Background
The use of antiviral agents, specifically tenofovir disoproxil fumarate (TDF), in pregnant women to prevent mother‐to‐child HBV transmission is a key step towards hepatitis elimination. ...However, data on using tenofovir alafenamide (TAF) is insufficient. The frequent occurrence of postpartum ALT flares may impact the clinical implementation.
Methods
The maternal and infant outcomes were compared in multi‐centre trials of high viral load HBsAg/HBeAg+ pregnant women receiving TAF or TDF from the third trimester until 2 weeks postpartum with intensive follow‐ups. To explore the dynamic pre‐ and postpartum changes in ALT levels, we used a group‐based trajectory model for analysing data of 332 women from three prospective studies.
Results
After treatment, the maternal HBV DNA levels significantly decreased from baseline to delivery: 7.87 ± 0.59 to 3.99 ± 1.07 Log10 IU/mL TAF (n = 78) and 8.30 ± 0.36 to 4.47 ± 0.86 Log10 IU/mL (TDF, n = 53), with viral load reductions of 3.87 versus 3.83 Log10 IU/mL. The HBsAg‐positive rates among 12‐month‐old infants were 1.28% (1/78) versus 1.82% (1/55) respectively (p = 1.00). Of the TAF or TDF‐treated mothers, 25.64% versus 16.98% experienced ALT > 2X ULN, and 11.54% versus 1.89% received extended antiviral treatment. Our model revealed four distinct ALT patterns: stable ALT (87.2%), moderate (8.0%) or marked (2.4%) postpartum flares, or prepartum elevations (2.4%).
Conclusions
TAF effectively reduces mother‐to‐child HBV transmission, but prophylaxis failure still occurred in few cases. Postpartum ALT flares are common in women receiving TAF or TDF during pregnancy. Approximately 12.8% of mothers may require extended postpartum antiviral treatment.
Clinical trial number: NCT03695029 (ClinicalTrials.gov).
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown impressive effects in reducing major vascular events in several randomized controlled trials (RCTs). The purpose of this study ...was to perform a meta-analysis to evaluate the effect of SGLT2 inhibitors on the risk of stroke and its subtypes. All data from prospective RCTs up to 20 October 2020 involving SGLT2 inhibitors that reported stroke events as the primary endpoint or safety in subjects with type 2 diabetes were subjected to meta-analysis. Five eligible RCTs (EMPA-REG, CANVAS, DECLARE-TIMI 58, CREDENCE and VERTIS CV) involving 46,969 participants were included. Pooled analysis of the RCTs showed no significant effect of SGLT2 inhibitors on total stroke risk ratio (RR) = 0.95; 95% confidence interval (CI) 0.79–1.13, P = 0.585. Subgroup analysis indicated that SGLT2 inhibitors had no significant effect against fatal stroke, non-fatal stroke, ischemic stroke or transient ischemic attack. When only hemorrhagic stroke was included, SGLT2 inhibitors were associated with a significant 50% reduction compared with placebo (RR = 0.49, 95% CI 0.30–0.82, P = 0.007). This meta-analysis shows that SGLT2 inhibitors have a neutral effect on the risk of stroke and its subtypes but a potential protective effect against hemorrhagic stroke.
Abstract
Context
Dipeptidyl peptidase IV (DPP4) is overexpressed in thyroid cancer and certain malignancies. Furthermore, DPP4 has been identified as a discriminatory marker for thyroid cancer. ...However, it remains unclear whether DPP4 expression plays a prognostic role.
Objective
The aim of this study was to investigate the expression and function of DPP4 in thyroid cancer and the mechanisms involved.
Design
We determined the expression of DPP4 by immunohistochemistry in tissue microarrays of thyroid tumors. In vitro functional studies were performed after genetic and pharmacological inhibition of DPP4. Gene expression and pathway analyses were used to identify downstream targets. The therapeutic potential of DPP4 inhibition was evaluated in a mouse xenograft model.
