The assessment of adverse drug events is an important basis for clinical safety evaluation and post-marketing risk control of drugs,and its causality assessment is gaining increasing attention.The existing methods for assessing the causal relationship between drugs and the occurrence of adverse reactions can be broadly classified into three categories:global introspective methods,standardized methods,and probabilistic methods.At present,there is no systematic introduction of the operational details of the various methods in the domestic literature.This paper compares representative causality assessment methods in terms of definition and concept,methodological steps,industry evaluation and advantages and disadvantages,clarifies the basic process of determining the causality of adverse drug reactions,and discusses how to further improve the adverse drug reaction monitoring and evaluation system,with a view to providing a reference for drug development and pharmacovigilance work in China.

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 evaluate the pharmacokinetics characteristics of single-dose of Etripamil nasal spray 70 mg in healthy adult Chinese subjects.Methods This was a single-center,randomized,double-blind,placebo-controlled study.Twelve healthy adult Chinese subjects were randomized to receive single-dose of Etripamil nasal spray 70 mg(n=10)or placebo nasal spray(n=2).Blood and urine samples were collected prior and post dose.Etripamil in plasma and urine were analyzed by liquid chromatography-tandem mass spectrometry.The pharmacokinetic parameters were calculated by WinNonlin non-compartmental model.Results Following the single-dose of Etripamil nasal spray 70 mg in healthy adult Chinese subjects,the peak concentration of Etripamil in plasma was quickly attained,with a Cmax of(66.76±56.61)ng·mL-1 and a median(range)tmax of 4.00(3.00-5.00)min.The plasma concentrations of Etripamil had fallen approximately 65％from peak value at 25 min after dosing,and close to 80％within 50 min.The AUC0-last and AUC0-∞ were(3 104.16±2 654.46)and(4 048.77±2 682.38)ng·min·mL-1,respectively.The urine excretion percentage of Etripamil during 24 h was(0.01±0.01)％.Among the 12 subjects who were treated with Etripamil or placebo,10 subjects reported a total of 29 treatment-emergent adverse events(TEAEs).All of the TEAEs were mild in severity.The most common TEAEs were rhinorrhoea and lacrimation increased.Conclusion Etripamil was quickly absorbed after intranasal administration,followed by rapid distribution and elimination(not primarily excreted by renal);Etripamil 70 mg was safe and well tolerated by the healthy Chinese adult subjects.

Objective To evaluate tolerability,safety and pharmacokinetics of JS026 and JS026-JS016 single dose intravenous infusion in healthy adults.Methods This phase 1,randomized,double-blind,placebo-controlled,dose-escalation study totally included 48 participants:32 healthy subjects were enrolled in JS026 single intravenous infusion groups and 16 healthy subjects were enrolled in JS026-JS016 groups.JS026 was sequentially administered from low dose to high dose(30-1 000 mg),with intravenous infusion of JS026 or placebo in JS026 single-dose groups,and intravenous infusion of JS026-JS016 or placebo in the combination drug groups.Blood was collected according to the time point designed for trial.Serum concentrations of JS026 and JS016 were determined by enzyme linked immunosorbnent assay(ELISA),and pharmacokinetics parameters were calculated by WinNonlin 8.2.The power model method was used to evaluate the linear analysis of dose and drug exposure.Results 47 subjects completed trial and 1 subject lost to follow-up.After a single intravenous injection of JS026 of 30 mg,100 mg,300 mg,600 mg,and 1 000 mg,mean Cmax were(9.47±1.53),(33.20±4.95),(96.10±13.70),(177.00±22.20)and(353.00±56.70)μg·mL-1,respectively;mean AUC0-∞ were(4 225.00±607.00),(1.78 × 104±3 268.00),(5.83 × 104±1 038.00),(1.07 × 105±152.00),(1.66 × 105±327.00)μg·h·mL-1,respectively;mean t1/2 of JS026 were 563-709 h.The Cmax and AUC0-∞ of JS026 were basically similar alone or in combination with JS016.The results of Power model showed that Cmax and AUC0-∞ increased approximately linearly with the increasing dose of JS026.Treatment emergent adverse event was not increasing when dose increased and most of adverse event associated with drugs were abnormal on laboratory tests and haematuria,thus JS026 and JS016 was well tolerated in all groups.Conclusion The single intravenous infusion of JS026 can almost be thought to be a linear relationship between the doses and drug serum exposure.JS016 had no significant effect on serum concentration of JS026 and JS026 was well tolerated and safe in healthy subjects within 30-1 000 mg.

