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Abstract Background Team-based learning (TBL) is a widely recognized instructional approach in medical education blending direct instruction with active-cooperative learning in small groups. While TBL is known to enhance knowledge acquisition, its impact on student motivation, particularly through situational interest, remains underexplored. This study aimed to investigate the development of situational interest across the distinct phases of TBL, focusing on how each phase (individual readiness assurance test; iRAT, team readiness assurance test; tRAT, and application exercise; AE) influences students’ situational interest. The study sought to provide insights into the motivational dynamics underpinning TBL in a medical education setting. Methods A total of 88 medical students participated in a TBL session on “Bleeding during Pregnancy.” Situational interest was measured after each TBL phase. A one-way repeated-measures analysis of variance (ANOVA) was conducted to assess the fluctuation of situational interest throughout the session. Results The analysis revealed significant variations in situational interest across different TBL stages. There was a significant increase in situational interest following the tRAT (p = .001). Post-tRAT, situational interest significantly decreased after the AE (p = .007), returning to levels observed at the session’s start. Post hoc correlation analysis suggested a negative association between tRAT performance and situational interest, indicating heightened interest in response to awareness of knowledge gaps during the tRAT. Conclusions The findings of this study may challenge the traditional view of TBL, suggesting a more integrated and dynamic interplay between knowledge acquisition and application phases. The results highlight the importance of the AE phase in clinical education and suggest that situational interest is one key driver in the learning process within TBL. Future research should focus on replicating these findings and comparing situational interest development between pre-clinical and clinical student cohorts to further understand the effects of situational interest on TBL in medical education.

Abstract Chemoresistance contributes to the majority of deaths in women with ovarian cancer (OC). Altered DNA repair and metabolic signaling is implicated in mediating therapeutic resistance. DNA damage checkpoint kinase 1 (CHK1) integrates cell cycle and DNA repair in replicating cells, and its inhibition causes replication stress, repair deficiency and cell cycle dysregulation. We observed elevated Poly-ADP-ribosylation (PAR) of proteins (PARylation) and subsequent decrease in cellular NAD+ levels in OC cells treated with the CHK1 inhibitor prexasertib, indicating activation of NAD+ dependent DNA repair enzymes poly-ADP-ribose polymerases (PARP1/2). While multiple PARP inhibitors are in clinical use in treating OC, tumor resistance to these drugs is highly imminent. We reasoned that inhibition of dePARylation by targeting Poly (ADP-ribose) glycohydrolase (PARG) would disrupt metabolic and DNA repair crosstalk to overcome chemoresistance. Although PARG inhibition (PARGi) trapped PARylation of the proteins and activated CHK1, it did not cause any significant OC cell death. However, OC cells deficient in CHK1 were hypersensitive to PARGi, suggesting a role for metabolic and DNA repair crosstalk in protection of OC cells. Correspondingly, OC cells treated with a combination of CHK1 and PARG inhibitors exhibited excessive replication stress-mediated DNA lesions, cell cycle dysregulation, and mitotic catastrophe compared to individual drugs. Interestingly, increased PARylation observed in combination treatment resulted in depletion of NAD+ levels. These decreased NAD+ levels were also paralleled with reduced aldehyde dehydrogenase (ALDH) activity, which requires NAD+ to maintain cancer stem cells. Furthermore, prexasertib and PARGi combinations exhibited synergistic cell death in OC cells, including an isogenic chemoresistant cell line and 3D organoid models of primary patient-derived OC cell lines. Collectively, our data highlight a novel crosstalk between metabolism and DNA repair involving replication stress and NAD+-dependent PARylation, and suggest a novel combination therapy of CHK1 and PARG inhibitors to overcome chemoresistance in OC.

Selective serotonin reuptake inhibitors (SSRIs), including citalopram, are widely used antidepressants during pregnancy. However, the effects of prenatal exposure to citalopram on neurodevelopment remain poorly understood. We aimed to investigate the impact of citalopram exposure on early neuronal differentiation of human embryonic stem cells using a multi-omics approach. Citalopram induced time- and dose-dependent effects on gene expression and DNA methylation of genes involved in neurodevelopmental processes or linked to depression, such as BDNF, GDF11, CCL2, STC1, DDIT4 and GAD2. Single-cell RNA-sequencing analysis revealed distinct clusters of stem cells, neuronal progenitors and neuroblasts, where exposure to citalopram subtly influenced progenitor subtypes. Pseudotemporal analysis showed enhanced neuronal differentiation. Our findings suggest that citalopram exposure during early neuronal differentiation influences gene expression patterns associated with neurodevelopment and depression, providing insights into its potential neurodevelopmental impact and highlighting the importance of further research to understand the long-term consequences of prenatal SSRI exposure.

Abstract Background Team-based learning (TBL) is an evidence-based pedagogical method that has been used in undergraduate medical education since 2001. However, its use in clinical disciplines is rarely reported, and the impact of its implementation is not known. The aim of this study was to explore and map the published literature on the impact of implementing TBL in clinical disciplines in undergraduate medical education. Methods A comprehensive search of Medline, Education Resources Information Center (ERIC), and Web of Science databases was performed on November 24, 2021 and updated April 6, 2023, using relevant Medical Subject Headings (MeSH) and free-text terms. Original research studies reporting on the implementation of TBL in clinical disciplines in undergraduate medical education published in peer-reviewed English language journals were included irrespective of their methodological design. Results The initial search identified 2,383 records. Of these, 49 met the inclusion criteria. Most of the studies (n = 44, 90%) described the implementation of a modified version of TBL in which one or more TBL steps were missing, and one study had undefined protocol for the implementation. The most reported outcomes were knowledge acquisition (n = 38, 78%) and students’ satisfaction or attitudes toward TBL (n = 34, 69%). Despite some differences in their results, the studies found that implementing TBL is associated with increased knowledge acquisition (n = 19, 39%), student engagement (n = 6, 12%), and student satisfaction (n = 31, 63%). Conclusions Most of the studies reported positive results in students’ satisfaction and students’ engagement, whilst the results on knowledge acquisition and retention were more contradictory. In most of the studies, TBL was implemented in a modified form and diverse comparators were used. The methodological quality also varied. Thus, no unequivocal conclusions could be drawn regarding the value of implementing TBL in clinical disciplines. More studies with rigorous methodologies are needed in this field.

