Antenatal steroids elicited neurodegenerative-associated transcriptional changes in the hippocampus of preterm fetal sheep independent of lung maturation.

BACKGROUND: Antenatal steroid therapy for fetal lung maturation is routinely administered to women at risk of preterm delivery. There is strong evidence to demonstrate benefit from antenatal steroids in terms of survival and respiratory disease, notably in infants delivered at or below 32 weeks' gestation. However, dosing remains unoptimized and lung benefits are highly variable. Current treatment regimens generate high-concentration, pulsatile fetal steroid exposures now associated with increased risk of childhood neurodevelopmental diseases. We hypothesized that damage-associated changes in the fetal hippocampal transcriptome would be independent of preterm lung function. METHODS: Date-mated ewes carrying a single fetus at 122 ± 2dGA (term = 150dGA) were randomized into 4 groups: (i) Saline Control Group, 4×2ml maternal saline intramuscular(IM) injections at 12hr intervals (n = 11); or (ii) Dex High Group, 2×12mg maternal IM dexamethasone phosphate injections at 12hr intervals followed by 2×2ml IM saline injections at 12hr intervals (n = 12; representing a clinical regimen used in Singapore); or (iii) Dex Low Group, 4×1.5mg maternal IM dexamethasone phosphate injections 12hr intervals (n = 12); or (iv) Beta-Acetate Group, 1×0.125mg/kg maternal IM betamethasone acetate injection followed by 3×2ml IM sterile normal saline injections 12hr intervals (n = 8). Lambs were surgically delivered 48hr after first maternal injection at 122-125dGA, ventilated for 30min to establish lung function, and euthanised for necropsy and tissue collection. RESULTS: Preterm lambs from the Dex Low and Beta-Acetate Groups had statistically and biologically significant lung function improvements (measured by gas exchange, lung compliance). Compared to the Saline Control Group, hippocampal transcriptomic data identified 879 differentially significant expressed genes (at least 1.5-fold change and FDR < 5%) in the steroid-treated groups. Pulsatile dexamethasone-only exposed groups (Dex High and Dex Low) had three common positively enriched differentially expressed pathways related in part to neurodegeneration ("Prion Disease", "Alzheimer's Disease", "Arachidonic Acid metabolism"). Adverse changes were independent of respiratory function during ventilation. CONCLUSIONS: Our data suggests that exposure to antenatal steroid therapy is an independent cause of damage- associated transcriptomic changes in the brain of preterm, fetal sheep. These data highlight an urgent need for careful reconsideration and balancing of how antenatal steroids are used, both for patient selection and dosing regimens.

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.

Postnatal budesonide improved lung function in preterm lambs exposed to antenatal steroids and chorioamnionitis.

BACKGROUND: A combination of budesonide and surfactant decreases the rates of BPD in infants and lung injury in preterm sheep. Whether this combination will show benefit in the setting of chorioamnionitis and antenatal steroids is not known. METHODS: Ewes at 123 ± 1 day gestational age received intra-amniotic (IA) injections of 10 mg LPS before being randomized to receive either 0.25 mg/kg maternal betamethasone phosphate and acetate or saline by intramuscular (IM) injection at 48 and 24 h prior to delivery at 125 ± 1 day. Lambs (N = 6-9/group) underwent intentionally injurious ventilation for 15 min, then lambs received surfactant mixed with either: (1) saline; or (2) Budesonide 0.25 mg/kg and were ventilated for 4 h. RESULTS: Compared with LPS-exposed animals that received no IM steroid treatment, betamethasone exposed fetuses had improved hemodynamic stability, lung compliance, and ventilation efficiency. The addition of budesonide to surfactant further improved markers of injury and pro-inflammatory cytokine mRNA in both betamethasone IM or no IM lambs exposed to LPS IA. Antenatal betamethasone and IA LPS exposures decreased budesonide levels in the fetal lung and plasma. CONCLUSION: Antenatal betamethasone stabilizes physiologic parameters in LPS treated lambs. Budesonide mixed with surfactant further decreases injury and improves respiratory physiology in betamethasone treated animals. IMPACT: Antenatal betamethasone improved lung and systemic physiology in the setting of intra-amniotic LPS. The addition of budesonide to the surfactant further improved lung function. Budesonide levels in the plasma and lung were lower in lambs exposed to either LPS or LPS and Betamethasone animals, and these findings were not explained by increased esterification in the lungs. The combination of antenatal steroids and budesonide with surfactant had the lowest markers of pro-inflammatory cytokines in the lung of LPS exposed animals.

Neurological outcomes in traffic accidents: A propensity score matching analysis of medical and non-medical origin cases of out-of-hospital cardiac arrest.

