Tenofovir alafenamide or tenofovir disoproxil fumarate in pregnancy to prevent HBV transmission: Maternal ALT trajectory and infant outcomes.

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).

Psychiatric disorders in term-born children with marginally low birth weight: a population-based study.

BACKGROUND: Marginally low birth weight (MLBW) is defined as a birth weight of 2000 ~ 2499 g. Inconsistent findings have been reported on whether children with low birth weight had higher rates of neurological, attention, or cognitive symptoms. No studies have explored the occurrence of clinically diagnosed psychiatric disorders in term- born MLBW infants. We aimed to investigate the risk of subsequent psychiatric disorders in term-born children with MLBW. METHODS: This is a nationwide retrospective cohort study, by analysing the data from Taiwan's National Health Insurance Research Database from 2008 to 2018. The study population includes propensity-score-matched term-born infants with MLBW and those without MLBW (birth weight ≥ 2500 g). Cox proportional hazard analysis was used after adjustment for potential demographic and perinatal comorbidity confounders. Incidence rates and hazard ratios (HR) of 11 psychiatric clinical diagnoses were evaluated. RESULTS: A total of 53,276 term-born MLBW infants and 1,323,930 term-born infants without MLBW were included in the study. After propensity score matching for demographic variables and perinatal comorbidities, we determined that the term-born MLBW infants (n = 50,060) were more likely to have attention deficit and hyperactivity disorder (HR = 1.26, 95% confidence interval (CI) [1.20, 1.33]), autism spectrum disorder (HR = 1.26, 95% CI [1.14, 1.40]), conduct disorder (HR = 1.25, 95% CI [1.03, 1.51]), emotional disturbance (HR: = 1.13, 95% CI [1.02, 1.26]), or specific developmental delays (HR = 1.38, 95% CI [1.33, 1.43]) than term-born infants without MLBW (n = 50,060). CONCLUSION: MLBW was significantly associated with the risk of subsequent psychiatric disorder development among term-born infants. The study findings demonstrate that further attention to mental health and neurodevelopment issues may be necessary in term-born children with MLBW. However, possibilities of misclassification in exposures or outcomes, and risks of residual and unmeasured confounding should be concerned when interpreting our data.

Clinical Application of a Graphene Oxide-Based Surface Plasmon Resonance Biosensor to Measure First-Trimester Serum Pregnancy-Associated Plasma Protein-A/A2 Ratio to Predict Preeclampsia.

Background: Preeclampsia, a major cause of adverse pregnancy outcomes, involves metalloproteinases pregnancy-associated plasma protein (PAPP)-A and PAPP-A2 from placental trophoblasts. The graphene oxide (GO)-based surface plasmon resonance (SPR) biosensor has higher sensitivity, affinity, and selective ability than the traditional SPR biosensor. The aim of this study was to explore the feasibility of measuring first-trimester serum PAPP-A/PAPP-A2 ratio as a novel predictor of preeclampsia using the GO-SPR biosensor. Methods: This prospective case-control study of pregnant women was conducted at MacKay Memorial Hospital, Taipei, Taiwan between January 2018 and June 2020. The SPR angle shifts of first-trimester serum PAPP-A, PAPP-A2, and PAPP-A/PAPP-A2 ratio measured using the GO-SPR biosensor were compared between preeclampsia and control groups. Results: Serum samples from 185 pregnant women were collected, of whom 30 had preeclampsia (5 early-onset; 25 late-onset). The response time between the antibody-antigen association and dissociation only took about 200 seconds. The SPR angle shift of PAPP-A in the preeclampsia group was significantly smaller than that in the control group (median (interquartile range): 5.33 (4.55) versus 6.89 (4.10) millidegrees (mDeg), P = 0.008). Conversely, the SPR angle shift of PAPP-A2 in the preeclampsia group was significantly larger than that in the control group (5.70 (3.81) versus 3.63 (2.38) mDeg, P < 0.001). Receiver operating characteristic (ROC) curve analysis revealed a cut-off PAPP-A/PAPP-A2 ratio to predict all preeclampsia of ≤ 0.76, with an area under the ROC curve (AUC) of 0.79 (95% CI 0.73-0.85, P < 0.001). Sub-group analysis revealed a cut-off PAPP-A/PAPP-A2 ratio to predict early-onset preeclampsia of ≤ 0.53 (AUC 0.99, 95% CI 0.96-1.00, P < 0.001), and ≤ 0.73 to predict late-onset preeclampsia (AUC 0.75, 95% CI 0.68-0.81, P < 0.001). Conclusion: Measuring first-trimester serum PAPP-A/PAPP-A2 ratio using the GO-SPR biosensor could be a valuable method for early prediction of preeclampsia.

