Systematic evaluation of genome sequencing for the diagnostic assessment of autism spectrum disorder and fetal structural anomalies.

Short-read genome sequencing (GS) holds the promise of becoming the primary diagnostic approach for the assessment of autism spectrum disorder (ASD) and fetal structural anomalies (FSAs). However, few studies have comprehensively evaluated its performance against current standard-of-care diagnostic tests: karyotype, chromosomal microarray (CMA), and exome sequencing (ES). To assess the clinical utility of GS, we compared its diagnostic yield against these three tests in 1,612 quartet families including an individual with ASD and in 295 prenatal families. Our GS analytic framework identified a diagnostic variant in 7.8% of ASD probands, almost 2-fold more than CMA (4.3%) and 3-fold more than ES (2.7%). However, when we systematically captured copy-number variants (CNVs) from the exome data, the diagnostic yield of ES (7.4%) was brought much closer to, but did not surpass, GS. Similarly, we estimated that GS could achieve an overall diagnostic yield of 46.1% in unselected FSAs, representing a 17.2% increased yield over karyotype, 14.1% over CMA, and 4.1% over ES with CNV calling or 36.1% increase without CNV discovery. Overall, GS provided an added diagnostic yield of 0.4% and 0.8% beyond the combination of all three standard-of-care tests in ASD and FSAs, respectively. This corresponded to nine GS unique diagnostic variants, including sequence variants in exons not captured by ES, structural variants (SVs) inaccessible to existing standard-of-care tests, and SVs where the resolution of GS changed variant classification. Overall, this large-scale evaluation demonstrated that GS significantly outperforms each individual standard-of-care test while also outperforming the combination of all three tests, thus warranting consideration as the first-tier diagnostic approach for the assessment of ASD and FSAs.

Whole-genome sequencing in prenatally detected congenital malformations: prospective cohort study in clinical setting.

OBJECTIVE: To investigate the diagnostic yield of trio whole-genome sequencing (WGS) in fetuses with various congenital malformations referred to a tertiary center for prenatal diagnosis. METHODS: In this prospective study, 50 pregnancies with different congenital malformations, negative for trisomies and causative copy-number variants, were analyzed further with fetal-parental trio WGS analysis. Parents were eligible for inclusion if they accepted further investigation following the detection of isolated or multiple malformations on prenatal ultrasound. Cases with isolated increased nuchal translucency, gamete donation or multiple pregnancy were excluded. WGS with the Illumina Inc. 30× polymerase-chain-reaction-free short-read sequencing included analysis of single-nucleotide variants, insertions and deletions, structural variants, short tandem repeats and copy-number identification of SMN1 and SMN2 genes. RESULTS: A molecular diagnosis was achieved in 13/50 (26%) cases. Causative sequence variants were identified in 12 genes: FGFR3 (n = 2), ACTA1 (n = 1), CDH2 (n = 1), COL1A2 (n = 1), DHCR7 (n = 1), EYA1 (n = 1), FBXO11 (n = 1), FRAS1 (n = 1), L1CAM (n = 1), OFD1 (n = 1), PDHA1 (n = 1) and SOX9 (n = 1). The phenotypes of the cases were divided into different groups, with the following diagnostic yields: skeletal malformation (4/9 (44%)), multisystem malformation (3/7 (43%)), central nervous system malformation (5/15 (33%)) and thoracic malformation (1/10 (10%)). Additionally, two cases carried variants that were considered potentially clinically relevant, even though they were assessed as variants of uncertain significance, according to the guidelines provided by the American College of Medical Genetics and Genomics. Overall, we identified a causative or potentially clinically relevant variant in 15/50 (30%) cases. CONCLUSIONS: We demonstrate a diagnostic yield of 26% with clinical WGS in prenatally detected congenital malformations. This study emphasizes the benefits that WGS can bring to the diagnosis of fetal structural anomalies. It is important to note that causative chromosomal aberrations were excluded from our cohort before WGS. As chromosomal aberrations are a well-known cause of prenatally detected congenital malformations, future studies using WGS as a primary diagnostic test, including assessment of chromosomal aberrations, may show that the detection rate exceeds the diagnostic yield of this study. WGS can add clinically relevant information, explaining the underlying cause of the fetal anomaly, which will provide information concerning the specific prognosis of the condition, as well as estimate the risk of recurrence. A genetic diagnosis can also provide more reproductive choice for future pregnancies. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Adverse pregnancy outcome in fetuses with early increased nuchal translucency: prospective cohort study.

