Efficacy and Long-term Safety of Telbivudine Usage During Second or Third Trimester in Hepatitis B Surface Antigen Positive Mothers With High Viral Load: A 10-year Prospective Study.

GOALS: The study is to evaluate the efficacy and long-term safety of telbivudine (LdT) usage for hepatitis B surface antigen (HBsAg) positive pregnant women with high viral load. BACKGROUND: The efficacy and safety of LdT during pregnancy were not assessed from a long-term perspective. STUDY: HBsAg-positive pregnant women were enrolled and grouped according to antiviral initiation time. Group A (n=100) and group B (n=100) were treated with LdT initiated in the second or third trimester. Group C (n=90) received no antiviral treatment. The efficacy and safety of LdT treatment were compared and infants were followed-up at 1, 5, and 10 years. Denver developmental screening test was conducted at 5 years. RESULTS: Viral loads before delivery in LdT-treated groups were lower than that in group C and group A was lower than that in group B ( P <0.001). No infants in LdT-treated groups were infected whereas 8.8% (8/90) infants in group C had positive HBsAg (χ 2 =23.20, P <0.001). All LdT-treated mothers were well tolerated and no LdT-related adverse events in infants were reported. Part of the physical growth index of infants was higher than Chinese standard values (SV) and showed significant differences. In groups A and B, the developmental screening test qualified rate of 100% (48/48) and 97.96% (48/49) showed no significant difference compared with 92% in normal Chinese children (χ 2 =5.72, P =0.06). CONCLUSIONS: Treatment initiated during the second trimester could strengthen the success of mother-to-child transmission blockage. LdT treatment during pregnancy is safe for both mothers and infants in the long term.

The relationship of maternal hepatitis B e antigen and response to vaccination of infants born to women with chronic infection.

BACKGROUND: The relationship of maternal HBeAg and infants' response to hepatitis B vaccine remains controversial. This study aims to observe the dynamic changes in infant birth HBV markers and study the time-varying effects of maternal HBeAg on vaccination response of infants born to women with chronic HBV infection. METHODS: 3163 infants born to HBsAg positive mothers including 1737 with maternal HBeAg positive in group A and 1426 negative in group B were enrolled eventually. Demographic information and laboratory tests were collected at birth, 7-12th and 24th month. The dynamic changes of infant HBV markers and HBsAb titers at different time points were compared between the two groups. RESULTS: The infant HBV markers at birth displayed different modes. During the follow-up, we observed a significant downward trend in the positive rates of HBsAg, HBeAg, HBeAb and HBcAb. The HBsAg of two groups switched to negative at 7-12 months and HBeAg in Group A became negative at 24 months. The HBsAb titers of the infants in the two groups were 576.91(192.8-1000.0) vs 719.67(208.1-1000.0) at 7-12 months (Z = -3.049, P = 0.002) and 783.5(227.8-1000.0) vs 891.4(234.0-1000.0) at 24 months (Z = -0.853, P = 0.394). High HBV DNA viral load (OR 1.260, 95% CI 1.139-1.395, P < 0.001) and maternal HBeAg level (OR 1.003, 95% CI 1.002-1.003, P < 0.001) were associated with the higher HBeAg positive rate of infants. CONCLUSIONS: Maternal HBeAg did affect the infants' immune response to vaccination and reduce the anti-response at 7-12th month temporarily, but these influences were negligible by 24th months after birth, which proved that the maternal HBeAg would not induce immune tolerance of infants from a long-term perspective.

Staging and clinical characteristics of pregnant women with chronic hepatitis B virus infection: A retrospective cohort study from Nanjing, China.

AIM: To investigate the immune status of Chinese chronic hepatitis B (CHB) pregnant women and their clinical characteristics. METHODS: About 1544 CHB pregnant women without antiviral therapy from 2013 to 2018 were selected from the hospital records. The definition of immune status is based on American Association for the Study of Liver Diseases (AASLD) 2018 Hepatitis B Guidance, and those who did not meet any criteria of the immune status were referred to in the gray zones (GZ). RESULTS: There were 284 patients in the immune-tolerance phase, 72 patients in the HBeAg-positive immune active phase, 553 patients in the inactive phase, 61 patients in the HBeAg-negative immune active phase. Of note, 574 (37.18%) patients did not fit into any of the above phases were defined as the GZ. Patients with elevated ALT had a higher rate of intrahepatic cholestasis of pregnancy (ICP). Mother to child HBV transmission was rare (only two cases) and occurred in mothers in the immune-tolerant phase. CONCLUSIONS: Our data showed that more than one-third of CHB pregnant women were classified into the GZ. In standard stages, advanced age is associated with HBeAg-negative and a higher cesarean rate in the inactive phase. The incidence of ICP was higher in immune active phases, including GB and GD. The probability of mother-to-child transmission in gray zones is low.