Abstract Background Triple-negative breast cancer (TNBC) affects young women and is the most aggressive subtype of breast cancer (BC). TNBCs disproportionally affect women of African-American (AA) descent compared to other ethnicities. We have identified DNA repair gene RAD51 as a poor prognosis marker in TNBC and its posttranscriptional regulation through microRNAs (miRNAs). This study aims to delineate the mechanisms leading to RAD51 upregulation and develop novel therapeutic combinations to effectively treat TNBCs and reduce disparity in clinical outcomes. Methods Analysis of TCGA data for BC cohorts using the UALCAN portal and PrognoScan identified the overexpression of RAD51 in TNBCs. miRNA sequencing identified significant downregulation of RAD51-targeting miRNAs miR-214-5P and miR-142-3P. RT-PCR assays were used to validate the levels of miRNAs and RAD51, and immunohistochemical and immunoblotting techniques were used similarly for RAD51 protein levels in TNBC tissues and cell lines. Luciferase assays were performed under the control of RAD51 3’-UTR to confirm that miR-214-5P regulates RAD51 expression. To examine the effect of miR-214-5P-mediated downregulation of RAD51 on homologous recombination (HR) in TNBC cells, Dr-GFP reporter assays were performed. To assess the levels of olaparib-induced DNA damage responses in miR-214-5P, transfected cells, immunoblots, and immunofluorescence assays were used. Furthermore, COMET assays were used to measure DNA lesions and colony assays were performed to assess the sensitivity of BRCA-proficient TNBC cells to olaparib. Results In-silico analysis identified upregulation of RAD51 as a poor prognostic marker in TNBCs. miRNA-seq data showed significant downregulation of miR-214-5P and miR-142-3P in TNBC cell lines derived from AA women compared to Caucasian-American (CA) women. miR-214-5P mimics downregulated RAD51 expression and induces HR deficiency as measured by Dr-GFP assays in these cell lines. Based on these results, we designed a combination treatment of miR-214-5P and olaparib in HR-proficient AA TNBC cell lines using clonogenic survival assays. The combination of miR-214-5P and olaparib showed synergistic lethality compared to individual treatments in these cell lines. Conclusions Our studies identified a novel epigenetic regulation of RAD51 in TNBCs by miR-214-5P suggesting a novel combination therapies involving miR-214-5P and olaparib to treat HR-proficient TNBCs and to reduce racial disparity in therapeutic outcomes.

Summary: Prenatal paracetamol exposure has been associated with neurodevelopmental outcomes in childhood. Pharmacoepigenetic studies show differences in cord blood DNA methylation between unexposed and paracetamol-exposed neonates, however, causality and impact of long-term prenatal paracetamol exposure on brain development remain unclear. Using a multi-omics approach, we investigated the effects of paracetamol on an in vitro model of early human neurodevelopment. We exposed human embryonic stem cells undergoing neuronal differentiation with paracetamol concentrations corresponding to maternal therapeutic doses. Single-cell RNA-seq and ATAC-seq integration identified paracetamol-induced chromatin opening changes linked to gene expression. Differentially methylated and/or expressed genes were involved in neurotransmission and cell fate determination trajectories. Some genes involved in neuronal injury and development-specific pathways, such as KCNE3, overlapped with differentially methylated genes previously identified in cord blood associated with prenatal paracetamol exposure. Our data suggest that paracetamol may play a causal role in impaired neurodevelopment.

Abstract Background The COVID-19 pandemic has contributed to unprecedented worries and challenges for pregnant women due to social restrictions and changes in maternity care provision. We aimed to investigate the mental health impact of COVID-19 pandemic on pregnant women in Sweden and explore factors associated with poor perinatal mental health in this specific context. Method This was a nation-wide cross-sectional survey of pregnant women living in Sweden. Validated questionnaires were distributed through non-profit organizations´ websites and social media channels from May 2020 to February 2021. Perinatal depression, anxiety, and acute stress reaction were assessed using the Edinburgh Postnatal Depression Scale (EPDS), Generalized Anxiety Disorder-7 (GAD-7) and Impact Event Scale (Revised) (IES-R), respectively. Sociodemographic characteristics and self-perceived mental well-being were also obtained. Factors associated with mental health outcomes were analyzed using multivariate logistic regression model. Results Among a total of 470 participants, 43.2% (n = 203) reported depression (EPDS ≥13), 25.7% (n = 121) moderate to severe anxiety (GAD-7 score ≥ 10), and 23.7% (n = 110) moderate to severe acute stress reaction (IES-R ≥ 33). 27.4% participants (n = 129) expressed concerns regarding their mental well-being during the pandemic. Pregnant mothers who had sick family members reported poorer mental health outcomes than those who did not (median [Interquartile range (IQR)] EPDS scores: 14.0 [8.75–18.0] vs 11.0 [6.25–15.0], p

Abstract Histology involves the observation of structural features in tissues using a microscope. While diffraction-limited optical microscopes are commonly used in histological investigations, their resolving capabilities are insufficient to visualize details at subcellular level. Although a novel set of super-resolution optical microscopy techniques can fulfill the resolution demands in such cases, the system complexity, high operating cost, lack of multi-modality, and low-throughput imaging of these methods limit their wide adoption for histological analysis. In this study, we introduce the photonic chip as a feasible high-throughput microscopy platform for super-resolution imaging of histological samples. Using cryopreserved ultrathin tissue sections of human placenta, mouse kidney, pig heart, and zebrafish eye retina prepared by the Tokuyasu method, we demonstrate diverse imaging capabilities of the photonic chip including total internal reflection fluorescence microscopy, intensity fluctuation-based optical nanoscopy, single-molecule localization microscopy, and correlative light-electron microscopy. Our results validate the photonic chip as a feasible imaging platform for tissue sections and pave the way for the adoption of super-resolution high-throughput multimodal analysis of cryopreserved tissue samples both in research and clinical settings.