Interferon-stimulated gene 15 polymorphisms are associated with spontaneous preterm birth in Taiwanese women.

PROBLEM: Immune and inflammatory responses are known to be major causes of preterm birth (PTB). The maternal genetic background plays an important role in the development of PTB. Interferon-stimulated gene 15 (ISG15) is an interferon-induced protein which can modulate immune cell activation and function. We aim to study if polymorphisms in the ISG15 gene are associated with spontaneous PTB (sPTB) risk in Taiwanese women. METHOD OF STUDY: ISG15 rs4615788 C/G, rs1921 G/A, and rs8997 A/G polymorphisms were genotyped in a hospital-based study of 112 women with sPTB and 1120 term controls. The plasma concentrations of ISG15 were determined by enzyme-linked immunosorbent assay. RESULTS: We found the ISG15 rs1921 G-rs8997 A haplotype was associated with decreased risk for PTB (χ2  = 6.26, p = .01, pc  = .04). The A/G genotype of ISG15 rs8997 polymorphism might have the potential to confer reduced risk of PTB women (χ2  = 4.09, p = .04, pc  = .08). Spontaneous PTB women displayed higher plasma ISG15 levels compared to term controls (p < .001). The plasma ISG15 levels among pregnant women with rs8997 A/G genotype were found significantly lower compared to G/G genotype (p = .03). CONCLUSIONS: Women with the ISG15 rs1921 G-rs8997 A haplotype may associate with spontaneous PTB. These findings provide new insights into the etiology of preterm birth.

Changes in cervical elastography, cervical length and endocervical canal width after cerclage for cervical insufficiency: an observational ultrasound study.

BACKGROUND: We previously demonstrated that pregnant women with a history of cervical insufficiency had a softer anterior cervical lip, shorter cervical length and wider endocervical canal in the first trimester. The aim of this study was to investigate changes in cervical elastography, cervical length, and endocervical canal width in the second trimester after cerclage, and further discuss whether these ultrasound parameters are predictive of preterm delivery. METHODS: This was a secondary analysis of cervical changes in singleton pregnancies after cerclage from January 2016 to June 2018. Cervical elastography, cervical length, and endocervical canal width were measured during the second trimester in the cervical insufficiency group and control group without cervical insufficiency. Strain elastography under transvaginal ultrasound was used to assess cervical stiffness and presented as percentage (strain rate). RESULTS: Among the 339 pregnant women enrolled, 24 had a history of cervical insufficiency and underwent cerclage. Both anterior and posterior cervical lips were significantly softer in the cervical insufficiency group even though they received cerclage (anterior strain rate: 0.18 ± 0.06% vs. 0.13 ± 0.04%; P = 0.001; posterior strain rate: 0.11 ± 0.03% vs. 0.09 ± 0.04%; P = 0.017). Cervical length was also shorter in the cervical insufficiency group (36.3 ± 3.6 mm vs. 38.3 ± 4.6 mm; P = 0.047). However, there was no significant difference in endocervical canal width between the two groups (5.4 ± 0.7 mm vs. 5.6 ± 0.7 mm; P = 0.159). Multivariate logistic regression analysis also revealed significant differences in anterior cervical lip strain rate (adjusted odds ratio [OR], 7.32, 95% confidence interval [CI], 1.70-31.41; P = 0.007), posterior cervical lip strain rate (adjusted OR, 5.22, 95% CI, 1.42-19.18; P = 0.013), and cervical length (adjusted OR, 3.17, 95% CI,1.08-9.29; P = 0.035). Among the four ultrasound parameters, softer anterior cervical lip (P = 0.024) and shorter cervical length (P < 0.001) were significantly related to preterm delivery. CONCLUSIONS: Cervical cerclage can prevent widening of the endocervical canal, but not improve cervical elasticity or cervical length. Measuring anterior cervical elastography and cervical length may be valuable to predict preterm delivery.