Results
High DPP4 expression was associated with extrathyroidal extension (P < 0.001), BRAF mutation (P < 0.001), and advanced tumor stage (P = 0.007) in papillary thyroid cancer. Patients in the high–DPP4 expression group were less likely to be classified as having no evidence of disease at final follow-up (P = 0.042). DPP4 silencing or treatment with DPP4 inhibitors significantly suppressed colony formation, cell migration, and invasion. Analysis of differentially expressed genes after DPP4 knockdown suggested that the transforming growth factor-β signaling pathway is involved. In vivo experiments revealed that sitagliptin treatment reduced tumor growth and xenograft transforming growth factor-β receptor I expression.
Conclusions
Increased DPP4 expression is associated with cellular invasion and more aggressive disease in papillary thyroid cancer. Targeting DPP4 may be a therapeutic strategy for DPP4-expressing thyroid cancer.
We studied DPP4 expression in thyroid tumors and found that DPP4 upregulation is associated with more advanced papillary thyroid cancer and may be a prognostic marker and therapeutic target.
Sleep disturbances are common in women, especially during pregnancy. Previous studies have confirmed the importance of sleep disturbances as a risk factor of adverse pregnancy outcomes and the need ...for screening and treatment of inadequate sleep. These reports, however, did not examine health-related quality of life which may be affected by sleep long before adverse clinical consequences are detectable in women during pregnancy.
To examine the cross-sectional and longitudinal association between sleep and health-related quality of life in pregnant women.
A prospective observational study.
A university-affiliated hospital in Taiwan and participants’ homes.
A total of 164 pregnant women completed questionnaires and wore a wrist actigraphy monitor for 7 days each trimester.
Objective sleep was measured by actigraphy, subjective sleep was measured by the Pittsburgh Sleep Quality Index, and health-related quality of life was measured using the SF-12v2 questionnaire across three trimesters. Multiple linear regression analyses were performed to evaluate the cross-sectional and longitudinal associations between sleep and health-related quality of life.
Sixty-four (39.0%) women consistently had an average sleep efficiency<85% by actigraphy and 40 (24.4%) had a Pittsburgh Sleep Quality Index global score>5 in all three trimesters. Cross-sectionally, more actigraphic daytime sleep (p=0.04) and better subjective sleep quality (p<0.01) were associated with better physical health-related quality of life in first-trimester pregnant women. Better actigraphic sleep efficiency (p=0.04) and better subjective sleep quality (p<0.01) were associated with better mental health-related quality of life in second-trimester pregnant women. Longer actigraphic total nighttime sleep (p<0.01) and better subjective sleep quality (p<0.01) were associated with better mental health-related quality of life in third-trimester pregnant women. Longitudinally, first-trimester actigraphic total nighttime sleep (p<0.05) and subjective sleep quality (p<0.01) predicted mental health-related quality of life in the second and third trimester.
Sleep disturbances are a highly prevalent and persistent problem in pregnant women. Adequate sleep is essential for women at all pregnancy stages and improving nocturnal sleep quantity and quality in early gestation is of utmost importance for an optimal health-related quality of life later in pregnancy.
Background
Pregnant women have an elevated risk of illness and hospitalisation from influenza. Pregnant women are recommended to be prioritised for influenza vaccination during any stage of ...pregnancy. The risk of seasonal influenza varies substantially throughout the year in temperate climates; however, there is limited knowledge of how vaccination timing during pregnancy impacts the benefits received by the mother and foetus.
Objectives
To compare antenatal vaccination timing with regard to influenza vaccine immunogenicity during pregnancy and transplacental transfer to their newborns.
Methods
Studies were eligible for inclusion if immunogenicity to influenza vaccine was evaluated in women stratified by trimester of pregnancy. Haemagglutination inhibition (HI) titres, stratified by trimester of vaccination, had to be measured at either pre‐vaccination and within one month post‐vaccination, post‐vaccination and at delivery in the mother, or in cord/newborn blood. Authors searched PubMed, Scopus, Web of Science and EMBASE databases from inception until June 2016 and authors of identified studies were contacted for additional data. Extracted data were tabulated and summarised via random‐effect meta‐analyses and qualitative methods.
Results
Sixteen studies met the inclusion criteria. Meta‐analyses found that compared with women vaccinated in an earlier trimester, those vaccinated in a later trimester had a greater fold increase in HI titres (1.33‐ to 1.96‐fold) and higher HI titres in cord/newborn blood (1.21‐ to 1.64‐fold).
