Congenital pulmonary valve stenosis（PS）is a common congenital heart disease. Simple PS makes up approximately 8%~10% of congenital heart disease，and 20% of complex congenital heart disease complicated with PS. Percutaneous balloon pulmonary valvuloplasty（PBPV），which has undergone nearly 40 years of continuous improvement，has emerged as the preferred treatment for PS due to its superior safety and less trauma. However，residual stenosis was found in some patients during long-term follow-up，and repeat PBPV or even surgical repair was required. Identifying the risk factors for postoperative restenosis will further improve postoperative outcomes and reduce the probability of reintervention in the future. This article reviews the risk factors for restenosis of PS after PBPV including age，severity，morphologic characteristics of the valve leaflets and the choice of the balloon.

Objective:To construct a eukaryotic expression vector for bacteriophage D29 LysinB/Holin fusion protein and study its bactericidal efficacy against Mycobacterium tuberculosis ( Mtb) in a cell infection model. Methods:A recombinant plasmid pET32a-LysinB was constructed and induced to express LysinB. The polyclonal antibody against LysinB was prepared after the purification of LysinB. A recombinant plasmid pcDNA3.1(+ )-LysinB/Holin was constructed and transfected into mononuclear macrophages RAW264.7. After the expression of the prepared polyclonal antibody was identified, a cell infection model was established and the bactericidal efficacy of LysinB/Holin fusion protein was measured by acid-fast staining and colony counting.Results:The polyclonal antibody against LysinB was successfully prepared. The recombinant plasmid pcDNA3.1(+ )-LysinB/Holin could effectively express LysinB/Holin fusion protein in eukaryotic cells without inducing significant cytotoxicity. LysinB/Holin fusion protein was effective in killing Mtb in cells. Conclusions:The recombinant plasmid pcDNA3.1(+ )-LysinB/Holin has a better killing effect on intracellular Mtb without inducing obvious cytotoxicity against eukaryotic cells, showing a potential in the treatment of tuberculosis.

Background::Intrauterine valvuloplasty is an innovative therapy, which promotes ventricular growth and function in some congenital heart diseases (CHDs). The technique remains challenging and can only be performed in a few centers. This study aimed to assess the feasibility and mid-term outcomes of fetal cardiac intervention (FCI) in fetuses with critical CHD in an experienced tertiary center.Methods::Five fetal aortic valvuloplasty (FAV) or fetal pulmonary valvuloplasty (FPV) procedures were performed in our fetal heart center between August 2018 and May 2022. Technical success was defined as crossing the aortic or pulmonary valve and balloon inflation, followed by evidence of increased blood flow across the valve and/or new regurgitation. Follow-up clinical records and echocardiography were obtained during the prenatal and postnatal periods.Results::Five fetuses received FAV or FPV, including critical aortic stenosis ( n = 2) and pulmonary atresia with intact ventricular septum ( n = 3). The mean maternal age was 33.0 ± 2.6 years. The median gestational age (GA) at diagnosis was 24 weeks (range, 22-26 weeks). The median GA at intervention was 29 weeks (range, 28-32 weeks). All five cases underwent successful or partially successful procedures. One patient had pulmonary valve perforation without balloon dilation. No procedure-related deaths or significant complications occurred. However, one neonatal death occurred due to heart and renal failure. The median follow-up period was 29.5 months (range, 8.0-48.0 months). The four surviving patients had achieved biventricular circulation, exhibited improved valve, and ventricular development at the last follow-up visit. Conclusion::Intrauterine FCI could be performed safely with good prognosis in critical CHD.