Prenatal lipopolysaccharide exposure induces anxiety-like behaviour in male mouse offspring and aberrant glial differentiation of embryonic neural stem cells.

BACKGROUND: Prenatal infection has been implicated in the development of neuropsychiatric disorders in children. We hypothesised that exposure to lipopolysaccharide during prenatal development could induce anxiety-like behaviour and sensorineural hearing loss in offspring, as well as disrupt neural differentiation during embryonic neural development. METHODS: We simulated prenatal infection in FVB mice and mouse embryonic stem cell (ESC) lines, specifically 46C and E14Tg2a, through lipopolysaccharide treatment. Gene expression profiling analyses and behavioural tests were utilized to study the effects of lipopolysaccharide on the offspring and alterations in toll-like receptor (TLR) 2-positive and TLR4-positive cells during neural differentiation in the ESCs. RESULTS: Exposure to lipopolysaccharide (25 µg/kg) on gestation day 9 resulted in anxiety-like behaviour specifically in male offspring, while no effects were detected in female offspring. We also found significant increases in the expression of GFAP and CNPase, as well as higher numbers of GFAP + astrocytes and O4+ oligodendrocytes in the prefrontal cortex of male offspring. Furthermore, increased scores for genes related to oligodendrocyte and lipid metabolism, particularly ApoE, were observed in the prefrontal cortex regions. Upon exposure to lipopolysaccharide during the ESC-to-neural stem cell (NSC) transition, Tuj1, Map2, Gfap, O4, and Oligo2 mRNA levels increased in the differentiated neural cells on day 14. In vitro experiments demonstrated that lipopolysaccharide exposure induced inflammatory responses, as evidenced by increased expression of IL1b and ApoB mRNA. CONCLUSIONS: Our findings suggest that prenatal infection at different stages of neural differentiation may result in distinct disturbances in neural differentiation during ESC-NSC transitions. Furthermore, early prenatal challenges with lipopolysaccharide selectively induce anxiety-like behaviour in male offspring. This behaviour may be attributed to the abnormal differentiation of astrocytes and oligodendrocytes in the brain, potentially mediated by ApoB/E signalling pathways in response to inflammatory stimuli.

Influence of pre-eclampsia on 2-year neurodevelopmental outcome of very-low-birth-weight infants.

OBJECTIVE: To evaluate the influence of maternal pre-eclampsia on neurodevelopmental outcome in very-low-birth-weight (VLBW) infants at 6, 12, and 24 months of corrected age. METHODS: We conducted a retrospective cohort study of singleton VLBW infants between 2011 and 2018. The participants were divided into three groups: (1) mothers without pre-eclampsia, (2) pre-eclampsia without severe features, and (3) pre-eclampsia with severe features. The Bayley Scales of Infant Development third edition (BSID-III) was used to assess the neurodevelopment of participants. A BSID-III score < 85 was defined as neurodevelopmental impairment (NDI). RESULTS: Overall, 482 VLBW infants born to 482 mothers were enrolled, of whom 327 mothers did not have pre-eclampsia and 155 mothers had pre-eclampsia (58 without and 97 with severe features). The infants born to mothers with pre-eclampsia with severe features had the lowest BSID-III scores at 6, 12, and 24 months. After adjustments, maternal pre-eclampsia with severe features was significantly associated with cognitive NDI in their infants (adjusted odds ratio [aOR] 4.14) and language NDI (aOR 3.37) at 2 years of corrected age. CONCLUSIONS: VLBW fetuses born to mothers with pre-eclampsia with severe features have poorer 2-year neurodevelopmental outcome, which mainly manifests in the cognitive and language domains.

Risk and protective factors related to immediate postpartum depression in a baby-friendly hospital of Taiwan.