OBJECTIVES: An increased nuchal translucency (NT) thickness of ≥ 3.5 mm is a well-established marker for congenital anomalies and adverse pregnancy outcome between 11 and 14 weeks' gestation, but little is known about its performance as a screening tool before 11 weeks. We aimed to investigate, in a prospective setting, whether fetuses with increased NT before 11 weeks are at risk for adverse pregnancy outcome. METHODS: This was a prospective cohort study including pregnant women with a viable fetus with NT ≥ 2.5 mm and a crown-rump length (CRL) < 45 mm. All included women were referred to our fetal medicine unit (FMU) and scheduled for a follow-up scan where the NT was remeasured after 1 week when the CRL was > 45 mm. Two groups were evaluated: cases with a normalized NT (< 3.5 mm) and cases with persistently increased NT (≥ 3.5 mm). The cases were monitored until 4 weeks after delivery. The main outcome was a composite adverse outcome of aneuploidy, other genetic disorders, structural anomalies and pregnancy loss. We performed subgroup analyses of NT thickness at inclusion and normalized or persistently increased NT at follow-up. RESULTS: The study included 109 cases, of which 39 (35.8%) had an adverse pregnancy outcome. Of these, 64.1% (25/39) were aneuploid, corresponding to 22.9% (25/109) of the total study population. In the subgroups of NT thickness at inclusion of 2.5-3.4 mm, 3.5-4.4 mm and ≥ 4.5 mm, an adverse outcome was reported in 22.0% (9/41), 40.0% (18/45) and 52.2% (12/23), respectively. In fetuses with a normalized NT and without ultrasound abnormalities at the follow-up scan, the incidence of adverse outcome was 8.5% (5/59), of which 5.1% (3/59) cases were aneuploid. CONCLUSIONS: Fetuses with an early increased NT thickness are at considerable risk of an adverse pregnancy outcome, even if the NT normalizes after 11 weeks. Not all congenital anomalies can be diagnosed with routine first-trimester screening, such as non-invasive prenatal testing and/or a first-trimester anomaly scan. Therefore, expectant parents should always be referred to a FMU for detailed ultrasonography. Invasive prenatal testing should be offered if an increased NT of ≥ 2.5 mm is observed before 11 weeks' gestation. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Resultado adverso del embarazo en fetos con aumento precoz de la translucencia nucal: estudio prospectivo de cohortes OBJETIVOS: El aumento del grosor de la translucencia nucal (TN) de ≥3,5 mm es un marcador bien establecido de anomalías congénitas y resultados adversos del embarazo entre las semanas 11 y 14 de gestación, pero se sabe poco sobre su rendimiento como herramienta de cribado antes de las 11 semanas. El objetivo fue investigar, en un contexto prospectivo, si los fetos con aumento de la TN antes de las 11 semanas corren riesgo de presentar resultados adversos del embarazo. MÉTODOS: Se trató de un estudio prospectivo de cohortes que incluyó a embarazadas con un feto viable con una TN ≥2,5 mm y una longitud céfalo­caudal (LCC) <45 mm. Todas las mujeres incluidas fueron remitidas a una unidad de medicina fetal (UMF) y con cita para una prueba de seguimiento en la que se volvió a medir la TN al cabo de 1 semana cuando la LCC era >45 mm. Se evaluaron dos grupos: casos con una TN normalizada (<3.5 mm) y casos con una TN persistentemente aumentada (≥3,5 mm). A los casos se les dio seguimiento hasta 4 semanas después del parto. El resultado principal fue un resultado adverso compuesto de aneuploidía, otros trastornos genéticos, anomalías estructurales y pérdida del embarazo. Se realizaron análisis de subgrupos del grosor de la TN en el momento de la inclusión y de la TN normalizada o persistentemente aumentada en el seguimiento. RESULTADOS: El estudio incluyó 109 casos, de los cuales 39 (35,8%) tuvieron un resultado adverso del embarazo. De ellos, el 64,1% (25/39) eran aneuploides, lo que supone el 22,9% (25/109) de la población total del estudio. En los subgrupos de grosor de la TN en el momento de la inclusión de 2,5­3,4 mm, 3,5­4,4 mm y ≥4,5 mm, se notificó un resultado adverso en el 22,0% (9/41), el 40,0% (18/45) y el 52,2% (12/23), respectivamente. En los fetos con una TN normalizada y sin anomalías ecográficas en la ecografía de seguimiento, la incidencia de resultados adversos fue del 8,5% (5/59), de los cuales el 5,1% (3/59) de los casos eran aneuploides. CONCLUSIONES: Los fetos con un aumento precoz del grosor de la TN corren un riesgo considerable de sufrir un resultado adverso del embarazo, incluso si la TN se normaliza después de 11 semanas. No todas las anomalías congénitas pueden diagnosticarse con un cribado rutinario en el primer trimestre, como las pruebas prenatales no invasivas y/o una ecografía de anomalías en el primer trimestre. Por lo tanto, los futuros padres siempre deben ser remitidos a una UMF para una ecografía detallada. Se debería ofrecer una prueba prenatal invasiva si se observa un aumento de la TN de ≥2,5 mm antes de las 11 semanas de gestación.

