Booster vaccinations are highly recommended in combating the SARS-CoV-2 Omicron variant and its subvariants. However, the optimal booster vaccination strategies and related immune mechanisms with different prior vaccinations are under-revealed. In this study, we systematically evaluated the immune responses in mice and hamsters with different prime-boost regimens before their protective efficacies against Omicron were detected. We found that boosting with Ad5-nCoV, S_WT-2P or S_Omicron-6P induced significantly higher levels of neutralization activities against Omicron variants than CoronaVac and ZF2001 by eliciting stronger germinal center (GC) responses. Specifically, S_Omicron-6P induced even stronger antibody responses against Omicron variants in CoronaVac and Ad5-nCoV-primed animals than non-Omicron-specific vaccines but with limited differences as compared to Ad5-nCoV and S_WT-2P. In addition, boosting with a specific vaccine has the potential to remodel the existing immune profiles. These findings indicated that adenovirus-vectored vaccines and mRNA vaccines would be more effective than other types of vaccines as booster shots in combating Omicron infections. Moreover, the protective efficacies of the vaccines in booster vaccinations are highly related to GC reactions in secondary lymphatic organs. In summary, these findings provide timely important information on prime-boost regimens and future vaccine design.

Objective This study aimed to investigate the antimicrobial resistance profiles of bacterial strains isolated from pediatric intensive care units(PICU)in China for better antimicrobial therapy.Methods Clinical isolates were collected from 17 institutions,including tertiary care children's hospitals and pediatric department of tertiary general hospitals in China from January 1,2020 to December 31,2022.Antimicrobial susceptibility testing was carried out according to a unified protocol using Kirby-Bauer method or automated systems.Results were interpreted according to the breakpoints released by the Clinical and Laboratory Standards Institute(CLSI)in 2020.Results A total of 10 688 isolates were collected,including gram-positive organisms(39.2％)and gram-negative organisms(60.8％).The top three organisms were S.aureus(13.6％,1 453/10 688),A.baumannii(10.0％,1 067/10 688),and coagulase-negative Staphylococcus(9.9％,1 058/10 688).Multi-drug resistant organisms(MDROs)were very common in children.The prevalence of methicillin-resistant Staphylococcus aureus(MRSA),carbapenem-resistant Enterobacterales(CRE),carbapenem-resistant E.coli,carbapenem-resistant K.pneumoniae(CRKP),carbapenem-resistant A.baumannii(CRAB),and carbapenem-resistant P.aeruginosa(CRPA)was 41.1％,19.4％,8.8％,30.9％,67.4％,and 28.8％,respectively.Overall,more than 50％of Enterobacteriales isolates were resistant to cephalosporins,while nearly 25％of Enterobacteriales isolates were resistant to carbapenems.MDROs were highly resistant to commonly used antibiotics.More than 80％of CRE and CRAB strains were resistant to all beta-lactam antibiotics.CRE and CRAB showed low resistance rates to tigecycline and polymyxin.CRPA showed lower resistance rates to piperacillin,beta-lactamase inhibitor combinations than the resistance rates to third and fourth generation cephalosporins.All of the Staphylococcus and Enterococcus isolates were susceptible to vancomycin and tigecycline.None of PRSP strains isolated from meningitis and nonmeningitis samples were resistant to rifampicin,vancomycin,or linezolid.The prevalence of β-lactamase-negative ampicillin-resistant(BLNAR)strains was 43.3％in Haemophilus influenzae.Conclusions MDROs were prevalent in PICU.It is necessary to establish an effective multidisciplinary team(MDT)to control the antimicrobial resistance.

