Transcatheter arterial embolization outperforms surgery in reducing blood transfusions for postpartum vulvovaginal hematoma.

BACKGROUND: Postpartum vulvovaginal hematoma is a complication of vaginal delivery that may progress to life-threatening conditions. However, the management of hematomas, including conservative therapy, surgery, and arterial embolization, is yet to be standardized. OBJECTIVE: This study aimed to: (1) evaluate hematoma features that can be treated conservatively, and (2) determine whether surgery or transcatheter arterial embolization is superior in reducing blood transfusion. STUDY DESIGN: This cross-sectional study included postpartum women transferred to Tohoku University Hospital, Japan, between January 2016 and September 2023 for postpartum vulvovaginal hematomas. Notably, all patients except 1 underwent contrast-enhanced computed tomography. The patients were classified into the following groups: (1) the conservative group who received neither surgery nor transcatheter arterial embolization and (2) the therapeutic intervention group who received surgery or transcatheter arterial embolization. The primary analysis included all patients. Variables for the choice of therapeutic intervention, including the shock index, hemoglobin concentration at arrival, hematoma size, and presence of extravasation, were assessed using a modified Poisson regression model. The secondary analysis included patients who received therapeutic intervention (ie, surgery or transcatheter arterial embolization). Variables for estimating the total amount of blood transfusion, including shock index, hemoglobin concentration at arrival, hematoma size, type of intervention, and presence of extravasation, were analyzed using multiple linear regression. RESULTS: Fifty-seven cases were included in this study. Patients underwent conservative treatment (n=19), surgery (n=11), or transcatheter arterial embolization (n=27). In primary analysis, only the presence of extravasation was significantly associated with the choice of therapeutic intervention (adjusted risk ratio [95% confidence interval], 5.30 [1.53-18.37]). In the secondary analysis, the choice of surgery as a therapeutic option (unstandardized coefficient [95% confidence interval], 4.64 [1.15-8.13]; reference: transcatheter arterial embolization), lower hemoglobin concentration at arrival (-2.84 [-4.71 to -0.97]; 1 g/dL increment), and larger hematoma size (3.38 [1.23-5.53]; 100 cm3 increments) were significantly associated with increased blood transfusion. CONCLUSION: When a vulvovaginal hematoma does not exhibit extravasation, it can be treated conservatively regardless of size. When a therapeutic intervention is selected, transcatheter arterial embolization reduces the total amount of blood transfusion compared with surgery.

Association between Maternal Birth Weight and Prevalence of Congenital Malformations in Offspring: The Japanese Environment and Children's Study.

Congenital malformations are functional and structural alterations in embryonic or foetal development resulting from a variety of factors including maternal health status. This study aimed to investigate the association between maternal birth weight (MBW) and the prevalence of congenital malformations in offspring using data from a nationwide birth cohort study in Japan including 103,060 pregnancies. A binary logistic regression model with adjustment for various covariates revealed that an MBW of <2500 g (low MBW) was associated with an increased risk of congenital heart disease (adjusted odds ratio: 1.388, [95% confidence interval: 1.075-1.792]), angioma (1.491 [1.079-2.059]), and inguinal hernia (1.746, [1.189-2.565]), while those with an MBW of ≥4000 g (high MBW) were associated with congenital anomalies of the urinary tract (2.194, [1.261-3.819]) and arrhythmia (1.775, [1.157-2.725]) compared with those with an MBW of 3000-3499 g. Low MBW was associated with cleft lip and/or palate (1.473, [1.052-2.064]), congenital heart disease (1.615, [1.119-2.332]), genital organs (1.648, [1.130-2.405]), hypospadias (1.804, [1.130-2.881]), and inguinal hernia (1.484, [1.189-1.851]) in male infants and CAKUT (1.619, [1.154-2.273]) in female infants, whereas high MBW was associated with congenital heart disease (1.745, [1.058-2.877]) and CAKUT (2.470, [1.350-4.517]) in male infants. The present study is the first to demonstrate a link between MBW and congenital malformations in Japanese children. While these results must be interpreted with caution, MBW should be considered a major predictor of congenital malformation risk.

Modeling embryo-endometrial interface recapitulating human embryo implantation.

The initiation of human pregnancy is marked by the implantation of an embryo into the uterine environment; however, the underlying mechanisms remain largely elusive. To address this knowledge gap, we developed hormone-responsive endometrial organoids (EMO), termed apical-out (AO)-EMO, which emulate the in vivo architecture of endometrial tissue. The AO-EMO comprise an exposed apical epithelium surface, dense stromal cells, and a self-formed endothelial network. When cocultured with human embryonic stem cell-derived blastoids, the three-dimensional feto-maternal assembloid system recapitulates critical implantation stages, including apposition, adhesion, and invasion. Endometrial epithelial cells were subsequently disrupted by syncytial cells, which invade and fuse with endometrial stromal cells. We validated this fusion of syncytiotrophoblasts and stromal cells using human blastocysts. Our model provides a foundation for investigating embryo implantation and feto-maternal interactions, offering valuable insights for advancing reproductive medicine.