Objective:To investigate the echocardiographic features, consistency of diagnosis between fetal and postnatal periods and postnatal clinical outcomes of fetal pulmonary valve stenosis (PS) with different degrees.Methods:This study was a retrospective cohort study comprising 108 cases of fetal PS diagnosed during the fetal period and followed up postnatally at Xinhua Hospital, Shanghai Jiaotong University School of Medicine from November 2012 to February 2023. Echocardiographic characteristics, including morphological and hemodynamic features were collected for all fetuses who were then were followed up to at least 6 months after birth. One-way analysis of variance and Kruskal-Wallis test were used to compare the differences in the echocardiographic features among fetuses with different degrees of PS. Subsequently, McNemar test was used to assess the consistency of diagnosis between the fetal and postnatal periods. Furthermore, Logistic regression analysis was applied to explore the risk factors for neonatal intervention in fetuses with moderate PS and the receiver operating characteristic (ROC) curve was utilized to ascertain the optimal cut-off value for continuous variables.Results:The age of the mothers of the 108 fetuses at the initial assessment was (30.8±4.0) years, and the gestational age was 26.5 (24.6, 30.0) weeks. The fetuses were categorized into mild (17 cases), moderate (49 cases), and severe groups (42 cases) based on the initial echocardiographic features. Mild PS was characterized by valve thickening and hyperechogenicity combined with systolic flow acceleration or dilation of main pulmonary artery. Moderate PS exhibited both restricted valve motion and a colorful blood flow pattern at the valve orifice. The peak flow velocities of fetuses with moderate and critical PS were notably higher than those in the mild group ((2.66±0.86) and (2.77±1.30) vs. (1.43±0.59)m/s, F=14.52, P<0.001). In critical PS, all cases showed retrograde ductal flow, with a significantly higher proportion of a small right ventricle compared to the mild and moderate PS (42.9% (18/42) vs. 0 and 2.0% (1/49), χ2=31.73, P<0.001). The proportion of severe tricuspid regurgitation was also higher (35.7% (15/42) vs. 0 and 10.2% (5/49), χ2=36.94, P<0.001). Compared to mild and severe PS, the consistency of diagnosis between fetal and postnatal periods in moderate PS was lower (40.8% (20/49) vs.13/17 and 80.3% (35/42), χ 2=12.45, P=0.006). The systolic flow velocity was identified as an independent risk factor for neonatal intervention in fetuses with moderate PS ( OR=7.21, 95% CI2.11-24.62). A flow velocity of ≥2.18 m/s in second trimester and ≥3.15 m/s in third trimester indicated the necessity of neonatal intervention for fetal moderate PS. Among the 108 fetuses, 68 underwent surgical intervention and all survived. Additionally, 39 fetuses were regularly followed up. A sole non-surgical fatality occurred, leading to a 6-month survival rate of 99.1% (107/108). Conclusions:Various degrees of fetal PS demonstrate distinctive morphological and hemodynamic alterations in echocardiography. The disparity in severity between the postnatal and fetal stages requires ongoing monitoring for fetal PS. The prognosis for fetal PS is generally favorable.

Immune checkpoint inhibitors (ICIs) have demonstrated unparalleled clinical responses and revolutionized the paradigm of tumor treatment, while substantial patients remain unresponsive or develop resistance to ICIs as a single agent, which is traceable to cellular metabolic dysfunction. Although dysregulated metabolism has long been adjudged as a hallmark of tumor, it is now increasingly accepted that metabolic reprogramming is not exclusive to tumor cells but is also characteristic of immunocytes. Correspondingly, people used to pay more attention to the effect of tumor cell metabolism on immunocytes, but in practice immunocytes interact intimately with their own metabolic function in a way that has never been realized before during their activation and differentiation, which opens up a whole new frontier called immunometabolism. The metabolic intervention for tumor-infiltrating immunocytes could offer fresh opportunities to break the resistance and ameliorate existing ICI immunotherapy, whose crux might be to ascertain synergistic combinations of metabolic intervention with ICIs to reap synergic benefits and facilitate an adjusted anti-tumor immune response. Herein, we elaborate potential mechanisms underlying immunotherapy resistance from a novel dimension of metabolic reprogramming in diverse tumor-infiltrating immunocytes, and related metabolic intervention in the hope of offering a reference for targeting metabolic vulnerabilities to circumvent immunotherapeutic resistance.
Humans ; Neoplasms/pathology* ; Immunotherapy/methods* ; Immune Checkpoint Inhibitors/therapeutic use*