Paternal age, risk of congenital anomalies, and birth outcomes: a population-based cohort study.

The objective of the study was to explore the impact of paternal age on the risk of congenital anomalies and birth outcomes in infants born in the USA between 2016 and 2021. This retrospective cohort study used data from the National Vital Statistics System (NVSS) database, a data set containing information on live birth in the USA between 2016 and 2021. Newborns were divided into four groups based on their paternal age (< 25, 25-34, 35-44, and > 44 years) and using the 25-34 age group as a reference. The primary outcomes were congenital anomalies involving structural anomalies and chromosome anomalies. Secondary outcomes were preterm birth, low birth weight, severe neonatal perinatal asphyxia, and admission to neonatal intensive care units (NICU). A multivariable logistic regression model was used to analyze the association between paternal age and outcomes. Overall, 17,764,695 live births were included in the final analyses. After adjusting confounding factors, advanced paternal age > 44 years was associated with increased odds of congenital anomalies (adjusted odds ratio (aOR) = 1.17, 95%CI 1.12-1.21) compared with the 25-34 age group, mainly for the chromosomal anomalies (aOR = 1.59, 95%CI 1.40-1.78) but not the structure anomalies (aOR = 1.03, 95%CI 0.97-1.09). The risk of preterm delivery, low birth weight, and NICU hospitalization in their infants was increased by advanced parental age as well.  Conclusion: Advanced paternal age increases the risk of congenital anomalies, especially chromosomal anomalies in their offspring, implying prenatal genetic counseling is required. What is Known: • There's a rising trend of advanced paternal age, which is associated with an increased likelihood of premature birth and low birth weight in their offspring. However, the exploration between paternal age and congenital abnormalities in offspring was limited and contradictory. What is New: • Infants with a paternal age > 44 years were more likely to be born with congenital anomalies, especially chromosomal anomalies.

Prenatal Diagnosis of Structural Anomaly Among Singletons and Twins: Eight-Year Experience in a Chinese Tertiary Center.

OBJECTIVES: This study was designed to reveal structural abnormalities in singleton and twin pregnancies in the Chinese population. METHODS: This retrospective study spanned 8 years and included 1228 singleton pregnancies (112,919 examinees) and 49 twin pregnancies (1865 examinees) with structural anomalies diagnosed by ultrasound. Detailed descriptions of anomalies, gestational weeks at diagnosis, and maternal age were recorded. The odds ratio was evaluated in twin pregnancies with detectable structural anomalies. RESULTS: The annual average "ultrasound prevalence of fetal anomalies" among singleton and twin pregnancies were 1.09 and 3.06%, respectively. Mothers with twin anomalies were older (P < .001), and twin pregnancies were diagnosed with anomalies in earlier gestational weeks than singleton (P = .011). No differences were found in the types of anomalies between singleton and twin pregnancies. Central nervous system anomaly was the most common type in singleton and twin pregnancies. Twin pregnancies had higher rates of major anomalies than singleton (total OR 2.45), especially cardiovascular, central nervous, and gastrointestinal systems and ear/eye/face/neck disorders. CONCLUSIONS: Compared with singleton, twin pregnancies had higher odds of detectable structural anomalies. Twin pregnancies with structural anomalies were diagnosed at earlier gestational age and associated with older maternal age. Central nervous system anomaly was the most common type in singleton and twin pregnancies.

Bayesian-Based Hyperparameter Optimization of 1D-CNN for Structural Anomaly Detection.

With the rapid development of sensor technology, structural health monitoring data have tended to become more massive. Deep learning has advantages when handling big data, and has therefore been widely researched for diagnosing structural anomalies. However, for the diagnosis of different structural abnormalities, the model hyperparameters need to be adjusted according to different application scenarios, which is a complicated process. In this paper, a new strategy for building and optimizing 1D-CNN models is proposed that is suitable for diagnosing damage to different types of structure. This strategy involves optimizing hyperparameters with the Bayesian algorithm and improving model recognition accuracy using data fusion technology. Under the condition of sparse sensor measurement points, the entire structure is monitored, and the high-precision diagnosis of structural damage is performed. This method improves the applicability of the model to different structure detection scenarios, and avoids the shortcomings of traditional hyperparameter adjustment methods based on experience and subjectivity. In preliminary research on the simply supported beam test case, the efficient and accurate identification of parameter changes in small local elements was achieved. Furthermore, publicly available structural datasets were utilized to verify the robustness of the method, and a high identification accuracy rate of 99.85% was achieved. Compared with other methods described in the literature, this strategy shows significant advantages in terms of sensor occupancy rate, computational cost, and identification accuracy.

Clinical efficiency of simultaneous CNV-seq and whole-exome sequencing for testing fetal structural anomalies.