Technical note: Implementing MRI/CT-based elemental concentration data to Monte Carlo simulation for yielding positron emitters in proton therapy.

BACKGROUND: The elemental concentration (especially oxygen and carbon) and mass density must be accurately assigned to perform Monte Carlo (MC) simulations for predicting proton-induced nuclear reactions in the human body. We recently proposed an approach to quantify elemental concentrations and mass densities of human soft tissues from water content (WC) data obtained by quantitative magnetic resonance (MR) imaging (which we called "MRWC"). PURPOSE: This study presents the first implementation of MRWC-derived elemental concentrations and mass densities as complementary inputs into MC simulations on a virtual head phantom, and demonstrates the simulation of positron emitter production yields in proton therapy. METHODS: An MC code, PHITS, was used to simulate proton therapy with a monoenergetic 140 MeV beam for a digital head phantom provided by BrainWeb. Three different head images were synthesized as inputs: a conventional CT image, an ideal CT image as a reference, and a WC image coupled with the bone-only CT image for a hybrid approach (MRWC/CT). Thereafter, the performance of the MRWC/CT method was evaluated by comparing its accuracy in predicting the production yields of positron emitters (11C and 15O) with the gold-standard CT-only method. RESULTS: The MRWC/CT method could predict 11C and 15O production yield maps that closely resembled the corresponding reference maps, while the CT-only method failed. The structural similarity index measures between the reference and CT- or MRWC/CT-derived maps were improved from 0.67 (CT-only) to 0.87 (MRWC/CT) for 11C and 0.76 (CT-only) to 0.93 (MRWC/CT) for 15O. Furthermore, applying post-processing normalizations to account for elemental density variations in the production yields of positron emitters facilitated the determination of distal fall-off positions in depth activity profiles. CONCLUSION: At least in the head area, the MRWC/CT method demonstrated potential for more precise predictions of proton-induced positron emitter distributions via MC simulations than that of the CT-only method.

Respiratory benefit in preterm lambs is progressively lost when the concentration of fetal plasma betamethasone is titrated below two nanograms per milliliter.

Antenatal steroid therapy is the standard of care for women at imminent risk of preterm delivery. Current dosing regimens use suprapharmacological doses to achieve extended fetal steroid exposures. We aimed to determine the lowest fetal plasma betamethasone concentration sufficient to achieve functional preterm lung maturation. Ewes with single fetuses underwent surgery to install a fetal jugular catheter. Adopting a stepwise design, ewes were randomized to either a saline-only group (negative control group; n = 9) or one of four betamethasone treatment groups. Each betamethasone group fetus received a fetal intravenous infusion to target a constant plasma betamethasone level of either 1) 2 ng/mL (2 ng/mL positive control group, n = 9); 2) 1 ng/mL, (1 ng/mL group, n = 10); 3) 0.5 ng/mL (0.5 ng/mL group, n = 10); or 4) 0.25 ng/mL (0.25 ng/mL group, n = 10). Fetuses were infused for 48 h, delivered, and ventilated. The positive control group, negative control group, and mid-point 0.5 ng/mL group animals were tested first. An interim analysis informed the final betamethasone group tested. Positive control group animals had large, statistically significant improvements in respiratory function. Based on an interim analysis, the 1.0 ng/mL group was studied in favor of the 0.25 ng/mL group. Treatment efficacy was progressively lost at plasma betamethasone concentrations lower than 2 ng/mL. We demonstrated that the acute respiratory benefit conveyed by antenatal steroid exposure in the fetal sheep is progressively lost when constant fetal plasma betamethasone concentrations are reduced below a targeted value of 2 ng/mL.NEW & NOTEWORTHY Lung maturation benefits in preterm lambs were progressively lost when fetal plasma betamethasone concentrations fell below 2 ng/mL. The effective floor threshold for a robust, lung-maturing exposure likely lies between 1 and 2 ng betamethasone per milliliter of plasma. Hypothalamic pituitary adrenal axis signaling and immunocyte populations remained materially disrupted at subtherapeutic steroid concentrations. These data demonstrate the potential to improve antenatal steroid therapy using reduced dose regimens informed by glucocorticoid pharmacokinetics and pharmacodynamics.

MRI-based quantification of carbon and oxygen concentrations in human soft tissues for range verification in proton therapy.