AIM: This study aimed to comprehensively compare the characteristics of out-of-hospital cardiac arrest (OHCA) with medical and non-medical origins attributed to traffic accidents and explore the potential association between the cases with a medical origin and neurologically favorable outcomes. METHODS: In this retrospective nationwide population-based study, baseline data were collected between January 2018 and December 2020. We analyzed 5091 OHCA associated with traffic accidents on the road scene. Only those encounters involving treatment or transport by prehospital emergency medical technicians were included. The characteristics of OHCA incidents and their outcomes were analyzed by categorizing patients into "medical origin" and "non-medical origin" groups. RESULTS: Medical-origin cases exhibited several distinct characteristics, including higher frequencies of occurrence during the daytime (79.3% [706/890] vs. 68.9% [2895/4201], p < 0.001), a higher prevalence among male (77.8% [692/890] vs. 68.3% [2871/4201], p < 0.001) and younger patients (median [25-75%]: 63 years [42-77] vs. 66 years [50-76], p = 0.003), a higher proportion of shockable initial rhythms(10.5% [93/890] vs. 1.1% [45/4201], p < 0.001), an increased number of cases requiring advanced airway management (33.8% [301/890] vs. 28.5% [1199/4201], p = 0.002) and adrenaline administration by emergency medical teams (26.9% [239/890] vs. 21.7% [910/4201], p < 0.001), and shorter transport times (55.3% [492/890] vs. 60.9% [2558/4201], p = 0.002) compared to non-medical-origin cases. However, medical-origin cases also had lower witness rates (42.8% [381/890] vs. 27.2% [1142/4201], p < 0.001) and were less likely to be transported to higher-level hospitals (55.3% [492/890] vs. 60.9% [2558/4201], p = 0.002). Propensity score matching analysis identified factors associated with favorable neurological outcomes in medical-origin traffic accidents. The adjusted odds ratios were as follows: 8.46 (3.47-20.61) for cases with shockable initial rhythms, 2.36 (1.01-5.52) for cases involving traffic accidents due to medical origin, and 0.09 (0.01-0.67) for cases where advanced airway management was provided. CONCLUSION: In this retrospective study, the occurrence of OHCAs of medical origin involving traffic accidents were associated with favorable neurological outcomes. These cases more frequently demonstrated favorable factors for survival compared to those classified as of non-medical origin. The findings have important implications for public health and EMS professionals, they will guide future research aimed at optimizing prehospital care strategies and improving survival rates for similar cases.

Designing a test battery for workers' well-being: the first wave of the Tsukuba Salutogenic Occupational Cohort Study.

BACKGROUND: In recent years, there has been a diversification of working styles. The concept of workers' well-being is no longer limited to material wealth, such as how satisfied they are with their wages. Psychological enrichment, encompassing factors like motivation and interpersonal relationships, is also important. This study was established to develop a scale to evaluate the well-being of workers, named the Abundance Index for Workers (AIW). This new concept proposed by the authors comprehensively considers both job-related resources and personal and societal resources. METHODS: This study was carried out as part of the Tsukuba Salutogenic Occupational Cohort Study (T-SOCS). We utilized data from a survey targeting workers affiliated with institutions under the Tsukuba Science City Network, examining aspects of their daily life, work, and mental health. The deviation scores for each survey item were averaged to calculate an overall score. The correlations of the comprehensive score with the Patient Health Questionnaire-9 (PHQ-9) index for depression and the Single-item Presenteeism Question (SPQ) index for presenteeism were analyzed to determine criterion-related validity. RESULTS: The number of participants analyzed was 2,745. Factor analysis categorized the data into three factors: workplace mental health, societal resources, and lifestyle habits. Cronbach's α coefficient was 0.688. There were correlations of -0.363 (p < 0.001) between the total score and SPQ, and -0.558 (p < 0.001) between the total score and PHQ-9, suggesting a degree of criterion-related validity. CONCLUSIONS: In this study, we designed a test battery that assesses workers' well-being based on job-related resources and the richness of societal resources. The internal consistency of this battery was not as high as expected due to the broad scope of well-being. Although it is difficult to evaluate workers' well-being on a single scale, we believe that the AIW functions well as a test battery by combining scales with different attributes, which enables well-being to be captured from as many different perspectives as possible. This tool is designed to assist individuals in evaluating their own well-being and recognizing factors that can enhance it. TRIAL REGISTRATION: Not applicable; this study is not an intervention trial.

Pretreatment periodontitis is predictive of a poorer prognosis after esophagectomy for esophageal cancer.