Summary: Neuronal differentiation of pluripotent stem cells is an established method to study physiology, disease, and medication safety. However, the sequence of events in human neuronal differentiation and the ability of in vitro models to recapitulate early brain development are poorly understood. We developed a protocol optimized for the study of early human brain development and neuropharmacological applications. We comprehensively characterized gene expression and epigenetic profiles at four timepoints, because the cells differentiate from embryonic stem cells towards a heterogeneous population of progenitors, immature and mature neurons bearing telencephalic signatures. A multi-omics roadmap of neuronal differentiation, combined with searchable interactive gene analysis tools, allows for extensive exploration of early neuronal development and the effect of medications.

Abstract Background The Norwegian Board of Health Supervision aims to contribute to the improvement of quality and patient safety in the healthcare services. Planned audits were performed to investigate how 12 selected Norwegian obstetric units reported and analyzed adverse events as the part of their quality assurance and patient safety work. Methods Serious adverse events coded as birth asphyxia, shoulder dystocia and severe postpartum hemorrhage that occurred during 2014 (the most recent year for which the quality assured data were available) were obtained from the Medical Birth Registry of Norway. The obstetric units were asked to submit medical records, internal adverse events reports, and their internal guidelines outlining which events should be reported to the quality assurance system. We identified the adverse events at each obstetric unit that were reported internally and/or to the central authorities. Two obstetricians carried out an evaluation of each event reported. Results Five hundred fifty-three serious adverse events were registered among 17,323 births that took place at the selected units. Twenty-one events were excluded because of incorrect coding or missing information. Eight events were registered in more than one category, and these were distributed to the category directly related to injury or adverse outcome. Nine of twelve (75 %) obstetric units had written guidelines describing which events should be reported. The obstetric units reported 49 of 524 (9.3 %) serious adverse events in their internal quality assurance system and 39 (7.4 %) to central authorities. Of the very serious adverse events, 29 of 149 (19.4 %) were reported. Twenty-three of 49 (47 %) reports did not contain relevant assessments or proposals for improving quality and patient safety. Conclusions This study showed that adverse event reporting and analyses by Norwegian obstetric units, as a part of quality assurance and patient safety work, are suboptimal. The reporting culture and compliance with guidelines need to be improved substantially for better safety in patient care, risk mitigation and clinical quality assurance.

Abstract High space-bandwidth product with high spatial phase sensitivity is indispensable for a single-shot quantitative phase microscopy (QPM) system. It opens avenue for widespread applications of QPM in the field of biomedical imaging. Temporally low coherence light sources are implemented to achieve high spatial phase sensitivity in QPM at the cost of either reduced temporal resolution or smaller field of view (FOV). In addition, such light sources have low photon degeneracy. On the contrary, high temporal coherence light sources like lasers are capable of exploiting the full FOV of the QPM systems at the expense of less spatial phase sensitivity. In the present work, we demonstrated that use of narrowband partially spatially coherent light source also called pseudo-thermal light source (PTLS) in QPM overcomes the limitations of conventional light sources. The performance of PTLS is compared with conventional light sources in terms of space bandwidth product, phase sensitivity and optical imaging quality. The capabilities of PTLS are demonstrated on both amplitude (USAF resolution chart) and phase (thin optical waveguide, height ~ 8 nm) objects. The spatial phase sensitivity of QPM using PTLS is measured to be equivalent to that for white light source and supports the FOV (18 times more) equivalent to that of laser light source. The high-speed capabilities of PTLS based QPM is demonstrated by imaging live sperm cells that is limited by the camera speed and large FOV is demonstrated by imaging histopathology human placenta tissue samples. Minimal invasive, high-throughput, spatially sensitive and single-shot QPM based on PTLS will enable wider penetration of QPM in life sciences and clinical applications.

Abstract Background Physiological adaptation in pregnancy is characterized by remodeling of endocrine, cardiovascular and renal functions leading to fluid retention, volume expansion, altered cardiac loading conditions and hyperdynamic circulation. Natriuretic peptides have been used as biomarkers of cardiovascular function, but their associations with gestational age-related changes in maternal cardiac, endothelial and renal function have not been elucidated. The aim of this study was to establish longitudinal reference values for maternal plasma atrial natriuretic peptide (proANP) and C-type natriuretic peptide (CNP) and investigate their temporal association with cardiovascular and renal function in the second half of pregnancy. Methods This study was a prospective longitudinal study of 53 low-risk pregnancies. Women were examined every 3–5 weeks during 22–40 weeks of gestation (252 observations). Fasting maternal blood samples were obtained to measure proANP, CNP, creatinine, cystatin C, uric acid, and fibrinogen levels. Cardiac function and systemic hemodynamics were assessed noninvasively by impedance cardiography (ICG) and vascular endothelial function by flow-mediated vasodilation of brachial artery (FMD). Results The plasma proANP (R2adj = 0.79; P = 0.007), CNP (R2adj = 0.54; P = 0.005) decreased between 22 and 40 weeks. The creatinine (R2adj = 0.90; P

Abstract Background Fetal superior vena cava (SVC) is essentially the single vessel returning blood from the upper body to the heart. With approximately 80-85% of SVC blood flow representing cerebral venous return, its interrogation may provide clinically relevant information about fetal brain circulation. However, normal reference values for fetal SVC Doppler velocities and pulsatility index are lacking. Our aim was to establish longitudinal reference intervals for blood flow velocities and pulsatility index of the SVC during the second half of pregnancy. Methods This was a prospective study of low-risk singleton pregnancies. Serial Doppler examinations were performed approximately every 4 weeks to obtain fetal SVC blood velocity waveforms during 20–41 weeks. Peak systolic (S) velocity, diastolic (D) velocity, time-averaged maximum velocity (TAMxV), time-averaged intensity-weighted mean velocity (TAMeanV), and end-diastolic velocity during atrial contraction (A-velocity) were measured. Pulsatility index for vein (PIV) was calculated. Results SVC blood flow velocities were successfully recorded in the 134 fetuses yielding 510 sets of observations. The velocities increased significantly with advancing gestation: mean S-velocity increased from 24.0 to 39.8 cm/s, D-velocity from 13.0 to 19.0 cm/s, and A-velocity from 4.8 to 7.1 cm/s. Mean TAMxV increased from 12.7 to 23.1 cm/s, and TAMeanV from 6.9 to 11.2 cm/s. The PIV remained stable at 1.5 throughout the second half of pregnancy. Conclusions Longitudinal reference intervals of SVC blood flow velocities and PIV were established for the second half of pregnancy. The SVC velocities increased with advancing gestation, while the PIV remained stable from 20 weeks to term.