BACKGROUND: Birth defects are responsible for approximately 7% of neonatal deaths worldwide by World Health Organization in 2004. Many methods have been utilized for examining the congenital anomalies in fetuses. This study aims to investigate the efficiency of simultaneous CNV-seq and whole-exome sequencing (WES) in the diagnosis of fetal anomaly based on a large Chinese cohort. METHODS: In this cohort study, 1800 pregnant women with singleton fetus in Hubei Province were recruited from 2018 to 2020 for prenatal ultrasonic screening. Those with fetal structural anomalies were transferred to the Maternal and Child Health Hospital of Hubei Province through a referral network in Hubei, China. After multidisciplinary consultation and decision on fetal outcome, products of conception (POC) samples were obtained. Simultaneous CNV-seq and WES was conducted to identify the fetal anomalies that can compress initial DNA and turnaround time of reports. RESULTS: In total, 959 couples were finally eligible for the enrollment. A total of 227 trios were identified with a causative alteration (CNV or variant), among which 191 (84.14%) were de novo. Double diagnosis of pathogenic CNVs and variants have been identified in 10 fetuses. The diagnostic yield of multisystem anomalies was significantly higher than single system anomalies (32.28% vs. 22.36%, P = 0.0183). The diagnostic rate of fetuses with consistent intra- and extra-uterine phenotypes (172/684) was significantly higher than the rate of these with inconsistent phenotypes (17/116, P = 0.0130). CONCLUSIONS: Simultaneous CNV-seq and WES analysis contributed to fetal anomaly diagnosis and played a vital role in elucidating complex anomalies with compound causes.

Diagnostic yield of exome sequencing in fetuses with multisystem malformations: systematic review and meta-analysis.

OBJECTIVE: To determine the diagnostic yield of exome sequencing (ES) above that of chromosomal microarray analysis (CMA) or karyotyping in fetuses with multisystem structural anomalies (at least two major anomalies in different anatomical systems). METHOD: This was a systematic review conducted in accordance with PRISMA guidelines. Searching PubMed, Web of Knowledge and Cochrane database, we identified studies describing ES, whole-genome and/or next-generation sequencing in fetuses with multisystem malformations. Included were observational studies involving five or more eligible fetuses. A fetus was eligible for inclusion if it had at least two major anomalies of different anatomical systems and a negative CMA or karyotyping result. Only positive variants classified as likely pathogenic or pathogenic determined to be causative of the fetal phenotype were considered. A negative CMA or karyotype result was treated as the reference standard. The diagnostic yield of the primary outcome was calculated by single-proportion analysis using random-effects modeling. A subgroup analysis was performed to compare the diagnostic yield of the solo approach (fetus alone sequenced) with that of the trio approach (fetus and both parents sequenced). RESULTS: Seventeen articles with data on ES diagnostic yield, including 694 individuals with multisystem malformations, were identified. Overall, a pathogenic or likely pathogenic variant potentially causative of the fetal phenotype was found in 213 fetuses, giving a 33% (95% CI, 27-40%) incremental yield of ES. A stratified analysis showed similar diagnostic yields of ES using the solo approach (30%; 95% CI, 11-52%) and the trio approach (35%; 95% CI, 26-44%). CONCLUSIONS: ES applied in fetuses with multisystem structural anomalies was able to identify a potentially causative gene when CMA or karyotyping had failed to do so in an additional one-third of cases. No differences were observed between the solo and trio approaches for ES. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Comparative Study of Structural Anomaly Diagnosis Based on ANN Model Using Random Displacement and Acceleration Responses with Incomplete Measurements.

Structural anomaly diagnosis, such as damage identification, is a continuously interesting issue. Artificial neural networks have an excellent ability to model complex structure dynamics. In this paper, an artificial neural network model is used to describe the relationship between structural responses and anomalies such as stiffness reduction due to damages. Random acceleration and displacement responses as generally measured data are used as the input to the artificial neural network, and the output of the artificial neural network is the anomaly severity. The artificial neural network model is set up by training and then validated using random vibration responses with different structural anomalies. The structural anomaly diagnosis method based on the artificial neural network model using random acceleration and displacement responses is applied to a five-story building structure under random base excitations (seismic loading). Anomalies in the structure are denoted by stiffness reduction. Structural anomaly diagnosis using random acceleration responses is compared with that using random displacement responses. The numerical results show the effects of different random vibration responses used on the accuracy of predicting stiffness reduction. The actual incomplete measurements include intensive noise, finite sampling time length, and limited measurement points. The effects of the incomplete measurements on the accuracy of predicting results are also discussed.

An alternative to array-based diagnostics: a prospectively recruited cohort, comparing arrayCGH to next-generation sequencing to evaluate foetal structural abnormalities.