BACKGROUND: Poor oral health is an independent risk factor for upper-aerodigestive tract cancers, including esophageal cancer. Several studies have investigated short-term outcomes after esophagectomy and the impact of periodontal disease, but few have examined the impact of periodontal disease on long-term outcomes. The purpose of this study was to investigate the rate of periodontitis among esophagectomy patients and the prognostic value of periodontitis and its effect on prognosis after esophagectomy. METHODS: A total of 508 patients who underwent esophagectomy received oral health care from a dentist before cancer treatment at Akita University Hospital between January 2009 and December 2021. We assessed the presence and severity of the patients' periodontitis and divided them into no-periodontitis, mild periodontitis, severe periodontitis and edentulous jaw groups. We then assessed 10-year overall survival (OS) and disease-specific survival (DSS) and determined whether periodontitis was an independent prognostic factor affecting OS and DSS. RESULTS: We found that 101 (19.9%) patients had no periodontitis, 207 (40.8%) had mild periodontitis, 176 (34.6%) had severe periodontitis requiring tooth extraction, and 24 (4.7%) had edentulous jaw. Both OS and DSS were significantly poorer in the periodontitis than no-periodontitis group (p < 0.001). In detail, the edentulous jaw group had the poorest prognosis (p < 0.001). Multivariate analysis showed that periodontitis was an independent risk factor affecting OS and DSS. CONCLUSION: Esophageal cancer patients had a high prevalence of periodontitis. Moreover, the presence of periodontitis and severity of periodontitis are independent risk factors contributing to a poorer prognosis after esophagectomy.

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.

The influence of information sources on intention changes to receive COVID-19 vaccination: A prospective cohort study in Japan.

BACKGROUND: Before the COVID-19 vaccine became available, many Japanese people were undecided about whether or not to receive them. Their decisions were keys to achieving herd immunity. The impact of the type of information source on the COVID-19 vaccine uptake decision-making process remains unclear. We aimed to investigate the association between information source usage on COVID-19 and subsequent vaccine uptake status among those who have yet to decide whether to receive vaccines from non-prioritized people for vaccination. METHODS: Prospective cohort online self-administered surveys were conducted in February 2021 (T1), before the start of the mass vaccination program, and September-October 2021 (T2), when the vaccines were available to all citizens. The survey's target population was registered monitors of an Internet research company. Participants who answered "I want to get vaccinated after waiting to see how it goes." at T1 were eligible for analysis. The outcome variable was the COVID-19 vaccine uptake status in T2, and the predictors were 20 types of information sources, categorized based on people (family members, etc.), institutions (governments, etc.), or media (TV news, etc.). Adjusted odds ratio and 95% confidence intervals were estimated using logistic regression adjusted for possible confounders. RESULTS: The 5,139 respondents, mean age and standard deviation was 42.8 ± 12.5, 55.7% female, were eligible for analysis. 85.7% completed vaccination (including reserved/intended people) in T2. In the multivariate logistic analysis, odds ratios (95% confidence interval) for vaccine uptake were 1.49 (1.18-1.89) for workplaces/schools, 1.81 (1.33-2.47) for LINE, 0.69 (0.55-0.86) for Internet news and 0.62 (0.48-0.82) for video sharing sites. CONCLUSIONS: The type of information source usage played an important role in the decision to vaccinate against COVID-19. Although caution is needed in interpreting the results, obtaining information from workplaces/schools and LINE was influential in promoting immunization.

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.

Continuous but not pulsed low-dose fetal betamethasone exposures extend the durability of antenatal steroid therapy.

Antenatal steroid (ANS) therapy is the standard care for women at imminent risk of preterm labor. Despite extensive and long-standing use, 40%-50% of babies exposed antenatally to steroids do not derive benefit; remaining undelivered 7 days or more after ANS treatment is associated with a lack of treatment benefit and increased risk of harm. We used a pregnant sheep model to evaluate the impact of continuous versus pulsed ANS treatments on fetal lung maturation at an extended, 8-day treatment to delivery interval. Continuous low-dose ANS treatments for more than 72 h in duration improved fetal lung maturation at 8 days after treatment initiation. If fetal ANS exposure was interrupted, the beneficial ANS effect was lost. Truncated treatments, including that simulating the current clinical treatment regimen, did not improve lung function. Variable fetal lung maturation was correlated to the amount of saturated phosphatidylcholine present in the lung fluid. These data demonstrate that 1) the durability of ANS therapy may be enhanced by employing an extended, low-dose treatment regimen by reducing total dose and 2) interrupting the continuity of fetal exposure by allowing it to fall below a minimal threshold was associated with comparably poor functional maturation of the preterm ovine lung.

The complex challenge of antenatal steroid therapy nonresponsiveness.