BACKGROUND: In-situ range verification of particle therapy based on the detection of secondary emitted radiation requires highly accurate assignment of elemental concentrations (particularly carbon and oxygen) in the human body. PURPOSE: A method for quantitatively predicting carbon and oxygen concentrations in human soft tissues is proposed. This method relies on an empirical one-to-one correspondence between the mass fraction and water content (WC), which is a measurable tissue quantity based on magnetic resonance (MR) imaging (referred to as "MRWC-based method"). METHODS: A numerical analysis of the MRWC-based method was performed for 47 standard human soft tissues tabulated in the literature as objects of interest with unknown mass fractions of the four main elements-C, O, H, and N. Thereafter, the method was evaluated in terms of the mass-fraction quantification accuracy by comparing it with the gold-standard CT-based method developed by Schneider et al. The MRWC-based method was also applied to the MR imaging data of a virtual head phantom obtained from a three-dimensional MRI-simulated brain database. RESULTS: The predicted mass fractions in a range of human soft tissues were in better agreement with the reference values than those predicted by the CT-based method. The mean absolute errors of the predicted mass% values for the overall standard soft tissues could be reduced from 4.8 percentage points (pp) (CT-based) to 0.5 pp (MRWC-based) for carbon and from 5.2 pp (CT-based) to 0.4 pp (MRWC-based) for oxygen. The application to the simulated MRI data confirmed the capability of the sufficient recognition of the boundaries between the white matter and gray matter in the brain that could not be realized by the CT-based method. Thus, the MRWC-based method exhibits superior performance in the prediction of carbon and oxygen concentrations in soft tissues. CONCLUSIONS: This study is limited to a proof-of-concept scope but demonstrates the feasibility of the MRWC-based method for the generation of elemental images of human soft tissues from MRI-derived water-content images.

Maternal lifestyle and nutrient intakes during pregnancy and exclusive breastfeeding in relation to risk factors for breast cancer: The Japan Environment and Children's Study.

Breastfeeding has many benefits for infant growth and maternal health, such as reducing breast cancer risk. However, data on maternal factors influencing breastfeeding are insufficient. To clarify the associations between maternal lifestyle and diet during pregnancy and exclusive breastfeeding (EBF), we conducted a prospective study of pregnant women within the framework of the Japan Environment and Children's Study (a nationwide birth cohort study). Of 97,413 pregnant women recruited between January 2011 and March 2014, 27,775 with a singleton first live birth whose dietary data during pregnancy and lactation data were complete were eligible. Using logistic regression, we evaluated the associations between lifestyle factors including smoking and prepregnancy body mass index and intake of nutrients (macronutrients, isoflavones, and dietary fiber), some of which are known risk factors of breast cancer, and EBF for one month postpartum (initiation of EBF). To investigate the associations of these factors with EBF for 6 months (continuation of EBF), 9582 women who had successfully completed one-month EBF were further followed up. Smoking and prepregnancy obesity were inversely associated with the initiation and continuation of EBF. Intakes of protein, fat, isoflavone, and dietary fiber were positively associated (p trend = 0.0001 for dietary fiber), and carbohydrate intake was inversely associated with the initiation of EBF. Dietary fiber intake was also associated with the continuation of EBF (p trend = 0.048). These findings indicate that maternal lifestyles during pregnancy affect lactation performance. Lifestyle adjustments during pregnancy may have favorable effects on maternal and children's health through successful breastfeeding.

Secondhand smoke exposure is associated with the risk of hypertensive disorders of pregnancy: the Japan Environment and Children's Study.

Hypertensive disorders of pregnancy (HDP) are associated with poor maternal and neonatal prognoses. Although several studies have indicated an effect of secondhand smoke (SHS) exposure on HDP, such evidence is lacking in Japan. Therefore, we analyzed data from the Japan Environment and Children's Study, a large-scale epidemiological investigation, to elucidate a possible link between SHS exposure and HDP risk. Data were obtained from the all-birth fixed datasets and included information on 104,062 fetuses and their parents. SHS exposure was assessed in terms of the frequency (rarely, 1-3, or 4-7 days/week) and the daily duration of exposure (<1, 1-2, or ≥2 h(s)/day). Modified Poisson regression model analyses were performed with adjustment for known risk factors for HDP. Additionally, the population attributable fractions (PAFs) of SHS exposure and maternal smoking to HDP prevalence were estimated. The relative risks of developing HDP among individuals with SHS exposures of 4-7 days/week and ≥2 h/day were 1.18 and 1.27 (95% confidence interval: 1.02-1.36 and 0.96-1.67), respectively, compared to the reference groups (rare exposure and <1 h/day). The PAFs for the risk of HDP due to SHS exposure and perinatal smoking were 3.8% and 1.8%, respectively. Japanese women with greater exposure to SHS have a higher risk of HDP after adjustment for possible confounding factors; thus, relevant measures are required to reduce SHS exposure to alleviate HDP risk. The association between second-hand smoking exposure and hypertensive disorders of pregnancy risk was analyzed using the JECS data. The relative risks in 4-7 days/week and ≥2 h/day of SHS exposures were 1.18 and 1.27, respectively. The PAFs due to SHS exposure and maternal smoking were 3.80% and 1.81%, respectively.

Risk Factors Associated With Peripartum Suicide Attempts in Japan.

