Guideline No. 452: Diagnosis and Management of Intrahepatic Cholestasis of Pregnancy.

OBJECTIVE: To summarize the current evidence and to make recommendations for the diagnosis and management of intrahepatic cholestasis of pregnancy. TARGET POPULATION: Pregnant people with intrahepatic cholestasis of pregnancy. OPTIONS: Diagnosing the condition using fasting or non-fasting bile acids, classifying disease severity, determining what treatment to offer, establishing how to monitor for antenatal fetal wellbeing, identifying when to perform elective birth. BENEFITS, HARMS, AND COSTS: Individuals with intrahepatic cholestasis of pregnancy are at increased risk of adverse perinatal outcomes including preterm birth, neonatal respiratory distress and admission to a neonatal intensive care unit, with an increased risk of stillbirth when bile acid levels are ≥100 µmol/L. There is inequity in bile acid testing availability and timely access to results, along with uncertainly of how to treat, monitor. and ultimately deliver these pregnancies. Optimization of diagnostic and management protocols can improve maternal and fetal postnatal outcomes. EVIDENCE: Medline, PubMed, Embase, and the Cochrane Library were searched from inception to March 2023, using medical subject headings (MeSH) and keywords related to pregnancy, intrahepatic cholestasis of pregnancy, bile acids, pruritis, ursodeoxycholic acid, and stillbirth. This document presents an abstraction of the evidence rather than a methodological review. VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See Appendix A (Tables A1 for definitions and A2 for interpretations). INTENDED AUDIENCE: Obstetric care providers, including obstetricians, family physicians, nurses, midwives, maternal-fetal medicine specialists, and radiologists. SOCIAL MEDIA ABSTRACT: Intrahepatic cholestasis of pregnancy requires adequate diagnosis with non-fasting bile acid levels which guide optimal management and delivery timing. SUMMARY STATEMENTS: RECOMMENDATIONS.

Identification of linear B cell epitopes on the leukotoxin protein of Fusobacterium necrophorum.

OBJECTIVE: Fusobacterium necrophorum can casuse Lemierre's syndrome in humans and a range of illnesses, including foot rot and liver abscesses, in animals. The main virulence factor released by F. necrophorum is leukotoxin, which has been shown to have a strong correlation with the severity of the disease. Leukotoxin is commonly employed as the key antigen in the formulation of subunit vaccines. Therefore, identification of the B-cell epitope of F. necrophorum leukotoxin is necessary. METHODS: In this research, we utilized lymphocyte hybridoma technology to develop a monoclonal antibody (mAb), 3D7, targeting the F. necrophorum leukotoxin protein. Identification of B-cell epitopes recognized by 3D7 mAb through Western blot, ELISA and dot blot using leukotoxin-truncated recombinant proteins and peptides, and through SWISS-MODEL homology modeling and PyMOL visualization. RESULTS: The 3D7 mAb was identified as belonging to the IgG1 subclass with a κ-chain light chain. It demonstrated reactivity with the natural leukotoxin. The results showed that the 3D7 mAb recognizes a B-cell epitope of the F. necrophorum leukotoxin protein, I2168SSFGVGV2175 (EP-3D7). Sequence comparison analysis showed that EP-3D7 was highly conserved in F. necrophorum strains, but less conserved in other bacteria, indicating the specificity of EP-3D7. EP-3D7 is present on the surface of leukotoxin proteins in a ß-folded manner. CONCLUSIONS: In summary, these results establish EP-3D7 as a conserved antigenic epitope of F. necrophorum leukotoxin. It could be valuable in the development of vaccines and diagnostic reagents for F. necrophorum epitopes.

Design, synthesis and biological evaluation of cajanonic acid A analogues as potent PPAR γ antagonists.