Abstract Background Saliva plays a significant role in maintaining oral health and oral bacterial milieu. Difference in oxidative stress (OS) levels in saliva in conjunction with bacterial load between pregnant and non-pregnant women has not been studied previously. We hypothesized that the physiological changes in pregnancy alter oral bacterial milieu by promoting growth of Streptococcus mutans (SM) and Lactobacillus (LB), and increase OS in saliva. The aim of this study was to measure and compare the oral bacterial milieu, OS and total anti-oxidative capacity (TAC) in the saliva of pregnant and non-pregnant women. Method In this cross-sectional study, we assessed oral bacterial milieu by culturing the SM and LB by using commercial kits, TAC by measuring 2, 2′-Azino-Bis-3-Ethylbenzothiazoline-6-Sulfonic Acid (ABTS) free radical scavenging activity spectrophotometrically and OS levels by measuring malondialdehyde (MDA) levels with commercial kits in the saliva of pregnant women (n = 38) at 18–20 weeks of gestation, who were compared with age-matching healthy non-pregnant women (n = 50). Results Streptococcus mutans were found to be more abundant in the saliva of pregnant women compared with non-pregnant women (p = 0.003) but the difference was not significant for the LB (p = 0.267). TAC was found to be 46% lower in pregnant women’s saliva compared to non-pregnant women [optical density (OD) measured at 731 nm as 0.118 ± 0.01 vs. 0.063 ± 0.02; p

Abstract Background Fetal anemia is associated with a hyperdynamic circulation and cardiac remodeling. Rapid intrauterine transfusion (IUT) of blood with high hematocrit and viscosity into the umbilical vein used to treat this condition can temporarily further affect fetal heart function. The aim of this study was to evaluate the short-term changes in fetal myocardial function caused by IUT using automated analysis of cine-loops of the fetal heart obtained by color tissue Doppler imaging (cTDI). Methods Fetal echocardiography was performed before and after IUT. cTDI recordings were obtained in a four-chamber view and regions of interest were placed at the atrioventricular plane in the left ventricular (LV), right ventricular (RV) and septal walls. Myocardial velocities were analyzed by an automated analysis software to obtain peak myocardial velocities during atrial contraction (Am), ventricular ejection (Sm), rapid ventricular filling (Em) and Em/Am ratio was calculated. Myocardial velocities were converted to z-scores using published reference ranges. Delta z-scores (after minus before IUT) were calculated. Correlations were assessed between variables and hemoglobin before IUT. Results Thirty-two fetuses underwent 70 IUTs. Fourteen were first time transfusions. In the LV and septal walls, all myocardial velocities were significantly increased compared to normal values, whereas in the RV only Sm was increased before IUT (z-scores 0.26–0.52). In first time IUTs, there was a negative correlation between LV Em (rho = − 0.61, p = 0.036) and LV Em/Am (rho = − 0.82, p = 0.001) z-scores and hemoglobin before IUT. The peak myocardial velocities that were increased before IUT decreased, whereas LV Em/Am increased significantly after IUT. Conclusions This study showed that peak myocardial velocities assessed by cTDI are increased in fetuses before IUT reflecting the physiology of hyperdynamic circulation. In these fetuses, the fetal heart is able to adapt and efficiently handle the volume load caused by IUT by altering its myocardial function.

Industrial chemicals such as persistent organic pollutants (POPs) have been associated with reduced fertility in women, including longer time-to-pregnancy (TTP), higher odds for infertility, and earlier reproductive senescence. Fertility is highly dependent on the ovarian reserve, which is composed of a prenatally determined stock of non-growing follicles. The quantity and quality of the follicles decline with age, thereby eventually leading to menopause. In the clinical setting, assessing ovarian reserve directly through the histological analysis of follicular density in ovaries is not practical. Therefore, surrogate markers of ovarian reserve, such as serum anti-Müllerian hormone (AMH) are typically used. Here, we studied associations between chemical exposure and ovarian reserve in a cohort of pregnant women undergoing elective caesarean section (n = 145) in Stockholm, Sweden. Full data (histological, clinical, serum) were available for 50 women. We estimated the size of the reserve both directly by determining the density of follicles in ovarian cortical tissue samples, and indirectly by measuring AMH in associated serum samples. Concentrations of 9 organochlorine pesticides (OCPs), 10 polychlorinated biphenyls (PCBs), 3 polybrominated diphenylethers (PBDEs) and 9 perfluoroalkyl substances (PFAS) were determined in serum, and clinical data were retrieved from electronic medical records. Healthy follicle densities (median 0, range 0–193 follicles/mm3) and AMH levels (median 2.33 ng/mL, range 0.1–14.8 ng/mL) varied substantially. AMH correlated with the density of growing follicles. Twenty-three chemicals detected in more than half of the samples were included in the analyses. None of the chemicals, alone or as a mixture, correlated with AMH, growing or atretic follicles. However, HCB, transnonachlor, PCBs 74 and 99 were associated with decreased non-growing follicle densities. HCB and transnonachlor were also negatively associated with healthy follicle density. Further, mixture of lipophilic POPs (PBDE 99, p,p’-DDE, and PCB 187) was associated with lower non-growing follicle densities. In addition, exposure to HCB, p,p’-DDE, and mixture of OCPs were significantly associated with higher odds of infertility. The results suggest that exposure to chemicals may reduce the size of ovarian reserve in humans, and strongly encourage to study mechanisms behind POP-associated infertility in women in more detail.