Long-term safety of infants from mothers with chronic hepatitis B treated with tenofovir disoproxil in China.

OBJECTIVE: The physical and neuromental development of infants remains uncertain after fetal exposure to tenofovir disoproxil fumarate (TDF) for the prevention of mother-to-child transmission of HBV. We aimed to investigate the safety of TDF therapy during the third trimester of pregnancy. DESIGN: Infants from a previous randomised controlled trial were recruited for our long-term follow-up (LTFU) study. Mothers with chronic hepatitis B were randomised to receive TDF therapy or no treatment during the third trimester. Infants' physical growth or malformation, bone mineral density (BMD) and neurodevelopment, as assessed using Bayley-III assessment, were examined at 192 weeks of age. RESULTS: Of 180 eligible infants, 176/180 (98%) were enrolled and 145/176 (82%) completed the LTFU (control group: 75; TDF-treated group: 70). In the TDF-treated group, the mean duration of fetal exposure to TDF was 8.57±0.53 weeks. Congenital malformation rates were similar between the two groups at week 192. The mean body weight of boys in the control and TDF-treated groups was significantly higher (19.84±3.46 kg vs. 18.47±2.34 kg; p=0.03) and within the normal range (18.48±2.35 kg vs. 17.80±2.50 kg; p=0.07), respectively, when compared with the national standard. Other prespecified outcomes (head circumference, height, BMD, and cognitive, motor, social-emotional, and adaptive behaviour measurements) were all comparable between the groups. CONCLUSION: Infants with fetal exposure to TDF had normal physical growth, BMD and neurodevelopment at week 192. Our findings provide evidence on the long-term safety of infants after fetal exposure to maternal TDF therapy for preventing hepatitis B transmission. TRIAL REGISTRATION NUMBER: NCT01488526.

Relationship between different hepatitis B virus infection status and gestational diabetes mellitus prevalence among pregnant women with chronic HBV infection: A retrospective study.

To investigate the relationships between different hepatitis B virus (HBV) infection status and gestational diabetes mellitus (GDM) and analyse the potential risk factors, we conducted an observational retrospective study in HBV-infected pregnant women to compare the differences of GDM prevalence and clinical outcomes between groups divided by HBV infection status. Spearman's correlation coefficient was used to evaluate the correlations among hepatitis B e antigen (HBeAg), HBV DNA and liver function. Logistic regression model was used to analyse the risk factors. In all, 1390 HBsAg-positive pregnant women were enrolled. HBeAg titre and HBV DNA, ALT and AST were correlated (r = 0.743, p < 0.001; r = 0.813, p < 0.001). Overall GDM prevalence was 21%. GDM prevalence of HBV-infected women with abnormal liver function was higher than those with normal liver function (26.8% vs. 20%, p = 0.027). Age over 35 years and abnormal liver function over 5 times ULN and 1-2 times ULN were independent risk factors for GDM prevalence with odds ratio (OR) of 1.858 (95% CI 1.227-2.815), 1.589 (95% CI 1.023-2.468) and 2.203 (95% CI 1.029-4.718), respectively. GDM prevalence in HBV-infected pregnancies with abnormal liver function was higher than those with normal liver function. Age over 35 years and abnormal liver function were independent risk factors for GDM in HBV-infected women.

Toward Collaborative Intelligence in IoV Systems: Recent Advances and Open Issues.

Internet of Vehicles (IoV) technology has been attracting great interest from both academia and industry due to its huge potential impact on improving driving experiences and enabling better transportation systems. While a large number of interesting IoV applications are expected, it is more challenging to design an efficient IoV system compared with conventional Internet of Things (IoT) applications due to the mobility of vehicles and complex road conditions. We discuss existing studies about enabling collaborative intelligence in IoV systems by focusing on collaborative communications, collaborative computing, and collaborative machine learning approaches. Based on comparison and discussion about the advantages and disadvantages of recent studies, we point out open research issues and future research directions.