Conclusions
This review provides comparative analysis of the effect of vaccination timing on maternal immunogenicity and protection of the infant that is informative and relevant to current vaccine scheduling for pregnant women.
The addition of maternal age to fasting plasma glucose (FPG) at 24-28 gestational weeks improves the performance of GDM screening as maternal age increases. However, this method delays the diagnosis ...of GDM. Since FPG at the first prenatal visit (FPV) is a screening option for pre-existing diabetes, we evaluated the performance of age plus FPG at the FPV to reduce the need for the OGTT. Pregnant women were recruited consecutively in 2013-2018 (the training cohort) and 2019 (the validation cohort). We excluded women with twin pregnancies, unavailable FPG at the FPV or OGTT data, pre-pregnancy diabetes, or a history of GDM. All participants underwent FPG and haemoglobin A1c (HbA1c) at the FPV and received 75-g OGTT at 24-28 gestational weeks if FPG at the FPV was <92 mg/dL. GDM was diagnosed by the IADPSG criteria. Two algorithms were developed with the cutoffs determined when the percentage requiring OGTT (OGTT%) was the lowest and the sensitivity was greater than or equal to90%. The incidence of GDM increased with age. The "FPG at the FPV" algorithm reduced OGTT% to 68.8% with the FPG cutoff at 79 mg/dl. The "age plus FPG at the FPV" algorithm, with the cutoff of 114, further reduced OGTT% to 58.3%, with the sensitivity of 90.7% (9.3% GDM missed) and the specificity of 100%. These findings were replicated in the validation cohort. Screening GDM by maternal age plus FPG at the FPV can reduce OGTT%, especially in populations with a significant proportion of pregnant women with advanced ages.
Objectives
The purpose of the study is to identify the recessive diseases currently affecting real‐world pediatric patients in Taiwan, and whether current extended carrier screening panels have the ...coverage and detective power to identify the pathogenic variants in the carrier parents.
Methods
A total of 132 trio‐samples were collected from May 2017 to March 2022. The participants were parents of pediatric intensive care unit patients who were critically ill or infants with abnormal newborn screening results. A retrospective carrier screening scheme was applied to analyze only the carrier status of pathogenic or likely pathogenic recessive variants resulting in diseases in their children. The recessive disorders diagnosed in our cohort were compared with the gene content in commercial panels.
Results
Mutations in COQ4, PEX1, OTC, and IKBKG were the most frequently identified. In the parents of 44 children with confirmed diagnoses of recessive diseases, 47 (53.40%) screened positive for being the carriers of the same recessive disorders diagnosed in their children. The commercial panels covered 35.13% to 54.05% of the disorders diagnosed in this cohort.
Conclusion
Clinicians and genetic counselors should be aware of the limitations of current extended carrier screening and interpret negative screening results with caution. Future panels should also consider genes with ethnically unique mutations such as pathogenic variants of the COQ4 gene in the East Asian population.
Synopsis
The design of carrier screening panels still needs to take into consideration ethnic uniqueness or founder mutations in the targeted population.
Male predominance of hepatocellular carcinoma (HCC) occurs particularly among young children aged 6‐9 years, indicative of a possible role of the Y chromosome–encoded oncogene in addition to an ...androgenic effect. The discovery of oncogenic activation of RBMY (RNA‐binding motif on Y chromosome), which is absent in normal hepatocytes but present in male HCC tissues, sheds light on this issue. Herein, we report on a critical hepatocarcinogenic role of RBMY and its ontogenic origin. During liver development, the Ser/Thr phosphorylated RBMY is expressed in the cytoplasm of human and rodent fetal livers. It is then silenced in mature hepatocytes and restricted to scarce expression in the bile ductular cells. Upon hepatocarcinogenesis, a noteworthy increase of cytoplasmic and nuclear RBMY is observed in HCC tissues; however, only the former is expressed dominantly in hepatic cancer stem cells and correlates significantly to a poor prognosis and decreased survival rate in HCC patients. Cytoplasmic expression of RBMY, which is mediated by binding to nuclear exporter chromosome region maintenance 1 and further enriched upon Wnt‐3a stimulation, confers upon tumor cells the traits of cancer stem cell by augmenting self‐renewal, chemoresistance, cell‐cycle progression, proliferation, and xenograft tumor growth. This is achieved mechanistically through increasing Ser9 phosphorylation‐inactivation of glycogen synthase kinase 3β by RBMY, thereby impeding the glycogen synthase kinase 3β–dependent degradation of β‐catenin and eventually inducing the nuclear entry of β‐catenin for the transcription of downstream oncogenes. Conclusion: RBMY is a novel oncofetal protein that plays a key role in attenuating glycogen synthase kinase 3β activity, leading to aberrant activation of Wnt/β‐catenin signaling, which facilitates malignant hepatic stemness; because of its absence from normal human tissues except the testis, RBMY represents a feasible therapeutic target for the selective eradication of HCC cells in male patients. (Hepatology 2015;62:1480–1496)
•Compare the whole-genome DNA methylation variation in GDM population.•Identified the top 200 loci with significant difference in methylation status.•GDM has epigenetic effects on both mother and ...their offspring.