Peroxisome proliferator-activated receptor γ (PPAR γ) antagonists are a key instrument of insulin sensitizers since they have the ability to sensitize insulin and can avoid adverse reactions caused by receptor agonist. In this paper, two series of 28 novel Cajanonic acid A (CAA) derivatives were designed and synthesized. The biological activity showed that a novel CAA derivative 9f was identified as a potential PPAR γ antagonist by medicinal chemistry efforts. The results in vitro displayed that compound 9f could improve the PPAR γ antagonist activity (96.2 % / 50.2 % decrease in PPAR γ transactivation at 10 µM / 1 µM, respectively). It also could improve the glucose consumption activity of insulin-resistant HepG2/3T3-L1 cell line (33.27 % / 72.61 % increase in glucose consumption). And in 3 T3-L1 adipocytes, it showed anti-adipogenesis activity (7.04 % increase in oil red staining). Further, in vivo study suggested that compound 9f could improve the oral glucose tolerance in db/db mice. Taken together, derivative 9f served as a promising candidate for anti-diabetic drug discovery and deserve further study.

[Physical growth and neurodevelopment of preterm infants at the corrected age of 18-24 months]. / æ—©äº§å„¿æ ¡æ­£18~24æœˆé¾„ä½“æ ¼ç”Ÿé•¿å’Œç¥žç»å‘è‚²æ°´å¹³ç ”ç©¶.

OBJECTIVES: To investigate the levels of physical growth and neurodevelopment in preterm infants at the corrected age of 18-24 months. METHODS: The physical growth data and neurodevelopment data of 484 preterm infants at corrected age of 18-24 months were prospectively collected by a post-discharge follow-up system for preterm infants. The infants were regularly followed up in Shenzhen Bao'an Maternal and Child Health Hospital Affiliated to Jinan University from April 2018 to December 2021. The neurodevelopment was evaluated by the Children Neuropsychological and Behavioral Scale-Revision 2016. A total of 219 full-term infants served as controls. The infants were divided into groups (extremely preterm, very preterm, moderate late preterm, and full-term) based on gestational age, and the groups were compared in the levels of physical growth and neurodevelopment. RESULTS: Except that the moderate preterm group had a higher length-for-age Z-score than the full-term group (P=0.038), there was no significant difference in physical growth indicators between the preterm groups and the full-term group (P>0.05). Each preterm group had a significantly lower total developmental quotient (DQ) than the full-term group (P<0.05). Except for the social behavior domain, the DQ of other domains in the extremely preterm and very preterm groups was significantly lower than that in the full-term group (P<0.05). The <32 weeks preterm group had a significantly higher incidence rate of global developmental delay than the full-term group (16.7% vs 6.4%, P=0.012), and the incidence rate of global developmental delay tended to increase with the reduction in gestational age (P=0.026). CONCLUSIONS: Preterm infants can catch up with full-term infants in terms of physical growth at the corrected age of 18-24 months, but with a lower neurodevelopmental level than full-term infants. Neurodevelopment monitoring and early intervention should be taken seriously for preterm infants with a gestational age of <32 weeks.

Assessment of growth pattern of preterm infants up to a corrected age of 24 months. / æ—©äº§å„¿æ ¡æ­£24æœˆé¾„å† ç”Ÿé•¿è½¨è¿¹ç ”ç©¶.

OBJECTIVES: To assess the growth of preterm infants up to a corrected age of 24 months, and to understand the growth trend and pattern of preterm infants. METHODS: A preterm infant follow-up database was established based on the Internet Plus follow-up system. A total of 3 188 preterm infants who were born from April 2018 to April 2021 were enrolled. Their length, weight, and head circumference were recorded at birth and at the corrected ages of 1, 3, 6, 12, 18, and 24 months. The preterm infants were grouped by perinatal factors. The growth curves of these infants were plotted and compared with the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) standard and World Health Organization (WHO) standard. RESULTS: The weight, length, and head circumference curves of each group of preterm infants grouped by various perinatal factors all rose rapidly within the corrected age of 6 months, but the growth rate slowed down after the corrected age of 6 months. Based on the actual age for the groups of preterm infants with different gestational ages (<28 weeks, 28-31+6 weeks, 32-33+6 weeks, and 34-36+6 weeks), the length curve gradually coincided with the WHO curve after the actual age of 9 months (P=0.082), while for the preterm infants with a gestational age of <32 weeks, the weight and head circumference curves were significantly lower than the WHO curves (P<0.001). Based on the corrected age, the physical growth curve of preterm infants with different gestational ages (<28 weeks, 28-31+6 weeks, 32-33+6 weeks, and 34-36+6 weeks) basically coincided with each other (P>0.05). For the infants with extremely low birth weight and the small-for-gestational-age infants, the length, weight, and head circumference curves were significantly lower than those of the INTERGROWTH-21st standard and the WHO standard (P<0.05). CONCLUSIONS: The physical growth rate of preterm infants is faster within the corrected age of 6 months, and the growth rate slows down after the corrected age of 6 months. Preterm infants with a smaller gestational age need longer time to catch up in weight and head circumference. More attention should be paid to the physical growth of extremely preterm infants, extremely low birth weight infants, and small-for-gestational-age infants.