Importance: Peripartum suicide attempt is a major psychiatric complication associated with pregnancy, but the risk factors remain largely uncertain. Objective: To identify the demographic characteristics and predisposing risks for peripartum suicide attempts and postpartum depression. Design, Setting, and Participants: This cohort study used retrospective data on pregnant women who delivered children between April 1, 2016, and March 31, 2021, at 712 hospitals in Japan. The nationwide Diagnosis Procedure Combination database was used. Exposures: Psychiatric and nonpsychiatric medical history, age, alcohol and tobacco use, and obstetric complications and procedures. Main Outcomes and Measures: Data on admissions for prepartum suicide attempt and delivery during the same hospital stay and readmissions for depression or suicide attempt within 1 year post partum were collected. Comparisons of prevalence of each study variable were performed, and multivariable logistic regression analyses were used to determine risk factors. Results: From a total of 39 908 649 hospitalization episodes, 804 617 cumulative pregnant women (median [IQR] age at childbirth, 33 [29-36] years) who delivered at the enrolled hospitals were identified, including 1202 who were admitted for suicide attempt and delivery during the same hospital stay and 111 readmitted for suicide attempt within 1 year post partum. Risk factors associated with prepartum suicide attempts included younger age (adjusted odds ratio [aOR], 0.99; 95% CI, 0.98-1.00) and histories of personality disorder (aOR, 10.81; 95% CI, 5.70-20.49), depression (aOR, 3.97; 95% CI, 2.35-6.70), schizophrenia (aOR, 2.89; 95% CI, 1.52-5.50), and adjustment disorder (aOR, 2.66; 95% CI, 1.07-6.58). Risk factors associated with postpartum suicide attempts included younger age (aOR, 0.96; 95% CI, 0.93-1.00), heavy tobacco use (aOR, 23.09; 95% CI, 5.46-97.62), and histories of alcohol use disorder (aOR, 163.54; 95% CI, 28.30-944.95), personality disorder (aOR, 10.28; 95% CI, 3.29-32.10), anxiety disorders (aOR, 8.13; 95% CI, 2.88-22.98), depression (aOR, 7.27; 95% CI, 2.95-17.91), schizophrenia (aOR, 5.77; 95% CI, 2.17-15.38), bipolar disorder (aOR, 3.98; 95% CI, 1.36-11.67), and insomnia (aOR, 3.17; 95% CI, 1.30-7.78). On sensitivity analysis, risk factors associated with postpartum depression after excluding those with prenatal depression included histories of personality disorder, adjustment disorder, bipolar disorder, insomnia, and anxiety disorders. Conclusions and Relevance: The findings of this cohort study suggest that histories of smoking and prenatal psychiatric disorders are potential risk factors for peripartum suicide attempts and may require additional treatment and prevention interventions.

Pregnancy outcomes among female childhood, adolescent, and young adult cancer survivors assessed using internet-based nationwide questionnaire surveys in Japan.

OBJECTIVE: Female cancer survivors planning to become pregnant are concerned about the impact of cancer treatment on their ability to maintain normal pregnancy and the negative impact on their offspring. However, studies on the pregnancy outcomes of cancer survivors in Japan are limited. Therefore, this study aimed to investigate the pregnancy outcomes of female cancer survivors by comparing them with women without a history of malignant tumors in Japan. METHODS: This cross-sectional study included 3308 subjects, based on an internet-based questionnaire (self-reported) survey conducted in Japan. Differences in pregnancy outcomes, including multiple pregnancies, stillbirth, preterm birth (PTB), and infant birthweight, between cancer survivors and subjects without a history of malignant tumors, were evaluated using a generalized linear mixed-effects model with adjustment for possible confounding factors. RESULTS: Of 3308 subjects included in this study, 629 (19.0%) were cancer survivors, among whom cervical (40.4%), breast (19.1%), and thyroid (7.0%) malignancies were most frequent. 71 (2.2%) and 53 (1.6%) participants had a history of multiple pregnancies and stillbirth, respectively; 385 (11.8%), 179 (5.5%), and 137 (4.2%) participants, respectively, had histories of PTB at less than 37, 34, and 32 weeks of gestation. Further, 302 (10.7%), 326 (11.6%), and 330 (11.7%) participants delivered to low birthweight (LBW), small-for-gestational-age (SGA), and large-for-gestational-age (LGA) infants, respectively. Subjects with a history of cervical or breast cancers had significantly higher odds of PTB at <37 weeks of gestation (adjusted odds ratios [ORs], 1.87 [95% CI: 1.25-2.81] and 2.61 [95% CI: 1.77-3.86], respectively), preterm LBW infants (adjusted ORs, 2.70 [95% CI: 1.39-5.24] and 2.76 [95% CI: 1.03-7.38], respectively), and LGA infants (1.98 [95% CI: 1.36-2.89] and 1.99 [95% CI: 1.14-3.49], respectively), compared to those without a history of a malignant tumor. Subjects with a history of thyroid cancer had significantly higher odds of stillbirth (adjusted OR, 5.11 [95% CI: 1.11-23.5]). CONCLUSION: Cancer survivors had a higher risk of adverse pregnancy outcomes than those without a history of malignant tumors in Japan. Healthcare providers should consider the high likelihood of adverse pregnancy outcomes during preconception counseling for cancer survivors.

