The use of off-label drugs， which accompanies the approval system for new drugs entering the market， is widespread in clinical practice in China， and the resulting medical damage liability is also controversial in theory and practice. Based on 129 judicial cases from 2014 to 2023， this paper conducted a quantitative analysis of medical damage liability caused by off-label drug use. Through sorting out， it was found that the cases of off-label drug use presented obvious characteristics in types and regional distribution， and their damage consequences and appeal rates were far higher than those of general medical damage cases， which need to attract more attention. Based on the liability reasons， this paper further categorized the cases into three types： no liability， single liability， and multiple liabilities. The number and liability ratio of off-label drug use under different liability types were analyzed， and the key factors affecting the establishment of medical damage liability for off-label drug use were sorted out and analyzed in depth. These key factors included the existence of off-label drug use and a clear causal relationship between off-label drug use and medical damage， inadequate informed consent， and lack of sufficient and solid evidence-based medical support. Additionally， it was confirmed that a medical ethics review is not a prerequisite for the legality of off-label drug use. Finally， recommendations for off-label drug use in clinical practice were proposed， such as ensuring timeliness， adequacy， and formality of informed consent， adhering to a clear causal relationship construction， as well as sorting out the scope and effectiveness level of evidence-based medicine to establish industry self-consistency.

Objective: To investigate the spatial clustering characteristics of varicella public health emergency events in Nanjing City from 2017 to 2022, so as to provide the evidence for the development of varicella prevention and control strategies. Methods: Data of varicella public health emergency events in Nanjing City from 2017 to 2022 were collected through Emergency Public Health Management Information System of Chinese Disease Prevention and Control Information System. The software ArcGIS 10.2 was employed for trend-surface analysis, spatial autocorrelation analysis and hotspot analysis to understand the spatial clustering characteristics of varicella public health emergency events. Results: A total of 84 varicella public health emergency events were reported in Nanjing City from 2017 to 2022, with an average attack rate of 2.53% (2 558 cases). Ⅳ-level events were predominant, accounting for 90.48% (76 events). The trend-surface analysis showed lower incidence of varicella public health emergency events in the west of Nanjing City and higher in the east, and lower in the north and higher in the south. The global spatial autocorrelation analysis showed that there was a positive spatial correlation in varicella public health emergency events in 2017 and 2019, indicating spatial clustering (P<0.05). The hot spots were Jiangning District, Gaochun District, Yuhuatai District and Jianye District. Conclusion The incidence of varicella public health emergency events in Nanjing City from 2017 to 2022 has spatial aggregation, with a concentration in suburban areas such as Jiangning District and Gaochun District.

Gastroparesis is a gastric disease characterized by delayed gastric emptying."Vomiting"is the main clinical manifestation of this disease,while"atrophy"indicates dysfunction of the stomach.Based on the theory of"atrophy,dyspnea and vomiting are ascribed to the upper part",originating from the Chapter of"Zhi Zhen Yao Da Lun"from the Suwen(Basic Questions)section this paper explored the pathogenesis and treatment idea of gastroparesis from the function of the lung.It is put forward that failure of lung qi in dispersion,so the lung qi cannot maintain the circulation of harmonizing qi and blood,leading to malnutrition of stomach and loss of stomach receiving food and drink function.Melancholy impairing lung,so lung cannot govern diffusion,leading to stomach governing the disfunction of dredging and descending.Impaired depurative descending of lung qi,so the large intestine and stomach are lost in the alternating operation of deficiency and excess,leading to stomach governing the disfunction of transportation and transformation.Therefore,the treatment approach is proposed to improve the stomach's function to receive food and drink,transport and transform and promote the recovery of gastric motility by replenishing and restoring lung qi,regulating emotions and catharsis and smoothing lung.Analyzing the effect of function of the lung on gastric motility is of great value for expanding the application of traditional Chinese medicine in gastrointestinal motility disorders,and digging new connotations of classic theories in modern clinical practice.

