Osimertinib is an irreversible third representative epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for the treatment of non-small cell lung cancer (NSCLC) with T790M resistance and classical EGFR mutations. However, the therapeutic effectiveness of osimertinib is limited by acquired drug-resistance, poor water solubility and low tumor accumulation rates. Nanodrug delivery systems can increase the solubility and stability of drugs, prolong the blood circulation time of drugs, improve the uptake rate of cells, promote drug accumulation in tumor tissues, and improve drug resistance. Thus, they are effective in overcoming the limitations of traditional targeted drugs. In this study, we reviewed the mechanism of action of the third-generation EGFR-TKI osimertinib, focused on research advances in osimertinib nanodrug delivery systems against NSCLC, and explored the challenges and future development direction in this field.

OBJECTIVE To investigate the clinical effect of Budigafol combined with Staphylococcus and neisseria tablets in maintenance treatment of patients with stable moderate to severe chronic obstructive pulmonary disease （COPD）. METHODS A total of 122 patients with stable moderate to severe COPD who were admitted to the infections diseases ward of the department of respiratory and critical care medicine in our hospital from October 1， 2021 to January 31， 2023 were divided into control group （n＝61） and observation group （n＝61） according to the random number table method. Patients in the control group were treated with Budigafol inhalation aerosol alone （2 presses each time， twice a day）， and patients in the observation group were treated with Staphylococcus and neisseria tablets （1.2 mg each time， 3 times a day） on the basis of the control group. The treatment course of both groups was 3 months. The quality of life， exercise tolerance， lung function， inflammatory indexes， immune function， as well as the number of acute attacks of COPD and the occurrence of adverse reactions were compared between the two groups before and after treatment. RESULTS Control group and observation group shed 12 and 9 patients， respectively. After treatment， the 6 minute walking distance of the two groups of patients was significantly prolonged compared with that before treatment （P＜0.05）. The COPD assessment test questionnaire score， St George’s respiratory questionnaire score， the ratio of residual volume to total lung capacity， the fractional exhaled nitric oxide， the serum levels of C-reactive protein and interleukin-6 were significantly E-mail：13956685295@163.com decreased compared with those before treatment （P＜0.05）. The forced expiratory volume in one second （FEV1）， the ratio E-mail：13966580920@163.com of FEV1 to forced vital capacity， the percentage of the measured value of carbon monoxide diffusion capacity to the predicted value， and the percentage of the measured value of FEV1 to the predicted value were significantly increased compared with those before treatment （P＜0.05）. The improvement of the above indicators in the observation group was significantly better than that in the control group （P＜0.05）. Compared with before treatment， there was no statistical significance in the immune function indexes of the control group or the serum levels of immunoglobulin A （IgA） and IgM in the observation group after treatment （P＞0.05）. The percentages of CD3+ ， CD4+ ， B lymphocytes and natural killer cells， the levels of CD4+/CD8+ and IgG were significantly increased in the observation group （P＜ 0.05）， the percentage of CD8+ cells was significantly decreased （P＜0.05）， and the improvement degree of the observation group was significantly better than that of the control group （P＜0.05）. There was no significant difference in the number of acute exacerbations of COPD during the follow-up period and the incidence of adverse events during treatment between the two groups （P＞0.05）. CONCLUSIONS Budigafol combined with Staphylococcus and neisseria tablets can effectively improve the immune function of patients with stable moderate to severe COPD， further reduce the level of inflammation， and improve their exercise tolerance and their quality of life with good safety.