Risk scores for predicting small for gestational age infants in Japan: The TMM birthree cohort study.

This study aimed to construct a prediction model for small-for-gestational-age (SGA) infants in Japan by creating a risk score during pregnancy. A total of 17,073 subjects were included in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study, a prospective cohort study. A multiple logistic regression model was used to construct risk scores during early and mid-gestational periods (11-17 and 18-21 weeks of gestation, respectively). The risk score during early gestation comprised the maternal age, height, body mass index (BMI) during early gestation, parity, assisted reproductive technology (ART) with frozen-thawed embryo transfer (FET), smoking status, blood pressure (BP) during early gestation, and maternal birth weight. The risk score during mid-gestation also consisted of the maternal age, height, BMI during mid-gestation, weight gain, parity, ART with FET, smoking status, BP level during mid-gestation, maternal birth weight, and estimated fetal weight during mid-gestation. The C-statistics of the risk scores during early- and mid-gestation were 0.658 (95% confidence interval [CI]: 0.642-0.675) and 0.725 (95% CI: 0.710-0.740), respectively. In conclusion, the predictive ability of the risk scores during mid-gestation for SGA infants was acceptable and better than that of the risk score during early gestation.

Chorioamnionitis Causes Kidney Inflammation, Podocyte Damage, and Pro-fibrotic Changes in Fetal Lambs.

Background: Perinatal complications, such as prematurity and intrauterine growth restriction, are associated with increased risk of chronic kidney disease. Although often associated with reduced nephron endowment, there is also evidence of increased susceptibility for sclerotic changes and podocyte alterations. Preterm birth is frequently associated with chorioamnionitis, though studies regarding the effect of chorioamnionitis on the kidney are scarce. In this study, we aim to unravel the consequences of premature birth and/or perinatal inflammation on kidney development using an ovine model. Methods: In a preterm sheep model, chorioamnionitis was induced by intra-amniotic injection of lipopolysaccharide (LPS) at either 2, 8, or 15 days prior to delivery. Control animals received intra-amniotic injections of sterile saline. All lambs were surgically delivered at 125 days' gestation (full term is 150 days) and immediately euthanized for necropsy. Kidneys were harvested and processed for staining with myeloperoxidase (MPO), Wilms tumor-1 (WT1) and alpha-smooth muscle actine (aSMA). mRNA expression of tumor necrosis factor alpha (TNFA), Interleukin 10 (IL10), desmin (DES), Platelet derived growth factor beta (PDGFB), Platelet derived growth factor receptor beta (PDGFRB), synaptopodin (SYNPO), and transforming growth factor beta (TGFB) was measured using quantitative PCR. Results: Animals with extended (but not acute) LPS exposure had an inflammatory response in the kidney. MPO staining was significantly increased after 8 and 15 days (p = 0.003 and p = 0.008, respectively). Expression of TNFA (p = 0.016) and IL10 (p = 0.026) transcripts was increased, peaking on day 8 after LPS exposure. Glomerular aSMA and expression of TGFB was increased on day 8, suggesting pro-fibrotic mesangial activation, however, this was not confirmed with PDFGB or PDGFRB. The number of WT1 positive nuclei in the glomerulus, as well as expression of synaptopodin, decreased, indicating podocyte injury. Conclusion: We report that, in an ovine model of prematurity, LPS-induced chorioamnionitis leads to inflammation of the immature kidney. In addition, this process was associated with podocyte injury and there are markers to support pro-fibrotic changes to the glomerular mesangium. These data suggest a potential important role for antenatal inflammation in the development of preterm-associated kidney disease, which is frequent.

One percent of the clinical dose used for antenatal steroid therapy is sufficient to induce lung maturation when administered directly to the preterm ovine fetus.

Antenatal steroids (ANSs) are routinely administered to women judged to be at imminent risk of preterm delivery. Their principal benefit is precocious functional maturation of the preterm fetal lung. Current dosing regimens expose the mother and fetus to high steroid levels that may be unnecessary, increasing the potential risks of disruption to the maternal and fetal hypothalamic-pituitary-adrenal (HPA) axis and glucose regulation, alterations in placental function, and reduced fetal growth. Using a sheep model of pregnancy, we tested the hypothesis that direct fetal administration of an ultra-low dose course of betamethasone phosphate (∼0.33 mg) would be sufficient to elicit functional maturation of the fetal lung. A jugular catheter was installed in singleton ovine fetuses at 122-day gestation under general anesthesia. Animals were randomized to receive either: 1) fetal intravenous betamethasone phosphate to target fetal plasma betamethasone mean levels of 2 ng/mL for 26 h (fetal treatment group; n = 16); 2) fetal intravenous saline for 26 h and two maternal intramuscular injections of 0.25 mg/kg betamethasone phosphate + betamethasone acetate, simulating a standard clinical treatment (maternal treatment group; n = 12); or 3) fetal intravenous saline only for 26 h (negative control group; n = 10). Fetuses were delivered 48 h after surgery, ventilated for 30 min to allow the collection of lung function and physiological data, and euthanized. Quantitative PCR and Western blots were used to assess markers of lung maturation. The average total betamethasone phosphate dose for the fetal treatment group was 1% (0.3 mg) of the maternal treatment group (31-mg betamethasone phosphate + betamethasone acetate). At 30 min of ventilation, arterial [Formula: see text], pH, heart rate, and ventilation efficacy index (VEI) were significantly (P < 0.05) and equivalently improved in both the fetal treatment group and maternal treatment group, relative to the negative control group. Similarly, SP-A, SP-C, and AQ-5 mRNA expression was significantly higher in both the fetal treatment group and maternal treatment group, relative to negative control. Maternal steroid administration was not required to generate preterm fetal lung maturation in sheep. Using a low dose and targeting steroid treatments directly to the fetus has the potential to significantly reduce maternal exposures, while simultaneously reducing the potential risk of adverse outcomes associated with current clinical dosing regimens.

