Human Liver Cells Expressing Albumin and Mesenchymal Characteristics Give Rise to Insulin-Producing Cells

Activation of the pancreatic lineage in the liver has been suggested as a potential autologous cell replacement therapy for diabetic patients. Transcription factors-induced liver-to-pancreas reprogramming has been demonstrated in numerous species both in vivo and in vitro. However, human-derived liver cells capable of acquiring the alternate pancreatic repertoire have never been characterized. It is yet unknown whether hepatic-like stem cells or rather adult liver cells give rise to insulin-producing cells. Using an in vitro experimental system, we demonstrate that proliferating adherent human liver cells acquire mesenchymal-like characteristics and a considerable level of cellular plasticity. However, using a lineage-tracing approach, we demonstrate that insulin-producing cells are primarily generated in cells enriched for adult hepatic markers that coexpress both albumin and mesenchymal markers. Taken together, our data suggest that adult human hepatic tissue retains a substantial level of developmental plasticity, which could be exploited in regenerative medicine approaches

Neonatal outcomes following early fetal growth restriction: a subgroup analysis of the EVERREST study

OBJECTIVE: To quantify the risks of mortality, morbidity and postnatal characteristics associated with extreme preterm fetal growth restriction (EP-FGR). DESIGN: The EVERREST (Do e s v ascular endothelial growth factor gene therapy saf e ly imp r ove outcome in seve r e e arly-onset fetal growth re st riction?) prospective multicentre study of women diagnosed with EP-FGR (singleton, estimated fetal weight (EFW) <3rd percentile, <600 g, 20+0-26+6 weeks of gestation). The UK subgroup of EP-FGR infants (<36 weeks) were sex-matched and gestation-matched to appropriate for age (AGA) infants born in University College London Hospital (1:2 design, EFW 25th-75th percentile). SETTING: Four tertiary perinatal units (UK, Germany, Spain, Sweden). MAIN OUTCOMES: Antenatal and postnatal mortality, bronchopulmonary dysplasia (BPD), sepsis, surgically treated necrotising enterocolitis (NEC), treated retinopathy of prematurity (ROP). RESULTS: Of 135 mothers recruited with EP-FGR, 42 had a stillbirth or termination of pregnancy (31%) and 93 had live births (69%). Postnatal genetic abnormalities were identified in 7/93 (8%) live births. Mean gestational age at birth was 31.4 weeks (SD 4.6). 54 UK-born preterm EP-FGR infants (<36 weeks) were matched to AGA controls. EP-FGR was associated with increased BPD (43% vs 26%, OR 3.6, 95% CI 1.4 to 9.4, p=0.01), surgical NEC (6% vs 0%, p=0.036) and ROP treatment (11% vs 0%, p=0.001). Mortality was probably higher among FGR infants (9% vs 2%, OR 5.0, 95% CI 1.0 to 25.8, p=0.054). FGR infants more frequently received invasive ventilation (65% vs 50%, OR 2.6, 95% CI 1.1 to 6.1, p=0.03), took longer to achieve full feeds and had longer neonatal stays (median difference 6.1 days, 95% CI 3.8 to 8.9 and 19 days, 95% CI 9 to 30 days, respectively, p<0.0001). CONCLUSIONS: Mortality following diagnosis of EP-FGR is high. Survivors experience increased neonatal morbidity compared with AGA preterm infants. TRIAL REGISTRATION NUMBER: NCT02097667

Maternal PlGF and umbilical Dopplers predict pregnancy outcomes at diagnosis of early-onset fetal growth restriction

BACKGROUND: Severe, early-onset fetal growth restriction (FGR) causes significant fetal and neonatal mortality and morbidity. Predicting the outcome of affected pregnancies at the time of diagnosis is difficult, thus preventing accurate patient counseling. We investigated the use of maternal serum protein and ultrasound measurements at diagnosis to predict fetal or neonatal death and 3 secondary outcomes: fetal death or delivery at or before 28+0 weeks, development of abnormal umbilical artery (UmA) Doppler velocimetry, and slow fetal growth. // METHODS: Women with singleton pregnancies (n = 142, estimated fetal weights [EFWs] below the third centile, less than 600 g, 20+0 to 26+6 weeks of gestation, no known chromosomal, genetic, or major structural abnormalities) were recruited from 4 European centers. Maternal serum from the discovery set (n = 63) was analyzed for 7 proteins linked to angiogenesis, 90 additional proteins associated with cardiovascular disease, and 5 proteins identified through pooled liquid chromatography and tandem mass spectrometry. Patient and clinician stakeholder priorities were used to select models tested in the validation set (n = 60), with final models calculated from combined data. // RESULTS: The most discriminative model for fetal or neonatal death included the EFW z score (Hadlock 3 formula/Marsal chart), gestational age, and UmA Doppler category (AUC, 0.91; 95% CI, 0.86–0.97) but was less well calibrated than the model containing only the EFW z score (Hadlock 3/Marsal). The most discriminative model for fetal death or delivery at or before 28+0 weeks included maternal serum placental growth factor (PlGF) concentration and UmA Doppler category (AUC, 0.89; 95% CI, 0.83–0.94). // CONCLUSION: Ultrasound measurements and maternal serum PlGF concentration at diagnosis of severe, early-onset FGR predicted pregnancy outcomes of importance to patients and clinicians. // TRIAL REGISTRATION: ClinicalTrials.gov NCT02097667. // FUNDING: The European Union, Rosetrees Trust, Mitchell Charitable Trust

Delivery Outcome of Fetuses with Congenital Heart Disease&mdash;Is It Influenced by Prenatal Diagnosis?