Antenatal steroid therapy is standard care for women at imminent risk of preterm delivery. When deliveries occur within 7 days of treatment, antenatal steroid therapy reduces the risk of neonatal death and improves preterm outcomes by exerting diverse developmental effects on the fetal organs, in particular the preterm lung and cardiovascular system. There is, however, sizable variability in antenatal steroid treatment efficacy, and an important percentage of fetuses exposed to antenatal steroid therapy do not respond sufficiently to derive benefit. Respiratory distress syndrome, for example, is a central metric of clinical trials to assess antenatal steroid outcomes. In the present analysis, we addressed the concept of antenatal steroid nonresponsiveness, and defined a failed or suboptimal response to antenatal steroids as death or a diagnosis of respiratory distress syndrome following treatment. For deliveries at 24 to 35 weeks' gestation, the number needed to treat to prevent 1 case of respiratory distress syndrome was 19 (95% confidence interval, 14-28). Reflecting gestation-dependent risk, for deliveries at >34 weeks' gestation the number needed to treat was 55 (95% confidence interval, 30-304), whereas for elective surgical deliveries at term this number was 106 (95% confidence interval, 61-421). We reviewed data from clinical and animal studies investigating antenatal steroid therapy to highlight the significant incidence of antenatal steroid therapy nonresponsiveness (ie, residual mortality or respiratory distress syndrome after treatment), and the potential mechanisms underpinning this outcome variability. The origins of this variability may be related to both the manner in which the therapy is applied (ie, the treatment regimen itself) and factors specific to the individual (ie, genetic variation, stress, infection). The primary aims of this review were: (1) to emphasize to the obstetrical and neonatal communities the extent of antenatal steroid response variability and its potential impact; (2) to propose approaches by which antenatal steroid therapy may be better applied to improve overall benefit; and (3) to stimulate further research toward the empirical optimization of this important antenatal therapy.

Low-dose antenatal betamethasone treatment achieves preterm lung maturation equivalent to that of the World Health Organization dexamethasone regimen but with reduced endocrine disruption in a sheep model of pregnancy.

BACKGROUND: The intramuscular administration of antenatal steroids to women at risk of preterm delivery achieves high maternal and fetal plasma steroid concentrations, which are associated with adverse effects and may reduce treatment efficacy. We have demonstrated that antenatal steroid efficacy is independent of peak maternofetal steroid levels once exposure is maintained above a low threshold. OBJECTIVE: This study aimed to test, using a sheep model of pregnancy, whether the low-dose antenatal steroid regimen proposed as part of the Antenatal Corticosteroids for Improving Outcomes in Preterm Newborns trial would achieve preterm lung maturation equivalent to that of the existing World Health Organization dexamethasone treatment regimen, but with reduced risk of adverse outcomes. STUDY DESIGN: Following ethical review and approval, date-mated ewes with single fetuses received intramuscular injections of either (1) four 6-mg maternal intramuscular injections of dexamethasone phosphate every 12 hours (n=22), (2) 4 2-mg maternal intramuscular injections of betamethasone phosphate every 12 hours (n=21), or (3) 4 2-mL maternal intramuscular injections of saline every 12 hours (n=16). Of note, 48 hours after first injection, (124±1 day), lambs were delivered, ventilated for 30 minutes, and euthanized for sampling. Arterial blood gas, respiratory, hematological, and biochemical data were analyzed for between-group differences with analysis of variance according to distribution and variance, with P<.05 taken as significant. RESULTS: After 30 minutes of ventilation, lambs from both steroid-treated groups had significant and equivalent improvements in lung function relative to saline control (P<.05). There was no significant difference in arterial blood pH, pO2, pCO2, lung compliance, ventilator efficiency index, or lung volume at necropsy with a static pressure of 40 cmH2O. The messenger RNA expression of surfactant protein (Sp)a, Spb, Spc, Spd, aquaporin (Aqp)1, Aqp5, and sodium channel epithelial 1 subunit beta (Scnn1b) was equivalent between both steroid groups. Maternal and fetal plasma neutrophil, glucose, and fetal plasma C-peptide levels were significantly elevated in the dexamethasone group, relative to the betamethasone group. Fetal plasma insulin-like growth factor 1 was significantly reduced in the dexamethasone group compared with the betamethasone group (P<0.05). Fetal adrenocorticotropic hormone (r=0.53), maternal glucose value (r=-0.52), and fetal glucose values (r=-0.42) were correlated with maternal weight in the betamethasone group (P<.05), whereas fetal pCO2 and pO2 were not correlated. There was no significant difference between male and female lamb outcomes in any groups for any of the items evaluated. CONCLUSION: This study reported that in preterm lambs, a low-dose treatment regimen of 8 mg betamethasone achieves lung maturation equivalent to that of a 24-mg dexamethasone-based regimen, but with smaller perturbations to the maternofetal hypothalamic-pituitary-adrenal axis. These data suggested that given steroid pharmacokinetic differences between sheep and humans, a betamethasone dose of 2 mg may remain above the minimum dose necessary for robust maturation of the preterm lung. Maternal weight-adjusted betamethasone doses might also be a key to reducing perturbations to the maternofetal hypothalamic-pituitary-adrenal axis.

Betamethasone phosphate reduces the efficacy of antenatal steroid therapy and is associated with lower birthweights when administered to pregnant sheep in combination with betamethasone acetate.