Objective:This study aims to explore the prevalence of hepatitis E virus (HEV) infection in patients and the screening value of serological indicators for HEV infection patients.Methods:Retrospective analysis was conducted on 97 440 cases of anti-HEV IgM and IgG simultaneously tested in two Beijing hospitals from January 1, 2018 to August 31, 2023. Among them, there were 61 005 males and 36 435 females, with an average age of 51.65±13.05 years old. According to the positivity of anti HEV specific antibodies, they were divided into anti-HEV IgM positive group (3 588 cases), anti-HEV IgG positive group (18 083 cases), and anti-HEV antibody negative group (78 892 cases). Results of HEV RNA, liver function, AFP, PIVKA-Ⅱ and PT were collected, and their basic clinical information were recorded. The prevalence of HEV infection in patients, as well as the relationship between the positivity of anti-HEV specific antibodies and the patient′s age group, HEV RNA, and clinical characteristics were analyzed.Results:Among 97 440 patients who tested anti-HEV IgM and IgG simultaneously, the positivity rate of anti-HEV IgM was 3.68% (3 588/97 440), and was 18.56% for anti-HEV IgG (18 083/97 440). The overall positivity rates of anti-HEV IgM in two Beijing hospitals from 2018 to 2023 were 2.51%, 2.53%, 3.02%, 4.59%, 5.72%, and 4.26% ( χ2=1 401.73, P<0.001), while the positivity rates of anti-HEV IgG were 12.56%, 12.32%, 12.85%, 22.65%, 27.42%, and 26.66% ( χ2=1 058.29, P<0.001). These rates showed a gradual increase until 2023 when a decline was observed. The positivity rates of anti-HEV IgM (2.28%, 3.60%, 4.47%) ( χ2=89.62, P<0.001) and IgG (4.71%, 17.86%, 25.94%) ( χ2=2 017.32, P<0.001) increased with age in patients who aged 1-30, >30-60, and over 60 years old. The age and ALB values of patients in the anti-HEV IgM positive group were lower than the IgG-positive group, while the proportion of males, TBIL, ALT, AFP and PT values were higher than the IgG-positive group, and the differences were statistically significance ( P<0.05). Furthermore, patients in both the anti-HEV IgM and IgG positive groups had higher age, male proportion, TBIL, ALT, AFP, PIVKA-Ⅱ, and PT values than the anti-HEV negative group. Additionally, both groups had lower ALB values than the anti-HEV negative group, all of which were statistically significant ( P<0.05). 2 162 HEV infected patients were grouped based on HEV RNA positivity. The proportion of anti-HEV IgM single positive, IgG single positive, IgM+IgG double positive, and antibody negative patients in the HEV RNA positive group were 5.42% (18/332), 3.62% (12/332), 90.36% (300/332), and 0.60% (2/332), respectively. Among them, the proportion of anti-HEV IgM+IgG double positive patients in the HEV RNA positive group was higher than that in the HEV RNA negative group ( χ2=302.87, P<0.001), while the proportion of anti-HEV IgG single positive ( χ2=174.36, P<0.001) and anti-HEV antibody negative patients ( χ2=59.28, P<0.001) were lower than that in the HEV RNA negative group, both of which were statistically significant ( P<0.001). In addition, the positive rates of HEV RNA in anti-HEV IgM positive, IgG positive, and antibody negative patients were 29.23% (318/1 088), 17.59% (312/1 774), and 0.65% (2/306), respectively. Conclusion:The HEV infection rate among patients declined in 2023. HEV infection is age-related, with older individuals being more susceptible. Abnormal liver function and jaundice were commonly observed during HEV infection. It is crucial to note that the absence of anti-HEV specific antibodies cannot rule out HEV infection; therefore, additional testing for HEV RNA and/or HEV Ag is necessary for accurate diagnosis.

Objective To observe the changes of plasma gastrointestinal hormones in motion sickness sensitive and insensitive individuals before and after vertical oscillation stimulation,and to construct a susceptibility prediction model for motion sickness.Methods A total of 60 healthy male volunteers were enrolled to receive sinusoidal vertical oscillation stimulation for 45 min.The motion sickness susceptibility questionnaire(MSSQ)was filled out before the experiment.Immediately after motion,the severity of motion sickness was evaluated by Graybiel scale.The motion sickness sensitive(Graybiel score≥8 and MSSQ susceptibility index＞21,n=15)and insensitive(Graybiel score≤2 and MSSQ susceptibility index＜5,n=15)participants were screened.Plasma levels of glucagon-like peptide-1(GLP-1),cholecystokinin(CCK),leptin,ghrelin,neuropeptide Y(NPY)and orexin A(OXA)were detected by enzyme-linked immunosorbent assay before and after vertical oscillation stimulation.Logistic regression model was used to analyze the predictive effect of plasma gastrointestinal hormone levels on susceptibility to motion sickness,and a combined predictive model was established.Receiver operating characteristic(ROC)curve was used to analyze predictive value of the model.Results Ghrelin and CCK levels were significantly increased in the sensitive group after stimulation compared with those before stimulation(both P＜0.01),while NPY and leptin levels were significantly decreased(both P＜0.01).Similar results were also observed when compared with the insensitive group after stimulation.Multivariate logistic regression analysis showed that plasma ghrelin,CCK and NPY were independent predictors of susceptibility to motion sickness.The established susceptibility prediction model for motion sickness was logit(P)=-0.051 ×ghrelin+0.060× NPY-0.169 ×CCK+33.397.ROC curve analysis showed that area under curve(AUC)value of the prediction model was 0.988,the sensitivity and specificity were 100.0％and 93.3％,respectively,and the prediction effect was better than ghrelin,CCK and NPY alone(AUC=0.792,0.880,0.838).Conclusion The changes of peripheral gastrointestinal appetite regulating hormone levels may be related to the susceptibility to motion sickness.The combined use of these indicators can predict the susceptibility to motion sickness.