Objective To explore the effects and mechanism of Shengxian Yixin Granules in treating ventricular remodeling in rats with myocardial infarction based on the PI3K/AKT signaling pathway.Methods A total of 60 SD rats were randomly selected six rats as the control group,and the remaining 54 rats were used as the modeling group.Sham-operation and left anterior descending coronary artery ligation were performed respectively.The modeled rats were divided into model group,Shengxian Yixin Granules group,740Y-P group and Shengxian Yixin Granules+740Y-P group,and were given corresponding intervention for 28 days.Left ventricular ejection fraction(LVEF)and left ventricular fractional shortening(LVFS)were measured by echocardiography,and left ventricular hypertrophy index was calculated,the myocardial morphology was observed by HE and Masson staining,and the protein expressions of p-PI3K,PI3K,p-AKT and AKT were detected by Western blot,RT-qPCR was used to detect the mRNA expressions of type Ⅰ collagen(Col1)and type Ⅲ collagen(Col3),and ELISA was used to detect the contents of serum cardiac troponin T(cTnT),creatine kinase-MB(CK-MB),Col1 and Col3.Results Compared with the control group,the LVEF and LVFS in the model group significantly decreased(P<0.01),the left ventricular hypertrophy index increased(P<0.01);myocardial cells were arranged disorderly,some cells were necrotic,ruptured and their nuclei were dissolved,with obvious neutrophil infiltration,the collagen fiber significantly increased,the protein expressions of p-PI3K and p-AKT in myocardial tissue significantly increased(P<0.05),and the mRNA expression of Col1 and Col3 significantly increased(P<0.01);the contents of serum cTnT,CK-MB,Col1 and Col3 significantly increased(P<0.05,P<0.01).Compared with the model group,the LVEF and LVFS in Shengxian Yixin Granules group significantly improved(P<0.05,P<0.01),and left ventricular hypertrophy index decreased(P<0.05);myocardial necrosis,neutrophil infiltration and collagen fiber deposition were reduced,the protein expressions of p-PI3K and p-AKT in myocardial tissue significantly decreased(P<0.05),and the mRNA expressions of Col1 and Col3 significantly decreased(P<0.01);the contents of serum cTnT,CK-MB,Col1 and Col3 significantly decreased(P<0.05,P<0.01).LVEF and LVFS in 740Y-P group significantly decreased(P<0.01),and left ventricular hypertrophy index increased(P<0.05);a large number of myocardial cells were necrotic and ruptured,fibers were torn obviously,and many scar tissues were formed,the protein expressions of p-PI3K and p-AKT in myocardial tissue significantly increased(P<0.05),the mRNA expressions of Col1 and Col3 significantly increased(P<0.01);the contents of serum cTnT,CK-MB,Col1 and Col3 significantly increased(P<0.05,P<0.01).Shengxian Yixin Granules+740Y-P could improve the damage of 740Y-P to the heart.Conclusion Shengxian Yixin Granules can improve ventricular remodeling in rats with heart failure,reduce myocardial fibrosis,and improve cardiac function through the PI3K/AKT signaling pathway.

BACKGROUND:Patients with Alzheimer's disease have severe brain energy disorders.In recent years,brain energy rescue strategies based on ketone body intervention have attracted more and more attention in the treatment of Alzheimer's disease.OBJECTIVE:To investigate whether β-hydroxybutyric acid can improve energy dysfunction by improving mitochondrial bioenergy function in HT22 cells of mouse hippocampal neurons induced by amyloid-β protein 1-42 (Aβ1-42).METHODS:HT22 cells were divided into four groups:Control,β-hydroxybutyric acid,Aβ1-42,Aβ1-42+β-hydroxybutyric acid.Related detection kits were respectively used to detect HT22 cell survival rate,adenosine triphosphate level,α-ketoglutarate dehydrogenase activity,Na+K+-ATPase activity,mitochondrial membrane potential,and reactive oxygen species levels.RESULTS AND CONCLUSION:Compared with the control group,the survival rate,adenosine triphosphate level,α-ketoglutarate dehydrogenase activity,Na+K+-ATPase activity,and mitochondrial membrane potential of HT22 cells were significantly decreased (P<0.05),and the level of reactive oxygen species was significantly increased (P<0.05) in the Aβ1-42 group.Compared with the Aβ1-42 group,the survival rate,adenosine triphosphate level,α-ketoglutarate dehydrogenase activity,Na+K+-ATPase activity,and mitochondrial membrane potential of HT22 cells were significantly increased (P<0.05),and the reactive oxygen species level was significantly decreased (P<0.05) in the Aβ1-42+β-hydroxybutyric acid group.These results showed that β-hydroxybutyric acid improved mitochondrial bioenergetic function and ultimately improved Aβ1-42-induced energy impairment and survival rate in HT22 cells.

