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Objective: Endometriosis affects up to 10% of reproductive age women and is associated with pelvic pain and subfertility. While previous studies have shown an association between deep and ovarian endometriosis to reduced ovarian reserve, there is no data on the effect of superficial endometriosis on ovarian reserve markers. Hence, we aimed to compare ovarian reserve markers of women with superficial endometriosis to that of women without endometriosis., Methods: This was a case control study in a tertiary medical center. The study group included women aged 18-40 with surgically and histopathology-proven superficial endometriosis with no deep lesions or ovarian involvement. The control group included women with no known or suspected endometriosis and was matched to the study group by age, BMI and parity. We excluded women with other known risk factors for ovarian failure and with other gynecological disorders. Participants completed a questionnaire with demographic, medical and gynecological data. Each patient underwent anti-Mullerian hormone (AMH) testing and an ultrasound to assess their antral follicular count (AFC). AMH and AFC were then compared between groups., Results: A total of 124 women participated in the study. Of these, 50% (n = 62) had surgically proven superficial endometriosis and 50% (n = 62) were without known or suspected endometriosis. Mean AMH levels of women with and without superficial endometriosis was 3.0 ± 2.8 ng/mL and 2.8 ± 1.9 ng/mL, respectively (P = 0.71). AFC also did not differ between groups (women with superficial endometriosis: 12.0 ± 6.6; women without endometriosis: 10.2 ± 5.0, P = 0.15)., Conclusions: In our cohort, superficial endometriosis was not associated with diminished ovarian reserve. While further studies are needed, to date, it does not appear to be justified to assess ovarian reserve for patients with superficial endometriosis., (© 2023 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Background: Preterm birth represents a significant clinical challenge, and the ability to predict it effectively is a priority in obstetrics. The cervix undergoes specific changes during pregnancy, and staging these changes may offer a valuable predictive model for preterm birth, particularly among women with a midtrimester short cervical length., Objective: The study aimed to validate a proposed staging model for asymptomatic women with midtrimester short cervical length and to evaluate its potential for predicting preterm birth. The integration of cervical examination and inspection with cervical length measurement was a novel approach to be assessed., Study Design: This was a multicenter, retrospective cohort study that included 925 pregnant women with a singleton fetus and a midtrimester cervical length measurement of ≤25 mm. Cervical conditions were assessed using ultrasonography, a speculum, and a physical examination and were classified into 1 of 5 cervical stages to correlate with the likelihood of preterm birth. Statistical analyses included Kaplan-Meier survival analysis to illustrate the time-to-event characteristics across the 5 stages and density plot evaluation to visualize the distribution of the gestational ages within the stages., Results: The staging model included 5 stages based on cervical length, appearance, and dilatation. Among the 925 participants, 649 were classified as being stage 1, 245 as stage 2, 18 as stage 3, 10 as stage 4, and 3 as stage 5. The observed rates of preterm birth before 37 weeks for individuals classified in stages 1, 2, 3, 4, and 5 were 22.3%, 26.5%, 44.4%, 60%, and 66.7%, respectively (P=.005). The overall observed rates of preterm birth before 28, 32, 34, and 37 weeks' gestation were 5.5%, 9.9%, 12.2%, and 24.1%, respectively (P=.005)., Conclusion: This study validated the proposed staging criteria as an effective predictor of preterm birth caused by cervical insufficiency. The results demonstrate a significant increase in the preterm birth rate with advancing stage classification, indicating that the staging effectively stratified women based on their risk for preterm birth and highlighting the potential use for targeted interventions. Implementing these staging criteria can potentially improve the counseling and management of pregnant women at risk for preterm birth., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: The modified myocardial performance index (mod-MPI) is a noninvasive Doppler-derived metric used to evaluate fetal cardiac function. However, the reference ranges for mod-MPI in normal fetuses are not clearly defined, which limits the use of this technology in fetuses with potential cardiac compromise. Thus, we aimed to perform a systematic review and meta-analysis of published mod-MPI reference ranges across gestation., Methods: The published literature was systematically searched, and all published articles in any language that provided values for the left ventricular mod-MPI obtained in low-risk, singleton fetuses were considered eligible for further review. All retrieved titles and abstracts were independently reviewed by two researchers. Mean and standard deviation by gestational week was extracted or calculated from published data. DerSimonian-Laird random-effects models were used to estimate pooled means and 95% confidence intervals (CIs)., Results: The search resulted in 618 unique citations, of which 583 did not meet inclusion criteria, leaving 35 abstracts selected for full-text review. Review of the references of these 35 articles identified another 5 studies of interest. Of the 40 articles reviewed, six met inclusion criteria. There was significant heterogeneity seen in the mod-MPI results reported. Mod-MPI increased as pregnancy progressed in all studies. The pooled mean mod-MPI at 11 weeks' gestation was 0.400 (95% CI 0.374-0.426) and increased to 0.585 (95% CI 0.533-0.637) at 41 weeks' gestation. The increase was linear in 5 of 6 studies, while in 1 study, the mod-MPI was stable until 27 weeks' gestation, and then increased throughout the third trimester. Despite all having trends increasing over pregnancy, there was no study in which all the weekly means fell within the pooled 95% CI., Conclusion: While mod-MPI does increase over gestation, the true "reference ranges" for fetuses remain elusive. Future efforts to further optimize calculation of time intervals possibly via automation are desperately needed to allow for reproducibility of this potentially very useful tool to assess fetal cardiac function., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Cholesterol is essential in the brain from the earliest stages of embryonic development. Disruption of cholesterol synthesis pathways that leads to cholesterol deficiency underlies a few syndromes, including desmosterolosis and Smith-Lemli-Opitz syndrome. In both syndromes, brain anomalies can occur. The LSS gene encodes lanosterol synthase (LSS), an important enzyme in the cholesterol biosynthesis pathway. Biallelic pathogenic variants in this gene cause alopecia-intellectual disability type 4 syndrome (APMR4, MIM 618840), a rare autosomal recessive disorder. Here, we describe two new LSS variants (c.1016C > T; p. Ser339Leu and c.1522G > C; p. Gly508Arg) found in a compound heterozygous fetus diagnosed prenatally with brain abnormalities by ultrasound scanning. Two of his siblings from the same parents also harbored these variants. Both siblings had alopecia, mild intellectual disability, autism spectrum disorder, and cataracts. To the best of our knowledge, this case represents the first prenatal diagnosis of APMR4 first suspected by ultrasound. In addition, the phenotypic features of the siblings are extensive compared with those described in previous reports and include abnormal corpus callosum, cataracts, alopecia, and developmental delay., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

We present data from the Heart Rate Variability and Emotion Regulation (HRV-ER) randomized clinical trial testing effects of HRV biofeedback. Younger (N = 121) and older (N = 72) participants completed baseline magnetic resonance imaging (MRI) including T 1 -weighted, resting and emotion regulation task functional MRI (fMRI), pulsed continuous arterial spin labeling (PCASL), and proton magnetic resonance spectroscopy ( 1 H MRS). During fMRI scans, physiological measures (blood pressure, pulse, respiration, and end-tidal CO 2 ) were continuously acquired. Participants were randomized to either increase heart rate oscillations or decrease heart rate oscillations during daily sessions. After 5 weeks of HRV biofeedback, they repeated the baseline measurements in addition to new measures (ultimatum game fMRI, training mimicking during blood oxygen level dependent (BOLD) and PCASL fMRI). Participants also wore a wristband sensor to estimate sleep time. Psychological assessment comprised three cognitive tests and ten questionnaires related to emotional well-being. A subset (N = 104) provided plasma samples pre- and post-intervention that were assayed for amyloid and tau. Data is publicly available via the OpenNeuro data sharing platform., (© 2023. The Author(s).)

Radiation therapy is an effective cancer treatment, although damage to healthy tissues is common. Here we analyzed cell-free, methylated DNA released from dying cells into the circulation to evaluate radiation-induced cellular damage in different tissues. To map the circulating DNA fragments to human and mouse tissues, we established sequencing-based, cell-type-specific reference DNA methylation atlases. We found that cell-type-specific DNA blocks were mostly hypomethylated and located within signature genes of cellular identity. Cell-free DNA fragments were captured from serum samples by hybridization to CpG-rich DNA panels and mapped to the DNA methylation atlases. In a mouse model, thoracic radiation-induced tissue damage was reflected by dose-dependent increases in lung endothelial and cardiomyocyte methylated DNA in serum. The analysis of serum samples from patients with breast cancer undergoing radiation treatment revealed distinct dose-dependent and tissue-specific epithelial and endothelial responses to radiation across multiple organs. Strikingly, patients treated for right-sided breast cancers also showed increased hepatocyte and liver endothelial DNA in the circulation, indicating the impact on liver tissues. Thus, changes in cell-free methylated DNA can uncover cell-type-specific effects of radiation and provide a readout of the biologically effective radiation dose received by healthy tissues.