OBJECTIVE: Postpartum depression (PPD) can occur in women soon after childbirth. The aim of this study was to investigate the risk and protective factors for immediate PPD in a baby-friendly hospital. MATERIALS AND METHODS: This cross-sectional study of singleton term pregnancies was performed at MacKay Memorial Hospital in Taiwan from January to September 2019. The enrolled women completed the Edinburgh Postnatal Depression Scale (EPDS) within 48 h after childbirth. Maternal characteristics, pregnancy and delivery factors, maternal comorbidities, supportive and childbirth factors, and neonatal outcomes were investigated. RESULTS: Of the 1197 enrolled women, 1104 (92.23%) were at low risk (EPDS score ≤9), 66 (5.51%) were at moderate risk (EPDS score 10 to 12), and 27 (2.26%) were at high risk (EPDS score ≥13) of PPD. Significant independent risk factors for immediate PPD included the number of miscarriages (adjusted odds ratio (aOR) 1.33, 95% confidence interval (CI) 1.03-1.72, p = 0.031) and intermediate care nursery (ICN) or neonatal intensive care unit (NICU) admission (aOR 2.29, 95% CI 1.13-4.64, p = 0.022). Significant independent protective factors included planned pregnancy (aOR 0.51, 95% CI 0.28-0.92, p = 0.026), husband accompanying his wife (aOR 0.41, 95% CI 0.22-0.75, p = 0.004), early mother and newborn skin-to-skin contact (aOR 0.44, 95% CI 0.24-0.84, p = 0.012), and breastfeeding (aOR 0.23, 95% CI 0.08-0.71, p = 0.010). CONCLUSION: The number of miscarriages and ICN or NICU admission were independent risk factors for immediate PPD. Planned pregnancy, husband accompanying his wife, early skin-to-skin contact, and breastfeeding were independent protective factors for immediate PPD. Health care providers should pay attention to the risk factors and promote the protective factors into hospital policies to prevent the consequences of PPD.

Decreased junctional adhesion molecule 3 expression induces reactive oxygen species production and apoptosis in trophoblasts†.

Junctional adhesion molecule 3 (JAM3) is involved in epithelial cell junction, cell polarity, and motility. The molecular mechanisms underlying the role of JAM3 in placental dysfunction remain unclear. We hypothesized that JAM3 expression regulates trophoblast fusion, differentiation, proliferation, and apoptosis. Our results revealed that JAM3 was expressed in the cytotrophoblasts and syncytiotrophoblasts of first-trimester and term placental villi. JAM3 expression in cell-cell junctions decreased with the formation of syncytiotrophoblasts. Using trophoblasts as an in vitro model, we observed that forskolin and JAM3 knockdown significantly reduced JAM3 expression and increased syncytium formation. JAM3 knockdown additionally inhibited trophoblast proliferation and increased the number of trophoblasts in the sub-G1 and G2/M phases, indicating cell-cycle disturbance and apoptosis. Cell-cycle arrest was associated with the engagement of checkpoint kinase 2-cell division cycle 25C-cyclin-dependent kinase 1/cyclin B1 signaling. Increased expression of BIM, NOXA, XAF1, cytochrome c, and cleaved caspase-3 further indicated trophoblast apoptosis. Overexpression of JAM3 or recombinant JAM3 protein enhanced trophoblast adhesion and migration, which were inhibited by JAM3 knockdown. JAM3 knockdown induced reactive oxygen species and syncytin 2 expression in trophoblasts. Furthermore, H2O2-induced oxidative stress reduced JAM3 expression in trophoblasts and cell culture supernatants. H2O2 simultaneously induced trophoblast apoptosis. JAM3 expression was significantly decreased in the plasmas and placentas of patients with early-onset severe preeclampsia. Thus, our results show that JAM3 may not only be a structural component of trophoblast cell junctions but also regulates trophoblast fusion, differentiation, proliferation, apoptosis, and motility. Dysregulated trophoblast JAM3 expression is crucial in preeclampsia development.

Functional antagonism between ΔNp63α and GCM1 regulates human trophoblast stemness and differentiation.

The combination of EGF, CHIR99021, A83-01, SB431542, VPA, and Y27632 (EGF/CASVY) facilitates the derivation of trophoblast stem (TS) cells from human blastocysts and first-trimester, but not term, cytotrophoblasts. The mechanism underlying this chemical induction of TS cells remains elusive. Here we demonstrate that the induction efficiency of cytotrophoblast is determined by functional antagonism of the placental transcription factor GCM1 and the stemness regulator ΔNp63α. ΔNp63α reduces GCM1 transcriptional activity, whereas GCM1 inhibits ΔNp63α oligomerization and autoregulation. EGF/CASVY cocktail activates ΔNp63α, thereby partially inhibiting GCM1 activity and reverting term cytotrophoblasts into stem cells. By applying hypoxia condition, we can further reduce GCM1 activity and successfully induce term cytotrophoblasts into TS cells. Consequently, we identify mitochondrial creatine kinase 1 (CKMT1) as a key GCM1 target crucial for syncytiotrophoblast differentiation and reveal decreased CKMT1 expression in preeclampsia. Our study delineates the molecular underpinnings of trophoblast stemness and differentiation and an efficient method to establish TS cells from term placentas.