Objective To investigate the therapeutic effect and mechanism of Jianwei Xiaozhang Tablets on rats with precancerous lesions of gastric cancer(PLGC).Methods Forty male SD rats were randomly divided into the normal group,the model group,the folic acid group and the Jianwei Xiaozhang Tablets group,with 10 rats in each group.In addition to the normal group,the other three groups of rats were prepared by gavage with Ranitidine Aqueous Solution combined with N-methyl-N'-nitro-N-nitrosoguanidine(MNNG)solution drinking method for the preparation of PLGC model.After successful modeling,drugs were administered accordingly for 7 weeks.The changes in body mass of rats during modeling and drug administration were recorded,the gross view of the stomach was observed and scored pathologically,the coefficients of spleen and liver were determined,the pathological changes in gastric tissue were observed by hematoxylin-eosin(HE)staining,enzyme-linked immunosorbent assay(ELISA)was used to measure serum gastrin(GAS),motilin(MTL)and glucagon(GC),Alisin Blue-Periodic Acid Schiff's(AB-PAS)staining was used to observe the thickness of the mucosal layer of gastric tissues,the expressions of phosphatidylinositol 3-kinase(PI3K),phosphorylated PI3K(p-PI3K),protein kinase B(Akt),phosphorylated Akt(p-Akt),and endothelial-type nitric oxide synthase(eNOS)proteins in gastric tissues were detected by protein immunoblotting(Western Blot),and the expression of vascular endothelial growth factor A(VEGFA)protein in gastric tissues was detected by immunofluorescence staining.Results Compared with the normal group,the body mass of rats in the model group grew slowly during the experimental period,gastric macroscopic pathological scores were significantly increased(P＜0.01),splenic coefficient and hepatic coefficient were significantly decreased(P＜0.01),the gastric tissues showed cuprocyte hyperplasia and intestinal chemotaxis,gastric tissues'inflammation scores were significantly increased(P＜0.01),the serum GAS content was significantly increased(P＜0.01),and the MTL,GC contents were significantly reduced(P＜0.05),and the thickness of the mucous membrane layer of gastric tissue was significantly reduced(P＜0.05),the protein expression levels of PI3K,p-PI3K,Akt,p-Akt and eNOS were reduced(P＜0.01),and the protein expression level of VEGFA was reduced(P＜0.01);compared with the model group,the above indexes of the Jianwei Xiaozhang Tablets group and the folic acid group were all significantly improved(P＜0.05 or P＜0.01),among which,the Jianwei Xiaozhang Tablets group had a better improvement effect in the proliferation of cup cells and intestinal chemotaxis in gastric tissues,the content of serum GAS,and the thickness of the mucous layer in gastric tissues.Conclusion The mechanism of the improvement of PLGC in rats by Jianwei Xiaozhang Tablets may be related to the activation of the PI3K-Akt-eNOS pathway,which in turn promotes the angiogenesis and repair of gastric damaged tissues.