Background: Cytomegalovirus seroconversion during pregnancy is common and has a substantial risk of congenital infection with longterm sequale. Screening during pregnancy or vaccination have not been shown to be effective for eliminating congenital infections. Preconception screening policy has not been evaluated adequately in a large scale. This nationwide study aimed to investigate epidemiological features of cytomegalovirus seropositivity and its geographic variation among Chinese women planning a pregnancy to gather epidemiological evidence as an essential for developing novel prevention strategies.Method: This cross-sectional sero-epidemiological survey enrolled women intending to become pregnant within 6 months in mainland China during 2010–2012. The primary outcomes in this study were cytomegalovirus Immunoglobulin G and M seropositivity. Secondary outcomes were the associations between Immunoglobulin G and Immunoglobulin M, with socio-demographic characteristics, including age, occupation, education level, place of residence, and ethnicity. The overall seropositivity and regional disparity was analyzed on the individual and regional level, respectively.Results: This study included data from 1,564,649 women from 31 provinces in mainland China. Among participants, 38.6% (n = 603,511) were cytomegalovirus immunoglobulin G+, 0.4% (n = 6,747) were immunoglobulin M+, and 0.2% (n = 2,879) were immunoglobulin M+ and immunoglobulin G+. On individual level, participant's age, ethnicity, and residing region were significantly associated with IgG+, IgM+, and IgM+IgG+ (P < 0.001), while occupation, education level, and place of residence were not statistically significant (P > 0.05). On regional level, cytomegalovirus immunoglobulin G and immunoglobulin M seropositivity was highest in the eastern region (49.5 and 0.5%, respectively), and lowest in the western region (26.9 and 0.4%, respectively). This geographic variation was also noted at the provincial level, characterized by higher provincial immunoglobulin M+ and immunoglobulin G+ rates associated with higher immunoglobulin G seropositivity. In the subgroup analysis of immunoglobulin G seropositivity, areas of higher immunoglobulin G positivity had a higher rate of immunoglobulin M+, indicating an expected increased risk of reinfection and primary infection.Conclusions: A substantial proportion of women (>60%) were susceptible to cytomegalovirus in preconception period in China, and immunoglobulin G seropositivity was seen at a low-medium level with substantial geographic variation. Integration of cytomegalovirus antibody testing in preconception screening program based on regional immunoglobulin G seropositivity, should be considered to promote strategies directed toward preventing sero-conversion during pregnancy to reduce the risk of this congenital infection.

Introduction: In the fetus, a large proportion of the superior vena cava blood flow (QSVC) comes from the brain. To provide the possibility of using this blood flow as a representation of fetal brain circulation, we aimed to determine the fetal QSVC and its fraction of cardiac output during the second half of physiological pregnancies.Materials and Methods: This was a prospective longitudinal study specifically designed for studying fetal hemodynamic development. Healthy women with singleton low-risk pregnancies were included. Ultrasonography was performed at 4-weekly intervals from 20+0 gestational weeks to term. Doppler velocity recordings of the superior vena cava (SVC) and cardiac ventricular outflow tracts were used to obtain the time-averaged maximum velocities (TAMxV). Vessel diameters were measured to calculate their cross-sectional areas (CSA): π(diameter/2)2. Blood flow (Q) was computed as: h*TAMxV*CSA, h being the spatial blood velocity profile, to obtain QSVC and cardiac outputs. The sum of left and right ventricular cardiac outputs constituted the combined cardiac output (CCO). Ultrasound biometry based estimated fetal weight and brain weight were used to normalize the flow. QSVC was also expressed as the fraction (%) of CCO. Gestational age specific percentiles were established for each blood flow parameter using multilevel modeling.Results: Totally, 134 of the 142 included women were eligible for the study with 575 sets of observations. The SVC mean diameter (19–52 mm), mean TAMxV (8.83–16.14 cm/s), and QSVC (15.4–192.0 ml/min) increased significantly during the second half of pregnancy (p < 0.001) while the mean QSVC normalized by estimated fetal weight (49 ml/min/kg) and by estimated brain weight (50 ml/min/100 g) were relatively stable. Similarly, the mean CCO increased (156–1,776 ml/min; p < 0.001) while the normalized CCO (509 ± 13 ml/min/kg) and QSVC as a fraction of CCO (10 ± 0.92%) did not change significantly with gestational age.Conclusion: We provide reference values for fetal QSVC which increases significantly with gestation, and constitutes roughly 10% of the fetal CCO at any time during the second half of pregnancy.

The natural polyphenol resveratrol (RES) has shown great potential as an antimicrobial, including against microbes associated with vaginal infections. To fully exploit the activities of RES, an all-natural ingredients formulation for RES delivery at vaginal site has been developed, namely liposomes loaded with RES, incorporated into a chitosan hydrogel as secondary vehicle. Although considered non-toxic and safe on their own, the compatibility of the final formulation must be evaluated for its biocompatibility and non-irritancy to the vaginal mucosa. As a preclinical safety assessment, the impact of RES formulation on the tissue viability, the effect on barrier function and cell monolayer integrity, and cytotoxicity were evaluated using the cell-based vaginal tissue model, the EpiVaginal™ tissue. RES liposomes-in-hydrogel formulations neither affected the mitochondrial activity, nor the integrity of the cell monolayer in RES concentration up to 60 µg/mL. Moreover, the barrier function was maintained to a greater extent by RES in formulation, emphasizing the benefits of the delivery system. Additionally, none of the tested formulations expressed an increase in lactate dehydrogenase activity compared to the non-treated tissues. The evaluation of the RES delivery system suggests that it is non-irritant and biocompatible with vaginal tissue in vitro in the RES concentrations considered as therapeutic.