Tenofovir to Prevent Hepatitis B Transmission in Mothers with High Viral Load.

BACKGROUND: Few data are available regarding the use of tenofovir disoproxil fumarate (TDF) during pregnancy for the prevention of mother-to-child transmission of hepatitis B virus (HBV). METHODS: In this trial, we included 200 mothers who were positive for hepatitis B e antigen (HBeAg) and who had an HBV DNA level higher than 200,000 IU per milliliter. Participants were randomly assigned, in a 1:1 ratio, to receive usual care without antiviral therapy or to receive TDF (at an oral dose of 300 mg per day) from 30 to 32 weeks of gestation until postpartum week 4; the participants were followed until postpartum week 28. All the infants received immunoprophylaxis. The primary outcomes were the rates of mother-to-child transmission and birth defects. The secondary outcomes were the safety of TDF, the percentage of mothers with an HBV DNA level of less than 200,000 IU per milliliter at delivery, and loss or seroconversion of HBeAg or hepatitis B surface antigen at postpartum week 28. RESULTS: At delivery, 68% of the mothers in the TDF group (66 of 97 women), as compared with 2% in the control group (2 of 100), had an HBV DNA level of less than 200,000 IU per milliliter (P<0.001). At postpartum week 28, the rate of mother-to-child transmission was significantly lower in the TDF group than in the control group, both in the intention-to-treat analysis (with transmission of virus to 5% of the infants [5 of 97] vs. 18% [18 of 100], P=0.007) and the per-protocol analysis (with transmission of virus to 0 vs. 7% [6 of 88], P=0.01). The maternal and infant safety profiles were similar in the TDF group and the control group, including birth-defect rates (2% [2 of 95 infants] and 1% [1 of 88], respectively; P=1.00), although more mothers in the TDF group had an increase in the creatine kinase level. After the discontinuation of TDF, alanine aminotransferase elevations above the normal range occurred more frequently in mothers in the TDF group than in those in the control group (45% [44 of 97 women] vs. 30% [30 of 100], P=0.03). The maternal HBV serologic outcomes did not differ significantly between the groups. CONCLUSIONS: In a cohort of HBeAg-positive mothers with an HBV DNA level of more than 200,000 IU per milliliter during the third trimester, the rate of mother-to-child transmission was lower among those who received TDF therapy than among those who received usual care without antiviral therapy. (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT01488526.).

Management Algorithm for Interrupting Mother-to-Child Transmission of Hepatitis B Virus.

In areas where hepatitis B virus (HBV) is endemic, mother-to-child transmission (MTCT) is the major route of infection of children. Blocking MTCT of HBV therefore would reduce its prevalence. The China Foundation of Hepatitis Prevention and Control organized a team of specialists in infectious diseases, hepatology, immunology, obstetrics, and public health to develop an algorithm for interrupting MTCT of HBV, based on the most recent hepatitis B guidelines and latest evidence. This algorithm comprises 10 steps and has been adopted in clinical practice in China. Four aspects (screening, antiviral intervention during pregnancy, immunoprophylaxis, and postvaccination serologic testing) are the core components of preventing MTCT. Although the combination of passive and active immunization in newborns of hepatitis B surface antigen-positive mothers reduces MTCT of HBV, this immunoprophylaxis cannot completely eradicate MTCT. In the past decade, administration of antiviral agents to pregnant women has been shown to be safe and effective in reducing MTCT of HBV in combination with immunoprophylaxis. Aiming to achieve zero MTCT, this algorithm recommends the use of antivirals during pregnancy by women with high viral loads. Preventing MTCT is key to achieving the goal of eliminating HBV as a public health threat by 2030. Implementation and enhancement of the standardized algorithm for pregnant women with chronic HBV infection and their infants is urgently needed to prevent MTCT.

[Comparison of combined immunization schemes influence on anti-HBs of babies born to mothers with high-load hepatitis B virus infection].