Molecular diagnostic investigations, following the identification of foetal abnormalities, are routinely performed using array comparative genomic hybridisation (aCGH). Despite the utility of this technique, contemporary approaches for the detection of copy number variation are typically based on next-generation sequencing (NGS). We sought to compare an in-house NGS-based workflow (CNVseq) with aCGH, for invasively obtained foetal samples from pregnancies complicated by foetal structural abnormality. DNA from 40 foetuses was screened using both 8 × 60 K aCGH oligoarrays and low-coverage whole genome sequencing. Sequencer-compatible libraries were combined in a ten-sample multiplex and sequenced using an Illumina HiSeq2500. The mean resolution of CNVseq was 29 kb, compared to 60 kb for aCGH analyses. Four clinically significant, concordant, copy number imbalances were detected using both techniques, however, genomic breakpoints were more precisely defined by CNVseq. This data indicates CNVseq is a robust and sensitive alternative to aCGH, for the prenatal investigation of foetuses with structural abnormalities. Impact statement What is already known about this subject? Copy number variant analysis using next-generation sequencing has been successfully applied to investigations of tumour specimens and patients with developmental delays. The application of our approach, to a prospective prenatal diagnosis cohort, has not hitherto been assessed. What do the results of this study add? Next-generation sequencing has a comparable turnaround time and assay sensitivity to copy number variant analysis performed using array CGH. We demonstrate that having established a next-generation sequencing facility, high-throughput CNVseq sample processing and analysis can be undertaken within the framework of a regional diagnostic service. What are the implications of these findings for clinical practice and/or further research? Array CGH is a legacy technology which is likely to be superseded by low-coverage whole genome sequencing, for the detection of copy number variants, in the prenatal diagnosis of structural abnormalities.

Possible Etiological Factors for the Development of Molar Incisor Hypomineralization (MIH) in Austrian Children.

BACKGROUND: Molar incisor hypomineralization (MIH) is a developmental enamel defect that primarily affects the first permanent molars and sometimes the incisors. Its increasing prevalence worldwide has raised clinical concerns, yet its exact cause remains unknown. This study aimed to assess potential factors influencing MIH development by analyzing the medical history of children aged 6 to 12 years using a questionnaire. METHODS: This study included 100 children aged 6-12 years diagnosed with MIH during dental examination, and 100 age-matched children in the non-MIH (healthy) group from the Department of Pediatric Dentistry, University Clinic of Dentistry, Medical University of Vienna. The parents of the participants completed a two-page questionnaire regarding possible etiological factors of MIH. RESULTS: The data analysis involved 100 children with MIH (mean age 8.5; ±1.3; 52% female) and 100 children in the healthy group (mean age 9.2; ±1.3; 42% female). The optimized binary logistic regression analysis revealed a significant association between MIH development and cesarean-section delivery (OR = 3; CI = [1.5-6.2]) and sixth disease (roseola) (OR = 3.5; CI = [1.5-8.0]). CONCLUSIONS: This study suggests that cesarean-section delivery and sixth disease (roseola) might increase the likelihood of MIH development in children.

Anatomical Variations of the Jugular Foramen Region in Patients with Pulsatile Tinnitus.

Objective Structural anomalies of the jugular foramen (JF) and adjacent structures may contribute to development of pulsatile tinnitus (PT). The goal of this study was to assess anatomical variants in the ipsilateral JF region in patients with PT and to explore possible predisposing factors for PT. Methods One hundred ninety-five patients with PT who underwent CT angiography and venography of the temporal bone were retrospectively analyzed. Anatomic variants including dominance of the ipsilateral JF, bony deficiency of the sigmoid sinus and internal carotid artery canal, high riding or dehiscent jugular bulb, dehiscence of the superior semicircular canal, tumors in the JF region, or cerebellopontine angle were assessed. Results Of 195 patients with PT, the prevalence of a dominant JF on the ipsilateral side of patients with PT was 67.2%. Furthermore, the dominant JF demonstrated a significant correlation with the presence of ipsilateral PT ( p < 0.001). No anatomical variants were present in 22 patients (11.3%), whereas in patients with structural variants, bony deficiency of the sigmoid sinus was most common (65.6%), followed by high riding (54.9%) or dehiscent jugular bulb (14.4%). Dehiscent internal carotid artery canal (3.1%) and superior semicircular canal (4.1%) were occasionally identified, while arteriovenous fistula, arterial aneurysm and tumors arising from the JF region or cerebellopontine angle were rarely encountered. Conclusion Structural abnormalities of the JF and adjacent structures may predispose to the development of PT. Knowledge of these anatomical variants in the JF region may help establish a clinical strategy for addressing PT.

Application of exome sequencing for prenatal diagnosis of fetal structural anomalies: clinical experience and lessons learned from a cohort of 1618 fetuses.