Introduction Mental health disorders are common during pregnancy and the postnatal period and can have serious adverse effects on women and their children. The consequences for global mental health due to COVID-19 are likely to be significant and may have a long-term impact on the global burden of disease. Besides physical vulnerability, pregnant women are at increased risk of mental health problems such as anxiety, depression and post-traumatic stress disorder due to the consequences of social distancing. It can result in altered healthcare routines, less support from the family and friends, and in some cases, partners not being allowed to be present during prenatal visits, labour and delivery. Higher than expected, rates of perinatal anxiety and depression have been already reported during the pandemic. Pregnant women may also feel insecure and worried about the effects of COVID-19 on their unborn child if they get infected during pregnancy. Today, young urban women are used to using internet services frequently and efficiently. Therefore, providing mental health support to pregnant women via internet may be effective in ameliorating their anxiety/depression, reducing the risk of serious mental health disorders, and lead to improved maternal and perinatal outcomes.Overarching aim Our aim is to explore the effectiveness of a web-based psychosocial peer-to-peer support intervention in reducing the risk and severity of perinatal mental health disorders and preventing adverse pregnancy outcomes among pregnant women living in metropolitan urban settings.Methods and analysis We plan to conduct a multicentre prospective randomised controlled trial, Mental health of Urban Mothers trial. Pregnant women living in large metropolitan cities will be recruited using internet-based application through non-profit organisations’ websites. The women who consent will be randomised to receive a web-based peer-to-peer support intervention or usual care. Data will be analysed to identify the effects of intervention on Edinburgh Postnatal Depression Score and Generalised Anxiety Disorder 7 scores as well as pregnancy outcomes. The impact of COVID-19 pandemic on maternal stress will be assesed using Impact Event Scale-R. Any differences in outcomes between cities will be addressed in subgroup analyses.Ethics and dissemination The study will be conducted according to the principles of Good Clinical Practice and will follow the ethical principles of the Declaration of Helsinki. The study protocol has been approved by the ethical review board of Chinese University of Hong Kong (IRB number 2019-8170) and Shanghai Center for Women’s and Children’s Health (international review board (IRB) number 2020-F001-12). The results will be disseminated at national and international scientific conferences, published in peer-reviewed medical journals and spread to the public through social media, news outlets and podcasts.Trial registration number NCT04363177; Trial sponsor Karolinska Institute, CLINTEC, Stockholm, Sweden.

Utero-placental development in pregnancy depends on direct maternal–fetal interaction in the uterine wall decidua. Abnormal uterine vascular remodeling preceding placental oxidative stress and placental dysfunction are associated with preeclampsia and fetal growth restriction (FGR). Oxidative stress is counteracted by antioxidants and oxidative repair mechanisms regulated by the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2). We aimed to determine the decidual regulation of the oxidative-stress response by NRF2 and its negative regulator Kelch-like ECH-associated protein 1 (KEAP1) in normal pregnancies and preeclamptic pregnancies with and without FGR. Decidual tissue from 145 pregnancies at delivery was assessed for oxidative stress, non-enzymatic antioxidant capacity, cellular NRF2- and KEAP1-protein expression, and NRF2-regulated transcriptional activation. Preeclampsia combined with FGR was associated with an increased oxidative-stress level and NRF2-regulated gene expression in the decidua, while decidual NRF2- and KEAP1-protein expression was unaffected. Although preeclampsia with normal fetal growth also showed increased decidual oxidative stress, NRF2-regulated gene expression was reduced, and KEAP1-protein expression was increased in areas of high trophoblast density. The trophoblast-dependent KEAP1-protein expression in preeclampsia with normal fetal growth indicates control of decidual oxidative stress by maternal–fetal interaction and underscores the importance of discriminating between preeclampsia with and without FGR.

The Karolinska Institutet Human Embryonic Stem Cell Bank (KI Stem Cell Bank) was established at KI, Stockholm, Sweden, when the first human embryonic stem cell (hESC) line was derived by Professor Hovatta and colleagues in 2002. Since then, the bank has grown to include 60 hESC lines. From the very beginning the aim of the bank has been derivation of hESC lines suitable for clinical use. Step by step progress has been made towards this goal, including removal of xeno components, establishment of chemically defined conditions and Good Manufacturing Practice (GMP) compliancy. Today our bank includes such clinical grade hESC line, KARO1, derived and banked according to GMP guidelines. Many of the hESC lines in the bank have been distributed to the scientific community and are deposited in the Stockholm Medical Biobank available for research on collaborative basis.

Abstract Background Sexual dimorphism in placental size and function has been described. Whether this influences the clinically important umbilical artery (UA) waveform remains controversial, although a few cross-sectional studies have shown sex differences in UA pulsatility index (PI). Therefore, we tested whether fetal sex influences the UA Doppler indices during the entire second half of pregnancy and aimed to establish sex-specific reference ranges for UA Doppler indices if needed. Methods Our main objective was to investigate gestational age-associated changes in UA Doppler indices during the second half of pregnancy and compare the values between male and female fetuses. This was a prospective longitudinal study in women with singleton low-risk pregnancies during 19–40 weeks of gestation. UA Doppler indices were serially obtained at a 4-weekly interval from a free loop of the umbilical cord using color-directed pulsed-wave Doppler ultrasonography. Sex-specific reference intervals were calculated for the fetal heart rate (HR), UA PI, resistance index (RI), and systolic/diastolic ratio (S/D) using multilevel modeling. Results Complete data from 294 pregnancies (a total of 1261 observations from 152 male and 142 female fetuses) were available for statistical analysis, and sex-specific reference ranges for the UA Doppler indices and fetal HR were established for the last half of pregnancy. UA Doppler indices were significantly associated with gestational age (P

