Intestinal organoids are constructed by crypts or stem cells from the intestine under the 3D support of the culture matrix. They contain all mature cells of the intestine, and have become a new and efficient platform for studying the mechanism of intestinal diseases. Compared with 2D cell culture, organoids can not only more effectively simulate the physiological structure and function of the intestine, but also better restore the true ecology of the intestine in different external environments. Therefore, it is more widely used in the study of pathogenesis of different intestinal diseases. This article reviewed the new progress of intestinal organoids culture, and the application and progress of intestinal organoids in the pathogenesis of inflammatory bowel diseases, colorectal cancer and celiac disease in recent years, and also discussed the application of intestinal organoids in drug research and development and screening.

In recent years, nucleic acid therapy, as a revolutionary therapeutic tool, has shown great potential in the treatment of genetic diseases, infectious diseases and cancer. Lipid nanoparticles (LNPs) are currently the most advanced mRNA delivery carriers, and their emergence is an important reason for the rapid approval and use of COVID-19 mRNA vaccines and the development of mRNA therapy. Currently, mRNA therapeutics using LNP as a carrier have been widely used in protein replacement therapy, vaccines and gene editing. Conventional LNP is composed of four components: ionizable lipids, phospholipids, cholesterol, and polyethylene glycol (PEG) lipids, which can effectively load mRNA to improve the stability of mRNA and promote the delivery of mRNA to the cytoplasm. However, in the face of the complexity and diversity of clinical diseases, the structure, properties and functions of existing LNPs are too homogeneous, and the lack of targeted delivery capability may result in the risk of off-targeting. LNPs are flexibly designed and structurally stable vectors, and the adjustment of the types or proportions of their components can give them additional functions without affecting the ability of LNPs to deliver mRNAs. For example, by replacing and optimizing the basic components of LNP, introducing a fifth component, and modifying its surface, LNP can be made to have more precise targeting ability to reduce the side effects caused by treatment, or be given additional functions to synergistically enhance the efficacy of mRNA therapy to respond to the clinical demand for nucleic acid therapy. It is also possible to further improve the efficiency of LNP delivery of mRNA through machine learning-assisted LNP iteration. This review can provide a reference method for the rational design of engineered lipid nanoparticles delivering mRNA to treat diseases.

This paper applied gas chromatography-mass spectrometry (GC-MS), network pharmacology and nuclear magnetic resonance hydrogen spectroscopy (¹H NMR) metabolomics techniques to study the material basis and mechanism of action of Ning Shen Essential Oil in anti-insomnia. The main volatile components of Ning Shen Essential Oil were analyzed by gas chromatography-mass spectrometry (GC-MS), and the insomnia-related targets were predicted using the Traditional Chinese Medicine Systematic Pharmacology Database and Analytical Platform (TCMSP) and the databases of GeneCards, OMIM and Drugbank. The insomnia model of rats was replicated by intraperitoneal injection of 4-chloro-DL-phenylalanine (PCPA). Animal experiments were approved by the Animal Ethics Committee of Shandong University of Traditional Chinese Medicine (Ethics No.: SDUTCM20221025010). The modulating effect of Compound Ning Shen Essential Oil on anxiety behavior of rats was evaluated by behavioral related indexes. The serum levels of corticotropin-releasing hormone (CRH), adrenotropic corticotropic hormone (ACTH) and melatonin (MT) were measured by enzyme-linked immunoassay (ELISA). Rat serum and hippocampus were taken for nuclear magnetic resonance (¹H NMR) metabolomics to detect the changes of endogenous metabolites in rat serum hippocampus, to designate the differential metabolites and to construct metabolic pathways. The results showed that the exercise distance in the open field experiment and the number of times and time to enter the open arm in the elevated cross maze experiment of the rats in the model group were significantly reduced (P < 0.05, P < 0.01). The behavioral indexes of rats improved to different degrees after the administration of Ning Shen Essential Oil. The serum CRH and ACTH levels of rats in the model group increased significantly (P < 0.05, P < 0.01), and the MT level decreased significantly (P < 0.01); After the intervention, serum CRH and ACTH levels were reduced to different degrees, and MT levels could be regressed. ¹H NMR metabolomics screened 10 potential biomarkers related to insomnia, which involved in 6 potential metabolic pathways. A total of 35 components of Ning Shen Essential Oil were detected by GC-MS, the main component targets of Ning Shen Essential Oil and insomnia disease targets were intersected, a total of 172 intersecting genes were screened, and 26 core targets were identified. The study demonstrated that Ning Shen Essential Oil had protective effects against PCPA-induced insomnia in rats, which was probably correlated with regulation of the hypothalamic-pituitary-adrenal axis (HPA) related hormones and metabolism of amino acids, lipids and choline.