Gestational diabetes mellitus (GDM) has always been a concerning issue for pregnant women. In recent studies, GDM was found to be related to epigenetic modifications, which would alter gene expressions, thus affecting the patients’ and their offspring’s health, leading to a higher probability of developing metabolic syndromes and diabetes later in life.
In this study, we collected both maternal and cord blood samples from 16 pregnant women and their newborns, including eight exposed to GDM. GDM was diagnosed via a 75g oral glucose tolerance test (OGTT) at 24–28weeks of pregnancy. DNA methylation was measured at 841,573 CpG sites via the Infinium HumanMethylationEPIC BeadChip. An Ingenuity Pathway Analysis was conducted afterwards to identify genes and pathways epigenetically affected by GDM.
We identified the top 200 loci and their corresponding genes in the maternal blood group (n=151) and cord blood group (n=167), both of which were methylated differently in the GDM and unexposed group. Metabolic disease-related pathways and molecules, such as interleukin-6 and interleukin-10 were identified in both groups. These results suggested that GDM has epigenetic effects on both mother and their offspring, which might result in future metabolic syndromes or diabetes.
The high-throughput platform enabled us to analyze methylation sites throughout the genome and identify the most promising genes and pathways associated with GDM.
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•SAXS study quantitatively evaluated the effect of Ag-addition on the concurrently-existing precipitation kinetics in the aged Al-Cu-Mg(-Ag) alloys.•Nanoscale disk-like Mg-Ag ...co-clusters (2.3 nm in diameter and 6.1 Å in thickness) were quantitatively examined by SAXS.•An increasing aspect ratio of Ω-precipitates with a nearly constant thickness (<2 nm) was quantitatively revealed by SAXS.•Stable structure behaviors in total surfaces/sizes of S-precipitates represented the effect of Ag-addition providing the resistance to the coalescence/coarsening mechanism.
Two Al-Cu-Mg(-Ag) aluminium alloys, having the same base composition of Al-5.11Cu-0.96 Mg-0.58Mn-0.12Zr (wt.%) but different Ag contents, 0 and 0.7 Ag (wt.%), and accordingly denoted 0A and 7A samples, were aged at 185 °C. In early-ageing, the formation of disk-like Mg-Cu and Mg-Ag nano(co–)clusters can be quantitatively examined by Small angle X-ray scattering (SAXS), respectively. In the prolonged ageing of the 0A samples, the thickening in the disk-like θ-precipitates leads to a lower aspect ratio. For S-precipitates, the change in the total surface area and the single-particle surface area indicates that the coalescence mechanism is prevalent from peak-ageing to over-ageing, and then after over-ageing, the precipitate coarsening dominates. The coarsening in S and θ precipitates presumably leads to a lower mechanical strength. Alternatively, in the aged 7A sample, the SAXS technique in conjunction with transmission electron microscopy (TEM) quantitatively reveals Ω-precipitates possessing a nearly constant thickness but an increase in diameter with ageing time. Additionally, the stable behaviors of the total surface and size of S-precipitates illuminate that the coalescence/coarsening mechanisms are significantly slowed down. The concurrently-existing precipitation kinetics of Ω and S have provided an in-depth understanding of the higher strength of the aged 7A sample.
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