Abstract Background Dentists’ and dental healthcare providers’ professional knowledge and attitude towards the prevention of oral diseases may have an impact on the oral health of the general population. The aim of this study was to describe Nepalese dentists’ competency in giving preventive education and treatment to their patients, and to assess their level of knowledge about preventive dental health. Methods This was a cross-sectional study of 195 dentists (71 males and 124 females). Knowledge of preventive oral healthcare and self-reported aspects of preventive oral healthcare were assessed using a close-ended multiple-choice questionnaire. Statistical evaluation was done using chi-squared test, independent sample t-test and factor analysis as appropriate. Results More than 90% of dentists self-reported to be competent in providing preventive treatment and oral hygiene education to their patients. Female dentists reported being more competent in giving oral hygiene education than their male counterparts (p = 0.045). Dentists scored a mean of 24.06 ± 3.8 [range (15–33)] out of 56 on knowledge based on self-reported awareness of seven different aspects of preventive dentistry. More than 70% of the dentists had relatively good knowledge regarding the use of fluoride, whereas the preventive knowledge in other aspects of dental health such as frequency of sugar consumption, xylitol use, dental visits, sealant, gingival health, dental and general health was found to be limited. Conclusions The majority of participating dentists reported a high level of general competency in providing preventive treatment and oral health education to their patients, whereas their knowledge was found to be limited in some aspects of preventive dentistry.

Chlamydia trachomatis is the most common cause of bacterial sexually transmitted infections and causes serious reproductive tract complications among women. The limitations of existing oral antibiotics and treatment of antimicrobial resistance require alternative treatment options. We are proposing, for the first time, the natural polyphenol resveratrol (RES) in an advanced delivery system comprising liposomes incorporated in chitosan hydrogel, for the localized treatment of C. trachomatis infection. Both free RES and RES liposomes-in-hydrogel inhibited the propagation of C. trachomatis in a concentration-dependent manner, assessed by the commonly used in vitro model comprising McCoy cells. However, for lower concentrations, the anti-chlamydial effect of RES was enhanced when incorporated into a liposomes-in-hydrogel delivery system, with inhibition of 78% and 94% for 1.5 and 3 µg/mL RES, respectively for RES liposomes-in-hydrogel, compared to 43% and 72%, respectively, for free RES. Furthermore, RES liposomes-in-hydrogel exhibited strong anti-inflammatory activity in vitro, in a concentration-dependent inhibition of nitric oxide production in the LPS-induced macrophages (RAW 264.7). The combination of a natural substance exhibiting multi-targeted pharmacological properties, and a delivery system that provides enhanced activity as well as applicability for vaginal administration, could be a promising option for the localized treatment of C. trachomatis infection.

OBJECTIVE:To compare cardiac function, systemic hemodynamics and preload reserve of women with increased (cases) and normal (controls) uterine artery (UtA) pulsatility index (PI) at 22-24 weeks of gestation. MATERIALS AND METHODS:A prospective cross-sectional study of 620 pregnant women. UtA blood flow velocities were measured using Doppler ultrasonography, and PI was calculated. Mean UtA PI ≥ 1.16 (90th percentile) was considered abnormal. Maternal hemodynamics was investigated at baseline and during passive leg raising (PLR) using impedance cardiography (ICG). Preload reserve was defined as percent increase in stroke volume (SV) 90 seconds after passive leg raising compared to baseline. RESULTS:Mean UtA PI was 1.49 among cases (n = 63) and 0.76 among controls (n = 557) (p < 0.0001). Eighteen (28.6%) cases and 53 (9.5%) controls developed pregnancy complications (p

Background : Tissue Doppler Imaging (TDI) is a sensitive index of myocardial function. Its role in the fetus has not been extensively evaluated. Objective: To compare myocardial tissue Doppler velocities in fetuses with hypoplastic left heart syndrome (HLHS) to those of normal fetuses (matched for gestational age.) Methods: Cross-sectional retrospective study conducted at 2 large perinatal centers (2003-2007). Fetuses with HLHS ( n = 13) were compared with normal fetuses ( n = 207) in 5 gestational age groups. TDI data included peak systolic (s′), peak early (e′), and late diastolic velocities (a′). Linear regression was used to compare TDI parameters in fetuses with HLHS to normal fetuses matched for gestational age. Results: Fetuses with HLHS had significantly reduced lateral tricuspid annular e′ as compared to normal fetuses. Both normal fetuses and those with HLHS had linear increase in TDI velocities with advancing gestational age. Conclusions: TDI velocities are abnormal in fetuses with HLHS. TDI can be useful in serial follow-up of cardiac function in fetuses with HLHS.

To investigate the effects of high intensity interval training (HIIT) on the maternal heart, fetuses and placentas of pregnant rats.Female Sprague-Dawley rats were randomly assigned to HIIT or sedentary control groups. The HIIT group was trained for 6 weeks with 10 bouts of high intensity uphill running on a treadmill for four minutes (at 85-90% of maximal oxygen consumption) for five days/week. After three weeks of HIIT, rats were mated. After six weeks (gestational day 20 in pregnant rats), echocardiography was performed to evaluate maternal cardiac function. Real-time PCR was performed for the quantification of gene expression, and oxidative stress and total antioxidant capacity was assessed in the tissue samples.Maternal heart weight and systolic function were not affected by HIIT or pregnancy. In the maternal heart, expression of 11 of 22 genes related to cardiac remodeling was influenced by pregnancy but none by HIIT. Litter size, fetal weight and placental weight were not affected by HIIT. Total antioxidant capacity, malondialdehyde content, peroxidase and superoxide dismutase activity measured in the placenta, fetal heart and liver were not influenced by HIIT. HIIT reduced the expression of eNOS (p = 0.03), hypoxia-inducible factor 1α (p = 0.04) and glutathione peroxidase 4.2 (p = 0.02) in the fetal liver and increased the expression of vascular endothelial growth factor-β (p = 0.014), superoxide dismutase 1 (p = 0.001) and tissue inhibitor of metallopeptidase 3 (p = 0.049) in the fetal heart.Maternal cardiac function and gene expression was not affected by HIIT. Although HIIT did not affect fetal growth, level of oxidative stress and total antioxidant capacity in the fetal tissues, some genes related to oxidative stress were altered in the fetal heart and liver indicating that protective mechanisms may be activated.