ObjectiveTo investigate the effects of Buyang Huanwutang （BYWHT） on reducing inflammatory injury and improving neurological function after cerebral ischemia-reperfusion in rats via activating the adiponectin （APN） pathway. MethodMale SD rats were randomized into sham， model， BYHWT （16 g·kg^-1， twice a day）， and BYHWT + APN inhibitor （GW9662） groups. In the sham group， blood vessels were isolated. The rat model of middle cerebral artery occlusion （MCAO） was established. The rats in the BYHWT+GW9662 group was treated with subcutaneous injection of GW9662 at 4 m·kg^-1 30 min before MCAO surgery and BYHWT at 16 g·kg^-1 by gavage after MCAO surgery， once in the morning and once in the evening. The immunofluorescence （IF） assay was employed to observe the expression of adiponectin receptor 1 （AdipoR1） and the colocalization of AdipoR1 with neuronal nuclei （NeuN） and ionized calcium binding adaptor molecule 1 （Iba1） in the brain. Enzyme-linked immunosorbent assay （ELISA） was employed to detect the expression of APN in the serum and brain. The balance beam test was carried out to examine the balance ability， and the grasping test to assess the recovery of limb strength. The immunofluorescence assay was used to detect the expression of myeloperoxidase （MPO）. Western blot was employed to determine the expression of tumor necrosis factor-alpha （TNF-α）， interleukin （IL）-1β， IL-6， and IL-10 and in the brain. ResultCompared with the sham group， the modeling promoted the expression of AdipoR1 （P<0.01）， lowered the APN levels in the serum and brain （P<0.05， P<0.01）， increased the score in the balance beam test （P<0.01）， and decreased the grasping strength of forepaw （P<0.01）， which were accompanied with increased MPO， TNF-α， IL-1β， and IL-6 levels （P<0.01） and decreased IL-10 level （P<0.01）. Compared with the model group， BYHWT promoted the expression of AdipoR1 （P<0.01）， elevated APN levels in the serum and brain （P<0.05， P<0.01）， and increased the grasping strength of forepaw （P<0.01）， which were accompanied with lowered MPO， TNF-α， IL-1β， and IL-6 levels （P<0.01） and elevated IL-10 level （P<0.01）. All the above effects were partially blocked by GW9662. ConclusionBYHWT can reduce inflammatory injury and improve neurological function in the rat model of cerebral ischemia-reperfusion by activating the APN pathway.

ObjectiveTo investigate the Alzheimer-associated neurofilament protein （AD7c-NTP） in urine of middle-aged and elderly people and its correlation between common metabolites. MethodsA total of 1 150 middle-aged and elderly people who did their physical exmanination in the health examination center of the Sichuan Science City Hospital and the Third Hopital of Mianyang were recruited from March 2017 to March 2020. The level of urine AD7c-NTP were measured by enzyme-linked immunosorbent assay （ELISA）， and common metabolites in blood were measured by biochemical analyzer. Based on urine AD7c-NTP level ≤1.5 ng/mL， the objects was divided into normal group （n=956） and elevated group （n=194）. Thier demographic data and blood biochemical indicators were collected. ResultsThe urine AD7c-NTP level in middle-aged and elderly people was 0.60（0.30~1.20） ng/mL. The urine AD7c-NTP level was higher in women than that in men ［1.04（0.40~1.30） ng/mL vs. 0.84（0.30~1.00） ng/mL， Z=4.202， P˂0.01］. And the urine AD7c-NTP level was lower in the normal group than that in the elevated group ［0.50（0.30~0.90） ng/mL vs. 2.10（1.70~2.10） ng/mL， Z=22.035， P˂0.01］. The results of the univariate comparison showed that， the differences between the two groups in age （Z=6.545）， fasting glucose （Z=3.506）， blood uric acid （Z=2.574）， urea nitrogen （Z=2.891）， creatinine （Z=2.243）， total bilirubin （Z=3.936）， glutathione （Z=0.969）， total cholesterol （t=3.956） and low density lipoprotein （Z=-5.678） were were statistically significant （P˂0.05 or 0.01）. Spearman correlation analysis showed that， the urine AD7c-NTP level was positively correlated with age and the levels of urea nitrogen， glucose， total cholesterol and low density lipoprotein （r=0.177， 0.178， 0.171， 0.109， 0.149， P˂0.01）， and negatively correlated with the level of total bilirubin （r=-0.172， P˂0.01）. Conclusionthe urine AD7c-NTP level in middle-aged and elderly females was signifitcantly higher than in middle-aged and elderly males.The urine AD7c-NTP level of middle-aged and elderly people was positively correlated with age， urea nitrogen， glucose， total cholesterol and low density lipoprotein， and negatively correlated with total bilirubin.