Objective: Data are lacking on the impact on pregnancy outcome of the position of the abnormal fetus in a discordant twin pregnancy undergoing selective termination (ST). Tissue maceration post ST of the presenting twin may lead to early rupture of membranes, amnionitis and preterm labor. The aim of this study was to evaluate pregnancy complications and outcome following ST of the presenting vs non-presenting twin., Methods: This was a multicenter retrospective cohort study of dichorionic diamniotic twin pregnancies that underwent ST due to a discordant fetal anomaly (structural or genetic) between 2007 and 2021. The study population was divided into two groups according to the position of the reduced twin (presenting or non-presenting) and outcomes were studied accordingly. The primary outcome was a composite of early complications following ST, including infection, preterm prelabor rupture of membranes and pregnancy loss., Results: A total of 190 dichorionic twin pregnancies were included, of which 73 underwent ST of the presenting twin and 117 of the non-presenting twin. The groups did not differ in either baseline demographic characteristics or mean gestational age at the time of the procedure. ST of the presenting twin resulted in a significantly higher rate of early complications compared with the non-presenting twin (19.2% vs 7.7%; P = 0.018). Moreover, the rates of preterm delivery (75.3% vs 37.6%; P < 0.001) and neonatal intensive care unit admission (45.3% vs 17.1%; P < 0.001) were higher, and birth weight was lower (P < 0.001), in those pregnancies in which the presenting twin was reduced., Conclusions: ST of the presenting twin resulted in a higher rate of adverse pregnancy outcome compared with that of the non-presenting twin. These findings should be acknowledged during patient counseling and, if legislation permits, taken into consideration when planning ST. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: To determine whether vaginal progesterone treatment for women with a short cervix, diagnosed after 24 weeks of pregnancy, reduces preterm birth rates., Methods: A retrospective cohort study that included women with a singleton pregnancy, threatened preterm labor, and a short cervix measured between 24 +0 and 33 +6 weeks. Women who received vaginal progesterone were compared with women who did not receive progesterone. The primary outcome was spontaneous preterm birth before 37 weeks of pregnancy., Results: Patients who received vaginal progesterone had a lower rate of preterm delivery at less than 37 weeks of pregnancy (18.2% [22/121] versus 28.9% [73/253]; adjusted hazard ratio 0.50; 95% confidence interval 0.28-0.73, P = 0.001). The diagnosis-to-delivery interval was significantly greater in patients who received progesterone than in those who did not-median time to delivery in weeks: 8.2 (interquartile range [IQR] 6.2-9.8) versus 6.6 (4.8-8.8), (P < 0.001). The frequency of neonatal intensive care unit admission was significantly lower in patients who received progesterone than in those who did not (8.3% [10/121] versus 16.2% [41/253], P = 0.04)., Conclusions: The administration of vaginal progesterone to patients with an episode of threatened premature labor and a short cervix presenting after 24 weeks of pregnancy was associated with lower rates of premature births., (© 2022 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Objectives: Compare two approaches of expectant management in the setting of term premature rupture of membranes (PROM) among women with prior cesarean delivery., Methods: A retrospective study conducted in a tertiary care center during 2006 to 2017, including primiparous women with singleton pregnancy and a prior low-transverse cesarean delivery who presented with term PROM and requested trial of labor after cesarean (TOLAC). Outcomes were compared between the two campuses at our center: campus A enabled expectant management up to 48 hours following PROM and campus B enabled up to 24 hours after PROM., Results: A total of 158 women met the inclusion criteria and were divided into two groups. Maternal characteristics of the two groups were similar. In campus B, the rate of oxytocin administration was significantly higher as compared with campus A (46.6% versus 26.0%, P = 0.01). The rate of successful TOLAC was similar between the groups (84.0% versus 84.5%, P = 0.96). Rates of chorioamnionitis, uterine rupture, postpartum hemorrhage, recurrent hospitalization, and Apg scores did not differ between the groups., Conclusion: Expectant management up to 48 hours in women with TOLAC presenting with term PROM was associated with a lower rate of induction of labor and similar maternal and neonatal outcomes., (© 2022 International Federation of Gynecology and Obstetrics.)

Slow paced breathing via heart rate variability (HRV) biofeedback stimulates vagus-nerve pathways that counter noradrenergic stress and arousal pathways that can influence production and clearance of Alzheimer's disease (AD)-related proteins. Thus, we examined whether HRV biofeedback intervention affects plasma Αβ40, Αβ42, total tau (tTau), and phosphorylated tau-181 (pTau-181) levels. We randomized healthy adults (N = 108) to use slow-paced breathing with HRV biofeedback to increase heart rate oscillations (Osc+) or to use personalized strategies with HRV biofeedback to decrease heart rate oscillations (Osc-). They practiced 20-40 min daily. Four weeks of practicing the Osc+ and Osc- conditions produced large effect size differences in change in plasma Aβ40 and Aβ42 levels. The Osc+ condition decreased plasma Αβ while the Osc- condition increased Αβ. Decreases in Αβ were associated with decreases in gene transcription indicators of β-adrenergic signaling, linking effects to the noradrenergic system. There were also opposing effects of the Osc+ and Osc- interventions on tTau for younger adults and pTau-181 for older adults. These results provide novel data supporting a causal role of autonomic activity in modulating plasma AD-related biomarkers.Trial registration: NCT03458910 (ClinicalTrials.gov); first posted on 03/08/2018., (© 2023. The Author(s).)

Objective: To assess the impact of progesterone treatment on maternal and neonatal outcomes in women with a history of preterm birth and short cervical length diagnosed after 24 weeks of gestation., Methods: A retrospective cohort study included women with a history of preterm birth and a transvaginal sonographic cervical length measurement of ≤ 25 mm, diagnosed between 24 +0 and 33 +6 weeks of gestation. Exclusion criteria included prior progesterone treatment, cervical cerclage, or pessary. The study population was divided into the progesterone treatment group and the non-treatment group., Results: The study included 104 women, with 46.2% (48/104) receiving progesterone treatment and 53.8% (56/104) not receiving treatment. The rate of spontaneous preterm birth before 37 weeks of gestation was 43% (24/56) in the non-treatment group and 31% (15/48) in the progesterone treatment group ( P = 0.14); the rate of spontaneous preterm birth before 34 weeks was 7% (4/56) in the non-treatment group and 0% (0/48) in the progesterone treatment group ( P = 0.05). Progesterone treatment was associated with a significant decrease in neonatal intensive care unit admissions (OR 0.20, 95% CI 0.05-0.74) and in the neonatal hospitalization period (mean difference in days 2.43, 95% CI 0.44-4.42). The risk of recurrent spontaneous preterm birth was highest (71%) among women with two or more previous preterm deliveries who did not receive progesterone treatment, and lowest (24%) among women with one previous preterm delivery who received progesterone treatment., Conclusion: Progesterone treatment was associated with a reduction in rates of spontaneous preterm birth before 34 weeks of gestation, neonatal intensive care unit admission, and neonatal length of stay in high-risk patients, even when initiated after 24 weeks of gestation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Luxenbourg, Porat, Romero, Raif Nesher, Haj Yahya, Sompolinsky, Hochler, Ezra and Kabiri.)