OBJECTIVE: To compare the various combined immunization schemes available for treatment of babies born to mothers with high-load hepatitis B virus (HBV) infection. METHODS: A total of 118 mothers with HBV infection status of hepatitis B surface antigen-positive (HBsAg+), hepatitis B e antigen-positive (HBeAg+) and HBV DNA load of more than 1.0 * 61og10 IU/mL were included in the study. All of the participants' babies received the main-passive immunization therapy according to the wishes of their families. For analysis,the infants were grouped according to the various dosages of the vaccine program (group A: hepatitis B immunoglobulin (HBIG) 200 IU and HBVac 20 mug intramuscular;group B:HBIG 200 IU and HBVac 10 mug intramuscular; group C HBIG 100 IU and HBVac 20 mug intramuscular injection) and times, and followed-up to 7 months of age.All results were statistically analyzed using SPSS software. RESULTS: All of the infants produced anti-HBs after vaccination.After the HBIG injection schedule was completed in January, the mean concentrations of anti-HBs in groups A, B, and C were 263.56 ± 50.98,231.06 ± 74.07, and 99.23 ± 29.82 mIU/mL respectively;the concentrations were significantly different between groups A and C, and between groups B and C (P < 0.001). In July, the titers of anti-HBs in groups A, B, and C were 788.10 ± 281.96,428.39 ± 347.48, and 708.44 ± 315.69 mIU/mL respectively; the concentrations were significantly different between groups A and B, and between groups B and C (P < 0.05). CONCLUSION: AdminisWation of the hepatitis B vaccine combined with HBIG at birth can achieve immune protection for babies born to highly viremic mothers. In January, the HBIG dosage of 200 IU was more reliable than 100 IU. The hepatitis B 20 tg dose vaccine was safe and effective.

Shikonin reduces M2 macrophage population in ovarian cancer by repressing exosome production and the exosomal galectin 3-mediated ß-catenin activation.

BACKGROUND: Shikonin (SK), a naphthoquinone with anti-tumor effects, has been found to decrease production of tumor-associated exosomes (exo). This study aims to verify the treatment effect of SK on ovarian cancer (OC) cells, especially on the production of exo and their subsequent effect on macrophage polarization. METHODS: OC cells SKOV3 and A2780 were treated with SK. The exo were isolated from OC cells with or without SK treatment, termed OC exo and SK OC exo, respectively. These exo were used to treat PMA-induced THP-1 cells (M0 macrophages). M2 polarization of macrophages was determined by measuring the M2 specific cell surface markers CD163 and CD206 as well as the secretion of M2 cytokine IL-10. The functions of galectin 3 (LGALS3/GAL3) and ß-catenin in macrophage polarization were determined by gain- or loss-of-function assays. CB-17 SCID mice were subcutaneously injected with SKOV3 cells to generate xenograft tumors, followed by OC exo or SK OC exo treatment for in vivo experiments. RESULTS: SK suppressed viability, migration and invasion, and apoptosis resistance of OC cells in vitro. Compared to OC exo, SK OC exo reduced the M2 polarization of macrophages. Regarding the mechanism, SK reduced exo production in cancer cells, and it decreased the protein level of GAL3 in exo and recipient macrophages, leading to decreased ß-catenin activation. M2 polarization of macrophages was restored by LGALS3 overexpression but decreased again by the ß-catenin inhibitor FH535. Compared to OC exo, the SK OC exo treatment reduced the xenograft tumor growth in mice, and it decreased the M2 macrophage infiltration within tumor tissues. CONCLUSION: This study suggests that SK reduces M2 macrophage population in OC by repressing exo production and blocking exosomal GAL3-mediated ß-catenin activation.

Real-world implementation of a multilevel interventions program to prevent mother-to-child transmission of HBV in China.

Reducing hepatitis B virus (HBV) mother-to-child transmission (MTCT) is a fundamental step toward the HBV elimination goal. The multicentred, multilevel SHIELD program aimed to use an intense intervention package to reduce HBV MTCT in China. This study was conducted in diverse health settings across China, encompassing 30,109 pregnant women from 178 hospitals, part of the interim analysis of stage II of the SHIELD program, and 8,642 pregnant women from 160 community-level health facilities in stage III of the SHIELD program. The study found that the overall MTCT rate was 0.23% (39 of 16,908; 95% confidence interval (CI): 0.16-0.32%) in stage II and 0.23% (12 of 5,290; 95% CI: 0.12-0.40%) in stage III. The MTCT rate was lower among participants who were compliant with the interventions (stage II: 0.16% (95% CI: 0.10-0.26%); stage III: 0.03% (95% CI: 0.00-0.19%)) than among those who were noncompliant (3.16% (95% CI: 1.94-4.85%); 1.91% (95% CI: 0.83-3.73%); P < 0.001). Our findings demonstrate that the comprehensive interventions among HBV-infected pregnant women were feasible and effective in dramatically reducing MTCT.