Neurodevelopmental outcomes at 6, 12, and 24 months of age in preterm infants with very low birth weights in Taiwan.

OBJECTIVE/PURPOSE: To identify perinatal antecedents associated with neurodevelopmental impairment for very low birth weight (VLBW) preterm infants at ages 6, 12, and 24 months and the stability of neurodevelopmental assessments. METHODS: A multicenter-based VLBW cohort was recruited, and the mental development index (MDI) and psychomotor development index (PDI) were used to evaluate children's neurodevelopment stages at ages 6, 12, and 24 months. Perinatal risk factors were determined through univariate and multivariate hierarchical linear analyses. Differences and predictability in MDI or PDI scores between ages 6 and 24 months were assessed. RESULTS: Covariates including father's education level; teenage pregnancy, multiple pregnancies; infant's gestational age, gender, and birth weight <999 gm, duration of neonatal intensive care unit stay; and presence of various diseases were adversely associated with poor MDI or PDI scores in 8517 eligible VLBW infants during the study period. Polyhydramnios, emergency cesarean delivery, birth weight of <1250 gm, and periventricular/intraventricular hemorrhage stage I-II were additional risk factors of VLBW infants with an adverse PDI score. An increased number of infants with a MDI or PDI score of <55 at age 24 months was observed. Six-month MDI or PDI assessments had a low ability to predict outcomes at 24 months, with sensitivity and positive predictive values under 60% and specificity and negative predictive values over 85%. CONCLUSION: Multiple perinatal risk factors are associated with poor MDI and PDI scores among VLBW preterm infants. Six-month developmental assessments exhibited low sensitivity and positive predictive values for outcomes at 24 months.

Bio-Functionalized Magnetic Nanoparticles for the Immunoassay of C-Reactive Protein and Procalcitonin in Cervicovaginal Secretions of Pregnant Women with Preterm Prelabor Rupture of Membranes to Predict Early-Onset Neonatal Sepsis.

PURPOSE: Early-onset sepsis is a major cause of neonatal morbidity and mortality. C-reactive protein (CRP) and procalcitonin (PCT) are acute phase reactants related to infection. The aim of this study was to explore the feasibility of measuring CRP and PCT concentrations in cervicovaginal secretions of pregnant women with preterm prelabor rupture of membranes (PPROM) using an immunomagnetic reduction (IMR) assay to predict early-onset neonatal sepsis. PATIENTS AND METHODS: This prospective study was performed at Mackay Memorial Hospital, Taipei, Taiwan from February 2015 to January 2018. Pregnant women with PPROM between 22 and 34 weeks of gestation were recruited. CRP and PCT concentrations in cervicovaginal secretions were measured using an IMR assay. RESULTS: Thirty-five cervicovaginal secretion samples were obtained. After excluding two neonatal deaths, early-onset neonatal sepsis was diagnosed in 15 of the 33 surviving neonates. There was no significant relationship between cervicovaginal secretion CRP level and neonatal sepsis; however, cervicovaginal secretion PCT levels were significantly higher in the neonatal sepsis group than in the non-sepsis group (45.99 vs 9.54 ng/mL, P = 0.039). Receiver operating characteristic (ROC) curve analysis revealed a PCT cut-off level of 20.60 ng/mL to predict early-onset sepsis, and the area under the ROC curve was 0.71 (95% confidence interval 0.52 to 0.90, P = 0.039), with sensitivity and specificity of 73.3% and 77.8%, respectively. CONCLUSION: Measuring the concentration of PCT in cervicovaginal secretions with an IMR assay can predict early-onset sepsis in neonates born to mothers with PPROM.

Umbilical Cord Mesenchymal Stromal Cell-Derived Exosomes Rescue the Loss of Outer Hair Cells and Repair Cochlear Damage in Cisplatin-Injected Mice.