Objective To analyze the literature related to diphenidol tablets poisoning,the characteristics of poisoning were summarized to provide reference for controlling the suicidal abuse risk of diphenidol tablets.Methods The global literature on suicide,overdose,poisoning,shock,and death related to difenidol published from January 1,2011 to December 31,2022 was analyzed,including gender,age,dosage,cardiac(blood)concentration,poisoning symptoms,etc.Results Young women were the majority of people with poisoning.The highest proportion of the age group is 11 to 30 years group.Patients who take medication doses greater than 3 000 mg may have a higher risk of death;patients with a heart(blood)concentration greater than 6 μg·mL-1 may have a higher risk of death.Malignant arrhythmia,consciousness disorders,coma,and apnea are common serious adverse events during poisoning.Conclusion It is recommended that the drug regulatory authorities should require the Listing permit holder of difenidol tablets to add the risk and symptoms of poisoning into the instructions.It is suggested that restricting individual consumers from purchasing large amounts of difenidol tablets in the short term.It is recommended that canceling the high-dose sales packaging of difenidol tablets.It is suggested that converting difenidol tablets into prescription drugs,even consider canceling the registration certificate of difenidol tablets.

Objective To obtain the occurrence and clinical characteristics of central nervous system adverse drug reactions(CNS-ADR)associated with three kinds of carbapenems,and to provide reference for clinical drug safety.Methods Based on adverse drug event active surveillance and assessment system-Ⅱ(ADE-ASAS-Ⅱ),retrospective automated monitoring of inpatients using imipenem,meropenem,and biapenem in a tertiary hospital from January 2022 to December 2022 was conducted.The incidence of carbapenem related CNS-ADR was calculated,and the basic conditions,disease conditions,drug use,occurrence time of ADR and symptoms of patients with CNS-ADR were analyzed by descriptive statistics.Results A total of 2 482 patients with 2 709 times of medication were included in this study,and a total of 93 positive cases of CNS-ADR occurred,with an overall incidence of 3.43％for all three medications,3.98％for imipenem,3.51％for meropenem,and 2.78％for biapenem.The indications for the 93 positive cases of CNS-ADR were mainly pulmonary infections(59.13％)and abdominal infections(25.80％);they occurred mostly within 7 days of the administration of the medication;with a variety of clinical manifestations,with anxiety/irritability being the most common,and epilepsy appearing most frequently in severe cases.Co-administration of proton pump inhibitors and cephalosporins accounted for a greater proportion of positive cases,50.54％of positive cases had a history of surgery,and 69.89％of positive cases were associated with electrolyte disturbances.Conclusion Clinical use of carbapenems should be based on the actual situation of the patient to develop an individualised drug regimen,and special attention should be paid to patients with comorbidities of renal disease,electrolyte disorders,and a history of previous surgery and neurological disorders,in order to reduce the risk of the occurrence of CNS-ADR.