Distribution of Amniotic Epithelial Cells After Intraportal Infusion in a Rat Model.

BACKGROUND: Human amniotic epithelial cells (hAECs) are increasingly gaining attention as novel sources for cell transplantation. In clinical practice, intraportal infusion is considered one of the leading approaches for transplantation; however, this has not yet been validated for in vivo transplantation of hAECs. Thus, this study aims to investigate the distribution of hAECs post intraportal infusion and compare this distribution with other cell administration routes. METHODS: Wistar/ST rats were divided into 4 groups (n = 3 for each) based on cell administration route: group 1, intraportal; group 2, the spleen; group 3, tail veins; and group 4, penile veins. Subsequently, hAECs (1 × 107) stained with XenoLight DiR were infused into each recipient. Cell distribution was evaluated using an in vivo imaging system. RESULTS: DiR signals were detected in the rat livers of groups 1 and 2 with those in group 2 being much weaker than those in group 1. Necrosis of small intestine was observed in 2 cases in group 2. DiR signals were detected in the lungs in groups 3 and 4 because of systemic circulation; however, all the animals died within 20 minutes of infusions. CONCLUSIONS: Intraportal infusion is potentially applicable for safe and efficient transplantation of hAECs into the liver, whereas hAECs administration via the spleen carries a risk of thrombosis in a narrow portal vein system. Our results also indicate that hAECs administration via the systemic circulation could cause pulmonary embolism in clinical settings.

Direct administration of the non-competitive interleukin-1 receptor antagonist rytvela transiently reduced intrauterine inflammation in an extremely preterm sheep model of chorioamnionitis.

BACKGROUND: Intraamniotic inflammation is associated with up to 40% of preterm births, most notably in deliveries occurring prior to 32 weeks' gestation. Despite this, there are few treatment options allowing the prevention of preterm birth and associated fetal injury. Recent studies have shown that the small, non-competitive allosteric interleukin (IL)-1 receptor inhibitor, rytvela, may be of use in resolving inflammation associated with preterm birth (PTB) and fetal injury. We aimed to use an extremely preterm sheep model of chorioamnionitis to investigate the anti-inflammatory efficacy of rytvela in response to established intra-amniotic (IA) lipopolysaccharide (LPS) exposure. We hypothesized that rytvela would reduce LPS-induced IA inflammation in amniotic fluid (AF) and fetal tissues. METHODS: Sheep with a single fetus at 95 days gestation (estimated fetal weight 1.0 kg) had surgery to place fetal jugular and IA catheters. Animals were recovered for 48 hours before being randomized to either: i) IA administration of 2 ml saline 24 hours before 2 ml IA and 2 ml fetal intravenous (IV) administration of saline (Saline Group, n = 7); ii) IA administration of 10 mg LPS in 2 ml saline 24 hours before 2 ml IA and 2 ml fetal IV saline (LPS Group, n = 10); 3) IA administration of 10 mg LPS in 2 ml saline 24 hours before 0.3 mg/fetal kg IA and 1 mg/fetal kg fetal IV rytvela in 2 ml saline, respectively (LPS + rytvela Group, n = 7). Serial AF samples were collected for 120 h. Inflammatory responses were characterized by quantitative polymerase chain reaction (qPCR), histology, fluorescent immunohistochemistry, enzyme-linked inmmunosorbent assay (ELISA), fluorescent western blotting and blood chemistry analysis. RESULTS: LPS-treated animals had endotoxin and AF monocyte chemoattractant protein (MCP)-1 concentrations that were significantly higher at 24 hours (immediately prior to rytvela administration) relative to values from Saline Group animals. Following rytvela administration, the average MCP-1 concentrations in the AF were significantly lower in the LPS + rytvela Group relative to in the LPS Group. In delivery samples, the expression of IL-1ß in fetal skin was significantly lower in the LPS + rytvela Group compared to the LPS Group. CONCLUSION: A single dose of rytvela was associated with partial, modest inhibition in the expression of a panel of cytokines/chemokines in fetal tissues undergoing an active inflammatory response.