BACKGROUND: Antenatal corticosteroid therapy is a standard of care for women at imminent risk of preterm labor. However, the optimal (maximum benefit and minimal risk of side effects) antenatal corticosteroid dosing strategy remains unclear. Although conveying overall benefit when given to the right patient at the right time, antenatal corticosteroid treatment efficacy is highly variable and is not risk-free. Building on earlier findings, we hypothesized that when administered in combination with slow-release betamethasone acetate, betamethasone phosphate and the high maternal-fetal betamethasone concentrations it generates are redundant for fetal lung maturation. OBJECTIVE: Using an established sheep model of prematurity and postnatal ventilation of the preterm lamb, we aimed to compare the pharmacodynamic effects of low-dosage treatment with betamethasone acetate only against a standard dosage of betamethasone phosphate and betamethasone acetate as recommended by the American College of Obstetricians and Gynecologists for women at risk of imminent preterm delivery between 24 0/7 and 35 6/7 weeks' gestation. STUDY DESIGN: Ewes carrying a single fetus at 122±1 days' gestation (term=150 days) were randomized to receive either (1) maternal intramuscular injections of sterile saline (the saline negative control group, n=12), (2) 2 maternal intramuscular injections of 0.25 mg/kg betamethasone phosphate+betamethasone acetate administered at 24-hour dosing intervals (the betamethasone phosphate+betamethasone acetate group, n=12); or (3) 2 maternal intramuscular injections of 0.125 mg/kg betamethasone acetate administered at 24-hour dosing intervals (the betamethasone acetate group, n=11). The fetuses were surgically delivered 48 hours after treatment initiation and ventilated for 30 minutes to determine functional lung maturation. The fetuses were euthanized after ventilation, and the lungs were collected for analysis using quantitative polymerase chain reaction and Western blot assays. Fetal plasma adrenocorticotropic hormone levels were measured in the cord blood samples taken at delivery. RESULTS: Preterm lambs were defined as either antenatal corticosteroid treatment responders or nonresponders using an arbitrary cutoff, being a PaCO2 level at 30 minutes of ventilation being more extreme than 2 standard deviations from the mean value of the normally distributed saline control group values. Compared with the animals in the saline control group, the animals in the antenatal corticosteroid treatment groups showed significantly improved lung physiological responses (blood gas and ventilation data) and had a biochemical signature (messenger RNA and surfactant protein assays) consistent with functional maturation. However, the betamethasone acetate group had a significantly higher treatment response rate than the betamethasone phosphate+betamethasone acetate group. These physiological results were strongly correlated to the amount of surfactant protein A. Birthweight was lower in the betamethasone phosphate+betamethasone acetate group and the fetal hypothalamic-pituitary-adrenal axis was suppressed to a greater extent in the betamethasone phosphate+betamethasone acetate group. CONCLUSION: Low-dosage antenatal corticosteroid therapy solely employing betamethasone acetate was sufficient for fetal lung maturation. The elevated maternal-fetal betamethasone concentrations associated with the coadministration of betamethasone phosphate did not in addition improve lung maturation but were associated with greater fetal hypothalamic-pituitary-adrenal axis suppression, a lower antenatal corticosteroid treatment response rate, and lower birthweight-outcomes not desirable in a clinical setting. These data warranted a clinical investigation of sustained low-dosage antenatal corticosteroid treatments that avoid high maternal-fetal betamethasone exposures.

Prevalence, characteristics, and psychological outcomes of workplace cyberbullying during the COVID-19 pandemic in Japan: a cross-sectional online survey.

BACKGROUND: The rapid introduction of teleworking due to the coronavirus disease 2019 pandemic has led to concerns about increases in cyberbullying (CB) worldwide. However, little is known about workplace CB in non-Western countries. The first objective was to clarify the prevalence and characteristics regarding workplace CB victimization in Japan. The second objective was to demonstrate the psychological outcomes of CB victimization in combination with traditional bullying (TB). METHODS: We conducted an anonymous, cross-sectional, Internet-based survey targeting regular employees in Japan (N = 1200) in January 2021. We investigated CB victimization using the Inventory of Cyberbullying Acts at Work and TB victimization by using the Short Negative Act Questionnaire. Possible explanatory factors for TB/CB victimization were sociodemographic variables, personality trait, chronic occupational stress, organizational climate, and gratitude at work. We also measured psychological distress, insomnia, and loneliness to assess adverse effects of workplace bullying. Two-step cluster analysis was used in determining the patterns combined with TB and CB victimization. Hierarchical binomial logistic regression analysis was used. RESULTS: In total, 8.0% of employees reported experiencing CB on a weekly basis. CB victimization was associated with younger age, managerial position, higher qualitative workload, and active information dissemination via the Internet, and frequency of teleworking. Three clusters based on TB and CB victimization patterns were identified: those who belong to the first cluster suffered neither from TB and CB (81.0%), the second cluster suffered only from TB (14.3%), and the third cluster suffered from both TB and CB (4.8%). The third cluster exhibited higher odds ratios (ORs) and 95% confidence intervals (CIs) for psychological distress (OR = 12.63, 95% CI = 4.20-38.03), insomnia (OR = 6.26, 95% CI = 2.80-14.01), and loneliness (OR = 3.24, 95% CI = 1.74-6.04) compared to the first cluster. CONCLUSIONS: These findings firstly clarify the prevalence and correlated factors of CB victimization among employees in Japan. Further, we showed that psychological wellbeing can be impaired by the coexistence of TB and CB. Our research could be the first step to develop the effective countermeasures against workplace CB.