Objective To explore the improving effects of motion sickness acclimatization training methods,namely sinusoidal vertical oscillation stimulation and sinusoidal vertical oscillation stimulation combined with visual virtual reality(VR)swell stimulation,on cognitive performance of individuals with extremely severe motion sickness.Methods A total of 90 individuals with extremely severe motion sickness screened by the Graybiel score during 6 h navigation were randomly divided into vertical group,vertical+VR group,and control group(n=30).The abilities of vigilance,memory,rapid calculation,information processing and visual manipulation were evaluated before and after the acclimatization training using a self-developed cognitive performance evaluation software.Results On the 1st day of training,the numbers of missed targets of the vertical group and vertical+VR group were increased in the vigilance test;the reaction time was prolonged in the short-term memory,rapid calculation,information processing and visual manipulation tasks;and the efficiency of rapid calculation was reduced.After acclimatization training,the numbers of missed targets were reduced to the baseline level in the vertical and vertical+VR groups,and the reaction time in the short-term memory,rapid calculation,information processing and visual manipulation tasks and the efficiency of rapid calculation were improved.Conclusion Motion sickness caused by vertical oscillation stimulation or vertical oscillation combined with visual VR swell stimulation can decrease vigilance,short-term memory,rapid calculation,information processing and visual manipulation abilities.Motion sickness acclimatization training can significantly improve the above cognitive abilities.

Objective To study the acclimatization time and effects for preventing motion sickness under sinusoidal vertical oscillation stimulation,visual virtual reality(VR)swell stimulation,and their combined stimulation.Methods Totally 120 individuals with extremely severe motion sickness during 6 h navigation were randomly divided into 4 groups(n=30):vertical group,VR group,vertical+VR group,and control group.The severity of symptoms during the training period was assessed daily by Graybiel scale,and the number of drops from flexible treadmill in the VR group was recorded.The Graybiel score of 0 for 3 d and/or the number of drops for 0 were considered as complete acclimatization.The training effect was validated by navigation under more severe sea conditions.Results The Graybiel scores of the vertical group and vertical+VR group,as well as the number of drops of the VR group were decreased with the increase of training days,and reached the acclimatization level on the 3rd,5th,and 2nd training day,respectively.The longest acclimatization time in the vertical,vertical+VR,and VR groups was 8,8,and 5 d,with an average acclimatization time of 3.6,3.9,and 2.7 d,respectively;the acclimatization rates within 5 d were 93.33％(28/30),76.67％(23/30),and 100.00％(30/30),respectively;the proportions of individuals with effective acclimatization training in the verification voyage were 86.67％(26/30),96.67％(29/30),and 66.67％(20/30),respectively;and the training efficiency was 85.19％,96.30％,and 62.97％,respectively.Conclusion Three training methods all have effects on motion sickness acclimatization,and the acclimatization period is 5-8 d.The acclimatization effects of the vertical oscillation and vertical oscillation+VR training are better than the VR training.

Objective To observe the effect of the supine-posture ripple wood training in preventing motion sickness caused by linear acceleration.Methods Totally 61 motion sickness sensitive males were screened by a vertical oscillation simulator and divided into mildly sensitive group(Graybiel score 1-15,n=28)and severely sensitive group(Graybiel score 16,n=33).The participants in the 2 groups received 5-d ripple wood training,30 min/d.The movement frequency of the ripper wood was maintained at 0.25-0.35 Hz,with an acceleration of 0.15-0.25 g.Graybiel score during the training period was recorded.The static balance function test was conducted before and after training on the 1st and 5th day.Results During the training period,the Graybiel scores and motion sickness incidence in the severely sensitive group were decreased with the increase of training days,and all participants achieved complete acclimatization on the 4th day.The Graybiel scores of the mildly sensitive group were low during the whole period,and the complete acclimatization period was 2 d.There was no significant difference in the sway area of the severely sensitive group in static balance function test before and after training(P＞0.05).The mean velocity of the severely sensitive group in static balance function test was significantly increased after training versus before training on the 1st day(P＜0.01),and there was no significant difference before and after training on the 5th day(P＞0.05).There were no significant differences in the sway area or mean velocity of the mildly sensitive group during the whole training period(all P＞0.05).The validation experiment showed that the motion sickness incidence and the symptom severity were significantly decreased in both groups;the motion sickness incidence of the mildly sensitive group decreased from 100.00％(28/28)to 35.71％(10/28);the incidence of severe symptoms in the severely sensitive group decreased from 100.00％(33/33)to 6.06％(2/33)and the vomiting incidence decreased from 96.97％(32/33)to 6.06％(2/33).Conclusion The supine-posture ripple wood training has great effect in preventing motion sickness,with widespread use and simple operation.