Objective:To investigate the self-healing of congenital auricular deformity (CAD) and the efficacy of the auricle corrector in infants.Methods:The infants with CAD who were born in the Affiliated Maternity and Child Health Care Hospital of Nantong University from January to December 2020 were collected. The patients who disagreed with the use of auricle corrector were included in the observation group. The patients were followed up on the day of one month and one year after birth by phone or WeChat, and the self-healing rate (the proportion of the number of ears found to be healed in the total number of affected ears after follow-up) of auricle was calculated. The patients treated with auricle corrector were included in the non-invasive correction group, which was treated with domestic auricle corrector. And according to the initial correction age, the patients were divided into ≤7 d, 8-28 d and >28 d three subgroups. The patients were followed up on the day of one month and one year after treatment by phone or WeChat, and the effective rate(the proportion of healed ears to the total number of affected ears after treatment) was calculated. And statistical analysis was used in the three subgroups of initial correction age ≤7 d, 8-28 d, >28 d. Variance analysis was used for general comparison between three groups, and LSD- t test for the comparison between two groups. P<0.05 was considered statistically significant. Results:A total of 43 children (71 ears, 34 left ears and 37 right ears) were included in the observation group, including 21 males and 22 females, (2.1±0.3) days after birth. In the non-invasive correction group, 24 children (41 ears, 20 left ears and 21 right ears) were included, including 8 males and 16 females, (29.1±23.8) days after birth. There were 6 cases (10 ears) in the initial correction age group ≤7 days, 6 cases (9 ears) in the 8-28 days group, and 12 cases (22 ears) in the >28 days group. In the observation group (71 ears), the rates of self-healing on the day of one month and one year after birth were 29/71 and 30/71, respectively, including 23/31 and 24/31 for lop ear, 3/6 for Stahl’s ear, 3/3 for complex deformity, and 0 for other ear deformities. The effective rates were 41/41 and 35/41 one month and one year after treatment in the 24 children (41 ears) in the non-invasive correction group, respectively. Among them, the helical rim deformity was 12/12, lop ear 3/3, cup ear 7/7 and 5/7, Stahl’s ear 4/4, contracted ear 6/6, 5/6, prominent ear 2/2 and 0, the complex deformity 6/6 and 5/6, and microtia(Ⅰ) 1/1. The auricular deformities reoccurred in a total of 4 children (6 ears) 1 year after the end of treatment. According to the initial correction age into three groups, the treatment duration of the auricle corrector was (31.8±11.2) days, (31.3±10.1) days and (41.8±13.8) days, and the difference among the three groups was statistically significant ( F=3.42, P=0.043). There was no statistical significance between the groups ≤7 days and 8-28 days ( P=0.936), but there was statistical significance in the treatment duration between the groups ≤7 days and >28 days ( P=0.043), and between the groups 8-28 days and > 28 days ( P=0.041). Conclusion:CAD can self-heal to some extent. Self-healing rate is higher in lop ear and Stahl’s ears. The domestic auricle corrector has a good effect on CAD. The older the age of initial correction is, the longer the time of correction is. The type of CAD has a certain influence on the correction effect.

