Natural human leukocyte antigen (HLA) antibodies refer to preformed antibodies present in the body that are not induced by prior exposure to allogeneic HLA antigens. In healthy individuals without a sensitization history, the detection rate of natural HLA antibodies is approximately 20%-29% when using screening assays with low sensitivity, and can reach up to 63% when more sensitive HLA-specific detection methods are employed. It is therefore inferred that natural HLA antibodies may also be present in transplant candidates with a similar prevalence. This review comprehensively discusses the potential mechanisms of natural HLA antibody generation, the characteristics of the recognized epitopes, detection techniques, clinical relevance in transplantation, their potential to confound therapeutic decisions, and approaches to distinguish and mitigate their impact. The goal is to raise clinician awareness of the objective existence of natural HLA antibodies, provide guidance on evaluating their association with allograft rejection, and inform appropriate clinical management strategies when encountering natural HLA antibody-positive transplant candidates.

Natural human leukocyte antigen (HLA) antibodies refer to preformed antibodies present in the body that are not induced by prior exposure to allogeneic HLA antigens. In healthy individuals without a sensitization history, the detection rate of natural HLA antibodies is approximately 20%-29% when using screening assays with low sensitivity, and can reach up to 63% when more sensitive HLA-specific detection methods are employed. It is therefore inferred that natural HLA antibodies may also be present in transplant candidates with a similar prevalence. This review comprehensively discusses the potential mechanisms of natural HLA antibody generation, the characteristics of the recognized epitopes, detection techniques, clinical relevance in transplantation, their potential to confound therapeutic decisions, and approaches to distinguish and mitigate their impact. The goal is to raise clinician awareness of the objective existence of natural HLA antibodies, provide guidance on evaluating their association with allograft rejection, and inform appropriate clinical management strategies when encountering natural HLA antibody-positive transplant candidates.

Objectives:To explore the imaging features of patients with isolated left ventricular apical hypoplasia(ILVAH). Methods:Twelve patients diagnosed with ILVAH(ILVAH group)in our hospital from April 2018 to August 2023 were enrolled,and all of them received transthoracic echocardiography(TTE)examination;9 patients underwent CMR examination;and 1 patient underwent CT examination.Clinical data and imaging characteristics of the patients were analyzed.At the same time,twelve healthy age and sex matched participants who underwent physical examination in the same period were selected as the control group. Results:TTE showed that:compared with the control group,the left ventricular transverse diameter([46.3±5.7]mm vs.[57.8±12.6]mm)and right ventricular long diameter([62.0±4.2]mm vs.[73.6±6.4]mm)were larger in the ILVAH group(P＜0.05),the left ventricular long diameter([63.0±3.5]mm vs.[53.4±8.2]mm)was smaller(P＜0.05).There was no significant difference in right ventricular transverse diameter between the two groups(P＞0.05).The interventricular septum was convex to the right ventricle,and the thickness at the apex was(5.2±2.0)mm in the ILVAH group.The papillary muscles were all attached to the flat left ventricular apex.Among the 9 patients who underwent CMR examination,adipose tissue replacement was found in the left ventricular apex in 7 out of the 9 patients,and endocardial fibrosis was found in 2 out of the 9 patients. Conclusions:The clinical presentation of ILVAH is non-specific,but there are specific imaging manifestations that may help improve the understanding of the disease.