Ibaraki's Amabie-chan usage and its association with infection prevention behavior and fear of COVID-19: a cross-sectional preliminary survey of the Tsukuba Salutogenic Occupational Cohort Study.

BACKGROUND: Ibaraki's Amabie-chan is a COVID-19 infection control system unique to Ibaraki prefecture, Japan. It requires residents to register each time they visit events, commercial facilities, and restaurants. The number of registrations has been limited, and its function alerting about people positive for COVID-19 infection seems not to be working. Nevertheless, registration with the system might have some impact on the user's behavior. In the current preliminary survey, the possible impact of Ibaraki's Amabie-chan on infection prevention behavior and fear of COVID-19 was investigated. METHODS: A cross-sectional, web-based, anonymous, and self-administered survey was conducted at two workplaces in Tsukuba Science City, Ibaraki, Japan. The first survey was conducted at one of the workplaces in November 2020, and the second survey, at the other workplace in February 2021. Variables of interest were sex, age group, marital status, employment status, Ibaraki's Amabie-chan use, COVID-19 Contact-Confirming Application use, ten items of infection prevention behaviors, and fear of COVID-19. Hierarchical linear regression analysis was performed. RESULTS: In both surveys, use of Ibaraki's Amabie-chan was significantly associated with COCOA use and with "physical condition management such as body temperature measurement." No association was found with other infection prevention behaviors or with fear of COVID-19. CONCLUSIONS: Our findings did not provide sufficient evidence for the effectiveness of Ibaraki's Amabie-chan in regard to users' infection control behavior. Further detailed study is needed to investigate the effectiveness in terms of infection prevention and the cost-effectiveness of Ibaraki's Amabie-chan.

Antenatal corticosteroids: a reappraisal of the drug formulation and dose.

We review the history of antenatal corticosteroid therapy (ACS) and present recent experimental data to demonstrate that this, one of the pillars of perinatal care, has been inadequately evaluated to minimize fetal exposure to these powerful medications. There have been concerns since 1972 that fetal exposures to ACS convey risk. However, this developmental modulator, with its multiple widespread biologic effects, has not been evaluated for drug choice, dose, or duration of treatment, despite over 30 randomized trials. The treatment used in the United States is two intramuscular doses of a mixture of 6 mg betamethasone phosphate (Beta P) and 6 mg betamethasone acetate (Beta Ac). To optimize outcomes with ACS, the goal should be to minimize fetal drug exposure. We have determined that the minimum exposure needed for fetal lung maturation in sheep, monkeys, and humans (based on published cord blood corticosteroid concentrations) is about 1 ng/ml for a 48-h continuous exposure, far lower than the concentration reached by the current dosing. Because the slowly released Beta Ac results in prolonged fetal exposure, a drug containing Beta Ac is not ideal for ACS use. IMPACT: Using sheep and monkey models, we have defined the minimum corticosteroid exposure for a fetal lung maturation. These results should generate new clinical trials of antenatal corticosteroids (ACS) at much lower fetal exposures to ACS, possibly given orally, with fewer risks for the fetus.

The duration of fetal antenatal steroid exposure determines the durability of preterm ovine lung maturation.