ObjectiveTo investigate the effects and potential mechanisms of Tongmai Yangxin Pills （通脉养心丸） （TYPs） in preventing ischemia-reperfusion （I/R）-induced arrhythmia. MethodsSixty male SD rats were randomly assigned to sham operation group， model group， amiodarone group， low-dose and high-dose TYPs group， with 12 rats in each group. The sham operation group and the model group received 10 g/（kg·d） normal saline by gavage， the amiodarone group received 60 mg/（kg·d） amiodarone， and the low-dose and high-dose TMP groups received 1 g/（kg·d） and 2 g/（kg·d） TYPs solution respectively， for 21 days， administered twice daily. On the day after the last administration， the I/R model was established in the model and medication groups by ligation of the left anterior descending coronary artery with a cannula， while the sham operation group underwent the same procedure without ligation. Electrocardiogram recordings were continuously monitored throughout the modeling process. Heart rate was recorded at five time points， before ischemia （t-0）， 5-10 min after ischemia （t-1）， 10-15 min after ischemia （t-2）， 15-30 min after ischemia （t-3）， and during the first 2 min of reperfusion （t-4）； the incidence of arrhythmia including ventricular premature beats （VPB）， ventricular tachycardia （VT）， and ventricular fibrillation （VF） was recorded； arrhythmia scores were calculated. After 24 hours of reperfusion， left ventricular myocardial tissue was collected. Hematoxylin-eosin （HE） staining was performed to observe pathological changes. RT-PCR was used to detect the mRNA expression of microRNA-1 （miRNA-1）， microRNA-133a （miRNA-133a）， and potassium （K⁺） and calcium （Ca²⁺） ion channel-related genes including KCND2， KCNH2， KCNE2， KCNQ1， KCNE1， KCNJ2， CACNA1C， and CACNB1. Western blot analysis was used to measure protein levels of transient outward potassium current protein （Kv4.2）， rapidly activating delayed rectifier potassium current protein （HERG）， slowly activating delayed rectifier potassium current protein （KvLQT1）， inward rectifier potassium current protein （Kir2.1）， and L-type calcium channel protein （Cav1.2）. ResultsCompared with sham operation group， the model group showed diffuse myocardial hemorrhage， inflammatory cell infiltration， myocardial necrosis， nuclear pyknosis， vacuolar degeneration， and disrupted myocardial fibers； the model group also exhibited a decreased heart rate （t-1 to t-4）， increased arrhythmia scores， elevated miRNA-1 and miRNA-133a expression， and decreased mRNA expression of KCND2， KCNH2， KCNE2， KCNQ1， KCNE1， KCNJ2， CACNA1C， and CACNB1 in myocardial tissue； additionally， Kv4.2， HERG， KvLQT1， Kir2.1， and Cav1.2 protein levels significantly reduced （P＜0.01）. Compared to the model group， all medication-treated groups showed reduced myocardial damage， including less hemorrhage， reduced inflammatory infiltration， and improved myocardial structure， with the high-dose TYPs group exhibiting the most significant improvement； the amiodarone group and high-dose TYPs group showed a significant increase in heart rate （t-1 to t-4）， lower arrhythmia scores， reduced miRNA-1 and miRNA-133a expression； the high-dose TYPs group exhibited significantly increased mRNA expression levels of KCND2， KCNH2， KCNQ1， KCNJ2， and CACNA1C， as well as elevated protein levels of Kv4.2， HERG， KvLQT1， Kir2.1， and Cav1.2 （P＜0.05 or P＜0.01）. ConclusionTMPs can improve myocardial damage and reduce the incidence of ventricular arrhythmia in I/R rats. The underlying mechanism may be related to the downregulation of miRNA-1 and miRNA-133a gene expression， as well as the upregulation of K⁺ and Ca²⁺ channel-related genes and proteins.