BACKGROUND: Exome sequencing (ES) is becoming more widely available in prenatal diagnosis. However, data on its clinical utility and integration into clinical management remain limited in practice. Herein, we report our experience implementing prenatal ES (pES) in a large cohort of fetuses with anomalies detected by ultrasonography using a hospital-based in-house multidisciplinary team (MDT) facilitated by a three-step genotype-driven followed by phenotype-driven analysis framework. METHODS: We performed pES in 1618 fetal cases with positive ultrasound findings but negative for karyotyping and chromosome microarray analysis between January 2014 and October 2021, including both retrospective (n=565) and prospective (n=1053) cohorts. The diagnostic efficiency and its correlation to organ systems involved, phenotypic spectrum, and the clinical impacts of pES results on pregnancy outcomes were analyzed. RESULTS: A genotype-driven followed by phenotype-driven three-step approach was carried out in all trio pES. Step 1, a genotype-driven analysis resulted in a diagnostic rate of 11.6% (187/1618). Step 2, a phenotype-driven comprehensive analysis yielded additional diagnostic findings for another 28 cases (1.7%; 28/1618). In the final step 3, data reanalyses based on new phenotypes and/or clinical requests found molecular diagnosis in 14 additional cases (0.9%; 14/1618). Altogether, 229 fetal cases (14.2%) received a molecular diagnosis, with a higher positive rate in the retrospective than the prospective cohort (17.3% vs. 12.4%, p<0.01). The diagnostic rates were highest in fetuses with skeletal anomalies (30.4%) and multiple organ involvements (25.9%), and lowest in fetuses with chest anomalies (0%). In addition, incidental and secondary findings with childhood-onset disorders were detected in 11 (0.7%) cases. Furthermore, we described the prenatal phenotypes for the first time for 27 gene-associated conditions (20.0%, 27/135) upon a systematic analysis of the diagnosed cases and expanded the phenotype spectrum for 26 (19.3%) genes where limited fetal phenotypic information was available. In the prospective cohort, the combined prenatal ultrasound and pES results had significantly impacted the clinical decisions (61.5%, 648/1053). CONCLUSIONS: The genotype-driven approach could identify about 81.7% positive cases (11.6% of the total cohort) with the initial limited fetal phenotype information considered. The following two steps of phenotype-driven analysis and data reanalyses helped us find the causative variants in an additional 2.6% of the entire cohort (18.3% of all positive findings). Our extensive phenotype analysis on a large number of molecularly confirmed prenatal cases had greatly enriched our current knowledge on fetal phenotype-genotype correlation, which may guide more focused prenatal ultrasound in the future. This is by far the largest pES cohort study that combines a robust trio sequence data analysis, systematic phenotype-genotype correlation, and well-established MDT in a single prenatal clinical setting. This work underlines the value of pES as an essential component in prenatal diagnosis in guiding medical management and parental decision making.

Repeat anatomic surveys performed for an initial incomplete study: the sonographer and physician factors.

BACKGROUND: Repeat obstetrical anatomic surveys are often performed because of incomplete initial studies despite conflicting evidence on their utility. OBJECTIVE: To determine the frequency and yield of repeat obstetrical anatomic surveys performed because of incomplete initial studies and to determine patient and provider factors associated with the recommendation for a second study. STUDY DESIGN: A 10-year retrospective cohort study of women having an initial anatomic survey at 18 weeks to 21 weeks and 6/7 days of gestation at a single nonreferral county hospital. We identified the number of patients needed to scan to detect an anatomic abnormality for the overall cohort and for women having a repeat study. Select patient, sonographer, and reading physician factors were compared between the repeat-ultrasound and no-repeat-ultrasound groups by the 2-sample t test, chi-squared analysis, or analysis of variance, as appropriate. Multivariate logistic regression was used to assess the significance of multiple factors contributing to the recommendation for repeat ultrasounds. RESULTS: A total of 18,911 women had an initial anatomic survey between 18 weeks and 21 weeks and 6/7 days of gestation, and 2310 (12.2%) had a repeat ultrasound because of an incomplete initial study. For the overall cohort, there were 642 structural anomalies detected, with the number of patients needed to scan being 29. Among the 2310 repeat ultrasounds, only 7 structural anomalies were detected, whereas the number of patients needed to scan was 330, representing only 1.1% of all prenatally-identified anomalies. The frequency of recommended repeat ultrasounds varied by performing sonographer (4.5%-45.8%) and reading physician (7.1%-21.6%), both with P<.001 by 1-way analysis of variance. Clinical factors significantly impacting the odds of repeat ultrasounds included body mass index, gestational age, and previous cesarean delivery, but were less impactful than the sonographer and physician. CONCLUSION: The primary determinants of the perceived need for a repeat ultrasound are the sonographer and physician reader, with clinical factors having less but still significant importance. Repeat anatomic surveys account for a significant fraction of our total anatomic surveys and are of limited diagnostic utility. Recommendation of repeat anatomic surveys should be considered within the context of these findings.