Objective:Migraine and tremor share some genetic mutation sites,and clinical studies have also confirmed their correlation.This study aims to explore the clinical and electrophysiological characteristics of migraine patients with concomitant tremor,and to analyze the relevant influential factors of tremor occurrence. Methods:We retrospectively analyzed the clinical data of 217 migraine patients who visited the Third Affiliated Hospital of Qiqihar Medical University from June 2022 to October 2023.The Clinical Rating Scale for Tremor(CRST),Numerical Rating Scale(NRS),Generalized Anxiety Disorder-7(GAD-7),and Patient Health Questionnaire-9(PHQ-9)were respectively used to assess the tremor symptoms,degree of headache,anxiety,and depression of patients.All patients underwent routine head MR scanning and electromyography examination,and were divided into a migraine with tremor group and a migraine without tremor group based on the electromyogram examination. Results:The migraine with tremor group and the migraine without tremor group were included 52 patients(23.96%)and 165 patients(76.04%),respectively.Compared with the migraine without tremor group,the migraine with tremor group had a longer course and duration of headache,higher frequency of headache attacks,higher NRS score,GAD-7 score,and PHQ-9 score,and fewer weekly physical exercises.The differences were statistically significant(all P<0.05).There were no statistically significant differences in the presence or absence of prodromal headache and white matter hyperintensities(WMHs)between the 2 groups(both P>0.05).The evaluation results of the CRST showed that out of 217 migraine patients,39 patients(17.97%)were accompanied by tremors.The electromyographic results showed that all 52 migraine patients with tremors had upper limb tremors,including 28 migraine patients with postural tremors and 24 migraine patients with static tremors.Compared with the migraine patients with static tremors,the migraine patients with postural tremors had lower average frequency,peak frequency,and headache onset frequency(all P<0.05).Multiple linear regression analysis showed that frequency of physical exercise,duration of illness,frequency of headache attacks,NRS score,GAD-7 score,and PHQ-9 score were risk factors for migraine patients with concomitant tremors(all P<0.05). Conclusion:Patients with migraine mainly experience upper limb postural tremors.Reduced physical exercise,long course of disease,long duration of headache,frequent headache attacks,severe headache,anxiety,and depression are risk factors for migraine patients with concomitant tremors.

Objective To clone the HnGUA gene from Hirudo nipponia and conduct bioinformatics analysis,protein prokaryotic expression analysis and gene differential expression analysis.Methods Based on the transcriptome data of H.nipponia in the previous study,the full-length cDNA of HnGUA was cloned by rapid amplification of cDNA ends(RACE),and bioinformatics analysis was performed.The prokaryotic expression vector was constructed,transformed into Escherichia coli BL21(DE3)competent cells and the expression of recombinant protein was induced by IPTG.The qPCR was used to further analyze the tissue-specific expression of HnGUA.Results The size of HnGUA gene was 504 bp,containing an open reading frame(ORF)of 231 bp and encoding 76 amino acids.Its protein molecular weight and isoelectric point are 8.17 kDa and 4.44,respectively.Multiple sequence alignment analysis showed that HnGUA was highly homologous to genes in other leech species that encode inhibitory proteins.The results of the prokaryotic expression analysis showed that the constructed pET32a-HnGUA vector could be successfully expressed in E.coli BL21(DE3),and the SDS-PAGE results showed that the induced recombinantly expressed HnGUA protein was around 6 kDa,which was basically consistent with the predicted protein size.The results of the Real-time PCR revealed spatial and temporal differences in the expression profiles of HnGUA,with high levels of expression detected in the skin and crop tissues.Conclusion This study represents the first successful cloning of the HnGUA gene from H.nipponia and the expression of the corresponding recombinant protein in E.coli.It provides a foundation for future exploration of the biosynthetic pathways and molecular regulatory mechanisms of active small anticoagulant molecules in leeches.