Objective To observe the changes of cervical sagittal parameters of digital radiography(DR)at bilateral oblique position of cervical spine in patients with neck type cervical spondylopathy(NTCS)after cervical rotation and lifting manipulations,and to evaluate the clinical significance of cervical sagittal parameters in assessing the efficacy of NTCS by combining the pain score of visual analogue scale(VAS).Methods A retrospective analysis was carried out in 36 NTCS patients admitted to the outpatient clinic of the Tuina Department of Foshan Hospital of Traditional Chinese Medicine from November 2020 to May 2021.According to the treatment method,the patients were divided into the trial group and the control group,with 18 patients in each group.The trial group was treated with cervical rotation and lifting manipulations,and the control group was treated with cervical vertebra traction.The two groups were treated once every other day for 2 continuous weeks.The changes of VAS pain score and sagittal parameters of DR such as sagittal vertical axis of cervical vertebra 2-7(C2-7 SVA),the T1 slope(T1S),neck tilt(NT),and thoracic inlet angle(TIA)in the two groups were observed before and after treatment.Spearman correlation analysis was used to explore the correlation between VAS scores of pain level and cervical sagittal parameters.Results(1)Before treatment,there was no statistically significant difference in the VAS pain scores between the two groups(P＞0.05).After treatment,the VAS pain scores in the two groups were significantly decreased compared with those before treatment(P＜0.05),and the decrease of the scores in the trial group was significantly superior to that in the control group(P＜0.01).(2)Before treatment,there was no statistically significant difference in the values of cervical sagittal parameters of C2-7 SVA,T1S,NT,and TIA between the two groups(P＞0.05).After treatment,the C2-7 SVA,T1S,and TIA of the trial group were significantly improved compared with those before treatment(P＜0.05),but the improvement of NT was not obvious(P＞0.05);the cervical sagittal parameters of the control group were not significantly improved compared with those before treatment(P＞0.05).The intergroup comparison showed that the improvement of C2-7 SVA,T1S,and TIA in the trial group was significantly superior to that in the control group(P＜0.05 or P＜0.01),while the difference in NT between the two groups after treatment was not statistically significant(P＞0.05).(3)The results of Spearman correlation analysis showed that before treatment,VAS pain score had no correlation with C2-7 SVA,T1S,NT,and TIA(P＞0.05),C2-7 SVA was negatively correlated with NT(r=-0.502,P＜0.05),and T1S was positively correlated with NT(r=0.601,P＜0.05).After treatment,VAS pain score was negatively correlated with C2-7 SVA(r=-0.362,P＜0.05)and positively correlated with TIA(r=0.476,P＜0.05),C2-7 SVA was positively correlated with NT(r=0.928,P＜0.05),and T1S was positively correlated with TIA(r=0.623,P＜0.05).Conclusion Both cervical rotation and lifting manipulations and cervical traction can relieve the pain and adjust cervical sagittal parameters in the patients with NTCS,but cervical rotation and lifting manipulations are more effective in treating NTCS.And there may be a correlation between the VAS scores of pain level and cervical sagittal parameters in patients with NTCS.

Objective To investigate the effect of varying blood pressure stratification on renal function in the diabetic population.Methods A prospective cohort study was conducted,enrolling 9 489 diabetic patients from a total of 101 510 Kailuan Group employees who underwent health examinations between July 2006 and October 2007.The follow-up period was(8.6±4.0)years.Participants were categorized into four groups based on their baseline blood pressure levels:normal blood pressure(systolic blood pressure<120 mmHg and diastolic blood pressure<80 mmHg),elevated blood pressure(systolic blood pressure 120-130 mmHg and diastolic blood pressure<80 mmHg),stage 1 hypertension(systolic blood pressure 130-140 mmHg and/or diastolic blood pressure 80-90 mmHg),and stage 2 hypertension(systolic blood pressure≥140 mmHg and/or diastolic blood pressure≥90 mmHg).The incidence density of chronic kidney disease(CKD)was compared among these groups.A multivariate Cox proportional hazards regression model was employed to assess the effects of different blood pressure levels on renal function in diabetic patients,with the stability of the results confirmed using a multivariate time-dependent Cox proportional hazards model.Sensitivity analysis was conducted after excluding cases of cardiovascular disease(CVD)during follow-up,and cases using antihypertensive and antidiabetic medications at baseline.Results(1)At baseline,stage 1 hypertension patients demonstrated statistically significant higher differences with age and body mass index(BMI)compared to normal blood pressure group(P<0.05).(2)By the end of the follow-up,2 294 cases of CKD were identified,including 1 117 cases of estimated glomerular filtration rate(eGFR)decline and 1 575 cases of urinary protein.The incidences density of CKD,eGFR decline and urinary protein for stage 1 hypertension group were 39.4,16.3 and 25.5 per thousand person-years,respectively,all of which were statistically significant different from normal blood pressure group(log-rank test,P<0.01).(3)Multivariate Cox regression analysis revealed that,compared to the normal blood pressure group,stage 1 hypertension was associated with a 29%increased risk of CKD(HR=1.29,95%CI 1.09-1.52)and a 40%increased risk of eGFR decline(HR=1.40,95%CI 1.08-1.80)in diabetic individuals.Conclusion Stage 1 hypertension significantly increases the risk of CKD and eGFR decline in diabetic individuals,with a particularly notable effect on the risk of eGFR decline.