Objective:To investigate the self-healing of congenital auricular deformity (CAD) and the efficacy of the auricle corrector in infants.Methods:The infants with CAD who were born in the Affiliated Maternity and Child Health Care Hospital of Nantong University from January to December 2020 were collected. The patients who disagreed with the use of auricle corrector were included in the observation group. The patients were followed up on the day of one month and one year after birth by phone or WeChat, and the self-healing rate (the proportion of the number of ears found to be healed in the total number of affected ears after follow-up) of auricle was calculated. The patients treated with auricle corrector were included in the non-invasive correction group, which was treated with domestic auricle corrector. And according to the initial correction age, the patients were divided into ≤7 d, 8-28 d and >28 d three subgroups. The patients were followed up on the day of one month and one year after treatment by phone or WeChat, and the effective rate(the proportion of healed ears to the total number of affected ears after treatment) was calculated. And statistical analysis was used in the three subgroups of initial correction age ≤7 d, 8-28 d, >28 d. Variance analysis was used for general comparison between three groups, and LSD- t test for the comparison between two groups. P<0.05 was considered statistically significant. Results:A total of 43 children (71 ears, 34 left ears and 37 right ears) were included in the observation group, including 21 males and 22 females, (2.1±0.3) days after birth. In the non-invasive correction group, 24 children (41 ears, 20 left ears and 21 right ears) were included, including 8 males and 16 females, (29.1±23.8) days after birth. There were 6 cases (10 ears) in the initial correction age group ≤7 days, 6 cases (9 ears) in the 8-28 days group, and 12 cases (22 ears) in the >28 days group. In the observation group (71 ears), the rates of self-healing on the day of one month and one year after birth were 29/71 and 30/71, respectively, including 23/31 and 24/31 for lop ear, 3/6 for Stahl’s ear, 3/3 for complex deformity, and 0 for other ear deformities. The effective rates were 41/41 and 35/41 one month and one year after treatment in the 24 children (41 ears) in the non-invasive correction group, respectively. Among them, the helical rim deformity was 12/12, lop ear 3/3, cup ear 7/7 and 5/7, Stahl’s ear 4/4, contracted ear 6/6, 5/6, prominent ear 2/2 and 0, the complex deformity 6/6 and 5/6, and microtia(Ⅰ) 1/1. The auricular deformities reoccurred in a total of 4 children (6 ears) 1 year after the end of treatment. According to the initial correction age into three groups, the treatment duration of the auricle corrector was (31.8±11.2) days, (31.3±10.1) days and (41.8±13.8) days, and the difference among the three groups was statistically significant ( F=3.42, P=0.043). There was no statistical significance between the groups ≤7 days and 8-28 days ( P=0.936), but there was statistical significance in the treatment duration between the groups ≤7 days and >28 days ( P=0.043), and between the groups 8-28 days and > 28 days ( P=0.041). Conclusion:CAD can self-heal to some extent. Self-healing rate is higher in lop ear and Stahl’s ears. The domestic auricle corrector has a good effect on CAD. The older the age of initial correction is, the longer the time of correction is. The type of CAD has a certain influence on the correction effect.

Objective:To investigate the predictive value of platelet-to-neutrophil ratio (PNR) on hemorrhagic transformation (HT) and poor outcomes at 90 d after intravenous thrombolysis (IVT) in patients with acute ischemic stroke (AIS).Methods:Patients with AIS received IVT in Hefei Second People's Hospital from July 2019 to June 2021 were retrospectively enrolled. HT was defined as intracerebral hemorrhage found by CT reexamination within 24 h after IVT, and the poor outcome was defined as the modified Rankin Scale score ≥3 at 90 d after onset. Multivariate logistic regression analysis was used to determine the independent predictors of HT and poor outcomes at 90 d, and the predictive value of PNR on HT and poor outcomes at 90 d was analyzed by receiver operating characteristic (ROC) curve. Results:A total of 202 patients with AIS treated with IVT were included, of which 32 had HT and 50 had poor outcomes at 90 d after onset. Multivariate logistic regression analysis showed that PNR at 24 h after IVT was significantly and independently negatively correlated with the poor outcomes (odds ratio [ OR] 0.959, 95% confidence interval [ CI] 0.928-0.991; P=0.012); PNR at admission ( OR 0.886, 95% CI 0.827-0.948; P<0.001) and PNR at 24 h after IVT ( OR 0.923, 95% CI 0.879-0.969; P=0.001) were significantly independently and negatively correlated with HT. ROC curve analysis showed that the area under the curve of PNR at 24 h after IVT for predicting poor outcomes was 0.733 (95% CI 0.659-0.807; P=0.012), the best cutoff value was 35.03, and the predictive sensitivity and specificity were 70.4% and 74%, respectively. The area under the curve of PNR at admission for predicting HT was 0.830 (95% CI 0.774-0.886; P<0.001), the best cutoff value was 34.81, and the predictive sensitivity and specificity were 70% and 93.7%, respectively. The area under the curve of PNR at 24 h after IVT for predicting HT was 0.770 (95% CI 0.702-0.839; P=0.001), the best cutoff value was 41.73, and the predictive sensitivity and specificity were 53.5% and 96.9%, respectively. Conclusion:For patients with AIS treated with IVT, lower PNR at 24 h after IVT is an independent predictor of the poor outcomes at 90 d, while PNR at admission and 24 h after IVT are the independent predictors of HT.