Prognostic significance of immune landscape in tumour microenvironment of endometrial cancer.

Tumour microenvironment (TME) is crucial to tumorigenesis. This study aimed to uncover the differences in immune phenotypes of TME in endometrial cancer (EC) using Uterine Corpus Endometrial Carcinoma (UCEC) cohort and explore the prognostic significance. We employed GVSA enrichment analysis to cluster The Cancer Genome Atlas (TCGA) EC samples into immune signature cluster modelling, evaluated immune cell profiling in UCEC cohort (n = 538) and defined four immune subtypes of EC. Next, we analysed the correlation between immune subtypes and clinical data including patient prognosis. Furthermore, we analysed the expression of immunomodulators and DNA methylation modification. The profiles of immune infiltration in TCGA UCEC cohort showed significant difference among four immune subtypes of EC. Among each immune subtype, natural killer T cells (NKT), dendritic cells (DCs) and CD8+ T cells were significantly associated with EC patients survival. Each immune subtype exhibited specific molecular classification, immune cell characterization and immunomodulators expression. Moreover, the expression immunomodulators were significantly related to DNA methylation level. In conclusion, the identification of immune subtypes in EC tissues could reveal unique immune microenvironments in EC and predict the prognosis of EC patients.

Screening of BHK-21 cellular proteins that interact with outer membrane protein 43K OMP of Fusobacterium necrophorum.

Fusobacterium necrophorum is a Gram negative, spore-free, anaerobic bacterium that can cause pyogenic and necrotic infections in animals and humans. It is a major bovine pathogen and causes hepatic abscesses, foot rot, and necrotic laryngitis. The 43K OMP of F. necrophorum is an outer membrane protein with molecular weight of 43 kDa, exhibiting similarity to pore-forming proteins of other Fusobacterium species that plays an important role in bacterial infections. However, the role of 43K OMP in F. necrophorum adhesion remains unknown. In this study, we evaluated whether the 43K OMP of F. necrophorum mediates adhesion to BHK-21 cells and performed a preliminary screen of the proteins that interact with 43K OMP of F. necrophorum by immunoprecipitation-mass spectrometry. The results showed that the natural 43K OMP and recombinant 43K OMP could bind to BHK-21 cells, and preincubation of F. necrophorum with an antibody against the recombinant 43K OMP of F. necrophorum decreased binding to BHK-21 cells. Seventy differential interacting proteins were successfully screened by immunoprecipitation-mass spectrometry. Among these seventy differential interacting proteins, seven cell membrane proteins and four extracellular matrix proteins shown to be relevant to bacteria adhesion through subcellular localization and single-molecule function analysis. These data increase our understanding of the pathogenesis of F. necrophorum and provide a new theoretical basis for the design of antimicrobial drugs against F. necrophorum.

Loss of exosomal miR-148b from cancer-associated fibroblasts promotes endometrial cancer cell invasion and cancer metastasis.

Cancer-associated fibroblasts (CAFs) play crucial roles in tumor progression, given the dependence of cancer cells on stromal support. Therefore, understanding how CAFs communicate with endometrial cancer cell in tumor environment is important for endometrial cancer therapy. Exosomes, which contain proteins and noncoding RNA, are identified as an important mediator of cell-cell communication. However, the function of exosomes in endometrial cancer metastasis remains poorly understood. In the current study we found that CAF-derived exosomes significantly promoted endometrial cancer cell invasion comparing to those from normal fibroblasts (NFs). We identified a significant decrease of miR-148b in CAFs and CAFs-derived exosomes. By exogenously transfect microRNAs, we demonstrated that miR-148b could be transferred from CAFs to endometrial cancer cell through exosomes. In vitro and in vivo studies further revealed that miR-148b functioned as a tumor suppressor by directly binding to its downstream target gene, DNMT1 to suppress endometrial cancer metastasis. In endometrial cancer DNMT1 presented a potential role in enhancing cancer cell metastasis by inducing epithelial-mesenchymal transition (EMT). Therefore, downregulated miR-148b induced EMT of endometrial cancer cell as a result of relieving the suppression of DNMT1. Taken together, these results suggest that CAFs-mediated endometrial cancer progression is partially related to the loss of miR-148b in the exosomes of CAFs and promoting the transfer of stromal cell-derived miR-148b might be a potential treatment to prevent endometrial cancer progression.