Telbivudine prevents vertical transmission from HBeAg-positive women with chronic hepatitis B.

BACKGROUND & AIMS: Telbivudine reduces hepatitis B virus (HBV) DNA and normalizes levels of alanine aminotransferase (ALT) in patients with chronic hepatitis B (CHB). We investigated its use in preventing vertical transmission. METHODS: We performed an open-label, prospective study of 88 hepatitis B (HB) e antigen (HBeAg)-positive pregnant women with CHB, levels of HBV DNA >6 log(10) copies/mL, and increased levels of ALT. Women were given telbivudine (n = 53) starting in the 2nd or 3rd trimester, or no treatment (controls, n = 35) and followed until postpartum week (PPW) 28. All infants received standard immunoprophylaxis after birth. RESULTS: At 28 weeks, none of the infants whose mothers received telbivudine had immunoprophylaxis failure, whereas 8.6% of the infants of control mothers did (P = .029). There were no differences between groups in mothers' adverse events or infants' congenital deformities, gestational age, height, and weight, or Apgar scores. At postpartum week 28, significantly more telbivudine-treated mothers had levels of HBV DNA <500 copies/mL, normalized levels of ALT, and hepatitis B e antigen seroconversion compared with controls (58% vs none, P < .001; 92% vs 71%; P = .008; and 15% vs none; P < .001, respectively) but none had loss of hepatitis B surface antigen. Telbivudine-treated mothers had no virologic breakthrough (HBV DNA >1 log(10) increase from <500 copies/mL) or discontinuations from adverse events. After delivery, 13/52 patients discontinued telbivudine due to preference. There were no episodes of severe hepatitis (levels of ALT >10 times the upper limit of normal) in either group during 28 weeks of postpartum observation. CONCLUSIONS: Women with CHB given telbivudine during the second or third trimester of pregnancy have reduced rates of perinatal transmission. Telbivudine produced no adverse events in mothers or infants by 28 weeks.

[Maternal-fetal outcomes of lamivudine treatment administered during late pregnancy to highly viremic mothers with HBeAg+ chronic hepatitis B].

OBJECTIVE: To evaluate the therapeutic efficacy and safety of lamivudine treatment in late pregnancy by analyzing the maternal-fetal outcomes of chronic hepatitis B (CHB) mothers featuring hepatitis B e antigen (HBeAg)-positivity and highly viremic status. METHODS: A total of 256 pregnant women in the second or third trimester with monoinfected CHB, HBeAg-positivity, and HBV DNA more than 6 log10 copies/mL were divided into two groups: lamivudine (lam) treatment (n=164) or no treatment (controls; n=92). All infants were treated with hepatitis B immune globin (HBIg; 200 IU) within 12 hrs of birth and 15 days later, and were given the recombinant HBV vaccine (20 mug) at 0, 1 and 6 months. All infants were followed-up to at least seven months and hepatitis B surface antigen (HBsAg) and HBV DNA levels were used to determine perinatal transmission (PT) rates. The mothers' data from routine blood analysis, tests of hepatic and renal function, detection of HBV markers and HBV DNA were retrospectively analyzed to determine changes associated with the lam treatment. Correlations of lam treatment with HBV PT rate, alanine aminotransferase (ALT) normalization, adverse reactions, pregnancy complications, congenital deformities, and infants' growth/development were determined by statistical analyses. RESULTS: Prior to delivery, the lam-treated mothers had significantly lower HBV DNA levels (3.72+/-1.78 vs. controls: 7.83+/-0.67 log10 c/ml; t=-22.359, P less than 0.001). The rate of virological response in the lam-treated group was 97.56% (160/164). The lam-treated group had significantly higher ALT normalization rate (90.20% vs. controls: 55.88%; X2=13.349, P less than 0.001) and significantly lower HBeAg titer (957.73+/-458.42 vs. controls: 1296.35+/-383.14 S/CO; t=-5.410, P less than 0.001). At birth, the infants from lam-treated mothers had significantly lower HBsAg-positivity (15.24% (25/164) vs. controls: 30.43% (28/92); X2=8.284, P=0.004). By 7-12 months after birth, none of the infants born to lam-treated mothers tested positive for HBsAg, compared to 8.70% (8/92) of the infants born to mothers in the control group (X2=14.721, P less than 0.001). None of the lam-treated mothers required treatment discontinuation due to adverse events or lam-resistance. No congenital deformities were observed during the study and follow-up periods. There were no differences between the lam-treated and control groups for postpartum hemorrhage, gestational age, infants' height/weight or Apgar scores. CONCLUSION: In highly viremic HBsAg+ mothers with CHB, lam treatment in the second or third trimester of pregnancy is safe and effective for reducing HBV maternal-neonatal transmission.