Background/Aims: Four-week treatment of linvencorvir (RO7049389) was generally safe and well tolerated, and showed anti-viral activity in chronic hepatitis B (CHB) patients. This study evaluated the efficacy, safety, and pharmacokinetics of 48-week treatment with linvencorvir plus standard of care (SoC) in CHB patients. Methods: This was a multicentre, non-randomized, non-controlled, open-label phase 2 study enrolling three cohorts: nucleos(t)ide analogue (NUC)-suppressed patients received linvencorvir plus NUC (Cohort A, n=32); treatment-naïve patients received linvencorvir plus NUC without (Cohort B, n=10) or with (Cohort C, n=30) pegylated interferon-α (Peg-IFN-α). Treatment duration was 48 weeks, followed by NUC alone for 24 weeks. Results: 68 patients completed the study. No patient achieved functional cure (sustained HBsAg loss and unquantifiable HBV DNA). By Week 48, 89% of treatment-naïve patients (10/10 Cohort B; 24/28 Cohort C) reached unquantifiable HBV DNA. Unquantifiable HBV RNA was achieved in 92% of patients with quantifiable baseline HBV RNA (14/15 Cohort A, 8/8 Cohort B, 22/25 Cohort C) at Week 48 along with partially sustained HBV RNA responses in treatment-naïve patients during follow-up period. Pronounced reductions in HBeAg and HBcrAg were observed in treatment-naïve patients, while HBsAg decline was only observed in Cohort C. Most adverse events were grade 1–2, and no linvencorvir-related serious adverse events were reported. Conclusions 48-week linvencorvir plus SoC was generally safe and well tolerated, and resulted in potent HBV DNA and RNA suppression. However, 48-week linvencorvir plus NUC with or without Peg-IFN did not result in the achievement of functional cure in any patient.

Frailty denotes a nonspecific clinical condition characterized by a decrease of physiological reservation in multiple systems, which makes individuals extremely vulnerable to stressors. Frailty increases the incidence of adverse outcomes and death of patients. However, frailty is reversible and preventable. Therefore, this article reviews theoretical models, assessment tools and influencing factors of frailty in elderly patients with hematologic maligilancy, so as to provide references for medical staff to carry out frailty management and related research in elderly patients with hematologic maligilancy.

Objective:To investigate the synergistic effect of physical intervention and chemotherapeutic drug therapy on tumor growth by blocking tumor microvessels and injecting chemotherapy drug Endostar (ecombinant human vascular endostatin injection) to inhibit tumor neovascularization by low intensity ultrasound induced microbubble cavitation combined with hemocoagulase.Methods:Seventy-five male NU/NU mice bearing human-derived lung adenocarcinoma, weighing 25-30 g, were randomly divided into microbubble-enhanced ultrasonic cavitation+ Endostar group (MEUC+ Endostar), microbubble-enhanced ultrasonic cavitation+ hemocoagulase+ Endostar group (MEUC+ HC+ Endostar), microbubble-enhanced ultrasonic cavitation (MEUC), Endostar group (Endostar) and sham group. Fifteen mice in each group were given the corresponding treatment intervention for 4 consecutive days followed by 4 days of aseptic feeding. Two-dimensional ultrasound and contrast-enhanced ultrasound (CEUS) were performed before intervention, immediately after intervention and 4 days after intervention, respectively. Tumor tissues were obtained for vascular endothelial growth factor immunofluorescence staining, and microvessel density (MVD) was observed.Results:There was no difference in tumor volume between the groups before the intervention ( P>0.05). Immediately after the intervention, filling defects were observed in MEUC+ Endostar group, MEUC+ HC+ Endostar group and MEUC group, while filling was good in Endostar group and sham group; 4 days after the intervention, filling defects were observed in MEUC+ Endostar group and MEUC+ HC+ Endostar group. The filling defect was still present in Endostar group, while partial recovery of perfusion was performed in MEUC group, and PI and AUC were still significantly lower in MEUC+ HC+ Endostar group than in the other groups ( P<0.05). When tumor tissues were obtained 4 days after the intervention, the MVD in MEUC+ HC+ Endostar group was significantly lower than that in the remaining groups, and the difference of MVD in tumor tissue was statistically significant ( P<0.05). Conclusions:Low intensity ultrasound induced microbubble cavitation combined with hemocoagulase and Endostar can produce a synergistic effect in blocking tumor microvessels and inhibiting tumor angiogenesis, which can more effectively inhibit tumor growth.