Objective:To investigate the role and mechanism of PM(2.5)exposure on airway inflammation in juvenile rats based on macrophage recruitment induced by JNK/CCl2 signaling pathway.Methods:A total of 50 juvenile SD rats were randomly divided into 5 groups(n=10).The control group received no treatment,the PM(2.5)group received PM(2.5)particulate matter expo-sure,and the PM(2.5)+Anisomycin group received PM(2.5)exposure and Anisomycin,an activator of JNK,intravenously.Rats in the PM(2.5)+SP600125 group received PM(2.5)exposure and intravenous administration of the JNK inhibitor SP600125,and rats in the PM(2.5)+Pirfenidone group received PM(2.5)exposure and intravenous administration of Pirfenidone,a CCl2 inhibitor.The rats were euthanized and lung tissue was harvested.JNK,phosphorylated JNK(p-JNK)and CCl2 protein expressions were detected by Western blot.Hematoxylin-eosin(HE)staining was used to detect the pathological changes of lung airway tissue and score the pulmo-nary bronchial inflammation.The number of macrophages in alveolar lavage fluid was analyzed by flow cytometry.The levels of IL-6,IL-1β,and TNF-α in alveolar lavage fluid were determined by ELISA.Results:The expression levels of JNK,p-JNK,and CCl2 among all groups(F=205.296,950.408,260.019;all P<0.001)and macrophage content(F=48.414;P<0.001),pulmonary bronchial inflammation score(F=101.703;P<0.001)and IL-6(H=44.890;P<0.001),IL-1β(H=42.071;P<0.001),TNF-α(F=297.154;P<0.001)were statistically significant.Compared with the control group,the expressions of JNK/CCl2 pathway proteins JNK,p-JNK,and CCl2 in PM(2.5)group were significantly up-regulated(all P<0.05),while the content of macrophages was increased(P<0.05),and the pulmonary and bronchial inflammation score was significantly increased(P<0.05).The levels of IL-6,IL-1β,and TNF-α were up-regulated(all P<0.05).Compared with PM(2.5)group,the content of macrophages in PM(2.5)+Anisomycin group was sig-nificantly increased(P<0.05),the pulmonary bronchial inflammation score was significantly increased(P<0.05),and the levels of IL-6,IL-1β,and TNF-α were increased(all P<0.05).The expression levels of JNK,p-JNK,and CCl2 were increased(all P<0.05).Compared with PM(2.5)group,the content of macrophages in PM(2.5)+SP600125 group and PM(2.5)+Pirfenidone group were signifi-cantly decreased(P<0.05),and the pulmonary bronchial inflammation score was significantly decreased(P<0.05).In addition,the levels of IL-6,IL-1β,and TNF-α were significantly decreased(all P<0.05).Compared with PM(2.5)group,the expression levels of JNK,p-JNK,and CCl2 in PM(2.5)+SP600125 group were down-regulated(all P<0.05),and the expression level of CCl2 in PM(2.5)+Pirfenidone group was down-regulated(all P<0.05).Conclusion:JNK/CCl2 pathway induces macrophage recruitment and pro-motes allergic airway inflammation induced by PM(2.5)particulate matter exposure in juvenile rats.

The long-acting cabotegravir and rilpivirine injection regimen（CAB+RPV regimen）is the first approved long-acting antiretroviral therapy（ART）for HIV in China，administered once every two months. This regimen provides an innovative alternative to daily oral ART，benefiting virologically suppressed patients. Several large clinical-studies have shown that the CAB+RPV regimen achieves comparable virologic suppression and safety to daily oral regimens，while significantly enhancing patient satisfaction. Based on international and domestic HIV/AIDs guidelines and clinical evidence，this consensus offers expert recommendations on patient selection，clinical management，and key communication strategies for healthcare providers to support the effective use of this regimen，aiming to improve quality of life for people living with HIV and accumulate domestic clinical experience with this advanced treatment approach.