Umbilical cord-derived mesenchymal stromal cells (UCMSCs) have potential applications in regenerative medicine. UCMSCs have been demonstrated to repair tissue damage in many inflammatory and degenerative diseases. We have previously shown that UCMSC exosomes reduce nerve injury-induced pain in rats. In this study, we characterized UCMSC exosomes using RNA sequencing and proteomic analyses and investigated their protective effects on cisplatin-induced hearing loss in mice. Two independent experiments were designed to investigate the protective effects on cisplatin-induced hearing loss in mice: (i) chronic intraperitoneal cisplatin administration (4 mg/kg) once per day for 5 consecutive days and intraperitoneal UCMSC exosome (1.2 µg/µL) injection at the same time point; and (ii) UCMSC exosome (1.2 µg/µL) injection through a round window niche 3 days after chronic cisplatin administration. Our data suggest that UCMSC exosomes exert protective effects in vivo. The post-traumatic administration of UCMSC exosomes significantly improved hearing loss and rescued the loss of cochlear hair cells in mice receiving chronic cisplatin injection. Neuropathological gene panel analyses further revealed the UCMSC exosomes treatment led to beneficial changes in the expression levels of many genes in the cochlear tissues of cisplatin-injected mice. In conclusion, UCMSC exosomes exerted protective effects in treating ototoxicity-induced hearing loss by promoting tissue remodeling and repair.

Interleukin-1ß-induced matrix metalloproteinase-3 via ERK1/2 pathway to promote mesenchymal stem cell migration.

Human umbilical cord Wharton's jelly derived mesenchymal stem cells (hUCMSCs), a source of cell therapy, have received a great deal of attention due to their homing or migrating ability in response to signals emanating from damaged sites. It has been found that IL-1ß possesses the ability to induce the expression of matrix metalloproteinase-3 (MMP-3) in bone marrow MSCs. MMP-3 is involved in cell migration in various types of cells, including glioblastoma, vascular smooth muscle, and adult neural progenitor cells. In this study, we proposed that IL-1ß influences hUCMSCs migration involving MMP-3. The expression level of MMP-3 in IL-1ß-induced hUCMSCs was verified using cDNA microarray analysis, quantitative real-time PCR, ELISA and Western blot. Wound-healing and trans-well assay were used to investigate the cell migration and invasion ability of IL-1ß-treated hUCMSCs. In addition, we pre-treated hUCMSCs with interleukin-1 receptor antagonist, MMP-3 inhibitors (ALX-260-165, UK 356618), or transfected with MMP-3 siRNA to confirm the role of MMP3 in IL-1ß-induced cell migration. Our results showed that IL-1ß induced MMP-3 expression is related to the migration of hUCMSCs. Moreover, extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) inhibitor U0126, p38 inhibitor SB205380, JNK inhibitor SP600125 and Akt inhibitor GSK 690693 decreased IL-1ß-induced MMP-3 mRNA and protein expression. The migration and invasion ability analyses showed that these inhibitors attenuated the IL-1ß-induced migration and invasion ability of hUCMSCs. In conclusion, we have found that IL-1ß induces the expression of MMP-3 through ERK1/2, JNK, p38 MAPK and Akt signaling pathways to enhance the migration of hUCMSCs. These results provide further understanding of the mechanisms in IL-1ß-induced hUCMSCs migration to injury sites.

Comparison of maternal and neonatal outcomes between acute fatty liver of pregnancy and hemolysis, elevated liver enzymes and low platelets syndrome: a retrospective cohort study.