BACKGROUND: Antenatal corticosteroids (ACS) are the standard of care for maturing the fetal lung and improving outcomes for preterm infants. Antenatal corticosteroid dosing remains nonoptimized, and there is little understanding of how different treatment-to-delivery intervals may affect treatment efficacy. The durability of a lung maturational response is important because the majority of women treated with antenatal corticosteroids do not deliver within the widely accepted 1- to 7-day window of treatment efficacy. OBJECTIVE: We used a sheep model to test the duration of fetal exposures for efficacy at delivery intervals from 1 to 10 days. MATERIALS AND METHODS: For infusion studies, ewes with single fetuses were randomized to receive an intravenous bolus and maintenance infusion of betamethasone phosphate to target 1-4 ng/mL fetal plasma betamethasone for 36 hours, with delivery at 2, 4 ,or 7 days posttreatment or sterile saline solution as control. Animals receiving the clinical treatment were randomised to receive either a single injection of 0.25 mg/kg with a 1:1 mixture of betamethasone phosphate + betamethasone acetate with delivery at either 1 or 7 days posttreatment, or 2 treatments of 0.25 mg/kg betamethasone phosphate + betamethasone acetate spaced at 24 hours (giving ∼48 hours of fetal steroid exposure) with delivery at 2, 5, 7, or 10 days posttreatment. Negative control animals were treated with saline solution. All lambs were delivered at 121 ± 3 days gestational age and ventilated for 30 minutes to assess lung function. RESULTS: Preterm lambs delivered at 1 or 2 days post-antenatal corticosteroid treatment had significant improvements in lung maturation for both intravenous and single-dose intramuscular treatments. After 2 days, the efficacy of 36-hour betamethasone phosphate infusions was lost. The single dose of 1:1 betamethasone phosphate + betamethasone acetate also was ineffective at 7 days. In contrast, animals treated with 2 doses had significant improvements in lung maturation at 2, 5, and 7 days, with treatment efficacy reduced by 10 days. CONCLUSION: In preterm lambs, the durability of antenatal corticosteroids treatment depends on the duration of fetal exposure and is independent of the intravenous or intramuscular maternal route of administration. For acute 24- to 48-hour posttreatment deliveries, a 24-hour fetal antenatal corticosteroids exposure was sufficient for lung maturation. A fetal exposure duration of at least 48 hours was necessary to maintain long-term treatment durability. A single-dose ACS treatment should be sufficient for women delivering within <48 hours of antenatal corticosteroids treatment.

Variability in the efficacy of a standardized antenatal steroid treatment was independent of maternal or fetal plasma drug levels: evidence from a sheep model of pregnancy.

BACKGROUND: Administration of antenatal steroids is standard of care for women assessed to be at imminent risk of preterm delivery. There is a marked variation in antenatal steroid dosing strategy, selection for treatment criteria, and agent choice worldwide. This, combined with very limited optimization of antenatal steroid use per se, means that treatment efficacy is highly variable, and the rate of respiratory distress syndrome is decreased to perhaps as low as 40%. In some cases, antenatal steroid use is associated with limited benefit and potential harm. OBJECTIVE: We hypothesized that individual differences in maternofetal steroid exposure would contribute to observed variability in antenatal steroid treatment efficacy. Using a chronically catheterized sheep model of pregnancy, we aimed to explore the relationship between maternofetal steroid exposure and antenatal steroid treatment efficacy as determined by functional lung maturation in preterm lambs undergoing ventilation. STUDY DESIGN: Ewes carrying a single fetus underwent surgery to catheterize a fetal and maternal jugular vein at 119 days' gestation. Animals recovered for 24 hours before being randomized to either (1) a single maternal intramuscular injection of 2 mL saline (negative control group, n=10) or (2) a single maternal intramuscular injection of 0.25 mg/kg betamethasone phosphate plus acetate (antenatal steroid group, n=20). Serial maternal and fetal plasma samples were collected from each animal after 48 hours before fetuses were delivered and ventilated for 30 minutes. Total and free plasma betamethasone concentration was measured by mass spectrometry. Fetal lung tissue was collected for analysis using quantitative polymerase chain reaction. RESULTS: One animal from the control group and one animal from the antenatal steroid group did not complete their treatment protocol and were removed from analyses. Animals in the antenatal steroid group were divided into a responder subgroup (n=12/19) and a nonresponder subgroup (n=7/19) using a cutoff of partial pressure of arterial CO2 at 30-minute ventilation within 2 standard deviations of the mean value from saline-treated negative control group animals. Although antenatal steroid improved fetal lung maturation in the undivided antenatal steroid group and in the responder subgroup both physiologically (blood gas- and ventilation-related data) and biochemically (messenger ribonucleic acid expression related to fetal lung maturation), these values did not improve relative to saline-treated control group animals in the antenatal steroid nonresponder subgroup. No differences in betamethasone distribution, clearance, or protein binding were identified between the antenatal steroid responder and nonresponder subgroups. CONCLUSION: This study correlated individual maternofetal steroid exposures with preterm lung maturation as determined by pulmonary ventilation. Herein, approximately 40% of preterm lambs exposed to antenatal steroids had lung maturation that was not significantly different to saline-treated control group animals. These nonresponsive animals received maternal and fetal betamethasone exposures identical to animals that had a significant improvement in functional lung maturation. These data suggest that the efficacy of antenatal steroid therapy is not solely determined by maternofetal drug levels and that individual fetal or maternal factors may play a role in determining treatment outcomes in response to glucocorticoid signaling.

Successful use of an artificial placenta-based life support system to treat extremely preterm ovine fetuses compromised by intrauterine inflammation.