Objective:To investigate the effect of metformin on the chemosensitivity of colon cancer cells to 5-fluorouracil (5-FU) and its possible mechanism.Methods:Colon cancer cell lines HCT-116 and HT-29 were cultured in vitro, and the CCK-8 method was used to determine cell viability after intervention with different concentrations (1.25, 2.5, 5, 10, 20, 40, 80 mmol/L) of metformin hydrochloride (MET-HCl) or different concentrations (1.25, 2.5, 5, 10, 20, 40 μmol/L) of 5-FU. The survival rate and 48-hour half maximal inhibitory concentration ( IC50) of the two drugs were calculated. The combined index (CI) of MET-HCl and 5-FU was calculated using the Chou-Talalay model, and the concentrations of MET-HCl and 5-FU in subsequent experiments were determined based on the concentration of the two drugs when the inhibition rate (Fa) was 0.5. The CCK-8 method and Annexin V-FITC/PI flow cytometry were used to detect the survival rate and apoptosis rate of HCT-116 cells or HT-29 cells treated with the two drugs alone and in combination at experimental concentrations, respectively. Cells treated with drug free culture flnid were used as the control group. CXCR4 specific small interfering RNA (siRNA) was transfected into HCT-116 cells and HT-29 cells, and the decreased ( P < 0.05) expression of CXCR4 protein detected by Western blotting indicated successful knockdown of CXCR4. CCK-8 method was used to detect the survival rate of cells with CXCR4 knockdown by two drugs alone and in combination, and the untransfected cells added drug free culture fluid were served as the si-control group. Western blotting was used to detect the expression of proteins related to the CXCR4/Akt signaling pathway in HCT-116 cells or HT-29 cells treated with two drugs alone or in combination. Results:CCK-8 assay showed that MET-HCl and 5-FU decreased the viability of HCT-116 and HT-29 cells in a concentration-time-dependent manner; at 48 h, IC50 of MET-HCl and 5-FU in HCT-116 cells were (13.0±5.8) mmol/L and (16.9±7.2) μmol/L, respectively, and IC50 in HT-29 cells were (8.6±2.8) mmol/L and (9.7±3.1) μmol/L, respectively. When the cell inhibition rates of HCT-116 cells or HT-29 cells detected by CCK-8 method were 50%, 75% and 90% after 48 h of treatment, the corresponding CI values of HCT-116 cells were 0.48, 0.37 and 0.25, and HT-29 cells were 0.57, 0.51 and 0.49, suggesting that the combination of the two drugs had a synergistic effect. Based on Fa = 0.5, the experimental concentrations of MET-HCl and 5-FU were determined to be 10 mmol/L and 5 μmol/L. CCK-8 method showed that after HCT-116 cells or HT-29 cells were treated with 10 mmol/L MET-HCl, 5 μmol/L 5-FU alone or in combination for 48 h, the cell viability of each drug group was lower than that of the control group (all P < 0.05), there was no statistically significant difference in cell viability between MET-HCl alone and 5-FU alone (both P > 0.05), and the cell viability of the combination of the two drugs was lower than that of the two drugs alone (both P < 0.01). After CXCR4 was knocked down, the cell viability of each drug group was lower than that of the si-control group (all P < 0.05), but there was no significant difference in cell viability between the two drugs alone and the combination of the two drugs (all P > 0.05). Flow cytometry showed that after 24 h of treatment, the apoptosis rate of HCT-116 cells or HT-29 cells treated with MET-HCl alone or the combination of the two drugs was higher than that of the control group (all P < 0.05), but there was no statistically significant difference in the apoptosis rate of cells treated with 5-FU alone compared to the control group (all P > 0.05); the apoptosis rate of HCT-116 cells treated with the combination of the two drugs was higher than that of the two drugs alone (both P < 0.05); the apoptosis rate of HT-29 cells treated with the combination of the two drugs was higher than that of 5-FU alone ( P < 0.05), but there was no significant difference with MET-HCl alone ( P > 0.05). Western blotting showed that the relative expression levels of CXCR4, p-Akt and XRCC1 proteins in HCT-116 or HT-29 cells treated with MET-HCl alone and in combination of two drugs were lower than those in the control group (all P < 0.05), but there was no statistically significant difference in the relative expression levels of the 3 proteins in the two cell lines treated with 5-FU alone compared to the control group (all P > 0.05); the relative expression levels of the 3 proteins in the two cell lines treated with MET-HCl alone and in combination of two drugs were lower than those treated with 5-FU alone (all P < 0.05), the relative expression levels of CXCR4 and p-Akt proteins in the two cell lines treated with the combination of two drugs were lower than those treated with MET-HCl alone (all P < 0.05), and the relative expression level of XRCC1 protein in HCT-116 cells treated with the combination of two drugs was lower than that in HCT-116 cells treated with MET-HCl alone ( P < 0.05), but there was no significant difference in the relative expression level of XRCC1 protein in HT-29 cells treated with the combination of two drugs and MET-HCl alone ( P > 0.05). Conclusions:MET-HCl may reduce the expression of XRCC1 through the CXCR4/Akt signaling pathway, thereby enhancing the sensitivity of colon cancer cells to 5-FU.