Protein as the allergens could lead to allergy. In addition, a widespread class of allergens were known as glycans of N-glycoprotein. N-glycoprotein contained oligosaccharide linked by covalent bonds with protein. Recently,studies implicated that allergy was associated with glycans of heterologous N-glycoprotein found in food, inhalants, insect toxins, etc. The N-glycan structure of N-glycoprotein allergen has exerted an influence on the binding between allergens and IgE, while the recognition and presentation of allergens by antigen-presenting cells (APCs) were also affected. Some researches showed thatN-glycan structure of allergen was remodeled by N-glycosidase, such as cFase I, gpcXylase, as binding of allergen and IgE partly decreased. Thus, allergic problems caused by N-glycoproteins could potentially be solved by modifying or altering the structure ofN-glycoprotein allergens, addressing the root of the issue. Mechanism of N-glycans associated allergy could also be elaborated through glycosylation enzymes, alterations of host glycosylation. This article hopes to provide a separate insight for glycoimmunology perspective, and an alternative strategy for clinical prevention or therapy of allergic diseases.

Objective To understand the application of skin disinfectant in neonatal intensive care units(NICUs)nationwide.Methods From April to May 2023,application of skin disinfectant in 93 NICUs nationwide was sur-veyed with convenience sampling method by a self-designed questionnaire.Questionnaire contents included types of disinfectant,disinfection tools,cleaning and disinfection frequency,disinfectant drying status,removal of disinfec-tant,and adverse reactions caused by disinfectant.Results A total of 93 nursing units in 71 medical institutions from 25 provinces/municipalities were included in this study.In NICUs,three most commonly used disinfectants were ethanol(79.57％),iodophor(74.19％),and anerdian(62.37％).In nursing units for neonates＜2 months of age,chlorhexidine was prohibited in 28 units(30.11％),used with caution in 23 units(24.73％),allowed in 9 units(9.68％),and there was no unified requirement in 33 units(35.48％).When using ethanol,staff only wiped once in 13(17.57％)nursing units.In some nursing units,there was no unified requirements on the wiping fre-quency of disinfectant.As for the removal of residual iodine,saline was used in 29(42.03％)nursing units,ethanol in 8(11.59％),and 19(27.54％)did not have unified requirements.The adverse reactions of disinfectant mainly included rash and contact dermatitis.Disinfectants that caused adverse reactions included ethanol,iodophor,aner-dian,and chlorhexidine.Conclusion In clinical practice,unified standards for the use of neonatal skin disinfectant remain absent.Selection and use of neonatal skin disinfectant vary considerably.Neonatal skin disinfectants have common adverse reactions.It is necessary to strengthen the training of health care workers on the standardized use of disinfectant,as well as carry out large-scale and rigorous randomized controlled trial designs to provide scientific basis for the correct selection of disinfectant.

Objective To investigate the effect of brachial plexus block on stress response in patients who underwent shoulder arthroscopic surgery.Methods A total of 150 patients with shoulder arthritis who underwent shoulder arthroscopic surgery in the Shanghai Fifth People's Hospital,Fudan University from December 2021 to December 2022 were selected as the study subjects.All patients were divided into the control group and the observation group by random number table method,with 75 cases in each group.Patients in the control group were given general anesthesia,while patients in the observation group were given brachial plexus block on the basis of the control group.The mean arterial pressure(MAP),heart rate(HR),norepinephrine(NE),cortisol(Cor)before operation(T0),10 minutes after operation(T1),30 minutes after operation(T2),at the end of operation(T3)and 30 minutes after extubation(T4)of the two groups were compared.The transforming growth factor-β1(TGF-β1),tumor necrosis factor-α(TNF-α),C-reactive protein(CRP)before and 3 days after operation of the two groups were compared.The visual analogue scale(VAS)scores at postoperative wakefulness and 6,12 and 24 hours after operation of the two groups were compared.Results Compared with T0,the levels of MAP and HR at T1,T2,T3,and T4 in the observation group and the control group were obviously decreased(P<0.01),the levels of NE and Cor were obviously increased(P<0.01),while the levels of MAP,HR,NE,and Cor at T1,T2,T3,and T4 in the observation group were obviously lower than those in the control group(P<0.01).The levels of TGF-β1,TNF-α,and CRP 3 days after operation in the observation group and the control group were obviously increased compared with those before operation (P<0. 01), and the above indicators after operation in the observation group were obviously lower than those in the control group (P<0. 01). The VAS scores at postoperative wakefulness and 6, 12 and 24 hours after operation in the observation group were obviously lower than those in the control group (P<0. 01). Conclusion Ultrasound-guided brachial plexus block by interscalene approach can ensure the stability of the vital signs of patients with shoulder arthritis during shoulder arthroscopic surgery, alleviate pain, reduce stress, and reduce inflammatory response.