Background: Instant messaging applications for mobile phones have recently grown in popularity among medical personnel, including both physicians and medical students. During the COVID-19 pandemic, medical education was largely transferred to virtual platforms, making such applications an increasingly important tool for medical education. "Siilo" is a secure instant messaging application that was designed for medical professionals, and offers several advantages over other instant messaging services that are vital for its use in medical settings, including information security, data encryption, and a built-in blurring tool to maintain patient privacy. In addition, Siilo allows for the creation of individual folders for each case, enabling users to conduct separate discussions about multiple patients simultaneously., Objective: To evaluate student satisfaction in a case-based learning program using Siilo as a medical education tool in improving student learning outcomes and motivation., Methods: A case-based learning program was conducted with 24 fifth-year medical students using Siilo to evaluate its effectiveness as a medical education tool. The program was evaluated through the use of pre- and post-program questionnaires and focus group discussions to assess student satisfaction., Results: The majority of students (83.3%) were highly satisfied with the Siilo platform and felt that it enhanced their learning experience, and a majority of students (79.1%) reported that the program was highly effective. Students reported that the platform was easy to use and provided a clear and organized way to follow discussions about cases. The focus group discussions further revealed that students appreciated the real-time communication and felt that the use of Siilo helped to improve the quality of communication and collaboration during the learning process. The use of Siilo as a medical education tool was found to contribute to positive relationships between doctors and students and improve student motivation for learning and outcomes., Conclusion: These findings suggest that Siilo can be a valuable resource for medical education, particularly due to its secure and convenient features, which are well-suited for use in medical settings. The use of Siilo in a case-based learning program was found to be effective in improving student satisfaction and learning outcomes and contributed to positive relationships between doctors and students. These results highlight the potential for utilizing mobile instant messaging apps as a tool for enhancing clinical teaching in medical education., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shahar, Tadmor, Dior, Porat, Safrai, Ezra and Kabiri.)

Background: SARS-CoV-2 infection during early infancy can result in severe disease. We evaluated the durability of maternally-derived anti-SARS-CoV-2 antibodies in infants and its relation to antenatal vaccination timing., Methods: Sera were prospectively collected at birth and 3 months after delivery from mother-infant pairs following antenatal BNT162b2 vaccination. SARS-CoV-2 receptor binding domain (RBD)-specific IgG levels and neutralizing activity were evaluated., Results: 56 mother-infant pairs were included: 15 (26.8%) were vaccinated in the first trimester, 16 (28.6%) in the second trimester, and 25 (44.6%) in the third trimester.At the time of delivery, all neonates were positive for anti-RBD-specific IgG with a median concentration of 4046 [IQR 2446-7896] AU/mL, with the highest concentration found after third trimester vaccination (median 6763 [IQR 3857-12561] AU/mL). At 3 months after delivery, anti RBD-specific IgG levels in infants significantly waned with a median concentration of 545 [IQR 344-810] AU/mL (P < .001). The half-life of anti-RBD-specific IgG was 66 days among mothers and 30 days among infants. While at the time of delivery, all neonates had detectable neutralizing activity regardless of gestational age at vaccination, at 3-months of age, a higher proportion of infants born to mothers vaccinated in third trimester had persistent neutralizing activity as compared to those born to mothers vaccinated in second trimester., Conclusions: Maternal vaccination leads to efficient transplacental antibody transfer, with persistent anti-SARS-CoV-2 antibodies detected at 3 months of age in all infants. The observed effect of antenatal immunization timing on the kinetics of maternally-derived antibodies may have implications for SARS-CoV-2 vaccination strategies., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose:  To conduct a systematic review and meta-analysis of published nomograms for fetal vermis biometry., Materials and Methods:  A structured literature search was conducted to identify studies that reported normal measurements of the fetal vermis. A customized quality assessment tool was used to review the selected articles. Random effects meta-analysis was used to calculate normal ranges for vermian craniocaudal diameter, anteroposterior diameter, and surface area., Results:  A total of 21 studies were included for qualitative review and 3 studies were included for quantitative synthesis. The 3 included articles comprised a total of 10 910 measurements from gestational ages 17-35 weeks. The quality assessment demonstrated that there was generally poor reporting regarding maternal characteristics and neonatal outcomes. Except for one article with a large sample size, the mean number of fetuses per week of gestational age was 15.9, with the lowest number being 5. There was significant statistical heterogeneity. Non-visualization rates ranged from 0-35.4 %. The craniocaudal diameter (reported in 3 articles) increased from a mean of 7.90 mm (95 % confidence interval [CI] 7.42, 8.38) at 17 weeks to 21.90 mm (95 % CI 20.63, 23.16) at 35 weeks gestation. The anteroposterior diameter (reported in 2 articles) increased from 6.30 mm (95 % CI 5.42, 7.18) at 17 weeks to 15.85 (95 %CI 15.49, 16.21) at 32 weeks., Conclusion:  Reference ranges for vermis biometry across gestation based on meta-analysis of existing references are provided. However, because many of the underlying studies suffered from significant methodological issues, the ranges should be used with caution., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

The yield of chromosomal microarray analysis (CMA) is well established in structurally normal fetuses (0.4-1.4%). We aimed to determine the incremental yield of exome sequencing (ES) in this population. From February 2017 to April 2022, 1,526 fetuses were subjected to ES; 482 of them were structurally normal (31.6%). Only pathogenic and likely pathogenic (P/LP) variants, per the American College of Medical Genetics and Genomics (ACMG) classification, were reported. Additionally, ACMG secondary findings relevant to childhood were reported. Four fetuses (4/482; 0.8%) had P/LP variants indicating a moderate to severe disease in ATP7B, NR2E3, SPRED1 and FGFR3, causing Wilson disease, Enhanced S-cone syndrome, Legius and Muenke syndromes, respectively. Two fetuses had secondary findings, in RET and DSP. Our data suggest that offering only CMA for structurally normal fetuses may provide false reassurance. Prenatal ES mandates restrictive analysis and careful management combined with pre and post-test genetic counseling., (© 2022. The Author(s), under exclusive licence to European Society of Human Genetics.)

Purpose: As the use of the messenger RNA (mRNA) BNT162b2 (Pfizer-BioNTech) Coronavirus disease 2019 vaccine has grown, reports on menstrual changes have arisen. We aimed to examine menstrual bleeding patterns and endometriosis-associated symptoms after receiving the mRNA BNT162b2 SARS-CoV-2 vaccine in women with endometriosis, as compared to the control group., Methods: This is a questionnaire-based cross-sectional study including a total of 174 women. The study group included 86 women with a confirmed diagnosis of endometriosis and the control group included 88 women with no diagnosis or suspected diagnosis of endometriosis. Each woman completed a questionnaire on menstrual bleeding patterns and endometriosis-associated symptoms before and after receiving two doses of the BNT162b2 vaccine. Primary outcomes were changes in amount or length of menstrual bleeding, rates of intermenstrual bleeding and worsening in dysmenorrhea in the endometriosis patient group, as compared to the control group. Secondary outcomes included changes in all endometriosis-associated symptoms., Results: In our cohort, women with endometriosis were more likely to experience changes in bleeding patterns (women with endometriosis: 39.5%, control group: 31.0%, p = 0.02), and a significant worsening in endometriosis-associated symptoms with an almost 4.3-fold worsening in dysmenorrhea [95% CI 1.9-9.9, p < 0.01] and 5.5-fold odds for any worsening in symptoms in endometriosis patients, as compared to the control group [95% CI 2.7-11.1, p < 0.01]., Conclusion: In our cohort, endometriosis was shown to be a significant risk factor for worsening of menstrual symptoms, after receiving the SARS-CoV-2 BNT162b2 mRNA vaccine. Further research is needed to confirm these findings., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

DNA methylation is a fundamental epigenetic mark that governs gene expression and chromatin organization, thus providing a window into cellular identity and developmental processes 1 . Current datasets typically include only a fraction of methylation sites and are often based either on cell lines that underwent massive changes in culture or on tissues containing unspecified mixtures of cells 2-5 . Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing, allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 205 healthy tissue samples. Replicates of the same cell type are more than 99.5% identical, demonstrating the robustness of cell identity programmes to environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny and identifies methylation patterns retained since embryonic development. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hypermethylated loci are rare and are enriched for CpG islands, Polycomb targets and CTCF binding sites, suggesting a new role in shaping cell-type-specific chromatin looping. The atlas provides an essential resource for study of gene regulation and disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies., (© 2023. The Author(s).)