[Efficacy and safety of telbivudine in pregnant women to prevent perinatal transmission of hepatitis B virus].

OBJECTIVE: To evaluate the efficacy and safety of telbivudine use during the second and third trimester of pregnancy for reducing hepatitis B virus (HBV) transmission from highly viremic hepatitis B e antigen-positive (HBeAg+) mothers to their fetuses. METHODS: Pregnant women, between weeks 20 to 32 of gestation, who were HBeAg+ and had HBV DNA more than 1.0*10(7) copies/mL were enrolled in our study. The women were offered inclusion into one of two treatment arms, based upon their personal preference: telbivudine or no telbivudine. The patients in the telbivudine treatment arm were administered 600 mg/d telbivudine at least until postpartum week 4. All delivered infants in both treatment arms were administered hepatitis B immune globulin (HBIG; 200 IU) within 12 hours of delivery and recombinant HBV vaccine (20 mug) at 0, 1 and 6 months. The HBV perinatal transmission rate was determined by measuring HBsAg and HBV DNA in infants at postpartum week 28. RESULTS: A total of 220 pregnant women were enrolled in our study, 120 chose the telbivudine arm and 100 chose the control arm. All telbivudine treated subjects were registered in the Antiretroviral Pregnancy Registry. Telbivudine treatment was associated with a marked reduction in the mothers' serum HBV DNA, HBeAg and ALT levels before delivery. A striking decline of HBV DNA levels in treated mothers was observed at week 2 of treatment, which was followed by a gradual and steady decrease that continued until delivery. Thirty-seven (31%) of the telbivudine-treated mothers and none (0%) of the untreated controls had polymerase chain reaction-undetectable viremia at delivery. At week 28, 0% of the infants delivered from telbivudine-treated mothers were HBsAg+ or HBV DNA+, as compared to 8% HBsAg+ or HBV DNA+ in the untreated control arm (P = 0.002). No telbivudine discontinuations occurred from adverse events, and no congenital deformities were observed in the infants delivered to telbivudine-treated mothers. Eighty mothers discontinued telbivudine at week 4 postpartum, and there were no cases of severe hepatitis. There were no significant differences between the two treatment arms for postpartum hemorrhage, adverse events during pregnancy, cesarean section, gestational age, or infants' height/weight or Apgar scores. CONCLUSIONS: Telbivudine use during the second and third trimester of pregnancy in HBeAg+ highly viremic mothers can safely reduce perinatal HBV transmission rates. Telbivudine was well-tolerated by our patient group. Furthermore, no safety concerns were observed in either the telbivudine-treated mothers or their delivered infants in short term follow-up.

ceRNA Network and Functional Enrichment Analysis of Preeclampsia by Weighted Gene Coexpression Network Analysis.