Objective:To investigate the effect of metformin on the chemosensitivity of colon cancer cells to 5-fluorouracil (5-FU) and its possible mechanism.Methods:Colon cancer cell lines HCT-116 and HT-29 were cultured in vitro, and the CCK-8 method was used to determine cell viability after intervention with different concentrations (1.25, 2.5, 5, 10, 20, 40, 80 mmol/L) of metformin hydrochloride (MET-HCl) or different concentrations (1.25, 2.5, 5, 10, 20, 40 μmol/L) of 5-FU. The survival rate and 48-hour half maximal inhibitory concentration ( IC50) of the two drugs were calculated. The combined index (CI) of MET-HCl and 5-FU was calculated using the Chou-Talalay model, and the concentrations of MET-HCl and 5-FU in subsequent experiments were determined based on the concentration of the two drugs when the inhibition rate (Fa) was 0.5. The CCK-8 method and Annexin V-FITC/PI flow cytometry were used to detect the survival rate and apoptosis rate of HCT-116 cells or HT-29 cells treated with the two drugs alone and in combination at experimental concentrations, respectively. Cells treated with drug free culture flnid were used as the control group. CXCR4 specific small interfering RNA (siRNA) was transfected into HCT-116 cells and HT-29 cells, and the decreased ( P < 0.05) expression of CXCR4 protein detected by Western blotting indicated successful knockdown of CXCR4. CCK-8 method was used to detect the survival rate of cells with CXCR4 knockdown by two drugs alone and in combination, and the untransfected cells added drug free culture fluid were served as the si-control group. Western blotting was used to detect the expression of proteins related to the CXCR4/Akt signaling pathway in HCT-116 cells or HT-29 cells treated with two drugs alone or in combination. Results:CCK-8 assay showed that MET-HCl and 5-FU decreased the viability of HCT-116 and HT-29 cells in a concentration-time-dependent manner; at 48 h, IC50 of MET-HCl and 5-FU in HCT-116 cells were (13.0±5.8) mmol/L and (16.9±7.2) μmol/L, respectively, and IC50 in HT-29 cells were (8.6±2.8) mmol/L and (9.7±3.1) μmol/L, respectively. When the cell inhibition rates of HCT-116 cells or HT-29 cells detected by CCK-8 method were 50%, 75% and 90% after 48 h of treatment, the corresponding CI values of HCT-116 cells were 0.48, 0.37 and 0.25, and HT-29 cells were 0.57, 0.51 and 0.49, suggesting that the combination of the two drugs had a synergistic effect. Based on Fa = 0.5, the experimental concentrations of MET-HCl and 5-FU were determined to be 10 mmol/L and 5 μmol/L. CCK-8 method showed that after HCT-116 cells or HT-29 cells were treated with 10 mmol/L MET-HCl, 5 μmol/L 5-FU alone or in combination for 48 h, the cell viability of each drug group was lower than that of the control group (all P < 0.05), there was no statistically significant difference in cell viability between MET-HCl alone and 5-FU alone (both P > 0.05), and the cell viability of the combination of the two drugs was lower than that of the two drugs alone (both P < 0.01). After CXCR4 was knocked down, the cell viability of each drug group was lower than that of the si-control group (all P < 0.05), but there was no significant difference in cell viability between the two drugs alone and the combination of the two drugs (all P > 0.05). Flow cytometry showed that after 24 h of treatment, the apoptosis rate of HCT-116 cells or HT-29 cells treated with MET-HCl alone or the combination of the two drugs was higher than that of the control group (all P < 0.05), but there was no statistically significant difference in the apoptosis rate of cells treated with 5-FU alone compared to the control group (all P > 0.05); the apoptosis rate of HCT-116 cells treated with the combination of the two drugs was higher than that of the two drugs alone (both P < 0.05); the apoptosis rate of HT-29 cells treated with the combination of the two drugs was higher than that of 5-FU alone ( P < 0.05), but there was no significant difference with MET-HCl alone ( P > 0.05). Western blotting showed that the relative expression levels of CXCR4, p-Akt and XRCC1 proteins in HCT-116 or HT-29 cells treated with MET-HCl alone and in combination of two drugs were lower than those in the control group (all P < 0.05), but there was no statistically significant difference in the relative expression levels of the 3 proteins in the two cell lines treated with 5-FU alone compared to the control group (all P > 0.05); the relative expression levels of the 3 proteins in the two cell lines treated with MET-HCl alone and in combination of two drugs were lower than those treated with 5-FU alone (all P < 0.05), the relative expression levels of CXCR4 and p-Akt proteins in the two cell lines treated with the combination of two drugs were lower than those treated with MET-HCl alone (all P < 0.05), and the relative expression level of XRCC1 protein in HCT-116 cells treated with the combination of two drugs was lower than that in HCT-116 cells treated with MET-HCl alone ( P < 0.05), but there was no significant difference in the relative expression level of XRCC1 protein in HT-29 cells treated with the combination of two drugs and MET-HCl alone ( P > 0.05). Conclusions:MET-HCl may reduce the expression of XRCC1 through the CXCR4/Akt signaling pathway, thereby enhancing the sensitivity of colon cancer cells to 5-FU.