Objective: To investigate the impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA BNT162b2 vaccine on women's menstrual cycle., Methods: In this questionnaire-based cross-sectional study, we assessed menstrual pattern and changes in women who completed the SARS-CoV-2 mRNA BNT162b2 vaccine 3 months before and after receiving the vaccine. Included were women aged 18-50 years without known gynecologic comorbidities who regularly monitor their menstruation through electronic calendars. All participants competed a detailed questionnaire on their menstrual symptoms including information on any irregular bleeding. To minimize bias, each woman served as a self-control before and after vaccination. Primary outcome was rate of irregular bleeding following vaccination and secondary outcome was presence of any menstrual change, including irregular bleeding, mood changes, or dysmenorrhea following the vaccine., Results: A total of 219 women met the inclusion critieria. Of them, 51 (23.3%) experienced irregular bleeding following the vaccine. Almost 40% (n = 83) of study participants reported any menstrual change following vaccination. Parity was positively asssociated with irregular bleeding with 26 (50%) of those suffering from irregular bleeding being multiparous compared with only 53 (31.5%) of women with no irregular bleeding (nulliparous 46% vs 60%, multiparous 50% vs 31%, rest 4% vs 8%, P = 0.049). The presence of medical comorbidities was also significantly higher among patients who experienced irregular bleeding (20.0% vs 6.0%, P = 0.003)., Conclusion: Our study shows relatively high rates of irregular bleeding and menstrual changes after receiving the SARS-CoV-2 mRNA BNT162b2 vaccine. Further research is needed to confirm our findings and to better characterize the magnitude of change and any possible long-term implications., (© 2022 International Federation of Gynecology and Obstetrics.)

Objective: Subgaleal hemorrhage (SGH) is a severe neonatal morbidity that is associated with vacuum-assisted delivery (VAD). Large sonographic head circumference (sHC) was previously associated with complicated VAD. Nevertheless, the association of large sHC with SGH formation following VAD is underreported. We aim to evaluate the role of sonographic head circumference (sHC) with SGH formation following attempted VAD., Methods: A retrospective case-control study. Cases comprised singleton pregnancies for whom attempted VAD resulted in SGH with an sHC measured within 2 weeks from delivery. Controls were VAD deliveries which not resulted in SGH, with an sHC measured within 2 weeks from delivery. We matched controls in a 1:1 ratio by gestational age, parity and year of delivery., Results: Overall, 118 women were included in the SGH study group and were matched to 118 controls. Baseline maternal and fetal characteristics were similar between the groups except for higher neonatal birth weight in the SGH group (median 3422 vs. 3195 grams, p  = .001). sHC did not vary between groups (median 336 mm in SGH groups vs. 333, p  = .08). Rate of sHC >90th and >95th percentile did not significantly differ between the groups (13.6% vs. 8.5%, 6.8% vs. 3.4%, p  = .21, p  = .37, for SGH vs. controls, respectively). In multivariate regression analysis, sHC was not found to be independently associated with SGH - aOR (95% CI) 1.004 (0.97-1.03). Receiver operating characteristic curves of sHC for SGH formation underlined an area under the curve of 0.58 (95% CI) (0.51-0.65)., Conclusions: sHC is not associated with SGH formation following VAD.

Objectives: To elucidate the influence of parental biometric factors on fetal birthweight (BW)., Study Design: This prospective study was conducted between 2015 and 2017 in Hadassah University Hospital. Inclusion criteria included singletons that were born to healthy mothers at 37-41 weeks' gestation and had no growth abnormality or congenital malformation. Maternal and paternal head circumference, weight, and height were measured. Other data including neonatal head circumference and neonatal birthweight were also collected. Neonatal head circumference and birthweight percentiles were converted to sex-specific ranks according to the neonatal Intergrowth 21 charts (rank = 1 for percentile <3, rank = 2 for percentile 3-10, etc.)., Results: One hundred and ninety-nine trios (mother, father, and neonate) were included in the final analysis. In univariate analysis, maternal head circumference ( p  = .006), maternal height ( p  = .001), maternal weight before pregnancy ( p  < .001), maternal weight at term ( p  < .001), gestational weight gain ( p  = .009), paternal height ( p  = .018), neonatal head circumference ( p  < .001), and neonatal head circumference percentile rank ( p  < .001) were significant predictors of neonatal birthweight percentile rank. In multivariate regression, the three factors that were significant independent predictors of neonatal birthweight percentile rank were maternal weight before pregnancy ( p  = .047), maternal weight at term ( p  = .01), and neonatal head circumference percentile rank ( p  < .001). No interaction was found between neonatal sex and any of the tested variables. Neonatal sex-specific multivariate analysis showed that maternal height ( p  = .013), gestational weight gain ( p  = .005), and neonatal head circumference percentile rank ( p  < .001) were predictors of birthweight percentile rank in males. Maternal weight at term ( p  < .001) and neonatal head circumference percentile rank ( p  < .001) were predictors of birthweight percentile rank in females., Conclusions: Maternal height and weight parameters as well as neonatal head circumference percentile rank were found to be independent predictors of birthweight percentile rank. Paternal parameters did not show any significant association in multivariable analysis. The biological regulation of fetal size is assumed to be the result of strong evolutionary selection. As the fetus must pass through the mother's birth canal, there should be a natural match between maternal and fetal size to ensure the successful birth and survival of mother and offspring.

Background: Currently, the use of FE is decreasing and neonatal adverse outcomes following FE are underreported. We aimed to evaluate the rate of neonatal adverse outcomes in current obstetric practice at two university hospitals with a low FE volume., Methods: A multicentre retrospective study. All singleton pregnancies delivered by forceps extraction between 2011 and 2020 were analyzed. The characteristics of the deliveries with a composite neonatal adverse outcome (CNAO) were analyzed and compared with those without., Results: The study cohort included 861 neonates delivered by FE. The CNAO was recorded in 131 (15.2%). Women in the CNAO group gained less weight during pregnancy (mean 13 kg vs. 15 kg, p  = .014). Factors found to be associated with CNAO were preterm delivery (gestational age < 37° /7 ) (26 (19.8%) vs. 44 (6.0%), OR [95% CI]: 3.86 (2.28-6.52), p  < .001), low birth weight (23 (17.6%) vs. 44 (6.0%), OR [95% CI] 3.32 (1.92-5.71), p  < .001), and smaller head circumference (329 vs. 331 mm, OR [95% CI] 0.79 (0.67-0.93), p  = .035). In a multivariate analysis, gestational age (adjusted OR [95% CI] 0.672 (0.546-0.826), p  < .001) and maternal weight gain during pregnancy (adjusted OR [95% CI]: 0.950 (0.904-0.998), p  = .042), were both negatively associated with CNAO. Among term deliveries, the only factor found to be independently associated with CNAO was maternal weight gain during pregnancy (adjusted OR [95% CI]: 0.951 (0.910-0.994), p  = .025)., Conclusions: In the setting of low volume FE, this mode of delivery is associated with a relatively low rate of neonatal morbidity., Synopsis: Performance of forceps extraction in the setting of low volume practice is associated with a relatively low rate of neonatal morbidity.

Objective: Although repeated antenatal corticosteroids (ACS) courses are not recommended, a single rescue ACS course has been shown to decrease neonatal morbidity among preterm singletons. However, little is known regarding the effects of rescue ACS course in twin pregnancies., Methods: A retrospective cohort study conducted during 2015-2017 at a tertiary-care center including all twins delivered between 24-34 weeks of gestation who received at least one course of ACS., Results: Overall, 162 (70.4%) twins were exposed to a single ACS course and 68 (29.6%) to an additional rescue ACS course. Rescue ACS course was associated with lower rates of respiratory distress syndrome (7.4% vs. 19.1%, p  = .03), surfactant use (7.4% vs 18.5%, p  = .04) and bronchopulmonary dysplasia (0 vs 8.6%, p  = .01) as compared to a single ACS course. In the rescue ACS group, compared to the single ACS group, the rates of composite respiratory adverse outcome (10.3% vs 22.2%, OR [95% CI]: 0.40 (0.17-0.95), p  = .04) and any adverse neonatal outcome (13.2% vs 26.5%, OR [95% CI]: 0.42 (0.19-0.92), p  = .04) were significantly lower. Hospital stay was also shorter among neonates born to mothers receiving a rescue ACS course (median 23 vs. 30 days, p  = .01). No differences were noted in neonatal birthweight, head circumference and the rate of neonatal hypoglycemia., Conclusion: Rescue ACS course was associated with improved respiratory and neonatal outcomes in twin gestations. Further studies are warranted to confirm our findings and better delineate the optimal regimen of rescue ACS in this setting.