BACKGROUND: Acute fatty liver of pregnancy (AFLP) and hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome are two uncommon disorders that mimic each other clinically, but are distinct pathophysiologically. This study aimed to compare maternal and neonatal outcomes between AFLP and HELLP syndrome. METHODS: This retrospective cohort study was performed at a tertiary referral center in Taiwan between June 2004 and April 2020. We used the Swansea Criteria to diagnose AFLP, and the Tennessee Classification System to diagnose HELLP syndrome. Maternal characteristics, laboratory data, complications, and neonatal outcomes were compared. We analyzed the categorical variables with Chi-square test or Fisher's exact test and continuous variables with Student's t test or Mann-Whitney U test. Subsequent logistic regression analyses adjusting by potential confounding factors with significant difference were analyzed. RESULTS: During the study period, 21 women had AFLP and 80 women had HELLP syndrome. There was a higher rate of preeclampsia (95.0 % versus 23.8 %) in the HELLP syndrome group compared to the AFLP group. However, the AFLP group had more other maternal complications including jaundice (85.7 % versus 13.8 %), acute kidney injury (61.9 % versus 15.0 %), disseminated intravascular coagulopathy (66.7 % versus 8.8 %), and sepsis (47.6 % versus 10.0 %) compared to the HELLP syndrome group. Nevertheless, higher rates of small for gestational age neonates (57.1 % versus 33.3 %), neonatal respiratory distress syndrome (39.2 % versus 8.3 %) and neonatal sepsis (34.2 % versus 12.5 %) were noted in the HELLP syndrome group. CONCLUSIONS: AFLP is associated with a higher rate of multiple organ dysfunction in mothers, whereas HELLP syndrome is associated with a higher rate of neonatal morbidity.

Prenatal diagnosis of left side congenital diaphragmatic hernia associated with gastric perforation.

OBJECTIVE: A congenital diaphragmatic hernia (CDH) complicated with gastric perforation is extremely rare. Herein, we report an unusual case of unexpected intrauterine gastric perforation of a left side CDH with concurrent pleural effusion and ascites. CASE REPORT: A 21-year-old female underwent prenatal ultrasound at 37 weeks of gestation and revealed a left side CDH, pleural effusion with a large thick-walled cystic mass over the left thorax, ascites, and polyhydramnios. Under the impression of CDH with suspected gastric perforation, Cesarean delivery was arranged and a male neonate was delivered. The neonate received emergency laparotomy soon and a herniation originated from the foramen of Bochdalek and a perforation located in the stomach body along the greater curvature were found. The pathologic diagnosis was consistent with a spontaneous gastric perforation with ischemic change. CONCLUSION: Sonographic findings of pleural effusion and ascites associated with CDH are clues of antenatal gastrointestinal perforation.

Placental multipotent mesenchymal stromal cell-derived Slit2 may regulate macrophage motility during placental infection.

Slit proteins have been reported to act as axonal repellents in Drosophila; however, their role in the placental microenvironment has not been explored. In this study, we found that human placental multipotent mesenchymal stromal cells (hPMSCs) constitutively express Slit2. Therefore, we hypothesized that Slit2 expressed by hPMSCs could be involved in macrophage migration during placental inflammation through membrane cognate Roundabout (Robo) receptor signaling. In order to develop a preclinical in vitro mouse model of hPMSCs in treatment of perinatal infection, RAW 264.7 cells were used in this study. Slit2 interacted with Robo4 that was highly expressed in RAW 264.7 macrophages: their interaction increased the adhesive ability of RAW 264.7 cells and inhibited migration. Lipopolysaccharide (LPS)-induced CD11bCD18 expression could be inhibited by Slit2 and by hPMSC-conditioned medium (CM). LPS-induced activation of p38 and Rap1 was also attenuated by Slit2 and by hPMSC-CM. Noticeably, these inhibitory effects of hPMSC-CM decreased after depletion of Slit2 from the CM. Furthermore, we found that p38 siRNA inhibited LPS-induced Rap1 expression in RAW 264.7 cells, indicating that Rap1 functions downstream of p38 signaling. p38 siRNA increased cell adhesion and inhibited migration through reducing LPS-stimulated CD11bCD18 expression in RAW 264.7 cells. Thus, hPMSC-derived Slit2 may inhibit LPS-induced CD11bCD18 expression to decrease cell migration and increase adhesion through modulating the activity and motility of inflammatory macrophages in placenta. This may represent a novel mechanism for LPS-induced placental infection.

Enhancement of the Peroxidase-Like Activity of Iodine-Capped Gold Nanoparticles for the Colorimetric Detection of Biothiols.