Purpose::Shaping and assembling contemporary external fixators rapidly for the severe mandibular fractures remains a challenge, especially in emergency circumstance. We designed a novel external fixator that incorporates universal joints to provide the stabilization for mandibular comminuted fractures. This study aims to confirm the efficacy of this novel external fixator through biomechanical tests in vitro and animal experiments. Methods::In vitro biomechanical tests were conducted using 6 fresh canine with mandibular defect to simulate critical comminuted fractures. Three mandibles were stabilized by the novel external fixator and other mandibles were fixed by 2.5 mm reconstruction plates. All fixed mandibles were subjected to loads of 350 N on the anterior regions of teeth and 550 N on the first molar of the unaffected side. The stability was evaluated based on the maximum displacement and the slope of the load-displacement curve. In animal experiments, 9 beagles with comminuted mandibular fractures were divided into 3 groups, which were treated with the novel external fixation, reconstruction plate, and dental arch bar, respectively. The general observation, the changes in animals’ weight, and the surgical duration were recorded and compared among 3 groups. The CT scans were performed at various intervals of 0 day (immediately after the surgery), 3 days, 7 days, 14 days, 21 days, and 28 days to analyze the displacement of feature points on the canine mandible and situation of fracture healing at 28 days. The statistical significance was assessed by the two-way analysis of variance test followed by the Bonferroni test, enabling multiple comparisons for all tests using GraphPad Prism10.1.0 (GraphPad Inc, USA). Results::The outcomes of the biomechanical tests indicated that no statistically significant differences were found in terms of the maximum displacement ( p = 0.496, 0.079) and the slope of load displacement curves ( p = 0.374, 0.349) under 2 load modes between the external and internal fixation groups. The animal experiment data showed that there were minor displacements of feature points between the external and internal fixation groups without statistic difference, while the arch bar group demonstrated inferior stability. The CT analysis revealed that the best fracture healing happened in the internal fixation group, followed by the external fixation and arch baring at 28 days after fixation. The external fixation group had the shortest fixation duration (25.67 ± 3.79) min compared to internal fixation ((70.67 ± 4.51) min, p < 0.001) and arch baring ((42.00 ± 3.00) min, p = 0.046). Conclusion::The conclusion of this study highlighted the efficacy and reliability of this novel external fixator in managing mandibular fractures rapidly, offering a viable option for the initial stabilization of comminuted mandibular fractures in the setting of emergency rescue.