Objectives: We aimed to assess the risk of preterm birth in those with real-time dynamic cervical shortening., Methods: A retrospective matched case-control study. The study group comprised all women with dynamic cervical shortening (≥4 mm) noted from 24 to 34 weeks of gestation during 2010-2017 at a university hospital. Two control groups of women were established by matching the minimal and maximal cervical length measured, as well as age, parity, gestational age, history of spontaneous preterm birth, symptoms of preterm labor, and delivery year., Results: Data from 339 women were analyzed, 113 with dynamic cervical shortening comprised the study group, and two groups with 113 women each, matched for the minimal and maximal cervical lengths measured comprised the control groups. Rates of spontaneous preterm birth rate at <37 weeks (32.7% vs. 15.9%; OR [95% CI]: 2.60 (1.36, 4.87), p  = .004) and <35 weeks (15.9% vs. 5.3%; OR [95% CI]: 3.38 (1.29, 8.86), p  = .013) were significantly higher among those with dynamic cervix than among the control group matched for the maximal cervical length, and comparable to the control group matched for the minimal cervical length. The negative predictive values of cervical length for preterm birth occurrence at various cutoff values were lower in those with dynamic cervix., Conclusions: The minimal cervical length measured should be used to guide patient management when dynamic cervix is noted. In the setting of dynamic cervical change, the value of cervical length as a negative predictor of preterm birth is limited.

We evaluated the neutralization efficiency against SARS-CoV-2 Omicron variant in maternal and cord blood sera after antenatal BNT162b2 vaccination. Neutralizing antibodies against Omicron were lacking at the time of delivery after 2-dose vaccination. A third booster dose was essential in building neutralizing antibody capacity against Omicron among mothers and neonates., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Induction of labor in women with a previous cesarean section (CS) is associated with increased rates of uterine rupture and failed attempt for vaginal delivery. Prostaglandins use is contraindicated in this population, limiting available options for cervical ripening., Objective: To evaluate the efficacy and safety of artificial rupture of membranes (AROM) as a mode of Induction of labor (IOL) in women with a previous cesarean section., Methods: A retrospective cohort study conducted in a single tertiary care center between January 2015 and October 2020. Women with one previous cesarean section and a current singleton term pregnancy requiring IOL, with an unfavorable cervix, were included. The primary outcome was a successful vaginal delivery (VBAC); secondary outcomes were rates of chorioamnionitis, uterine rupture and low Apgar score (< 7)., Results: Of the 665 women who met the inclusion criteria, 492 (74%) did not receive subsequent oxytocin and 173 (26%) did. There were significant differences in the baseline characteristics between these two groups, including maternal age, cervical dilation at presentation, parity, and a history of a previous VBAC. Among women who were induced solely by AROM the rate of a successful TOLAC was higher (81.3% vs 73.9%), total time of IOL was shorter (mean 8.7 h vs.16.1 h) and the risk of chorioamnionitis was lower (7.3% vs 18.4%). When subdividing the women who received oxytocin into early (< 12 h after AROM) vs late (> 12 h after AROM) administration, there were no significant changes in the rates of successful VBAC or of chorioamnionitis., Conclusion: AROM as a single mode of IOL in women with a previous CS is a safe and efficient practice with high rates of successful VBAC. When spontaneous labor does not develop, there is no advantage to delay the administration of oxytocin., (© 2022. The Author(s).)

Previous studies indicate that the structure and function of medial prefrontal cortex (PFC) and lateral orbitofrontal cortex (OFC) are associated with heart rate variability (HRV). Typically, this association is assumed to reflect the PFC's role in controlling HRV and emotion regulation, with better prefrontal structural integrity supporting greater HRV and better emotion regulation. However, as a control system, the PFC must monitor and respond to heart rate oscillatory activity. Thus, engaging in regulatory feedback during heart rate oscillatory activity may over time help shape PFC structure, as relevant circuits and connections are modified. In the current study with younger and older adults, we tested whether 5 weeks of daily sessions of biofeedback to increase heart rate oscillations (Osc+ condition) vs. to decrease heart rate oscillations (Osc- condition) affected cortical volume in left OFC and right OFC, two regions particularly associated with HRV in prior studies. The left OFC showed significant differences in volume change across conditions, with Osc+ increasing volume relative to Osc-. The volume changes in left OFC were significantly correlated with changes in mood disturbance. In addition, resting low frequency HRV increased more in the Osc+ than in the Osc- condition. These findings indicate that daily biofeedback sessions regulating heart rate oscillatory activity can shape both resting HRV and the brain circuits that help control HRV and regulate emotion., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest with respect to authorship or the publication of this article., (Copyright © 2022 Elsevier B.V. All rights reserved.)

We conducted a systematic review and meta-analysis of published nomograms for fetal corpus callosum and cavum septi pellucid biometry. A structured literature search was conducted to identify studies that reported normal measurements of the fetal corpus callosum and cavum septi pellucidi. Random effects metaanalysis was used to calculate normal ranges, and reference curves are provided. The quality assessment demonstrated that there was generally poor reporting regarding maternal characteristics and neonatal outcomes. Our findings emphasize that standardization of research protocols and publishing criteria for normal biometric ranges is needed., (© 2021 American Institute of Ultrasound in Medicine.)

Objectives: To determine the risk of spontaneous preterm birth (sPTB) associated with the length of second stage of labour in the first term delivery., Design: Retrospective cohort study., Setting: University hospital., Population: Women with first two consecutive singleton births and the first birth at term. Those who did not reach the second stage of labour in the first delivery were excluded., Methods: Charts from 2007 to 2019 were reviewed., Main Outcome Measures: Rate of sPTB (<37 weeks of gestation) in the second delivery., Results: Of 13 958 women who met study inclusion criteria, 1464 (10.5%) parturients had a prolonged second stage (≥180 min) in their first term delivery. The rate of sPTB in the second delivery was similar in those with and without a prolonged second stage in first delivery (2.8% versus 2.8%; adjusted odds ratio [aOR] 1.35, 95% CI 0.96-1.90). After adjustment for mode of delivery, prolonged second stage was also not associated with subsequent sPTB in those who delivered by spontaneous and operative vaginal delivery. Those delivered by second-stage caesarean section in the first delivery had a higher risk of sPTB in the second delivery (25/526, 4.8%; aOR 2.66, 95% CI 1.71-4.12; p < 0.001), with a more pronounced risk in those with second-stage caesarean following a prolonged second stage of labour (15/259, 5.8%; aOR 3.40, 95% CI 1.94-5.94; p < 0.001)., Conclusion: Second-stage duration in a first term vaginal delivery is not associated with subsequent sPTB. The risk of sPTB is increased following second-stage caesarean section, particularly if performed after a prolonged second stage., Tweetable Abstract: Second-stage caesarean delivery, particularly after prolonged second stage, increases the risk of preterm birth., (© 2022 John Wiley & Sons Ltd.)

Background: Coronavirus disease 2019 (COVID-19) during pregnancy and early infancy can result in severe disease. Evaluating the effect of gestational age at the time of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination on maternal antibody levels and transplacental antibody transfer has important implications for maternal care and vaccination strategies., Methods: Maternal and cord blood sera were collected from mother-newborn dyads (n = 402), following term delivery after antenatal 2-dose SARS-CoV-2 BNT162b2 mRNA vaccination. SARS-CoV-2 spike protein (S) and receptor binding domain (RBD)-specific IgG levels were evaluated in the samples collected., Results: Median anti-S and anti-RBD-specific IgG levels in maternal sera at the time of delivery were lowest following first-trimester vaccination (n = 90; anti-S IgG: 76 AU/mL; anti-RBD-specific IgG: 478 AU/mL), intermediate in those vaccinated in the second trimester (n = 124; anti-S IgG: 126 AU/mL; anti-RBD-specific IgG: 1263 AU/mL), and highest after third-trimester vaccination (n = 188; anti-S IgG: 240 AU/mL; anti-RBD-specific IgG: 5855 AU/mL). Antibody levels in neonatal sera followed a similar pattern and were lowest following antenatal vaccination in the first trimester (anti-S IgG: 126 AU/mL; anti-RBD-specific IgG: 1140 AU/mL). In a subgroup of parturients vaccinated in the first trimester (n = 30), a third booster dose was associated with significantly higher maternal and neonatal antibody levels., Conclusions: These results suggest a considerable antibody waning throughout pregnancy in those vaccinated at early gestation. The observed boosting effect of a third vaccine dose hints at its potential benefit in those who completed the 2-dose vaccine series at early pregnancy or before conception. The impact of antenatal immunization timing on SARS-CoV-2 transplacental antibody transfer may influence neonatal seroprotection., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Group A Streptococcus (GAS; Streptococcus pyogenes ) is a facultative gram-positive coccus, uncommonly colonizing parturient genitalia, where its presence can potentially lead to a life-threatening invasive infection after delivery. GAS infection typically occurs within the first 4 days post-partum and is characterized by high fever, chills, flashing, abdominal pain, and uterine tenderness. Nonetheless, patients with GAS puerperal sepsis may have an unusual presentation, when fever is absent, and the symptoms and signs can be mild, non-specific, and not indicative of the severity of infection. This unusual presentation may lead to a delayed diagnosis and increase the risk for severe puerperal sepsis. Therefore, in these cases, a high index of suspicion and prompt early antibiotic and surgical treatment is crucial to saving the parturient's life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kabiri, Prus, Alter, Gordon, Porat and Ezra.)