BACKGROUND: Preeclampsia (PE) is a multisystemic syndrome which has short- and long-term risk to mothers and children and has pluralistic etiology. OBJECTIVE: This study is aimed at constructing a competitive endogenous RNA (ceRNA) network for pathways most related to PE using a data mining strategy based on weighted gene coexpression network analysis (WGCNA). METHODS: We focused on pathways involving hypoxia, angiogenesis, and epithelial mesenchymal transition according to the gene set variation analysis (GSVA) scores. The gene sets of these three pathways were enriched by gene set enrichment analysis (GSEA). WGCNA was used to study the underlying molecular mechanisms of the three pathways in the pathogenesis of PE by analyzing the relationship among pathways and genes. The soft threshold power (ß) and topological overlap matrix allowed us to obtain 15 modules, among which the red module was chosen for the downstream analysis. We chose 10 hub genes that satisfied ∣log2Fold Change | >2 and had a higher degree of connectivity within the module. These candidate genes were subsequently confirmed to have higher gene significance and module membership in the red module. Coexpression networks were established for the hub genes to unfold the connection between the genes in the red module and PE. Finally, ceRNA networks were constructed to further clarify the underlying molecular mechanism involved in the occurrence of PE. 56 circRNAs, 17 lncRNAs, and 20 miRNAs participated in the regulation of the hub genes. Coagulation factor II thrombin receptor (F2R) and lumican (LUM) were considered the most relevant genes, and ceRNA networks of them were constructed. CONCLUSION: The microarray data mining process based on bioinformatics methods constructed lncRNA and miRNA networks for ten hub genes that were closely related to PE and focused on ceRNAs of F2R and LUM finally. The results of our study may provide insight into the mechanisms underlying PE occurrence.

Long non-coding RNA WAC antisense RNA 1 mediates hepatitis B virus replication in vitro by reinforcing miR-192-5p/ATG7-induced autophagy.

Long non-coding RNA WAC antisense RNA 1 (lncRNA WAC-AS1) is involved in the replication of the hepatitis B virus (HBV). The purpose of this study was to determine its functions and specific mechanism. The levels of lncRNA WAC-AS1, RNA (miR)-192-5p and were examined in serum of HBV-infected patients and in HepG2.2.15 cells using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blotting. Using the database starBase, the target binding sites of lncRNA WAC-AS1 and miR-192-5p were predicted and confirmed by dual-luciferase reporter assay and RNA pull-down assay. The expression of pgRNA and HBV DNA was determined by qRT-PCR, while the levels of HBeAg and HBsAg were measured by enzyme-linked immunosorbent assay (ELISA). Using laser scanning confocal microscopy, the light chain 3 (LC3) expression was analyzed. qRT-PCR and Western blotting were used to assess the expression of beclin-1, p62, and LC3I/II. Overexpression of lncRNA WAC-AS1, upregulation of ATG7. and downregulation of miR-192-5p were observed in the serum of HBV-infected patients and the in vitro model. miR-192-5p directly targets lncRNA WAC-AS1. LncRNA WAC-AS1 was downregulated in lncRNA WAC-AS1-shRNA‒transfected cells. miR-192-5p was upregulated in lncRNA WAC-AS1-shRNA-transfected cells and downregulated in cells transfected with a miR-192-5p inhibitor. In HepG2 2.15 cells, the downregulation of lncRNA WAC-AS1 inhibited HBV replication and autophagy. In contrast, the miR-192-5p inhibitor-transfected group exhibited the opposite results, and ATG7 overexpression reversed the effects of miR-192-5p mimic or lncRNA WAC-AS1-shRNA on HBV replication and cell autophagy. Our findings indicate that lncRNA WAC-AS1 regulates HBV replication by reinforcing the autophagy induced by miR-192-5p/ATG7. Consequently, lncRNA WAC-AS1 may serve as a therapeutically-promising target in HBV patients.

Exosomal Circular RNA hsa_circ_0046060 of Umbilical Cord Mesenchymal Stromal Cell Ameliorates Glucose Metabolism and Insulin Resistance in Gestational Diabetes Mellitus via the miR-338-3p/G6PC2 Axis.