Assessment of HCMV-encoded microRNAs in plasma as potential biomarkers in pregnant women with adverse pregnancy outcomes.

BACKGROUND: Human cytomegalovirus (HCMV) is the most frequent cause of congenital infections and can lead to adverse pregnancy outcomes (APOs). HCMV encodes multiple microRNAs (miRNAs) that have been reported to be partially related to host immune responses, cell cycle regulation, viral replication, and viral latency, and can be detected in human plasma. However, the relevance for HCMV-encoded miRNAs in maternal plasma as an indicator for APOs has never been evaluated. METHODS: Expression profiles of 22 HCMV-encoded miRNAs were first measured in plasma samples from 20 pregnant women with APOs and 28 normal controls using quantitative reverse-transcription polymerase chain reaction. Next, markedly changed miRNAs were validated in another independent validation set consisting of 20 pregnant women with APOs and 27 control subjects. Markedly changed miRNAs were further assessed in the placenta tissues. HCMV DNA in peripheral blood leukocytes (PBLs) and anti-HCMV immunoglobulin M (IgM) and anti-HCMV immunoglobulin G (IgG) in plasma were also examined in both training and validation sets. Diagnostic value and risk factors were compared between APO cohorts and normal controls. RESULTS: Analysis of the training and validation data sets revealed that plasma concentrations of hcmv-miR-UL148D, hcmv-miR-US25-1-5p and hcmv-miR-US5-1 were significantly increased in pregnant women with APOs compared with normal controls. Hcmv-miR-US25-1-5p presented the largest area under the receiver-operating characteristic (ROC) curve (AUC) (0.735; 95% CI, 0.635-0.836), with a sensitivity of 68% and specificity of 71%. Furthermore, plasma levels of hcmv-miR-US25-1-5p and hcmv-miR-US5-1 correlated positively with APOs (P=0.029 and 0.035, respectively). Hcmv-miR-US25-1-5p in the placenta tissues were dramatically increased in APOs, and correlated with plasma hcmv-miR-US25-1-5p. Nevertheless, neither the concentration of HCMV DNA in PBLs nor the positivity rates of anti-HCMV IgM and anti-HCMV IgG in plasma showed a statistically significant correlation with APOs. CONCLUSIONS: We identified a unique signature of HCMV-encoded miRNAs in pregnant women with APOs that may be useful as a potential noninvasive biomarker for predicting and monitoring APOs during HCMV infection.

Maternal Mental Health following Ultrasonographic Detection of Fetal Structural Anomaly in the Midst of the COVID-19 Pandemic.

Prenatal ultrasonographic detection of fetal structural anomaly may adversely affect maternal mental health throughout pregnancy, particularly in the current COVID-19 pandemic. This study aims to prospectively assess maternal stress, anxiety, and depression following ultrasonographic detection of fetal structural anomaly from diagnosis until delivery during the COVID-19 pandemic. A total of 141 pregnant women at a tertiary hospital who underwent detailed scans between 16 and 24 gestational weeks were included and categorized into the study (anomaly finding, n = 65) and comparison (normal finding, n = 76) groups. Self-administered questionnaires of 10-item Perceived Stress Scale (PSS-10) and Hospital Anxiety and Depression Scale (HADS) were used to assess maternal stress, anxiety, and depression at prior detection (T1), two-to-four weeks post-detection (T2), one-to-two weeks prior to delivery (T3), and one-to-two weeks post-delivery (T4). Repeated measures of analysis of variance (ANOVA) were conducted to assess time-, between-group, and time-group interaction effect. In general, maternal stress improved, but anxiety worsened, while depression persisted, over the time from T1 to T4. The average maternal stress and anxiety levels were significantly higher among groups with fetal anomaly. The maternal stress and anxiety level were significantly affected within one-to-two weeks post-detection of fetal structural anomaly. In conclusion, maternal mental health parameters were affected differently during the COVID-19 pandemic, with higher vulnerability of stress and anxiety among pregnant women with fetal structural anomaly particularly within one-to-two weeks post-detection.

Preformed pediatric zirconia crown versus preformed pediatric metal crown: study protocol for a randomized clinical trial.