Objective: To determine the factors associated with neonatal hypoglycemia among neonates exposed to antenatal corticosteroid (ACS)., Methods: A retrospective study conducted during 2017-2019 at a tertiary-care center including all neonates delivered between 24 and 34 weeks of gestation after ACS administration. The primary outcome was neonatal hypoglycemia (<40 mg/dl)., Results: Overall, 362 early preterm neonates, including 205 singletons and 157 twins, were exposed to ACS before delivery and constituted the study group. Of them, 275 (76.0%) were exposed to a single ACS course and 87 (24.0%) to an additional rescue ACS course. Neonatal hypoglycemia occurred in 84 (23.2%) neonates. The incidence of neonatal hypoglycemia was significantly higher in those delivered between 24 and 48 h after ACS administration compared with those delivered outside this time interval (10/25, 40.0% vs 74/337, 21.9%; P = 0.049). In multivariate analysis, after adjusting for neonatal birth weight and gestational age, delivery within 24-48 h after ACS administration was the only independent risk factor associated with neonatal hypoglycemia (adjusted odds ratio 2.41, 95% confidence interval 1.03-5.68; P = 0.044)., Conclusion: Neonatal hypoglycemia occurred in over one-fifth of those exposed to ACS, and was independently associated with delivery between 24 and 48 h after ACS administration., (© 2021 International Federation of Gynecology and Obstetrics.)

Key Message: Spontaneous labor onset, epidural anesthesia and prior cesarean for non-arrest disorders are strong predictors of successful vaginal birth after cesarean in women delivering a macrosomic fetus., Purpose: Lower rates of successful vaginal birth after cesarean in association with increasing birthweight were previously reported. We aimed to determine the factors associated with successful trial of labor after cesarean (TOLAC) among primiparous women with fetal macrosomia., Methods: A retrospective cohort study conducted during 2005-2019 at two university hospitals, including all primiparous women delivering a singleton fetus weighing ≥ 4000 g, after cesarean delivery at their first delivery. A multivariate analysis was performed to evaluate the characteristics associated with TOLAC success (primary outcome)., Results: Of 551 primiparous women who met the inclusion criteria, 50.1% (n = 276) attempted a TOLAC and 174 (63.0%) successfully delivered vaginally. In a multivariate analysis, spontaneous onset of labor (aOR [95% CI] 3.68 (2.05, 6.61), P < 0.001), epidural anesthesia (aOR [95% CI] 2.38 (1.35, 4.20), P = 0.003) and history of cesarean delivery due to non-arrest disorder (aOR [95% CI] 2.25 (1.32, 3.85), P = 0.003) were the only independent factors associated with TOLAC success. Successful TOLAC was achieved in 82.0% (82/100) in the presence of all three favorable factors, 61.3% (65/106) in the presence of two factors and 38.6% (27/70) in the presence of one or less of these three factors (P < 0.001)., Conclusion: Spontaneous onset of labor, epidural anesthesia and prior cesarean delivery due to non-arrest disorders were independently associated with higher vaginal birth after cesarean rate among women with fetal macrosomia, with an overall favorable success rate in the presence of these factors. These findings should be implemented in patient counseling in those contemplating a vaginal birth in this setting., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To explain the importance of identifying an etiology for the pathological finding of nonimmune hydrops fetalis (NIHF) and to explore the impact of exome sequencing in recurrent NIHF. In addition, we present two cases of pregnancies affected with recurrent NIHF, in which genetic investigation was advantageous., Methods: Our study aimed to investigate the genetic background, if available, of all fetuses with NIHF referred to our tertiary medical center from January 2013 to August 2020. We summarized the etiology of NIHF if known, sonographic findings, genetic investigation and the pregnancies' outcomes., Results: We encountered 144 families with NIHF. Genetic investigation was performed by chromosomal microarray analysis (CMA) in 63 (63/144. 44%) fetuses. Seventeen of 63 (27%) had a positive CMA result. In the negative CMA group, 15 (15/46, 33%) opted for exome sequencing, of which seven exomes were positive (47%). Among these, there were four couples with recurrent pregnancies affected by hydrops. Among the remaining 11 exome investigations for non-recurrent hydrops, another three were diagnostic., Conclusion: As identifying the etiology of the NIHF is an invaluable tool for the prognosis of the pregnancy, exome sequencing can provide further elucidation of the underlying pathogenesis of NIHF. Thus, genetic investigation should be recommended for cases of NIHF., (© 2021 John Wiley & Sons Ltd.)

Objectives: Although hyponatremia in preeclamptic patients was previously described, its significance remains unknown. We aimed to describe the prevalence and clinical significance of hyponatremia among a cohort of preeclamptic patients., Methods: An electronic medical record based retrospective cohort study included all singleton deliveries at Hadassah University Medical Center between 2003 and 2015. Preeclampsia, with and without severe features, was defined using the American College of Obstetrics and Gynecology (ACOG) Hypertension in Pregnancy Guidelines. Hyponatremia was defined as a sodium (Na) level ≤130 mEq/L, and severe hyponatremia as <125 mEq/L. A group of normotensive pregnant women, matched for gestational age, gravdity and parity, served as control., Results: A total of 700 preeclamptic patients were identified during the study period. Hyponatremia was noted in 14.6% compared to 0 of 79 patients in the control group. Hyponatremia was strongly correlated with severe features of preeclampsia, adverse neonatal and obstetrical outcome. Severe hyponatremia was strongly correlated with preeclampsia with severe features. Furthermore, even among subgroup of preeclamptic patients without severe features, hyponatremia correlated with less favorable pregnancy outcomes., Conclusions: Among relatively large cohort of preeclamptic patients, hyponatremia was not a rare finding. We found it more common in patients with preeclampsia and severe features. As women with preeclampsia are at risk for hyponatremia, serum sodium levels should be monitored, especially in those with severe features. In preeclamptic patients without severe features, hyponatremia may indicate a need for closer surveillance. However, larger studies are needed to establish hyponatremia as a marker of severity., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

The noradrenergic locus coeruleus (LC) is a small brainstem nucleus that promotes arousal and attention. Recent studies have examined the microstructural properties of the LC using diffusion-weighted magnetic resonance imaging and found unexpected age-related differences in fractional anisotropy - a measure of white matter integrity. Here, we used two datasets (Berlin Aging Study-II, N = 301, the Leipzig Study for Mind-Body-Emotion Interactions, N = 220), to replicate published findings and expand them by investigating diffusivity in the LC's ascending noradrenergic bundle. In younger adults, LC fractional anisotropy was significantly lower, compared to older adults. However, in the LC's ascending noradrenergic bundle, we observed significantly higher fractional anisotropy in younger adults, relative to older adults. These findings indicate that diffusivity in the LC versus the ascending noradrenergic bundle are both susceptible to structural changes in aging that have opposing effects on fractional anisotropy., Competing Interests: Declaration of Competing Interest None., (Published by Elsevier Inc.)