Objective To explore the effect of Kümmell's disease with kyphosis on the sagittal morphology of the spine-pelvis.Methods A retrospective analysis of 34 patients of Kümmell's disease with kyphosis(Kümmell group)admitted from August 2015 to September 2022,including 10 males and 24 females with an average age of(71.1±8.5)years old.A control group of 37 asymptomatic population aged(69.3±6.7)years old was matched.Spinal-pelvic sagittal parameters were measured on the anterior-posterior and lateral X-rays of the whole spine in the standing position,including segmental kyphosis(SK)or thoracolumbar kyphosis(TLK),thoracic kyphosis(TK),lumbar lordosis(LL),pelvic incidence(PI),pelvic tilt(PT),sacral slope(SS),sagittal vertical axis(SVA),T1 pelvic angle(TPA)and PI-LL.Vertebral wedge angle(WA)in Kümmell was mea-sured and differences in parameters among groups were analyzed and the relationship between spino-pelvic parameters and WA,SK were also investigated.Results TK,SK,PT,SVA,TPA and PI-LL in Kümmell group were significantly larger than those in control group(P＜0.05),LL and SS in Kümmell group were significantly decreased than those in control group(P＜0.05),and there was no significant difference in PI between two groups(P＞0.05).In Kümmell group,WA(30.8±5.9)° showed a positive correlation with SK and TK(r=0.366,0.597,P＜0.05),and SK was significantly correlated with LL and SS(r=0.539,-0.591,P＜0.05).Strong positive correlation between LL and PI,SS,SVA,TPA,PI-LL were also confirmed in patients with Kümmell with kyphosis(r=0.559,0.741,-0.273,-0.356,-0.882,P＜0.05).Conclusion Patients with Kümmell with kyphosis not only have segmental kyphosis,but also changes the overall spinal-pelvic sagittal parameters,including loss of lumbar lordosis,pelvic retrorotation,trunk forward tilt.The surgical treatment of Kümmell disease should not only pay attention to the recovery of the height of the collapsed vertebra,but also focus on the overall balance of the spine-pelvic sagittal plane for patients with kyphosis.

Objective To explore the potential value of three-dimensional fast spin echo(3D-SPACE)combined with multilayer spiral CT(MSCT)in the diagnosis of knee cruciate ligament injury,to provide a new direction for the optimization of subsequent clinical diagnosis.Methods A total of 120 patients with knee cruciate ligament injury were treated from April 2020 to April 2021,aged from 21 to 68 with an average of(41.52±4.13)years old.For all patients,separate MSCT scanner scans,3D-SPACE sequence scans alone and 3D-SPACE sequence combined with MSCT scans were used.The injury and classifica-tion of the anterior and posterior cruciate ligament of the knee were compared,the length of the anterior-medial bundle and posterolateral bundle and its angle of the knee with the horizontal plane were observed,the diagnostic value of 3 diagnostic methods in knee cruciate ligament injury were determined.Results There was no significant difference between the 3D-SPACE sequence scan alone and the MSCT test alone on the total diagnostic rate and grading total diagnostic rate(P＞0.05).The total diagnostic rate and grading total diagnostic rate of 3D-SPACE scan combined with MSCT were significantly higher than those of 3D-SPACE scan or MSCT alone(P＜0.05).The 3D-SPACE sequence scan alone and the MSCT detection alone had no signifi-cant difference in the measurement values related to the anterior and posterior cruciate ligaments of the knee joint(P＞0.05).3D-SPACE sequence scanning combined with MSCT detection on the knee joint anterior and posterior cruciate ligament related mea-surements were significantly higher than the 3D-SPACE sequence scan or MSCT detection alone(P＜0.05).The area under the ROC curve estimated by 3D-SPACE sequence scanning combined with MSCT was 0.960,which was significantly higher than that of 3D-SPACE sequence scanning and MSCT alone evaluating the area under the ROC curve line of 0.756 and 0.795.The com-bined 3D-SPACE sequence scanning and 3D-SPACE sequence scanning MSCT analysis and prediction models were statistically different(Z=2.236,P＜0.05),and MSCT alone and 3D-SPACE sequence scanning combined with MSCT analysis and prediction models were statistically different(Z=2.653,P＜0.05).Conclusion The application of 3D-SPACE sequence combined with MSCT scanning for knee cruciate ligament injury can improve the diagnosis rate of patients with knee cruciate ligament injury.It can be used as a diagnostic tool for patients with knee cruciate ligament injury and is worthy of clinical application.