Cardiovascular response to passive leg raising (PLR) is useful in assessing preload reserve, but it has not been studied longitudinally during pregnancy. We aimed to investigate gestational age associated serial changes in maternal functional hemodynamics and establish longitudinal reference ranges for the second half of pregnancy.This was a prospective longitudinal study on 98 healthy pregnant women who were examined 3-5 times during 20-40 weeks of gestation (a total of 441 observations). Maternal cardiac function and systemic hemodynamics were assessed at baseline and 90 seconds after PLR using impedance cardiography (ICG). The main outcome measures were gestational age specific changes in ICG-derived variables of maternal cardiovascular function and functional hemodynamic response to PLR.Hemodynamic response to PLR varied during pregnancy. PLR led to an insignificant increase in stroke volume during 20+0 to 31+6 weeks, but later in gestation the stroke volume was slightly lower at PLR compared to baseline. PLR caused no significant change in cardiac output between 20+0 and 23+6 weeks and a significant decrease after 24+0 weeks. A decrease in heart rate, mean arterial pressure, and cardiac contractility was observed during PLR throughout the second half of pregnancy. Systemic vascular resistance was reduced by PLR up to 32+0 weeks, but increased slightly thereafter.Healthy pregnant women appear to have limited preload reserve and reduced cardiac contractility, especially in the third trimester, which makes them vulnerable to fluid overload and cardiac failure.

OBJECTIVE: To investigate functional hemodynamic response to passive leg raising in healthy pregnant women and compare it with non-pregnant controls. MATERIALS AND METHODS: This was a prospective cross-sectional study with a case-control design. A total of 108 healthy pregnant women at 22-24 weeks of gestation and 54 non-pregnant women were included. Cardiac function and systemic hemodynamics were studied at baseline and 90 seconds after passive leg raising using non-invasive impedance cardiography. MAIN OUTCOME MEASURES: Trends and magnitudes of changes in impedance cardiography derived parameters of cardiac function and systemic hemodynamics caused by passive leg raising, and preload responsiveness defined as >10% increase in stroke volume or cardiac output after passive leg raising compared to baseline. RESULTS: The hemodynamic parameters in both pregnant and non-pregnant women changed significantly during passive leg raising compared to baseline, but the magnitude and trend of change was similar in both groups. The stroke volume increased both in pregnant (p = 0.042) and non-pregnant (p = 0.018) women, whereas the blood pressure and systemic vascular resistance decreased (p

Coronary flow reserve (CFR) is used as a measure of coronary endothelial function. We investigated the effect of increased afterload on CFR of pregnant and non-pregnant rats.Afterload increase in Wister rats (both pregnant and non-pregnant) was achieved by the infusion of angiotensin II (Ang II) for ∼10 days or by subjecting them to transverse aortic constriction (TAC) for ∼14 days. Control groups were infused with 0.9% NaCl or had sham surgery, respectively. In pregnant rats, the experiments were performed close to term gestation. Doppler velocity waveforms of the left main coronary artery were recorded using a high resolution ultrasound imaging system (Vevo 770, VisualSonics, Canada) at baseline while the animals were anesthetized with 1.5% inhaled isoflurane, and during maximal coronary dilatation obtained by the inhalation of 3.5% of isoflurane. CFR was calculated as the ratio between the peak coronary flow velocities (CFRpeak) and the velocity-time integrals (CFRVTI) recorded at hyperemia and at baseline.CFR could be calculated in 60 of 75 (80%) animals. There were no differences in CFR between intervention and control groups irrespective of whether afterload was increased by Ang II or TAC. In the TAC-study CFRpeak (1.54±0.07 vs 1.85±0.17; p = 0.03) was decreased in pregnant compared to non-pregnant shams. When sham animals from both studies were pooled together both CFRpeak (1.42±0.07 vs 1.86±0.16; p = 0.005) as well as CFRVTI (1.45±0.07 vs 1.78±0.12; p = 0.03) were significantly lower in pregnant rats compared to non-pregnant.CFR can be measured non-invasively in rats using Doppler echocardiography and high concentrations of inhaled isoflurane as a coronary vasodilator. In pregnant rats, CFR is reduced close to term. CFR is not affected by increased left ventricular afterload caused by chronic Ang II infusion or TAC.

BACKGROUND: There is an increased risk of heart failure and pulmonary edema in pregnancies complicated by hypertensive disorders. However, in a previous study we found that pregnancy protects against fibrosis and preserves angiogenesis in a rat model of angiotensin II induced cardiac hypertrophy. In this study we test the hypothesis that pregnancy protects against negative effects of increased afterload. METHODS: Pregnant (gestational day 5.5-8.5) and non-pregnant Wistar rats were randomized to transverse aortic constriction (TAC) or sham surgery. After 14.2 ± 0.14 days echocardiography was performed. Aortic blood pressure and left ventricular (LV) pressure-volume loops were obtained using a conductance catheter. LV collagen content and cardiomyocyte circumference were measured. Myocardial gene expression was assessed by real-time polymerase chain reaction. RESULTS: Heart weight was increased by TAC (p

We tested the hypothesis that, in acute metabolic acidemia, the fetal left ventricle (LV) has the capacity to increase its contractility in response to angiotensin II infusion. Eleven ewes and their fetuses were instrumented at 127–138/145 days of gestation. The effect of angiotensin II on fetal LV function was assessed using intraventricular pressure catheter and tissue Doppler imaging (TDI). Angiotensin II increased fetal arterial blood pressure, whereas pH and pO2 decreased. The heart rate and systemic venous pressure were not affected significantly. The LV end-diastolic and end-systolic pressures, as well as dP/dtmax, increased. The TDI-derived LV longitudinal myocardial isovolumic contraction velocity and its acceleration and velocity during early filling were higher than those at baseline. The incidence of absent isovolumic relaxation velocity was greater during angiotensin II infusion. In summary, during acute metabolic acidemia, the fetal left ventricle could increase its contractility in response to inotropic stimulus even in the presence of increased afterload. The diastolic LV function parameters were altered by angiotensin II.