Objective To observe the distribution characteristics of motion sickness susceptibility and compare the efficacy of modified motion sickness susceptibility questionnaire(MSSQ),motion sickness history questionnaire and Graybiel scale in evaluating motion sickness.Methods The susceptibility to motion sickness and historical symptoms were investigated using MSSQ and motion sickness history questionnaire among 1 661 males in navy units A,B,and C.A total of 389 people from the unit C were selected for simulating vertical oscillation stimulation,and the severity of motion sickness was evaluated by Graybiel scale during the stimulation process.The evaluation efficacy of MSSQ,motion sickness history questionnaire and Graybiel scale for motion sickness was analyzed by receiver operating characteristic(ROC)curves.Results The overall distribution of motion sickness susceptibility assessed by MSSQ and motion sickness history questionnaire in this population was right skewed.The distribution characteristics in the units A,B,and C were consistent with the overall distribution,and there was no significant difference among the 3 units.A positive correlation was observed between the MSSQ and the motion sickness history questionnaire in the units A,B,and C(rs=0.565,0.565,0.554),and both of them were comparable in assessing the incidence of motion sickness and severe motion sickness.However,the incidence of motion sickness assessed by Graybiel scale was significantly lower than that assessed by MSSQ and motion sickness history questionnaire(both P＜0.05),and the incidence of severe motion sickness was significantly higher than that assessed by MSSQ and motion sickness history questionnaire(both P＜0.05).ROC curve analysis showed that MSSQ had good predictive value for motion sickness susceptibility and severe motion sickness(area under curve[AUC]=0.736,0.750),while the Graybiel scale had poor predictive ability(AUC=0.559,0.557).Conclusion The right skewed distribution of susceptibility to motion sickness is preliminarily determined.During the acclimatization training for motion sickness,the susceptible individuals can be screened by MSSQ and then subjected to vertical oscillation stimulation to improve the training efficiency.

Objective:To evaluate the value of synthetic MRI combined with three dimensional-arterial spin labeling (3D-ASL) imaging in the grading of diffuse glioma and its correlation with tumor cell proliferative activity (Ki-67).Methods:This study was prospective. The clinical and imaging manifestations of 66 patients with diffuse glioma who underwent synthetic MRI combined with 3D-ASL imaging from August 2020 to June 2021 in General Hospital of Ningxia Medical University were analyzed. Among 66 patients, there were 36 males and 30 females, aged 4-76 years, and divided into low grade glioma (LGG) group ( n=25) (WHO Ⅱ) and high grade glioma (HGG) group ( n=41) (WHO Ⅲ and vⅣ). T 1, T 2, proton density (PD) and cerebral blood flow (CBF) of tumor parenchyma were measured by GE ADW4.7 postprocessing software. The Ki-67 label index (Ki-67 LI) in postoperative pathological sections was detected by immunohistochemistry. Independent sample t test or Mann-Whitney U test was used to compare the differences of quantitative parameters between HGG group and LGG group. Receiver operating characteristic (ROC) curve was used to analyze the diagnostic efficacy of T 1, PD, CBF and the combination. Spearman test was used to analyze the correlation between the parameters and Ki-67 label index (LI). Results:T 1[(1 573±173)ms], PD[(86.2±2.4)pu] and CBF[(129±48)ml·100 g -1·min -1] in HGG group were significantly higher than those in LGG group [(1 376±134)ms, (83.0±2.5)pu and (77±49)ml·100g -1·min -1 respectively], and difference had statistical significance ( t=-4.86, -5.08, -4.24, P<0.01). ROC confirmed that the area under curve (AUC) of T 1, PD and CBF in differentiating HGG from LGG were 0.847, 0.843 and 0.777, respectively. In multi-parameter analysis, the combination of three parameters had the best diagnostic efficiency (AUC=0.973) and the sensitivity and specificity were 87.8% and 100%, respectively. In LGG and HGG groups, there was no correlation between T 1, T 2, PD, CBF and Ki-67 LI. In the overall cohort, T 1, PD and CBF had slight positive correlation with Ki-67 LI ( r=0.394, 0.411 and 0.406, respectively, all P<0.01). There was no correlation between T 2 and Ki-67 LI ( r=-0.100, P=0.423). Conclusion:Synthetic MRI and 3D-ASL can noninvasively evaluate the pathological grade of glioma and predict the expression of Ki-67, among which T 1 and PD are novel imaging marks.