Dengue Virus Impairs Mitochondrial Fusion by Cleaving Mitofusins.

Mitochondria are highly dynamic subcellular organelles participating in many signaling pathways such as antiviral innate immunity and cell death cascades. Here we found that mitochondrial fusion was impaired in dengue virus (DENV) infected cells. Two mitofusins (MFN1 and MFN2), which mediate mitochondrial fusion and participate in the proper function of mitochondria, were cleaved by DENV protease NS2B3. By knockdown and overexpression approaches, these two MFNs showed diverse functions in DENV infection. MFN1 was required for efficient antiviral retinoic acid-inducible gene I-like receptor signaling to suppress DENV replication, while MFN2 participated in maintaining mitochondrial membrane potential (MMP) to attenuate DENV-induced cell death. Cleaving MFN1 and MFN2 by DENV protease suppressed mitochondrial fusion and deteriorated DENV-induced cytopathic effects through subverting interferon production and facilitating MMP disruption. Thus, MFNs participate in host defense against DENV infection by promoting the antiviral response and cell survival, and DENV regulates mitochondrial morphology by cleaving MFNs to manipulate the outcome of infection.

Japanese encephalitis virus nonstructural protein NS5 interacts with mitochondrial trifunctional protein and impairs fatty acid ß-oxidation.

Infection with Japanese encephalitis virus (JEV) can induce the expression of pro-inflammatory cytokines and cause acute encephalitis in humans. ß-oxidation breaks down fatty acids for ATP production in mitochondria, and impaired ß-oxidation can induce pro-inflammatory cytokine expression. To address the role of fatty-acid ß-oxidation in JEV infection, we measured the oxygen consumption rate of mock- and JEV-infected cells cultured with or without long chain fatty acid (LCFA) palmitate. Cells with JEV infection showed impaired LCFA ß-oxidation and increased interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) expression. JEV nonstructural protein 5 (NS5) interacted with hydroxyacyl-CoA dehydrogenase α and ß subunits, two components of the mitochondrial trifunctional protein (MTP) involved in LCFA ß-oxidation, and NS5 proteins were detected in mitochondria and co-localized with MTP. LCFA ß-oxidation was impaired and higher cytokines were induced in cells overexpressing NS5 protein as compared with control cells. Deletion and mutation studies showed that the N-terminus of NS5 was involved in the MTP association, and a single point mutation of NS5 residue 19 from methionine to alanine (NS5-M19A) reduced its binding ability with MTP. The recombinant JEV with NS5-M19A mutation (JEV-NS5-M19A) was less able to block LCFA ß-oxidation and induced lower levels of IL-6 and TNF-α than wild-type JEV. Moreover, mice challenged with JEV-NS5-M19A showed less neurovirulence and neuroinvasiveness. We identified a novel function of JEV NS5 in viral pathogenesis by impairing LCFA ß-oxidation and inducing cytokine expression by association with MTP.

High Anti-Dengue Virus Activity of the OAS Gene Family Is Associated With Increased Severity of Dengue.