Association of subjective health and abnormal cervical cytology in Japanese pregnant women: An adjunct study of the Japan Environment and Children's Study.

This study examines the association between abnormal cervical cytology and subjective health in pregnant women, as an adjunct to the Japan Environment and Children's Study, which cross-sectionally analyzed a subset of the prospective cohort. A total of 3024 pregnant women at a childbirth facility whose medical records of cervical cytology in the first trimester of pregnancy were transcribed and who responded to the subjective health questionnaire were included herein. They were classified into excellent, good, fair, and poor groups based on their subjective health. Cervical cytology results obtained from perinatal medical records were classified into normal and abnormal cytology based on the Bethesda classification. Logistic regression analysis adjusted for baseline characteristics, including age, pre-pregnancy body mass index, parity, and other possible confounding factors, was used. Of 3024 pregnant women, 106 (3.5%) had abnormal cytology, with the prevalence being 1.3%, 3.7%, 3.9%, and 4.0%, respectively (p = 0.055) in the poor, fair, good, and excellent groups. The baseline characteristics, namely age, history of gynecological diseases, Kessler 6-item psychological distress scale score, and history of mental illness, were significantly different between groups. Compared to the poor group, the other three groups had a significantly higher abnormal cytology risk after adjusting for confounding factors (Fair: adjusted OR [aOR] = 3.6, 95% CI [1.0-12.1]; Good: aOR = 4.6 [1.3-15.5]; Excellent: aOR = 4.6 [1.2-17.8]). This study encourages young women to undergo cervical cancer screening because they are at risk for cervical cancer even if they think that they are healthy, and preventive activities like regular screening are essential.

Quadratic relation for mass density calibration in human body using dual-energy CT data.

PURPOSE: To derive the mass density (ρ) from dual-energy computed tomography (DECT) data by calibrating electron density (ρe ) and effective atomic numbers (Zeff ) of human tissues. METHODS: We propose the DEEDZ-MD method, in which a single polynomial parameterization covers the entire human-tissue range to establish an empirical quadratic relation between the atomic number-to-mass ratio and Zeff . Then, we numerically evaluate the DEEDZ-MD method in reference human tissues listed in the ICRP Publication 110 and ICRU Report 46. The tissues are considered to have unknown ρ values. The attenuation coefficients of these tissues are calculated using the XCOM Photon Cross Sections Database. The DEEDZ-MD method is also applied to experimental DECT data acquired from a tissue characterization phantom and an anthropomorphic phantom at 90 kV and 150 kV/Sn. RESULTS: The numerical analysis of the DEEDZ-MD method reveals a single quadratic relation between the atomic number-to-mass ratio and Zeff in a wide range of human tissues. The simulated ρ values are in excellent agreement with the reference values over ρ values from 0.260 (lung) to 3.225 (hydroxyapatite). The relative deviations from the reference ρ remain within ±0.6% for all the reference human tissues, except for the eye lens (approximate deviation of -1.0%). The overall root-mean-square error is 0.24%. The application of the DEEDZ-MD method to experimental dual-energy CT data confirms this agreement within experimental accuracy, indicating the practical feasibility of the method. The DEEDZ-MD method enables the generation of ρ images with less image noise than the existing DECT-based conversion of ρ from ρe and with fewer beam-hardening artifacts than conventional single-energy CT images. CONCLUSIONS: The DEEDZ-MD method can facilitate the generation of ρ images from dual-energy CT data without relying on the nontrivial segmentation of different tissues.

Sequential Exposure to Antenatal Microbial Triggers Attenuates Alveolar Growth and Pulmonary Vascular Development and Impacts Pulmonary Epithelial Stem/Progenitor Cells.

Perinatal inflammatory stress is strongly associated with adverse pulmonary outcomes after preterm birth. Antenatal infections are an essential perinatal stress factor and contribute to preterm delivery, induction of lung inflammation and injury, pre-disposing preterm infants to bronchopulmonary dysplasia. Considering the polymicrobial nature of antenatal infection, which was reported to result in diverse effects and outcomes in preterm lungs, the aim was to examine the consequences of sequential inflammatory stimuli on endogenous epithelial stem/progenitor cells and vascular maturation, which are crucial drivers of lung development. Therefore, a translational ovine model of antenatal infection/inflammation with consecutive exposures to chronic and acute stimuli was used. Ovine fetuses were exposed intra-amniotically to Ureaplasma parvum 42 days (chronic stimulus) and/or to lipopolysaccharide 2 or 7 days (acute stimulus) prior to preterm delivery at 125 days of gestation. Pulmonary inflammation, endogenous epithelial stem cell populations, vascular modulators and morphology were investigated in preterm lungs. Pre-exposure to UP attenuated neutrophil infiltration in 7d LPS-exposed lungs and prevented reduction of SOX-9 expression and increased SP-B expression, which could indicate protective responses induced by re-exposure. Sequential exposures did not markedly impact stem/progenitors of the proximal airways (P63+ basal cells) compared to single exposure to LPS. In contrast, the alveolar size was increased solely in the UP+7d LPS group. In line, the most pronounced reduction of AEC2 and proliferating cells (Ki67+) was detected in these sequentially UP + 7d LPS-exposed lambs. A similar sensitization effect of UP pre-exposure was reflected by the vessel density and expression of vascular markers VEGFR-2 and Ang-1 that were significantly reduced after UP exposure prior to 2d LPS, when compared to UP and LPS exposure alone. Strikingly, while morphological changes of alveoli and vessels were seen after sequential microbial exposure, improved lung function was observed in UP, 7d LPS, and UP+7d LPS-exposed lambs. In conclusion, although sequential exposures did not markedly further impact epithelial stem/progenitor cell populations, re-exposure to an inflammatory stimulus resulted in disturbed alveolarization and abnormal pulmonary vascular development. Whether these negative effects on lung development can be rescued by the potentially protective responses observed, should be examined at later time points.