A colorimetric assay was developed for the detection of biothiols, based on the peroxidase-like activity of iodine-capped gold nanoparticles (AuNPs). These AuNPs show a synergetic effect in the form of peroxidase-mimicking activity at the interface of AuNPs, while free AuNPs and iodine alone have weak catalytic properties. Thus, iodine-capped AuNPs possess good intrinsic enzymatic activity and trigger the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB), leading to a change in color from colorless to yellow. When added to solution, biothiols, such as cysteine, strongly bind to the interface of AuNPs via gold-thiol bonds, inhibiting the catalytic activity of AuNPs, resulting in a decrease in oxidized TMB. Using this strategy, cysteine could be linearly determined, at a wide range of concentrations (0.5 to 20 µM), with a detection limit of 0.5 µM using UV-Vis spectroscopy. This method was applied for the detection of cysteine in diluted human urine.

Outcomes of ultrasound-indicated cerclage in twin pregnancies with a short cervical length.

OBJECTIVE: To investigate the outcomes of ultrasound-indicated cerclage in dichorionic-diamniotic (DCDA) twin pregnancies with a short cervical length. MATERIALS AND METHODS: This was a retrospective cohort study of DCDA twin pregnancies with a short cervical length (≤25 mm) from January 2000 to July 2017 to compare maternal and neonatal outcomes. Additional sub-analysis was performed by dividing the patients into two subgroups by a cervical length ≤15 mm and between 16 and 25 mm. RESULTS: One hundred and eight women were initially diagnosed with twin pregnancies and cervical insufficiency. After excluding cases not meeting the study criteria, 46 women were recruited for analysis, of whom 33 underwent ultrasound-indicated cerclage. The delivery age of the cerclage group was significantly later than the non-cerclage group (34.85 ± 3.91 versus 31.08 ± 5.25 weeks, p = 0.011), and the latency was significantly longer in the cerclage group than in the non-cerclage group (86.09 ± 41.32 versus 52.31 ± 33.24 days, p = 0.014). Sub-analysis revealed that these benefits were significant in the subgroup of a cervical length ≤15 mm. Both first twin (twin A) and second twin (twin B) had a significantly decreased rate of neonatal intensive care unit admission in the cerclage group. However, twin A had more promising outcomes with significantly decreased rates of neonatal respiratory distress syndrome (6.7% versus 50.0%, p = 0.004) and sepsis (0% versus 25.0%, p = 0.019). CONCLUSION: Ultrasound-indicated cerclage in DCDA twin pregnancies can decrease preterm birth and prolong the latency. It also decreases neonatal morbidity, and is especially beneficial for twin A.

Assessment of the cervix in pregnant women with a history of cervical insufficiency during the first trimester using elastography.

INTRODUCTION: To investigate changes in first trimester cervical elastography, cervical length and endocervical canal width in pregnant women with a history of cervical insufficiency, and further discuss the possibility of using these markers as predictors of cervical insufficiency in early pregnancy. MATERIAL AND METHODS: This was an observational ultrasound study of first trimester cervical changes in singleton pregnancies between January 2016 and June 2018. Cervical elastography, cervical length and endocervical canal width were measured during the first trimester. Strain elastography was used to estimate the softness of anterior and posterior cervical lips and was expressed as percentages (strain rate). RESULTS: Of the 339 pregnant women enrolled, 24 had a history of cervical insufficiency. The anterior cervical lip was significantly softer in the cervical insufficiency group (strain rate: 0.19% ± 0.05% vs 0.11% ± 0.04%; P < .001). Cervical length was significantly shorter in the cervical insufficiency group (36.3 ± 4.8 mm vs 38.3 ± 3.8 mm; P = .014). Endocervical canal width was significantly wider in the cervical insufficiency group (5.7 ± 1.1 mm vs 5.2 ± 0.7 mm; P = .001). Receiver operating characteristic curve analyses revealed that the optimal cut-off values of anterior cervical lip, cervical length and endocervical canal width to confirm the diagnosis of cervical insufficiency were 0.15%, 35.5 mm and 5.75 mm, respectively. In multivariate logistic regression analysis, significant differences were still observed in anterior cervical strain rate (adjusted odds ratio [OR] 53.78, 95% [confidence interval [CI] 11-270; P < .001) and endocervical canal width (adjusted OR, 5.41, 95% CI,1.2-24.7; P = .029). CONCLUSIONS: First trimester cervical elastography is a valuable tool in the assessment of women with a history of cervical insufficiency. The anterior cervical lip was significantly softer in women with a history of cervical insufficiency, and the sensitivity and specificity of anterior cervical lip strain were better than that of cervical length and endocervical canal width.