Background: Impaired glucose metabolism and insulin sensitivity have been linked to the pathogenesis of gestational diabetes mellitus (GDM). Exosomes secreted by the umbilical cord mesenchymal stromal cells (UMSCs) and circular RNAs (circRNAs) derived from exosomes have been shown to be associated with the progression of GDM-related complications. Methods: UMSCs were isolated from umbilical cords and identified through flow cytometry. Exosomes were isolated from UMSCs and were then characterized. The expression levels of RNA of hsa_circ_0046060, mmu_circ_0002819, and miR-338-3p were determined by quantitative real-time polymerase chain reaction (RT-qPCR). The intracellular glucose intake and glycogen content were measured using a High Sensitivity Glucose Assay Kit and Glycogen Assay Kit, respectively. Bioinformatics analysis and luciferase reporter assay were used to validate interactions among hsa_circ_0046060, miR-338-3p, and G6PC2. The expression of insulin receptor substrate-1 (IRS-1) and its phosphorylated form, (p-IRS-1), as well as G6PC2, was determined through western blotting. Results: UMSCs and exosomes were successfully isolated and identified. The upregulation of hsa_circ_0046060 decreased the intracellular glucose content in L-02 cells (43.45 vs. 16.87 pM/mg, P=0.0002), whereas shRNA-mediated downregulation reversed this effect (16.87 vs. 33.16 pM/mg, P=0.0011). Mmu_circ_0002819 in mice aggravated dysregulated glucose metabolism (49.88 vs. 21.69 pM/mg, P=0.0031) and insulin sensitivity (0.20 vs. 0.11 mg/mL, P=0.03) in GDM mice, which was abrogated by the knockdown of mmu_circ_0002819. The results of luciferase reporter assay revealed that miR-338-3p and G6PC2 were the potential targets of has_circ_0046060. Western blotting results showed that the reduced activation of IRS-1 induced by GDM (1.25 vs. 0.54, P=0.0001) could be rescued by the administration of si-circ-G-UMSC-EXOs (0.54 vs. 1.17, P=0.0001). Conclusion: Taken together, the inhibition of hsa_circ_0046060 expression in exosomes from GDM-derived UMSCs can alleviate GDM by reversing abnormal glucose metabolism and insulin resistance in vivo and in vitro.

Tenofovir alafenamide in blocking mother-to-child transmission of hepatitis B virus: a multi-center, prospective study.

BACKGROUND: Data of tenofovir alafenamide (TAF) in preventing mother-to-child transmission (MTCT) of hepatitis B virus (HBV) are limited. This study aimed to evaluate the effectiveness and safety of TAF for preventing MTCT. METHODS: Pregnant women with chronic HBV infection, positive for HBeAg and high-level HBV DNA, received oral TAF from gestational weeks 24-28 until postpartum week 4. All infants received HBV immunoprophylaxis. All mothers and infants were followed up until postpartum seven month. The primary outcome was the rate of MTCT at seven month. RESULTS: Eighty-nine mothers delivered and 91 infants were born. All were followed up to postpartum seven month. TAF was initiated at a mean gestational age of 25.0 (±1.0) weeks with the mean treatment duration of 14.3 (±1.2) weeks before delivery; 92.1% (82/89) mothers discontinued TAF, the median [IQR] time was 5.9 [4.7] weeks postpartum. The HBsAg positive rate was 0% at seven months in 91 infants, no growth retardation and congenital defects. All mothers were tolerated during TAF treatment. At delivery, 82.02% (73/89) mothers achieved HBV DNA < 200,000 IU/ml, 21.35% (19/89) achieved HBV DNA < 500 IU/ml. No significant changes on the mean (±SD) serum phosphate between baseline (1.20 ± 0.10 mmol/L) and at delivery (1.21 ± 0.13 mmol/L, p > .05). Serum creatinine at delivery (52.23 ± 8.50 µmol/L) was higher than baseline (45.97 ± 5.60 µmol/L, p < .05), but within normal range. Nine of 82 mothers stopped TAF treatment after delivery had mild ALT elevation. CONCLUSION: TAF therapy initiated during the second trimester was effective in preventing MTCT with no safety concerns for mothers and infants (ClinicalTrials.gov number, NCT04065230).

Management Algorithm for Prevention of Mother-to-child Transmission of Hepatitis B Virus (2022).

The World Health Organization (WHO) has set the goal of eliminating hepatitis as a threat to public health by 2030. Blocking mother-to-child transmission (MTCT) of hepatitis B virus (HBV) is not only the key to eliminating viral hepatitis, but also a hot issue in the field of hepatitis B prevention and treatment. To standardize the clinical management of preventing MTCT of HBV and achieve zero HBV infection among infants, the Chinese Foundation for Hepatitis Prevention and Control organized experts to compile a management algorithm for prevention of MTCT of HBV based on the latest research progress and guidelines, including 10 steps of pregnancy management and postpartum follow-up, among which screening, antiviral treatment, and infant immunization are its core components.