Objective:To investigate the effects of mixed probiotics on food allergy and the underlying mechanism.Methods:BALB/c mice on the 15 th day of pregnancy were randomly (random number table method) classified into the control group, food allergy model group and mixed probiotics group.Mice in the food allergy model and mixed pro-biotics group were subjected to ovalbumin (OVA) sensitization after birth, and those in the mixed probiotics group were then given probiotic solution by gavage from day 21 to day 35.Mice in control group were similarly given 9 g/L saline.Twenty-four hours after the last OVA sensitization, intestinal histopathological sections were prepared to observe intestinal pathological changes.Blood smears were prepared to detect eosinophil count.In addition, serum samples were collected to measure cytokine levels and OVA specific antibodies.The number of dendritic cells (DCs) and regulatory T cells (Tregs) in mouse mesenteric lymph nodes was calculated.Differences among 3 groups were compared by the One- Way ANOVA or Kruskal- Wallis H test. Results:Compared with those of food allergy model group, diarrhea score, the ratio of eosinophils and serum levels of interleukin(IL)-4, IL-5, IL-13, mast cell protease 1 (MCPT-1), and OVA specific antibodies IgE and IgG were significantly lower in mixed probiotics group[(2.00±0.71) points vs.(3.22±0.97) points, (2.28±1.61)% vs.(10.99±2.26)%, (413.68±22.81) ng/L vs.(708.78±27.66) ng/L, (36.64±3.74) ng/L vs.(46.05±4.95) ng/L, (201.37±65.61) ng/L vs.(495.22±96.66) ng/L, (31 924.15±1 177.77) ng/L vs.(36 175.77±618.29) ng/L, (9.10±8.08) ng/L vs.(19.69±0.84) ng/L, (30.50±8.81) ng/L vs.(190.32±6.40) ng/L], while IL-10 level was significantly higher[(164.12±3.88) ng/L vs.(123.90±7.31) ng/L] ( t=3.37, 8.72, 16.07, 3.90, 7.40, 7.95, 3.91, 44.00 and 7.76, respectively, all P<0.01). Compared with those of food allergy model group, programmed cell death ligand 1 (PD-L1) level on the surface of CD 103+ DCs and CD 103+ CD 80-CD 40-DCs, the proportion of Tregs in CD4 + T cells, and the level of programmed cell death 1 (PD-1) on the surface of Tregs were significantly higher in mixed probiotics group[(75.59±0.45)% vs.(45.60±4.73)%, (67.56±1.87)% vs.(37.12±6.07)%, (8.24±0.69)% vs.(6.20±0.66)%, (11.25±3.12)% vs.(4.08±2.33)%]( t=7.88, 4.48, 3.63 and 3.71, all P<0.01). Conclusions:Mixed probiotics can alleviate the symptoms of food allergy and inflammatory response of young rats through mediating Tregs via the PD-1/PD-L1 pathway.

Objective:To retrieve, evaluate, and summarize the best evidence for the assessment of gastrointestinal function in critically ill patients by bedside ultrasound.Methods:Guidelines, evidence summaries, group standards, expert consensus, systematic reviews, and randomized controlled trials on the assessment of gastrointestinal function in critically ill patients by bedside ultrasound were retrieved by computer on domestic and foreign guideline websites, society websites and databases based on evidence-based nursing. The search period was from January 1, 2010 to April 30, 2021. The quality of the article was independently assessed by two researchers using the Appraisal of Guidelines for Research and Evaluation Ⅱ and the critical appraisal tool of the Joanna Briggs Institute (JBI) in Australia (2016) . Combined with the judgment of the research team, the data from the article that met the criteria were extracted and the evidence was graded and recommended according to the JBI quality level of evidence system (2014 Edition) .Results:A total of 22 articles were included, involving 5 guidelines, 1 evidence summary, 1 group standard, 6 expert consensuses, 4 systematic reviews, and 5 randomized controlled trials. A total of 33 pieces of evidence were summarized from 6 aspects, namely, the feasibility of nurses applying bedside ultrasound, fundamentals of ultrasound assessment of gastrointestinal tract, ultrasound assessment of gastric contents, ultrasound assessment of gastric motility, ultrasound assessment of bowel, ultrasound guided enteral nutrition program.Conclusions:Nurses who have been systematically trained can use ultrasound to assess gastrointestinal function in critically ill patients in real time. Ultrasound-guided enteral nutrition for critically ill patients needs to be standardized and improved, and many studies need to be carried out.