Chorioamnionitis induces changes in ovine pulmonary endogenous epithelial stem/progenitor cells in utero.

BACKGROUND: Chorioamnionitis, an intrauterine infection of the placenta and fetal membranes, is a common risk factor for adverse pulmonary outcomes in premature infants including BPD, which is characterized by an arrest in alveolar development. As endogenous epithelial stem/progenitor cells are crucial for organogenesis and tissue repair, we examined whether intrauterine inflammation negatively affects these essential progenitor pools. METHODS: In an ovine chorioamnionitis model, fetuses were intra-amniotically exposed to LPS, 2d or 7d (acute inflammation) before preterm delivery at 125d of gestation, or to intra-amniotic Ureaplasma parvum for 42d (chronic inflammation). Lung function, pulmonary endogenous epithelial stem/progenitor pools, and downstream functional markers were studied. RESULTS: Lung function was improved in the 7d LPS and 42d Ureaplasma groups. However, intrauterine inflammation caused a loss of P63+ basal cells in proximal airways and reduced SOX-9 expression and TTF-1+ Club cells in distal airways. Attenuated type-2 cell numbers were associated with lower proliferation and reduced type-1 cell marker Aqp5 expression, indicative for impaired progenitor function. Chronic Ureaplasma infection only affected distal airways, whereas acute inflammation affected stem/progenitor populations throughout the lungs. CONCLUSIONS: Acute and chronic prenatal inflammation improve lung function at the expense of stem/progenitor alterations that potentially disrupt normal lung development, thereby predisposing to adverse postnatal outcomes. IMPACT: In this study, prenatal inflammation improved lung function at the expense of stem/progenitor alterations that potentially disrupt normal lung development, thereby predisposing to adverse postnatal outcomes. Importantly, we demonstrate that these essential alterations can already be initiated before birth. So far, stem/progenitor dysfunction has only been shown postnatally. This study indicates that clinical protocols to target the consequences of perinatal inflammatory stress for the immature lungs should be initiated as early as possible and ideally in utero. Within this context, our data suggest that interventions, which promote function or repair of endogenous stem cells in the lungs, hold great promise.

Proton dose calculation based on converting dual-energy CT data to stopping power ratio (DEEDZ-SPR): a beam-hardening assessment.

To achieve an accurate stopping power ratio (SPR) prediction in particle therapy treatment planning, we previously proposed a simple conversion to the SPR from dual-energy (DE) computed tomography (CT) data via electron density and effective atomic number (Z eff) calibration (DEEDZ-SPR). This study was conducted to carry out an initial implementation of the DEEDZ-SPR conversion method with a clinical treatment planning system (TPS; VQA, Hitachi Ltd., Tokyo) for proton beam therapy. Consequently, this paper presents a proton therapy plan for an anthropomorphic phantom to evaluate the stability of the dose calculations obtained by the DEEDZ-SPR conversion against the variation of the calibration phantom size. Dual-energy x-ray CT images were acquired using a dual-source CT (DSCT) scanner. A single-energy CT (SECT) scan using the same DSCT scanner was also performed to compare the DEEDZ-SPR conversion with the SECT-based SPR (SECT-SPR) conversion. The scanner-specific parameters necessary for the SPR calibration were obtained from the CT images of tissue substitutes in a calibration phantom. Two calibration phantoms with different sizes (a 33 cm diameter phantom and an 18 cm diameter phantom) were used for the SPR calibrations to investigate the beam-hardening effect on dosimetric uncertainties. Each set of calibrated SPR data was applied to the proton therapy plan designed using the VQA TPS with a pencil beam algorithm for the anthropomorphic phantom. The treatment plans with the SECT-SPR conversion exhibited discrepancies between the dose distributions and the dose-volume histograms (DVHs) of the 33 cm and 18 cm phantom calibrations. In contrast, the corresponding dose distributions and the DVHs obtained using the DEEDZ-SPR conversion method coincided almost perfectly with each other. The DEEDZ-SPR conversion appears to be a promising method for providing proton dose plans that are stable against the size variations of the calibration phantom and the patient.