Objective:To compare the clinical features of severe Mycoplasma pneumoniae pneumonia (SMPP) in pediatric intensive care units (PICU) before and after the COVID-19 pandemic.Methods:A retrospective study was conducted in the PICU of Shanghai Children's Hospital. Clinical and laboratory data were collected from medical records of SMPP patients admitted to the PICU before (January to December 2019) and after (March 2023 to February 2024) the COVID-19 pandemic. Patients admitted in 2019 were categorized as the pre-COVID-19 group, while those admitted in 2023-2024 were classified as the post-COVID-19 group.Results:A total of 287 children with SMPP were included, comprising 155 males and 132 females. The pre-pandemic group consisted of 180 cases, while the post-pandemic group had 107 cases. Macrolide-resistant Mycoplasma pneumoniae (MRMP) was detected in 270 cases (94.1%), with no significant difference in MRMP prevalence between the two groups [101 cases (94.4%) vs. 169 cases (93.9%), Z= 0.031, P = 0.861]. The median age of the post-pandemic group was higher than that of the pre-pandemic group [72 (42, 108) months vs. 42 (24, 68) months, Z= 6.438, P < 0.001].Comparisons of complications between the post-pandemic and pre-pandemic groups were as follows: pleural effusion [20 cases (18.7%) vs. 81 cases (45.0%), χ2=20.365, P< 0.001], shock [4 cases (3.7%) vs. 79 cases (43.9%), χ2=52.628, P< 0.001], gastrointestinal dysfunction [2 cases (1.9%) vs. 24 cases (13.3%), χ 2=9.359, P=0.002], liver dysfunction [9 cases (8.4%) vs. 46 cases (25.6%), χ2=12.733, P< 0.001], and renal injury [0 cases vs. 10 cases (5.6%), P=0.015].There was no significant difference in the incidence of respiratory failure [102 cases (95.3%) vs. 172 cases (95.6%), χ2=0.008, P=0.928]. However, the number of cases requiring high-flow oxygen therapy and mechanical ventilation was significantly lower in the post-pandemic group compared to the pre-pandemic group [14 cases (13.3%) vs. 48 cases (26.7%), 21 cases (20.3%) vs. 122 cases (67.8%), all P<0.05].The time from symptom onset to the initiation of tetracycline/quinolone therapy was shorter in the post-pandemic group compared to the pre-pandemic group [7 (3, 10) days vs. 9 (6.3, 11) days, χ2=-3.565, P< 0.001]. The proportion of patients who had already received tetracycline/quinolone therapy before admission to the PICU was significantly higher in the post-pandemic group compared to the pre-pandemic group [25 cases (23.4%) vs. 2 cases (1.1%), χ 2=10.009, P=0.002].Both the total hospital stay and PICU stay were shorter in the post-pandemic group compared to the pre-pandemic group [10.0 (8.0, 14.0) days vs. 15.5 (12.0, 22.0) days, 5 (3.0, 8.0) days vs. 7.0 (5.0, 10.0) days, all P=0.000]. All 7 deaths occurred in the pre-pandemic group, including 5 cases with co-infections and 2 cases with underlying diseases. Conclusions:In the post-COVID-19 era, SMPP cases in the PICU were predominantly observed in children over 5 years old, with a lower incidence of shock, gastrointestinal disorders, liver injury, and kidney injury compared to the pre-pandemic period. Patients with macrolide-resistant Mycoplasma pneumoniae who received timely treatment with tetracycline/quinolones exhibited favorable outcomes.