Dengue is a mosquito-borne viral disease that afflicts millions of individuals worldwide every year. Infection by any of the 4 dengue virus (DENV) serotypes can result in a spectrum of disease severity. We investigated the impact of variants of interferon-regulated innate immunity genes with a potent antiviral effect on the outcome of DENV infection. We compared the effect of OAS gene family variants on 2 DENV serotypes in cell culture. While both OAS1-p42 and p46 showed antiviral activity against DENV-2, only OAS1-p42 presented anti-DENV-1 activity. Conversely, whereas both OAS3_S381 and R381 variants were able to block DENV-1 infection, the anti-DENV-2 activity observed for OAS3_S381 was largely lost for the R381 variant. By means of an allelic association study of a cohort of 740 patients with dengue, we found a protective effect of OAS3_R381 against shock (odds ratio [OR], 0.37; P < .001). This effect was due to DENV-2 infections (OR, 0.13; P = .007) but was absent for DENV-1, in accordance with the serotype-dependent OAS3 activity found in the functional study. Severe dengue has long been associated with a cytokine storm of unclear origin. This work identifies an early innate immunity process that could lead to the immune overreaction observed in severe dengue and could be triggered by a specific host genotype-pathogen genotype interaction.

MCPIP1 ribonuclease exhibits broad-spectrum antiviral effects through viral RNA binding and degradation.

Monocyte chemoattractant protein 1-induced protein 1 (MCPIP1), belonging to the MCPIP family with highly conserved CCCH-type zinc finger and Nedd4-BP1, YacP Nuclease domains, has been implicated in negative regulation of the cellular inflammatory responses. In this report, we demonstrate for the first time that this RNA-binding nuclease also targets viral RNA and possesses potent antiviral activities. Overexpression of the human MCPIP1, but not MCPIP2, MCPIP3 or MCPIP4, inhibited Japanese encephalitis virus (JEV) and dengue virus (DEN) replication. The functional analysis of MCPIP1 revealed that the activities of RNase, RNA binding and oligomerization, but not deubiqutinase, are required for its antiviral potential. Furthermore, infection of other positive-sense RNA viruses, such as sindbis virus and encephalomyocarditis virus, and negative-sense RNA virus, such as influenza virus, as well as DNA virus, such as adenovirus, can also be blocked by MCPIP1. Moreover, the endogenous MCPIP1 gene expression was induced by JEV and DEN infection, and knockdown of MCPIP1 expression enhanced the replication of JEV and DEN in human cells. Thus, MCPIP1 can act as a host innate defense via RNase activity for targeting and degrading viral RNA.

Correlation of cord blood pH, base excess, and lactate concentration measured with a portable device for identifying fetal acidosis.

OBJECTIVE: To determine the effectiveness of portable lactate analyzers in identifying fetal acidosis by correlating arterial and venous lactate values from umbilical cord blood with lactate, pH, and base excess measurements from central laboratory analyzers. METHODS: We performed a prospective study using arterial and venous cord blood from 52 women with a singleton fetus delivered at term. We evaluated the correlation between the cord blood lactate concentration measured using two of the same portable devices (Lactate Plus, Nova Biomedical) with the result from a central laboratory analyzer. Analyses of the correlation between arterial lactate concentration measured on the portable device with arterial pH and base excess were then performed. RESULTS: We observed a median arterial pH of 7.24 (range 7.05 to 7.35) and a median arterial lactate concentration of 3.7 mmol/L (range 1.7 to 8.8 mmol/L). An excellent correlation was observed between lactate concentrations measured by the two portable devices (arterial R² = 0.98 and venous R² = 0.98), and between the portable device and the central laboratory analyzer (arterial R² = 0.94 and venous R² = 0.95). In our population, the optimal cut-offs to predict a pH < 7.20 or a base excess > -8.0 mmol/L were a lactate concentration of 4.9 mmol/L and 5.3 mmol/L, respectively, according to receiver operator characteristic analysis. With a lactate concentration > 4.9 mmol/L, the portable device had a sensitivity of 82% and a specificity of 90% to identify samples with an arterial pH < 7.20. CONCLUSION: Cord blood lactate concentration measured with a portable device is a good predictor of cord blood base excess and pH. Future studies should be designed to correlate scalp blood lactate measurements with clinical outcomes.