BACKGROUND: Guidelines in pediatric restorative dentistry recommend the use of preformed pediatric stainless steel crowns (SSCs) in cases of severe tooth decay of at least two surfaces. This clinically effective and safe restorative option is frequently refused by parents for esthetic reasons; they prefer conventional restorations using esthetic filling materials (composites, glass ionomer) if lesion severity limited to two surfaces permits. Recently, manufacturers have proposed esthetic preformed pediatric zirconia crowns (ZCs) but these have been assessed in only two randomized clinical trials (RCT) with follow-ups of 6 and 12 months. Only one of these RCTs was carried out on primary molars to test ZCs (NuSmile ZR) without a groove in its inner surface. The primary objective of this proposed RCT is to assess the effectiveness of ZCs compared with SSCs. Our hypothesis is that the effectiveness of ZCs will be equivalent to that of SSCs. METHODS: In this split-mouth, 2-year RCT, pairs of primary molars in 101 child participants will be randomized and restored with SSCs (ESPE, 3M) and ZCs (EZCrowns, Sprig Oral Health Technologies) characterized by grooves on their inner surface. Primary molars will first be allocated to SSCs, and 1 to 2 weeks later the other primary molar of the same pair will be restored by ZC. The primary outcome is the success defined by the "absence of major clinical and radiographic failure" (e.g., pain, pulp infection, dental abscess or periradicular pathology visible on radiographs). The secondary outcomes include the retention and fracture rates, the gingival condition, the wear of the antagonist of the treated teeth, as well as both parental and child satisfaction. DISCUSSION: This study will investigate two types of preformed pediatric crowns for the management of severe decay on primary molars. The results may help practitioners choose the better therapeutic option and to explain to parents the advantages and disadvantages of these two therapies. TRIAL REGISTRATION: NCT03296709 . Registered on  27 September 2017.

Layered patterns in nature, medicine, and materials: quantifying anisotropic structures and cyclicity.

Various natural patterns-such as terrestrial sand dune ripples, lamellae in vertebrate bones, growth increments in fish scales and corals, aortas and lamellar corpuscles in humans and animals-comprise layers of different thicknesses and lengths. Microstructures in manmade materials-such as alloys, perlite steels, polymers, ceramics, and ripples induced by laser on the surface of graphen-also exhibit layered structures. These layered patterns form a record of internal and external factors regulating pattern formation in their various systems, making it potentially possible to recognize and identify in their incremental sequences trends, periodicities, and events in the formation history of these systems. The morphology of layered systems plays a vital role in developing new materials and in biomimetic research. The structures and sizes of these two-dimensional (2D) patterns are characteristically anisotropic: That is, the number of layers and their absolute thicknesses vary significantly in different directions. The present work develops a method to quantify the morphological characteristics of 2D layered patterns that accounts for anisotropy in the object of study. To reach this goal, we use Boolean functions and an N-partite graph to formalize layer structure and thickness across a 2D plane and to construct charts of (1) "layer thickness vs. layer number" and (2) "layer area vs. layer number." We present a parameter disorder of layer structure (DStr) to describe the deviation of a study object's anisotropic structure from an isotropic analog and illustrate that charts and DStr could be used as local and global morphological characteristics describing various layered systems such as images of, for example, geological, atmospheric, medical, materials, forensic, plants, and animals. Suggested future experiments could lead to new insights into layered pattern formation.

The Value of Increased Nuchal Translucency(NT) for the Prediction of Abnormal Pregnancy Outcome / 대한주산의학회잡지

PURPOSE: To evaluate the NT in the first trimester associated with fetal chromosomal abnormality, fetal structural abnormality and adverse pregnancy outcome. METHODS: From Mar. 1993 to Dec. 1997, 133 cases of increased NT were reviewed retrospectively. All these fetues were taken a karyotyping and/or a high resolution ultrasonography for associated anomaly. The NT was measured by transvaginal ultrasonography(TVS) and transabdominal ultrasonography(TAS) if difficulty was encountered with TVS in the period of the 10th-14th week of gestation. The increased NT is approved when it is over 3mm. RESULTS: Of these 133 cases, 102 cases(76.7%) revealed normal outcomes and 31 cases(23.3%) revealed abnormal outcomes such as chromosomal abnormality, structural abnormality and adverse pregnancy outcome, The mean value of NT was 3.44+/-0.68mm in the normal group and 4.93+/-2.70mm in the abnormal group, respectively. The chromosomal abnormalities were found in 16 of the 31 cases: nine Down SD, two Patau syndrome, one Tuner synrome, one triploidy, one 46, XX,i(18q), one 47,iso(Xp)/46,XX one confined placental mosaicism. In 12 cases of the 31 cases, the structural anomalies were detected. Of these 12 cases, 3 cases were eventually developed to cytsic hygroma, 3 cases were cardiac anomaly, 3 cases were renal anomaly, 1 case was congenital diaphragmatic hernia, 1 case was skeletal dysplasia and 1 case was suspected syndrome. The adverse pregnancy outcome such as intrauterine growth restriction, intrauterine fetal death and preterm labor was revealed in 3 cases. In the cases of NT over 7mm, the result was 100% abnormal outcome. CONCLUSION: Increased NT in the first trimester could be a highly efficient the predictor for detection of chromosomal abnormality, structural anomaly and adverse pregnancy outcome.