The long-acting cabotegravir and rilpivirine injection regimen（CAB+RPV regimen）is the first approved long-acting antiretroviral therapy（ART）for HIV in China，administered once every two months. This regimen provides an innovative alternative to daily oral ART，benefiting virologically suppressed patients. Several large clinical-studies have shown that the CAB+RPV regimen achieves comparable virologic suppression and safety to daily oral regimens，while significantly enhancing patient satisfaction. Based on international and domestic HIV/AIDs guidelines and clinical evidence，this consensus offers expert recommendations on patient selection，clinical management，and key communication strategies for healthcare providers to support the effective use of this regimen，aiming to improve quality of life for people living with HIV and accumulate domestic clinical experience with this advanced treatment approach.

Humans ; HIV-1/genetics* ; Anti-Retroviral Agents/therapeutic use* ; Mutation/genetics* ; Treatment Failure ; HIV Infections/genetics* ; Drug Resistance, Viral/genetics* ; Anti-HIV Agents/therapeutic use* ; Genotype

Objective:To study the distribution and antibiotics resistance of the main pathogens of neonatal purulent meningitis in different regions of China.Methods:A retrospective descriptive clinical epidemiological study was conducted in children with neonatal purulent meningitis which admitted to 18 tertiary hospitals in different regions of China between January 2015 to December 2019. The test results of blood and cerebrospinal fluid, and drug sensitivity test results of the main pathogens were collected. The distributions of pathogenic bacteria in children with neonatal purulent meningitis in preterm and term infants, early and late onset infants, in Zhejiang Province and other regions outside Zhejiang Province, and in Wenzhou region and other regions of Zhejiang Province were analyzed. The chi-square test was used for statistical analysis.Results:A total of 210 neonatal purulent meningitis cases were collected. The common pathogens were Escherichia coli ( E. coli)(41.4%(87/210)) and Streptococcus agalactiae ( S. agalactiae)(27.1%(57/210)). The proportion of Gram-negative bacteria in preterm infants (77.6%(45/58)) with neonatal purulent meningitis was higher than that in term infants (47.4%(72/152)), and the difference was statistically significant ( χ2=15.54, P=0.001). There were no significant differences in the constituent ratios of E. coli (36.5%(31/85) vs 44.8%(56/125)) and S. agalactiae (24.7%(21/85) vs 28.8%(36/125)) between early onset and late onset cases (both P>0.05). The most common pathogen was E. coli in different regions, with 46.7%(64/137) in Zhejiang Province and 31.5%(23/73) in other regions outside Zhejiang Province. In Zhejiang Province, S. agalactiae was detected in 49 out of 137 cases (35.8%), which was significantly higher than other regions outside Zhejiang Province (11.0%(8/73)). The proportions of Klebsiella pneumoniae, and coagulase-negative Staphylococcus in other regions outside Zhejiang Province (17.8%(13/73) and 16.4%(12/73)) were both higher than those in Zhejiang Province (2.9%(4/137) and 5.1%(7/137)). The differences were all statistically significant ( χ2=14.82, 12.26 and 7.43, respectively, all P<0.05). The proportion of Gram-positive bacteria in Wenzhou City (60.8%(31/51)) was higher than that in other regions in Zhejiang Province (38.4%(33/86)), and the difference was statistically significant ( χ2=6.46, P=0.011). E. coli was sensitive to meropenem (0/45), and 74.4%(32/43) of them were resistant to ampicillin. E. coli had different degrees of resistance to other common cephalosporins, among which, cefotaxime had the highest resistance rate of 41.8%(23/55), followed by ceftriaxone (32.4%(23/71)). S. agalactiae was sensitive to penicillin, vancomycin and linezolid. Conclusions:The composition ratios of pathogenic bacteria of neonatal purulent meningitis are different in different regions of China. The most common pathogen is E. coli, which is sensitive to meropenem, while it has different degrees of resistance to other common cephalosporins, especially to cefotaxime.