Objectif : Déterminer l'efficacité des analyseurs de lactate portatifs, pour ce qui est de l'identification de l'acidose fœtale, en mettant en corrélation les valeurs artérielle et veineuse du lactate constatées dans le sang de cordon ombilical et les mesures du lactate, du pH et de l'excès de bases révélées par les analyseurs du laboratoire central. Méthodes : Nous avons mené une étude prospective en utilisant le sang de cordon artériel et veineux prélevé chez 52 femmes qui ont connu une grossesse monofœtale s'étant soldée en un accouchement à terme. Nous avons évalué la corrélation entre la concentration en lactate du sang de cordon mesurée au moyen de deux exemplaires du même appareil portatif (Lactate Plus, Nova Biomedical) et le résultat obtenu au moyen d'un analyseur du laboratoire central. Nous avons par la suite procédé à des analyses de la corrélation entre la concentration artérielle en lactate mesurée au moyen de l'appareil portatif et les valeurs artérielles du pH et de l'excès de bases. Résultats : Nous avons constaté un pH artériel médian de 7,24 (plage : 7,05 - 7,35) et une concentration artérielle en lactate médiane de 3,7 mmol/l (plage : 1,7 - 8,8 mmol/l). Une excellente corrélation a été constatée entre les concentrations en lactate mesurées par les deux appareils portatifs (R2 artériel = 0,98 et R2 veineux = 0,98) et entre les concentrations mesurées par l'appareil portatif et par l'analyseur du laboratoire central (R2 artériel = 0,94 et R2 veineux = 0,95). Au sein de notre population, les seuils optimaux permettant de prédire un pH < 7,20 ou un excès de bases > −8,0 mmol/l ont été des concentrations en lactate de 4,9 mmol/l et de 5,3 mmol/l, respectivement, selon l'analyse de la fonction d'efficacité du récepteur. En présence d'une concentration en lactate > 4,9 mmol/l, l'appareil portatif comptait une sensibilité de 82 % et une spécificité de 90 % pour ce qui est de l'identification des prélèvements présentant un pH artériel < 7,20. Conclusion : La concentration en lactate du sang de cordon qui est mesurée au moyen d'un appareil portatif constitue un bon facteur prédictif pour ce qui est du pH et de l'excès de bases du sang de cordon. De futures études devraient être conçues de façon à pouvoir mettre en corrélation les concentrations en lactate dans le sang prélevé sur le cuir chevelu et les résultats cliniques.

CpG island hypermethylation-associated silencing of microRNAs promotes human endometrial cancer.

BACKGROUND: Endometrial cancer (EC) is the most common gynecologic malignancy, but the molecular events involved in the development and progression of EC remain unclear. This study aimed to explore epigenetic modification of genes and miRNAs involved in EC development. METHODS: Ishikawa and AN3CA cells were treated with 5'-Aza-2-deoxycytidine or histone deacetylase inhibitor. The expression of miRNAs and related genes were detected by PCR and Western blot. Promoter methylation was detected by bisulfite specific PCR sequencing. The proliferation, colony formation, cell cycle progression, migration and invasion of EC cells were evaluated by MTT, soft agar assay, flow cytometry, wound healing and invasion assay, respectively. RESULTS: Aberrant expression of miRNAs including miR-200b, miR-130a/b, miR-625 and miR-222 was associated with tumorigenesis and metastasis in endometrial cancer. Silencing of miR-130b induced E-cadherin expression, while ectopic expression of miR-130b and knockdown of DICER1 increased the expression of Vimentin, zeb2, N-cadherin, Twist and Snail in EC cells. Furthermore, 5'-Aza-2-deoxycytidine and Histone deacetylase (HDAC) inhibitor inhibited the proliferation, colony formation, migration and invasion of EC cells, accompanied by reduced MMP secretion. CONCLUSIONS: Our study provides the first description of epigenetic modification of epithelial mesenchymal transition associated genes and miRNAs in EC cells, which are extensively involved in the regulation of gene expression and subsequent accumulation of malignant features of EC cells.

Early amniotomy and early oxytocin for prevention of, or therapy for, delay in first stage spontaneous labour compared with routine care.