ObjectiveTo evaluate the clinical effectiveness and safety of Modified Zhigancao Granules （炙甘草汤加味颗粒） for preventing the early recurrence following radiofrequency ablation in patients with atrial fibrillation （AF） of qi-yin deficiency syndrome. MethodsA multi-center， randomized， double-blind， placebo-controlled trial was designed. A total of 116 patients with atrial fibrillation of qi-yin deficiency syndrome who underwent radiofrequency ablation for the first time were enrolled from 3 centers， and they were randomly divided into a treatment group （59 cases） and a control group （57 cases）. Both groups received basic western medicine treatment after surgery. In addition， the treatment group was given oral Modified Zhigancao Granules， while the control group was given oral placebo granules. The dosage for both groups was 20 g each time， twice a day， with continuous treatment for 12 weeks. The recurrence of atrial fibrillation in both groups was recorded at 24 hours， 4 weeks， 8 weeks， and 12 weeks after surgery. The serum levels of B-type natriuretic peptide （BNP）， interleukin-6 （IL-6）， high-sensitivity C-reactive protein （hs-CRP）， and tumor necrosis factor-α （TNF-α） were detected before treatment and 12 weeks after treatment in both groups. The scores of Atrial Fibrillation Effect on QualiTy-of-life （AFEQT） Questionnaire （including scores of the daily life dimension， symptom dimension， treatment worry dimension， treatment satisfaction dimension， and total score） and traditional Chinese medicine （TCM） syndrome scores were compared before treatment and at 4 weeks， 8 weeks， and 12 weeks between groups. Safety indicators such as blood routine， urine routine， liver function， and renal function were monitored before and after treatment. ResultsNine of the treatment group and seven of the control group dropped out. Finally， 50 patients in each group were included in the statistical analysis. At 24 hours， 4 weeks， 8 weeks， and 12 weeks after surgery， the recurrence rates of AF in the treatment group were 2.0% （1/50）， 2.0% （1/50）， 4.0% （2/50）， and 10.0% （5/50）， respectively； while those in the control group were 2.0% （1/50）， 26.0% （13/50）， 28.0% （14/50）， and 34.0% （17/50）， respectively. Compared with the control group at the same time points， the early recurrence rates of AF in the treatment group were significantly lower at 4 weeks， 8 weeks， and 12 weeks after surgery （P＜0.01）. Compared with the baseline within group， BNP， hs-CRP， IL-6， and TNF-α in the treatment group all decreased after 12 weeks of treatment （P＜0.05）； the difference in hs-CRP levels （before vs. after treatment） in the treatment group was higher than that in the control group （P＜0.01）. Compared with the baseline within group， both groups showed decreases in the total score of AFEQT Questionnaire， scores of the daily life dimension， treatment worry dimension， symptom dimension， and TCM syndrome scores at 4 weeks， 8 weeks， and 12 weeks after treatment. Meanwhile， the score of the treatment satisfaction dimension of AFEQT increased in both groups （P＜0.01）， and the improvements in all the above scores in the treatment group were superior to those in the control group at all time points （P＜0.05 or P＜0.01）. All safety indicators of patients in both groups were within the normal range before treatment and at 12 weeks after treatment， and no adverse reactions or adverse events occurred in either group. ConclusionModified Zhigancao Granules can reduce the early recurrence rate following radiofrequency ablation in AF patients with qi-yin deficiency syndrome， improve clinical symptoms and quality of life， suppress inflammatory response， and show good safety.

Objective·To screen a long non-coding RNA(lncRNA)signature and construct a competing endogenous RNA(ceRNA)network associated with the prognosis of pediatric sepsis based on the Gene Expression Omnibus(GEO)database,and explore their potential application value in the prognosis assessment of children with sepsis.Methods·Microarray data in GSE4607,GSE26440,GSE26378,and GSE9692 in the GEO database were used to compare the differences in lncRNA profiles between the survival and non-survival groups of children with septic shock.Then,multivariate linear regression,LASSO analysis,and receiver operating characteristic(ROC)curves were used to evaluate the capacity of the lncRNA signature for predicting the outcome of pediatric sepsis.The potential targeted microRNAs(miRNAs)and their downstream mRNAs,targeted by the screened lncRNAs,were used to construct a protein-protein interaction(PPI)network and perform pathway enrichment analysis.Results·Transcriptomic data from GSE4607,GSE26440,GSE26378 and GSE9692 revealed 55 differentially expressed lncRNAs associated with prognosis,and miR503 host gene(MIR503HG),TAPT1 antisense RNA 1(TAPT1-AS1),apoptosis-associated transcript in bladder cancer(AATBC),SBF2 antisense RNA 1(SBF2-AS1),MGC16275,and small nucleolar RNA host gene 15(SNHG15)were identified as a 6-lncRNA signature(lncSig6)associated with the prognosis of pediatric septic shock by LASSO regression analysis.The area under the ROC curve(AUC)of lncSig6 was 0.859(95％CI 0.722-0.996)and 0.854(95％CI 0.687-1.000)in internal and external validation,respectively.As lncRNA act as miRNA sponge,a lncRNA-miRNA-mRNA network based on 3 lncRNAs(MIR503HG,SNHG15,and SBF2-AS1)was constructed and involved in the regulation of signaling pathways,including forkhead box O(FoxO)signaling pathway,phosphatidylinositol 3 kinase-protein kinase B(PI3K-AKT)signaling pathway,cell senescence,insulin signaling pathway,hypoxia-inducible protein-1(HIF-1)signaling pathway and advanced glycation end products(AGEs)and receptor of AGEs(RAGE)signaling pathway.Conclusion·The lncSig6 can be used as an evaluation method to predict the prognosis of septic shock in children,and the constructed ceRNA molecular networks can provide an experimental basis for the study of signaling pathways.