Researchers generally agree that when upregulating and downregulating emotion, control regions in the prefrontal cortex turn up or down activity in affect-generating brain areas. However, the "affective dial hypothesis" that turning up and down emotions produces opposite effects in the same affect-generating regions is untested. We tested this hypothesis by examining the overlap between the regions activated during upregulation and those deactivated during downregulation in 54 male and 51 female humans. We found that upregulation and downregulation both recruit regulatory regions, such as the inferior frontal gyrus and dorsal anterior cingulate gyrus, but act on distinct affect-generating regions. Upregulation increased activity in regions associated with emotional experience, such as the amygdala, anterior insula, striatum, and anterior cingulate gyrus as well as in regions associated with sympathetic vascular activity, such as periventricular white matter, while downregulation decreased activity in regions receiving interoceptive input, such as the posterior insula and postcentral gyrus. Nevertheless, participants' subjective sense of emotional intensity was associated with activity in overlapping brain regions (dorsal anterior cingulate, insula, thalamus, and frontal pole) across upregulation and downregulation. These findings indicate that upregulation and downregulation rely on overlapping brain regions to control and assess emotions but target different affect-generating brain regions. SIGNIFICANCE STATEMENT Many contexts require modulating one's own emotions. Identifying the brain areas implementing these regulatory processes should advance understanding emotional disorders and designing potential interventions. The emotion regulation field has an implicit assumption we call the affective dial hypothesis: both emotion upregulation and downregulation modulate the same emotion-generating brain areas. Countering the hypothesis, our findings indicate that up- and down-modulating emotions target different brain areas. Thus, the mechanisms underlying emotion regulation might differ more than previously appreciated for upregulation versus downregulation. In addition to their theoretical importance, these findings are critical for researchers attempting to target activity in particular brain regions during an emotion regulation intervention., (Copyright © 2022 the authors.)

Objective: We aimed to assess the impact of early versus late third-trimester maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination on transplacental transfer and neonatal levels of SARS-CoV-2 antibodies., Methods: Maternal and cord blood sera were collected following term delivery after antenatal SARS-CoV-2 BNT162b2 mRNA vaccination, with the first vaccine dose administered between 27 and 36 weeks of gestation. SARS-CoV-2 spike protein (S) and receptor-binding domain (RBD) -specific, IgG levels and neutralizing potency were evaluated in maternal and cord blood samples., Results: The study cohort consisted of 171 parturients-median age 31 years (interquartile range (IQR) 27-35 years); median gestational age 39 +5  weeks (IQR 38 +5 -40 +4  weeks)-83 (48.5%) were immunized in early thrird-trimester (first dose at 27-31 weeks) and 88 (51.5%) were immunized in late third trimester (first dose at 32-36 weeks). All mother-infant paired sera were positive for anti S- and anti-RBD-specific IgG. Anti-RBD-specific IgG concentrations in neonatal sera were higher following early versus late third-trimester vaccination (median 9620 AU/mL (IQR 5131-15332 AU/mL) versus 6697 AU/mL (IQR 3157-14731 AU/mL), p 0.02), and were positively correlated with increasing time since vaccination (r = 0.26; p 0.001). Median antibody placental transfer ratios were increased following early versus late third-trimester immunization (anti-S ratio: 1.3 (IQR 1.1-1.6) versus 0.9 (IQR 0.6-1.1); anti-RBD-specific ratio: 2.3 (IQR 1.7-3.0) versus 0.7 (IQR 0.5-1.2), p < 0.001). Neutralizing antibodies placental transfer ratio was greater following early versus late third-trimester immunization (median 1.9 (IQR 1.7-2.5) versus 0.8 (IQR 0.5-1.1), p < 0.001), and was positively associated with longer duration from vaccination (r = 0.77; p < 0.001)., Conclusions: Early compared with late third-trimester maternal SARS-CoV-2 immunization enhanced transplacental antibody transfer and increased neonatal neutralizing antibody levels. Our findings highlight that vaccination of pregnant women early in the third trimester may enhance neonatal seroprotection., (Copyright © 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Maternal and cord blood sera were collected from 20 parturients who received the BNT162b2 vaccine. All women and infants were positive for anti S- and anti-receptor binding domain antibody-specific immunoglobulin G. Cord blood antibody concentrations were correlated to maternal levels and to time since vaccination. Antenatal severe acute respiratory syndrome coronavirus 2 vaccination may provide maternal and neonatal protection., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Phage therapy is a promising antibacterial strategy for resistant respiratory tract infections. Phage inhalation may serve this goal; however, it requires a careful assessment of their delivery by this approach. Here we present an in vitro model to evaluate phage inhalation. Eight phages, most of which target pathogens common in cystic fibrosis, were aerosolised by jet nebuliser and administered to a real-scale computed tomography-derived 3D airways model with a breathing simulator. Viable phage loads reaching the output of the nebuliser and the tracheal level of the model were determined and compared to the loaded amount. Phage inhalation resulted in a diverse range of titre reduction, primarily associated with the nebulisation process. No correlation was found between phage delivery to the phage physical or genomic dimensions. These findings highlight the need for tailored simulations of phage delivery, ideally by a patient-specific model in addition to proper phage matching, to increase the potential of phage therapy success., Competing Interests: Conflict of interest: None declared., (Copyright ©The authors 2021.)

Phage therapy is a promising solution for bacterial infections that are not eradicated by conventional antibiotics. A crucial element of this approach is appropriate matching of bacteriophages and antibiotics to the bacterial target according to the clinical setting. However, there is currently little consistency in the protocols used for the laboratory evaluation of bacteriophages intended for antibacterial treatment. In this Personal View, we suggest a framework aimed to match appropriate bacteriophage-based treatments in clinical microbiology laboratories. This framework, which we have termed Clinical Phage Microbiology, is based on the current research on phage treatments. In addition, we discuss special cases that might require additional relevant evaluation, including bacteriophage interactions with the host immune response, biofilm-associated infections, and polymicrobial infections. The Clinical Phage Microbiology pipeline could serve as the basis for future standardisation of laboratory protocols for personalised phage therapy., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Serum bile acid (BA) levels testing is used for the diagnosis of intrahepatic cholestasis of pregnancy (ICP). We aimed to determine the performance of routine liver tests in the evaluation of ICP., Methods: A retrospective cohort study conducted at a university hospital, including all pregnant women who underwent serum BA levels testing due to suspected ICP during 2007-2019. Liver tests were performed in all women including: aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALK), gamma-glutamyl transferase (GGT), and total bilirubin (TB). The optimal combination of laboratory values was determined by an algorithm developed in the Python programming language., Results: Of 640 women who met the inclusion criteria, 22% (n = 142) were diagnosed with ICP (serum BA>10 μmol/L). A combined laboratory score of: (TB>11 μmol/L) or (ALK>255 U/L) or (GGT>32 U/L) or (AST>31 U/L), had a sensitivity of 94%, negative predictive value (NPV) of 97%, specificity of 50%, positive predictive value of 35%, and a negative likelihood ratio of 0.11 for the diagnosis of ICP. The AUC of the laboratory model alone was 0.72 (95% CI: 0.69-0.75). The addition of history of ICP to the suggested laboratory score resulted in a sensitivity of 97%, NPV of 98% and a negative likelihood ratio of 0.06. The AUC of the final model was 0.76 (95% CI: 0.72-0.79)., Conclusions: A combined laboratory score incorporating AST, GGT, ALK and TB was shown to reliably exclude the diagnosis of ICP. This may be particularly useful in settings with limited access to BA levels testing., (Copyright © 2021. Published by Elsevier B.V.)