BACKGROUND: Caesarean section rates are over 20% in many developed countries. The main diagnosis contributing to the high rate in nulliparae is dystocia or prolonged labour. The present review assesses the effects of a policy of early amniotomy with early oxytocin administration for the prevention of, or the therapy for, delay in labour progress. OBJECTIVES: To estimate the effects of early augmentation with amniotomy and oxytocin for prevention of, or therapy for, delay in labour progress on the caesarean birth rate and on indicators of maternal and neonatal morbidity. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2013), MEDLINE (1966 to 4 July 2013), Embase (1980 to 4 July 2013), CINAHL (1982 to 4 July 2013), MIDIRS (1985 to 4 July 2013) and contacted authors for data from unpublished trials. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials that compared oxytocin and amniotomy with expectant management. DATA COLLECTION AND ANALYSIS: Three review authors extracted data independently. We stratified the analyses into 'Prevention Trials' and 'Therapy Trials' according to the status of the woman at the time of randomization. Participants in the 'Prevention Trials' were unselected women, without slow progress in labour, who were randomized to a policy of early augmentation or to routine care. In 'Treatment Trials' women were eligible if they had an established delay in labour progress. MAIN RESULTS: For the 2013 update, we identified and excluded one new clinical trial. This updated review includes 14 trials, randomizing a total of 8033 women. The unstratified analysis found early intervention with amniotomy and oxytocin to be associated with a modest reduction in the risk of caesarean section; however, the confidence interval (CI) included the null effect (risk ratio (RR) 0.89; 95% CI 0.79 to 1.01; 14 trials; 8033 women). In prevention trials, early augmentation was associated with a modest reduction in the number of caesarean births (RR 0.87; 95% CI 0.77 to 0.99; 11 trials; 7753). A policy of early amniotomy and early oxytocin was associated with a shortened duration of labour (average mean difference (MD) - 1.28 hours; 95% CI -1.97 to -0.59; eight trials; 4816 women). Sensitivity analyses excluding four trials with a full package of active management did not substantially affect the point estimate for risk of caesarean section (RR 0.87; 95% CI 0.73 to 1.05; 10 trials; 5165 women). We found no other significant effects for the other indicators of maternal or neonatal morbidity. AUTHORS' CONCLUSIONS: In prevention trials, early intervention with amniotomy and oxytocin appears to be associated with a modest reduction in the rate of caesarean section over standard care.

Treatment of women with mild gestational diabetes mellitus decreases the risk of adverse perinatal outcomes.

AIMS: Glycemic thresholds used to diagnose gestational diabetes mellitus (GDM) are a continued subject of debate. Lower glycemic thresholds identify women with milder GDM for whom treatment benefit is unclear. We compared adverse maternal and neonatal outcomes in treated and untreated women with mild hyperglycemia. METHODS: We reviewed 11 553 patient charts from two tertiary care centers and included singleton pregnancies >32-week gestation. GDM was diagnosed using the one- or two-step 75 g oral glucose tolerance test (OGTT) depending on the center. All OGTT results were reviewed. Women with glycemic values falling between the thresholds of the two tests, referred to as intermediate hyperglycemic (IH), defined as FPG 5.1-5.2 mmol/L, 1 h PG 10.0-10.5 mmol/L, or 2 h PG 8.5-8.9 mmol/L at 75 g OGTT, were untreated at center A and treated at center B. RESULTS: There were 630 women with IH, 334 were untreated (center A) and 296 who were treated (center B). After adjusting for covariates, untreated IH women had significantly higher rates of gestational hypertension (aOR 6.02, P = 0.002), large for gestational age (LGA) (aOR 3.73, P < 0.001) and birthweights > 4000 g (aOR 3.35, P = 0.001). Our results indicate that treating 11 women with IH would prevent one LGA birth and treating 13 would prevent 1 birthweight > 4000 g. CONCLUSION: The diagnosis of GDM using the two-step OGTT fails to identify subgroups of women with mild hyperglycemia that would benefit from treatment to lower the risk for adverse maternal and neonatal outcomes. Treatment of women with mild hyperglycemia decreased the risk of LGA and birthweight >4000 g by 3-fold.

Lowering the threshold of alanine aminotransferase for enhanced identification of significant hepatic injury in chronic hepatitis B patients.