Critically ill with capillary leakage syndrome（CLS）presents with damaged vascular endothelial cells with glycocalyx degraded,which increases vascular permeability,and leads to the protein-rich fluid from the intravascular extravasate into the interstitial space.CLS can concomitant symptoms of hypovolemia and fluid overload.Fluid therapy is the most critical element in the treatment of CLS,but still lack of sufficient evidence to guide the choice of fluid management.Based on accurately hemodynamic monitoring,balanced salt or crystalloid + albumin or fresh frozen plasma may be input to ensure effective circulating blood volume.Albumin or fresh frozen plasma is particularly suitable for CLS patients failed to respond to crystalloids during the leakage period.In the later stage of leakage,conservative fluid management with “de-resuscitation”strategy was mainly used with diuretic and hemofiltration (renal replacement therapy/continuous renal replacement therapy) for attenuating fluid overload.Steroids and ulinastatin may be effective in CLS caused by sepsis.

Objective This study aimed to investigate the antimicrobial resistance profiles of bacterial strains isolated from pediatric intensive care units(PICU)in China for better antimicrobial therapy.Methods Clinical isolates were collected from 17 institutions,including tertiary care children's hospitals and pediatric department of tertiary general hospitals in China from January 1,2020 to December 31,2022.Antimicrobial susceptibility testing was carried out according to a unified protocol using Kirby-Bauer method or automated systems.Results were interpreted according to the breakpoints released by the Clinical and Laboratory Standards Institute(CLSI)in 2020.Results A total of 10 688 isolates were collected,including gram-positive organisms(39.2％)and gram-negative organisms(60.8％).The top three organisms were S.aureus(13.6％,1 453/10 688),A.baumannii(10.0％,1 067/10 688),and coagulase-negative Staphylococcus(9.9％,1 058/10 688).Multi-drug resistant organisms(MDROs)were very common in children.The prevalence of methicillin-resistant Staphylococcus aureus(MRSA),carbapenem-resistant Enterobacterales(CRE),carbapenem-resistant E.coli,carbapenem-resistant K.pneumoniae(CRKP),carbapenem-resistant A.baumannii(CRAB),and carbapenem-resistant P.aeruginosa(CRPA)was 41.1％,19.4％,8.8％,30.9％,67.4％,and 28.8％,respectively.Overall,more than 50％of Enterobacteriales isolates were resistant to cephalosporins,while nearly 25％of Enterobacteriales isolates were resistant to carbapenems.MDROs were highly resistant to commonly used antibiotics.More than 80％of CRE and CRAB strains were resistant to all beta-lactam antibiotics.CRE and CRAB showed low resistance rates to tigecycline and polymyxin.CRPA showed lower resistance rates to piperacillin,beta-lactamase inhibitor combinations than the resistance rates to third and fourth generation cephalosporins.All of the Staphylococcus and Enterococcus isolates were susceptible to vancomycin and tigecycline.None of PRSP strains isolated from meningitis and nonmeningitis samples were resistant to rifampicin,vancomycin,or linezolid.The prevalence of β-lactamase-negative ampicillin-resistant(BLNAR)strains was 43.3％in Haemophilus influenzae.Conclusions MDROs were prevalent in PICU.It is necessary to establish an effective multidisciplinary team(MDT)to control the antimicrobial resistance.