The accessibility and transparency of the cornea permit robust stem cell labeling and in vivo cell fate mapping. Limbal epithelial stem cells (LSCs) that renew the cornea are traditionally viewed as rare, slow-cycling cells that follow deterministic rules dictating their self-renewal or differentiation. Here, we combined single-cell RNA sequencing and advanced quantitative lineage tracing for in-depth analysis of the murine limbal epithelium. These analysis revealed the co-existence of two LSC populations localized in separate and well-defined sub-compartments, termed the "outer" and "inner" limbus. The primitive population of quiescent outer LSCs participates in wound healing and boundary formation, and these cells are regulated by T cells, which serve as a niche. In contrast, the inner peri-corneal limbus hosts active LSCs that maintain corneal epithelial homeostasis. Quantitative analyses suggest that LSC populations are abundant, following stochastic rules and neutral drift dynamics. Together these results demonstrate that discrete LSC populations mediate corneal homeostasis and regeneration., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Fetal growth restriction (FGR) is a major contributor to fetal and neonatal morbidity and mortality with intrauterine, neonatal and lifelong complications. This study explores maternal obstructive sleep apnoea (OSA) as a potentially modifiable risk factor for FGR. We hypothesise that, in pregnancies complicated by FGR, treating mothers who have OSA using positive airway pressure (PAP) will improve birth weight and neonatal outcomes., Methods and Analysis: The Sleep Apnea and Fetal Growth Restriction study is a prospective, block-randomised, single-blinded, multicentre, pragmatic controlled trial. We enrol pregnant women aged 18-50, between 22 and 31 weeks of gestation, with established FGR based on second trimester ultrasound, who do not have other prespecified known causes of FGR (such as congenital anomalies or intrauterine infection). In stage 1, participants are screened by questionnaire for OSA risk. If OSA risk is identified, participants proceed to stage 2, where they undergo home sleep apnoea testing. Participants are determined to have OSA if they have an apnoea-hypopnoea index (AHI) ≥5 (if the oxygen desaturation index (ODI) is also ≥5) or if they have an AHI ≥10 (even if the ODI is <5). These participants proceed to stage 3, where they are randomised to nightly treatment with PAP or no PAP (standard care control), which is maintained until delivery. The primary outcome is unadjusted birth weight; secondary outcomes include fetal growth velocity on ultrasound, enrolment-to-delivery interval, gestational age at delivery, birth weight corrected for gestational age, stillbirth, Apgar score, rate of admission to higher levels of care (neonatal intensive care unit or special care nursery) and length of neonatal stay. These outcomes are compared between PAP and control using intention-to-treat analysis., Ethics and Dissemination: This study has been approved by the Institutional Review Boards at Washington University in St Louis, Missouri; Hadassah Hebrew University Medical Center, Jerusalem; and the University of Rochester, New York. Recruitment began in Washington University in November 2019 but stopped from March to November 2020 due to COVID-19. Recruitment began in Hadassah Hebrew University in March 2021, and in the University of Rochester in May 2021. Dissemination plans include presentations at scientific conferences and scientific publications., Trial Registration Number: NCT04084990., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Key Message: Among SARS-CoV-2-infected mothers, vaginal delivery rates were high and associated with favorable outcomes with no cases of neonatal COVID-19., Purpose: To investigate the mode of delivery and its impact on immediate neonatal outcome in SARS-CoV-2-infected women., Methods: A prospective study following pregnant women diagnosed with COVID-19 who delivered between March 15th and July 4th in seven university affiliated hospitals in Israel., Results: A total of 52 women with a confirmed diagnosis of COVID-19 delivered in the participating centers during the study period. The median gestational age at the time of delivery was 38 weeks, with 16 (30.8%) cases complicated by spontaneous preterm birth. Forty-three women (82.7%) underwent a trial of labor. The remaining 9 women underwent pre-labor cesarean delivery mostly due to obstetric indications, whereas one woman with a critical COVID-19 course underwent urgent cesarean delivery due to maternal deterioration. Among those who underwent a trial of labor (n = 43), 39 (90.7%) delivered vaginally, whereas 4 (9.3%) cases resulted in cesarean delivery. Neonatal RT-PCR nasopharyngeal swabs tested negative in all cases, and none of the infants developed pneumonia. No maternal and neonatal deaths were encountered., Conclusions: In this prospective study among SARS-CoV-2-infected mothers, vaginal delivery rates were high and associated with favorable outcomes with no cases of neonatal COVID-19. Our findings underscore that delivery management among SARS-CoV-2-infected mothers should be based on obstetric indications and may potentially reduce the high rates of cesarean delivery previously reported in this setting.

Objectives: To evaluate the yield and utility of the routine use of chromosomal microarray analysis (CMA) for prenatal genetic diagnosis in a large cohort of pregnancies with normal ultrasound (US) at the time of genetic testing, compared with pregnancies with abnormal US findings., Methods: We reviewed all prenatal CMA results in our center between November 2013 and December 2018. The prevalence of different CMA results in pregnancies with normal US at the time of genetic testing ('low-risk pregnancies'), was compared with that in pregnancies with abnormal US findings ('high-risk pregnancies'). Medical records were searched in order to evaluate subsequent US follow-up and the outcome of pregnancies with a clinically relevant copy-number variant (CNV), i.e. a pathogenic or likely pathogenic CNV or a susceptibility locus for disease with > 10% penetrance, related to early-onset disease in the low-risk group., Results: In a cohort of 6431 low-risk pregnancies that underwent CMA, the prevalence of a clinically significant CNV related to early-onset disease was 1.1% (72/6431), which was significantly lower than the prevalence in high-risk pregnancies (4.9% (65/1326)). Of the low-risk pregnancies, 0.4% (27/6431) had a pathogenic or likely pathogenic CNV, and another 0.7% (45/6431) had a susceptibility locus with more than 10% penetrance. Follow-up of the low-risk pregnancies with a clinically significant early-onset CNV revealed that 31.9% (23/72) were terminated, while outcome data were missing in 26.4% (19/72). In 16.7% (12/72) of low-risk pregnancies, an US abnormality was discovered later on in gestation, after genetic testing had been performed., Conclusion: Although the background risk of identifying a clinically significant early-onset abnormal CMA result in pregnancies with a low a-priori risk is lower than that observed in high-risk pregnancies, the risk is substantial and should be conveyed to all pregnant women. © 2020 International Society of Ultrasound in Obstetrics and Gynecology., (© 2020 International Society of Ultrasound in Obstetrics and Gynecology.)

Providencia spp. are emerging pathogens mainly in nosocomial infections. Providencia stuartii in particular is involved in urinary tract infections and contributes significantly to the high incidence of biofilm-formation in catheterized patients. Furthermore, recent reports suggested a role for multiple drug resistant (MDR) P. stuartii in hospital-associated outbreaks which leads to excessive complications resulting in challenging treatments. Phage therapy is currently one of the most promising solutions to combat antibiotic-resistant infections. However, the number of available phages targeting Providencia spp. is extremely limited, restricting the use of phage therapy in such cases. In the present study, we describe the isolation and characterization of 17 lytic and temperate bacteriophages targeting clinical isolates of Providencia spp. as part of the Israeli Phage Bank (IPB). These phages, isolated from sewage samples, were evaluated for host range activity and effectively eradicated 95% of the tested bacterial strains isolated from different geographic locations and displaying a wide range of antibiotic resistance. Their lytic activity is demonstrated on agar plates, planktonic cultures, and biofilm formed in a catheter model. The results suggest that these bacteriophages can potentially be used for treatment of antibiotic-resistant Providencia spp. infections in general and of urinary tract infections in particular.

Background: While the ratio of male to female births (sex-ratio at birth [SRB]) in humans is remarkably stable on the population level, there are many families with multiple same-sex offspring., Objectives: To identify a putative sub-population with skewed SRB and explore potential factors affecting the SRB., Methods: A retrospective cohort study including 66,054 families with up to nine same-sex offspring evaluated between 2003 and 2015 at Hadassah-Hebrew University Medical Center. Outcome measures were observed prevalence and SRB of families with up to nine same-sex offspring in a single family. Analyses included the effect of parity, month and year of delivery, inter-delivery interval, and presence of a sequence of previous same-sex offspring on the SRB., Results: The study comprised 193,411 live-born babies with SRB of 1.057 in favor of males. The proportion of SRB in families with up to nine same-sex offspring did not differ from the calculated presumed proportion. Furthermore, none of the tested factors (parity, month and year of delivery, inter-delivery interval, and the sequence of previous same-sex offspring) were significantly associated with SRB., Conclusions: SRB was not associated with any of the tested demographic characteristics. We could not identify a skew in SRB even in families with up to nine consecutive same sex offspring. This finding suggests that in the majority of the population the chance of a male or female fetus in each pregnancy remains similar in every pregnancy, regardless of any of the tested variables.

A key element in phage therapy is the establishment of large phage collections, termed herein "banks", where many well-characterized phages, ready to be used in the clinic, are stored. These phage banks serve for both research and clinical purposes. Phage banks are also a key element in clinical phage microbiology, the prior treatment matching of phages and antibiotics to specific bacterial targets. A worldwide network of phage banks can promote a phage-based solution for any isolated bacteria. Herein, we describe the Israeli Phage Bank (IPB) established in the Hebrew University, Jerusalem, which currently has over 300 phages matching 16 bacteria, mainly pathogens. The phage bank is constantly isolating new phages and developing methods for phage isolation and characterization. The information on the phages and bacteria stored in the bank is available online.