Objective To explore the left and right ventricular myocardial strain and dyssynchrony in patients with Micra AV leadless pacing implantation,and to further analyze the impact of implantation site on myocardial strain and dyssynchrony.Methods A retrospective study was conducted on 43 patients with Micra AV implantation and 20 patients with high-degree atrioventricular block(Ⅱdegree typeⅡandⅢdegree atrioventricular block)at the Department of Cardiology,Zhongshan Hospital from April 2023 to December 2023.The demographic information and clinical characteristics of the patients were collected.Echocardiography and speckle tracking imaging techniques were used to obtain conventional echocardiographic parameters,myocardial strain,and dyssynchrony indices of patients in the two groups,including global longitudinal strain(GLS),free wall longitudinal strain(FWLS),peak strain dispersion(PSD)of 18 left ventricular segments,PSD of 6 right ventricular segments,and other indices.According to the implantation location of Micra AV,the patients were further divided into middle group(right ventricular septum),high group(right ventricular inflow tract),and low group(apical region),and the differences in myocardial strain and dyssynchrony indices among the three subgroups were compared.Results The left ventricular GLS(LVGLS),right ventricular GLS(RVGLS),and right ventricular FWLS(RVFWLS)of the Micra AV group were significantly lower than those of the conduction block group(P＜0.001),and the right ventricular dyssynchrony of the Micra AV group was significantly higher than that of the conduction block group(P＜0.05).Comparison of myocardial strain and dyssynchrony at different implantation sites showed that the LVGLS of the high implantation group was significantly higher than that of the middle and low implantation groups,and the left ventricular dyssynchrony index Yu was significantly lower than that of the middle group(P＜0.05);the right ventricular ejection fraction(RVEF)of the low implantation group was significantly lower than that of the high group,and the right ventricular 6-segment PSD was significantly higher than that of the middle and high implantation groups(P＜0.05).Conclusions Compared with patients with high-degree atrioventricular block,patients with Micra AV leadless pacing have reduced left and right ventricular strain,and the implantation of low position had greater effect.

Objective:This study aimed to clarify the clinical characteristics of children infected with rhinovirus in the context of the Corona Virus Disease 2019 (COVID-19) pandemic and to explore the impact of recent COVID-19 infection history on their clinical features.Methods:Clinical data and laboratory test result of 286 children diagnosed with rhinovirus infection at Hangzhou Children′s Hospital from July 2022 to October 2023 were collected. A retrospective survey was conducted to determine whether all study participants had a history of COVID-19 infection within the 6 months prior to hospitalization.Results:Among the 286 children with rhinovirus infection, 180 (62.94%) had simple rhinovirus infection, while 106 (37.06%) had co-infections with other pathogens; Among the 180 rhinovirus simplex-positive children, 56.67% had wheezing symptoms; among them, 15 cases (15/180, 8.33%) were diagnosed with acute asthma attacks; 7 cases (7/180, 3.88%) were diagnosed with severe pneumonia. Based on whether the children had a history of COVID-19 infection in the 6 months prior to hospitalization, they were divided into a group with previous COVID-19 infection and a group without previous COVID-19 infection. There were no significant differences between the two groups in terms of gender, age of onset, peak fever, incidence of wheezing, incidence of pneumonia, proportion of severe pneumonia, proportion of severe asthma attacks, duration of fever, time to relief of wheezing, length of stay, white blood cell count, eosinophil count, C-reactive protein, procalcitonin, immunoglobulin E, oxygen therapy requirements, and use of intravenous steroids ( P>0.05). Conclusions:A history of COVID-19 infection in the past 6 months does not exacerbate the clinical symptoms of children with rhinovirus infection, nor does it increase the incidence of wheezing.