BACKGROUND: Ex vivo uterine environment therapy is an experimental intensive care strategy for extremely preterm infants born between 21 and 24 weeks of gestation. Gas exchange is performed by membranous oxygenators connected by catheters to the umbilical vessels. The fetus is submerged in a bath of synthetic amniotic fluid. The lungs remain fluid filled, and pulmonary respiration does not occur. Intrauterine inflammation is strongly associated with extremely preterm birth and fetal injury. At present, there are no data that we are aware of to show that artificial placenta-based systems can be used to support extremely preterm fetuses compromised by exposure to intrauterine inflammation. OBJECTIVE: To evaluate the ability of our ex vivo uterine environment therapy platform to support extremely preterm ovine fetuses (95-day gestational age; approximately equivalent to 24 weeks of human gestation) exposed to intrauterine inflammation for a period of 120 hours, the following primary endpoints were chosen: (1) maintenance of key physiological variables within normal ranges, (2) absence of infection and inflammation, (3) absence of brain injury, and (4) gross fetal growth and cardiovascular function matching that of age-matched in utero controls. STUDY DESIGN: Ten ewes with singleton pregnancies were each given a single intraamniotic injection of 10-mg Escherichia coli lipopolysaccharides under ultrasound guidance 48 hours before undergoing surgical delivery for adaptation to ex vivo uterine environment therapy at 95-day gestation (term=150 days). Fetuses were adapted to ex vivo uterine environment therapy and maintained for 120 hours with constant monitoring of key vital parameters (ex vivo uterine environment group) before being killed at 100-day equivalent gestational age. Umbilical artery blood samples were regularly collected to assess blood gas data, differential counts, biochemical parameters, inflammatory markers, and microbial load to exclude infection. Ultrasound was conducted at 48 hours after intraamniotic lipopolysaccharides (before surgery) to confirm fetal viability and at the conclusion of the experiments (before euthanasia) to evaluate cardiac function. Brain injury was evaluated by gross anatomic and histopathologic investigations. Eight singleton pregnant control animals were similarly exposed to intraamniotic lipopolysaccharides at 93-day gestation and were killed at 100-day gestation to allow comparative postmortem analyses (control group). Biobanked samples from age-matched saline-treated animals served as an additional comparison group. Successful instillation of lipopolysaccharides into the amniotic fluid exposure was confirmed by amniotic fluid analysis at the time of administration and by analyzing cytokine levels in fetal plasma and amniotic fluid. Data were tested for mean differences using analysis of variance. RESULTS: Six of 8 lipopolysaccharide control group (75%) and 8 of 10 ex vivo uterine environment group fetuses (80%) successfully completed their protocols. Six of 8 ex vivo uterine environment group fetuses required dexamethasone phosphate treatment to manage profound refractory hypotension. Weight and crown-rump length were reduced in ex vivo uterine environment group fetuses at euthanasia than those in lipopolysaccharide control group fetuses (P<.05). There were no biologically significant differences in cardiac ultrasound measurement, differential leukocyte counts (P>.05), plasma tumor necrosis factor α, monocyte chemoattractant protein-1 concentrations (P>.05), or liver function tests between groups. Daily blood cultures were negative for aerobic and anaerobic growth in all ex vivo uterine environment group animals. No cases of intraventricular hemorrhage were observed. White matter injury was identified in 3 of 6 lipopolysaccharide control group fetuses and 3 of 8 vivo uterine environment group fetuses. CONCLUSION: We report the use of an artificial placenta-based system to support extremely preterm lambs compromised by exposure to intrauterine inflammation. Our data highlight key challenges (refractory hypotension, growth restriction, and white matter injury) to be overcome in the development and use of artificial placenta technology for extremely preterm infants. As such challenges seem largely absent from studies based on healthy pregnancies, additional experiments of this nature using clinically relevant model systems are essential for further development of this technology and its eventual clinical application.

School Ijime (Bullying) Experience Is a Possible Risk Factor for Current Psychological Distress among Science City Workers: A Cross-Sectional Study in Tsukuba, Japan.

Early-life adversities are considered to have long-term impact on health. There have been many studies regarding the experience of being bullied and its harmful psychological influence, but such influence on workers remains to be investigated in Japan. We therefore aimed to examine the prevalence of workers with experiences of being bullied or bullying others during childhood and adolescence and to clarify the relation between those experiences and current psychological distress. A cross-sectional study using an anonymous self-report web questionnaire was conducted in November 2017. The study population was 19,481 workers belonging to the Tsukuba Science City Network, and we analyzed the data of 6,015 participants (3,715 men and 2,300 women, aged between 20 years and 59 years). The percentages of participants with experiences of being bullied were 51.5% for men and 56.2% for women; those with experiences of bullying others were 36.5% of men and 29.4% of women. Relations between experiences of bullying and psychological distress were assessed using Chi-squared tests. Logistic regression analyses with psychological distress as an objective variable and experiences of bulling as explanatory variables were performed using those who had no bulling experiences as control. In both men and women, experiences of being bullied were significantly associated with psychological distress after adjustment socioeconomic factors (the odds ratios were 1.26 for men (95% CI = 1.05-1.52) and 1.72 for women (95% CI = 1.39-2.13)). Consideration of past social experiences, such as being bullied, is useful for mental health management among workers reporting psychological distress.