Objective: The objective of this study is to assess the delivery outcomes of neonates with congenital heart defects (CHD), and to explore the effect of prenatal diagnosis on these outcomes. Methods: A retrospective study including singleton deliveries between 2011 and 2020. All singleton neonates delivered at &gt;24 weeks of gestation were included in this study. Fetuses with known prenatal anomalies other than CHD were excluded from this study. Pregnancy and neonatal outcomes were analyzed. A comparison was made between pregnancies with CHD and controls; and between pregnancies with prenatal diagnosis of CHD and postnatal diagnosis of CHD. Results: A total of 1598 neonates with CHD (688, 43.1% diagnosed prenatally) comprised the study group, compared to 85,576 singleton controls. Pregnancies with CHD had significantly increased BMI before pregnancy, suffered more from diabetes and chronic hypertension, had more inductions of labor, and had more cesarean deliveries (CD) including both elective CD and urgent CD due to non-reassuring fetal monitor (NRFHR) (OR = 1.75; 95%CI 1.45&ndash;2.14). Prenatal diagnosis of CHD is associated with a significant increased rate of induction of labor compared to postnatal diagnosis of CHD (OR = 1.59; 95% CI 1.15&ndash;2.22), but did not affect the mode of delivery including the rate of CD and CD due to non-reassuring fetal heart rate (NRFHR). Gestational age at birth and birthweight were significantly lower in pregnancies with CHD compared to controls, with no difference between prenatal to postnatal diagnosis of the anomaly. Neonates with CHD had a higher incidence of hypoxic ischemic encephalopathy and seizures compared to controls without any impact by prenatal diagnosis. Conclusion: Prenatal diagnosis of CHD is associated with an increased rate of induction of labor, with no increased rate of CD and CD due to NRFHR. The 5-min Apgar score is lower in pregnancies with postnatal diagnosis of CHD

“One-stop shop” for the evaluation of the infertile patient: hystero-salpingo foam sonography combined with two and three dimensional ultrasound and sonohysterography

Hysterosalpingo-foam sonography (HyFoSy) is considered an acceptable alternative for hysterosalpingography (HSG). By combining HyFoSy with two and three-dimensional (2D and 3D) ultrasound and hysterosonography, a complete fertility work-up can be done. We aimed to evaluate the value of a combined ultrasound examination for fertility work-up. During the study period 113 women were examined. Five of 113 (4.4%) examinations were abandoned due to intra-uterine adhesions that were detected by hysterosonography, and five (4.4%) were abandoned due to technical difficulties. Of 103 women who had completed the examination, 2D ultrasound revealed six patients with hydrosalpinx (5.8%) and sonographic signs of adenomyosis in 13 (12.6%) patients. By combining 2D ultrasound with hysterosonography, two (1.9%) fibroids that were penetrating the uterine cavity and seven (6.8%) endometrial polyps were detected. HyFoSy showed bilateral patent tubes in 58 patients (56.3%), unilateral tubal occlusion in 29 (28.1%) and bilateral tubal occlusion in 16 (15.5%). This study shows that the ‘one-stop shop’ examination is feasible. The combined examination had detected 16 pathological findings that would have not been detected by HyFoSy alone. Hence, it should be offered to couples undergoing routine infertility work-up.IMPACT STATEMENT What is already known on this subject? The accuracy of the HyFoSy alone has been evaluated in different studies, but this presented ultrasound scan is integrating 4 different modalities in one exam (2D scanning of the pelvis, 3D scanning of the uterus, hysterosonography and HyFoSy) and we were able to evaluate the female pelvic organs, including the uterine cavity, the tubes and the ovaries, in order to expand the range of diagnosed pathologies. What do the results of this study add? The concept of ‘one-stop shop’ for the evaluation of female pelvis in couples suffering from infertility is feasible, has comparable accuracy as HSG for tubal occlusion, and higher detection rate for uterine malformations. What are the implications of these findings for clinical practice and/or further research? We suggest to incorporate this examination in routine fertility work-up

The “No ARSA” Sign: A Novel Method of Prenatal Screening for Aberrant Right Subclavian Artery

An aberrant right subclavian artery (ARSA) can be overlooked by the conventional method as described by Chaoui et al., due to acoustic shadowing. The aim of this study was to evaluate the feasibility and accuracy of a novel screening method for ARSA by demonstrating the brachiocephalic artery bifurcation, referred to as the &ldquo;No ARSA&rdquo; sign. A prospective study conducted at a tertiary care center between 2018 and 2019 included unselected pregnant patients at a median gestational age of 15.1 (14.2&ndash;22.1; IQR (inter-quartile range)) weeks, who had been referred for a routine or targeted anomaly scan. All participants were scanned for the presence or absence of ARSA using both the conventional and the novel &ldquo;No ARSA&rdquo; methods for validation purposes. A total of 226 unselected patients were enrolled in the study. The &ldquo;No ARSA&rdquo; sign was visualized in 218 fetuses (96.5%). In the remaining 8 cases (3.5%), the &ldquo;No ARSA&rdquo; sign was not demonstrated. In these fetuses, an ARSA was visualized by the conventional method. The new method exhibited 100% feasibility and was in complete agreement with the conventional method. Intra- and inter-observer agreement was excellent (&kappa; = 1). The results of the study suggest that the &ldquo;No ARSA&rdquo; sign is an efficient and reliable screening tool for ARSA