BACKGROUND: The clinical and histological features of chronic hepatitis B (CHB) patients who fall into the "grey zone (GZ)" and do not fit into conventional natural phases are unclear. AIM: To explore the impact of varying the threshold of alanine aminotransferase (ALT) levels in identifying significant liver injury among GZ patients. METHODS: This retrospective analysis involved a cohort of 1617 adult patients diagnosed with CHB who underwent liver biopsy. The clinical phases of CHB patients were determined based on the European Association for the Study of the Liver 2017 Clinical Practice Guidelines. GZ CHB patients were classified into four groups: GZ-A (HBeAg positive, normal ALT levels, and HBV DNA ≤ 107 IU/mL), GZ-B (HBeAg positive, elevated ALT levels, and HBV DNA < 104 or > 107 IU/mL), GZ-C (HBeAg negative, normal ALT levels, and HBV DNA ≥ 2000 IU/mL), and GZ-D (HBeAg negative, elevated ALT levels, and HBV DNA ≤ 2000 IU/mL). Significant hepatic injury (SHI) was defined as the presence of notable liver inflammation (≥ G2) and/or significant fibrosis (≥ S2). RESULTS: The results showed that 50.22% of patients were classified as GZ, and 63.7% of GZ patients developed SHI. The study also found that lowering the ALT treatment thresholds to the American Association for the Study of Liver Diseases 2018 treatment criteria (35 U/L for men and 25 U/L for women) can more accurately identify patients with significant liver damage in the GZ phases. In total, the proportion of patients with ALT ≤ 40 U/L who required antiviral therapy was 64.86% [(221 + 294)/794]. When we lowered the ALT treatment threshold to the new criteria (30 U/L for men and 19 U/L for women), the same outcome was revealed, and the proportion of patients with ALT ≤ 40 U/L who required antiviral therapy was 75.44% [(401 + 198)/794]. Additionally, the proportion of SHI was 49.1% in patients under 30 years old and increased to 55.3% in patients over 30 years old (P = 0.136). CONCLUSION: These findings suggest the importance of redefining the natural phases of CHB and using new ALT treatment thresholds for better diagnosis and management of CHB patients in the GZ phases.

Early amniotomy and early oxytocin for prevention of, or therapy for, delay in first stage spontaneous labour compared with routine care.

BACKGROUND: Caesarean section rates are over 20% in many developed countries. The main diagnosis contributing to the high rate in nulliparae is dystocia or prolonged labour. The present review assesses the effects of a policy of early amniotomy with early oxytocin administration for the prevention of, or the therapy for, delay in labour progress. OBJECTIVES: To estimate the effects of early augmentation with amniotomy and oxytocin for prevention of, or therapy for, delay in labour progress on the caesarean birth rate and on indicators of maternal and neonatal morbidity. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (15 February 2012), MEDLINE (1966 to 15 February 2012), EMBASE (1980 to 15 February 2012), CINAHL (1982 to 15 February 2012), MIDIRS (1985 to February 2012) and contacted authors for data from unpublished trials. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials that compared oxytocin and amniotomy with expectant management. DATA COLLECTION AND ANALYSIS: Three review authors extracted data independently. We stratified the analyses into 'Prevention Trials' and 'Therapy Trials' according to the status of the woman at the time of randomization. Participants in the 'Prevention Trials' were unselected women, without slow progress in labour, who were randomized to a policy of early augmentation or to routine care. In 'Treatment Trials' women were eligible if they had an established delay in labour progress. MAIN RESULTS: For this update, we have included a further two new clinical trials. This updated review includes 14 trials, randomizing a total of 8033 women. The unstratified analysis found early intervention with amniotomy and oxytocin to be associated with a modest reduction in the risk of caesarean section; however, the confidence interval (CI) included the null effect (risk ratio (RR) 0.89; 95% CI 0.79 to 1.01; 14 trials; 8033 women). In prevention trials, early augmentation was associated with a modest reduction in the number of caesarean births (RR 0.87; 95% CI 0.77 to 0.99; 11 trials; 7753). A policy of early amniotomy and early oxytocin was associated with a shortened duration of labour (average mean difference (MD) - 1.28 hours; 95% CI -1.97 to -0.59; eight trials; 4816 women). Sensitivity analyses excluding four trials with a full package of active management did not substantially affect the point estimate for risk of caesarean section (RR 0.87; 95% CI 0.73 to 1.05; 10 trials; 5165 women). We found no other significant effects for the other indicators of maternal or neonatal morbidity. AUTHORS' CONCLUSIONS: In prevention trials, early intervention with amniotomy and oxytocin appears to be associated with a modest reduction in the rate of caesarean section over standard care.