the expression of one or more m6A-associated enzymes to control cellular methylation levels.
Adenosine/analogs & derivatives* ; Humans ; Leukemia, Myeloid, Acute/genetics* ; RNA, Messenger/metabolism* ; Transcriptome

OBJECTIVES: To establish a method to identify unknown sample based on the combined use of Fourier transform infrared spectroscopy (FTIR), gas chromatography-quadrupole time-of-flight mass spectrometry (GC-QTOF-MS), ultra-high performance liquid chromatography-linear ion trap quadrupole-orbitrap mass spectrometry (UPLC-LTQ-Orbitrap MS) and ¹H-nuclear magnetic resonance spectroscopy (¹H-NMR) technique. METHODS: The unknown sample was directly analyzed by FTIR. The unknown sample was dissolved in methanol solution containing internal standard SKF_525A and the supernatant was detected by GC-QTOF-MS and UPLC-LTQ-Orbitrap MS. The unknown sample was dissolved in methanol-d4 solution for structural analysis of ¹H-NMR. RESULTS: The characteristic absorption peaks of FTIR spectra obtained from unknown sample were 1 682 (C=O bond), 1 503, 1 488, 1 436, 1 363, 1 256, 1 092, 1 035, 935, 840 and 800 cm^-1, the characteristic fragment ions (m/z) of GC-QTOF-MS were 86.096 4 (base peak), 58.065 1, 149.023 5, 121.028 6 and 65.038 6, the accurate mass [M+H]⁺ detected by UPLC-LTQ-Orbitrap MS was 236.127 7. The sample was identified as synthetic cathinone new psychoactive substance Eutylone by ¹H-NMR. CONCLUSIONS The method established in this study can be used for structural confirmation of Eutylone.
Methanol ; Chromatography, High Pressure Liquid/methods* ; Mass Spectrometry ; Gas Chromatography-Mass Spectrometry/methods* ; Magnetic Resonance Spectroscopy

OBJECTIVE Corona-virus disease 2019 (COVID-19) is an infectious disease caused by SARS-CoV-2 virus. The variant of corona-virus first identified in India, known as Delta, has become the dominant strain in China. Unfortunately, more conta-gious and unknown variants are coming, leading to a number of close contacts under quarantine. Chinese medicine (TCM) has been recommended to prevention and treatment due to the satisfactory therapeutic effects. However, the effect of TCM to decrease positive rate in close contacts remains unknown. METHODS We conducted an retrospective cohort study in Yangzhou, China to assess the effect of Chinese medicine on decreasing positive rate in close contacts under quarantine. The primary observation outcome was positive rate of Nucleic Acid Amplification Tests (NAATs). The secondary observation outcome was a composite of viral load of positive NAATs, severity levels of confirmed cases (asymptomatic, mild, moderate, or severe), daily body temperature, and levels of close contact (primary or secondary). RESULTS A total of 1286 subjects were collected, of which 1016 (79.00％) in TCM group and 270 (21.00％) in control group with 55 participants tested positive. The incidence of the primary outcome, positive rate of NAATs was significantly lower in the Chinese medicine group than in the control group, occurring in male and age≥60 years subjects. Multi-varia-ble logistic regression (excluding NO viral load) indicated that the risk of testing positive was reduced by 0.547 times in TCM groupcompared to control group. CT value of TCM group was higher than that of control group in all subjects and female subjects, and the re-sult showed statistically significant difference. CONCLUSIONS In our study involving close contacts under quarantine, Chinese medicine resulted in lower positive rate of NAATs and viral load than control.