Severe hemolysis, elevated liver enzymes, and low platelet syndrome requiring differentiation of thrombotic microangiopathy: Four cases from a nationwide survey in Japan.

Severe cases of hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome requiring plasma exchange or dialysis should be differentiated from other thrombotic microangiopathy (TMA) and treated appropriately. To evaluate the prevalence and clinical characteristics of such cases in Japan, a questionnaire-based survey was conducted among obstetricians who are members of the Perinatal Research Network Group in Japan. There were a total of 335 cases of HELLP syndrome over a 3-year period in the 48 facilities that responded to the survey. Four patients required plasma exchange or dialysis, of which two were diagnosed with atypical hemolytic uremic syndrome and two with TMA secondary to systemic lupus erythematosus. Although such severe HELLP syndrome is rare, identifying the clinical features and making accurate differential diagnosis are critical for optimal clinical outcomes for mothers and neonates.

High-mobility group box-1 peptide ameliorates bronchopulmonary dysplasia by suppressing inflammation and fibrosis in a mouse model.

BACKGROUND: This study aimed to examine the effect of the HMGB1 peptide on Bronchopulmonary dysplasia (BPD)-related lung injury in a mouse model. RESULTS: HMGB1 peptide ameliorates lung injury by suppressing the release of inflammatory cytokines and decreasing soluble collagen levels in the lungs. Single-cell RNA sequencing showed that the peptide suppressed the hyperoxia-induced inflammatory signature in macrophages and the fibrotic signature in fibroblasts. These changes in the transcriptome were confirmed using protein assays. CONCLUSION: Systemic administration of HMGB1 peptide exerts anti-inflammatory and anti-fibrotic effects in a mouse model of BPD. This study provides a foundation for the development of new and effective therapies for BPD.

Outcome of Inducing Labor in Pregnancies with Suspected Fetal Growth Restriction: Oxytocin Discontinuation during the Active Phase of Labor versus Conventional Management.

OBJECTIVE: Although fetal growth restriction (FGR) is associated with an increased risk of cesarean delivery during induced labor, there is limited evidence to guide labor management. This study aimed to investigate the prognosis of induced labor in pregnancies with suspected FGR and whether oxytocin discontinuation during the active phase of labor affects maternal and neonatal outcomes. STUDY DESIGN: This retrospective cohort study investigated singleton pregnancies with vertex presentation and indications for labor induction owing to FGR after 34.0 weeks of gestation at Osaka University Hospital. From January 2010 to December 2013, women were conventionally managed, and oxytocin was continued until delivery unless there was an indication for discontinuation (conventional management group). From January 2013 to December 2020, oxytocin was routinely discontinued, or the dose was reduced at the beginning of the active phase of labor (oxytocin discontinuation group). RESULTS: A total of 161 women (conventional management group, n = 74; oxytocin discontinuation group, n = 87) were included. After the active phase of induced labor, the total incidence of cesarean delivery was very low (3.1%), and the duration was short (173 ± 145 minutes). Oxytocin discontinuation was associated with lower cesarean delivery (1.1 vs. 5.4%; p = 0.12) and uterine tachysystole (9.8 vs. 23.0%; p = 0.08) rates and longer duration of the second stage of labor (mean: 56.5 ± 90 vs. 34.2 ± 45 minutes; p = 0.08) than conventional management; however, the difference was not significant. The other maternal and neonatal outcomes, including postpartum hemorrhage, did not also significantly differ between them. CONCLUSION: After the active phase of induced labor for suspected FGR, the risk of cesarean delivery is low, and the high incidence of uterine tachysystole and rapid labor progression should be considered cautiously. Oxytocin can be safely discontinued during the active phase of labor in women undergoing labor induction for FGR without an increased risk of cesarean delivery or other unfavorable outcomes. KEY POINTS: · The cesarean delivery rate was low after the active phase.. · The labor progress after the active phase was rapid.. · Oxytocin can be safely discontinued during the active phase..

Safety and efficacy of Ninjin'yoeito along with iron supplementation therapy for preoperative anemia, fatigue, and anxiety in patients with gynecological disease: an open-label, single-center, randomized phase-II trial.

BACKGROUND: Preoperative anemia affects perioperative outcomes and often causes fatigue and psychological disorders. Therefore, anemia should be treated before a patient undergoes surgery. Ninjin'yoeito (NYT), a Japanese Kampo medicine composed of ginseng and Japanese angelica root with the other 10 herbs, is administered for anemia, fatigue and anxiety; however, there are a few reports that have prospectively examined the effects of NYT before surgery for gynecological diseases. Hence, we tended to investigate its efficacy and safety. METHODS: In this open-label randomized trial, women with gynecological diseases accompanied by preoperative anemia (defined as < 11.0 g/dL Hemoglobin [Hb]) were randomly assigned (1:1) into the iron supplementation and NYT groups. Patients of the iron supplementation group and the NYT group received 100 mg/day iron supplementation with and without NYT (7.5 g/day) for at least 10 days before surgery. The primary endpoint was improvement in Hb levels before and after treatment, and Cancer Fatigue Scale (CFS) and Visual Analogue Scale for Anxiety (VAS-A) scores between groups. Statistical analyses were performed with Wilcoxon signed rank test, Wilcoxon rank sum test, and Fisher's exact test as appropriate. RESULTS: Forty patients were enrolled of whom 30 patients were finally analyzed after allocating 15 to each group. There was no difference in the characteristics between both groups. Hb significantly increased in both groups (iron supplementation group, 9.9 ± 0.8 g/dL vs. 11.9 ± 1.6 g/dL; NYT group, 9.8 ± 1.0 g/dL vs. 12.0 ± 1.0 g/dL); the difference in the elevations in Hb between both groups was statistically insignificant (P = 0.72). Contrarily, CFS (17.9 ± 10.2 vs. 8.1 ± 5.2) and VAS-A (56 mm (50-70) vs. 23 mm (6-48)) scores were significantly decreased only in the NYT group and these changes were greater in the NYT group (∆CFS, P = 0.015; ∆VAS-A, P = 0.014). Liver dysfunction occurred in one patient of the NYT group. CONCLUSIONS: For treating preoperative anemia in women with gynecological conditions, NYT administration along with iron supplementation safely and efficiently improved the preoperative fatigue and anxiety in addition to the recovery from anemia. TRIAL REGISTRATION: jRCT1051190012 (28/April/2019, retrospectively registered).

Postoperative lymphocyst formation after pelvic lymphadenectomy for gynecologic cancers: comparison between laparoscopy and laparotomy.

PURPOSE: The goal of this study was to evaluate, using definitive diagnostic criteria, the incidence of lymphocyst formation following pelvic lymphadenectomy for gynecological cancer, and to compare rates between the approaches of laparoscopy and laparotomy. METHODS: We retrospectively reviewed the medical records of all patients who underwent pelvic lymphadenectomy for cervical or endometrial cancer between March of 2010 and March of 2016. We defined a lymphocyst as a circumscribed collection of fluid within the pelvic cavity, with a diameter of 2 cm or more, as diagnosed with ultrasound or computed tomography. RESULTS: During the six-year observational period, a pelvic lymphadenectomy was conducted in 196 women with clinical stage I uterine cancer; 90 cases underwent laparoscopy, 106 underwent laparotomy. The minimally invasive laparoscopic group had a lower estimated blood loss (p < 0.01), shorter hospital stay (p < 0.01). Lymphocysts were observed in 14.4% (13/90) of the laparoscopy cases, and in 15.1% (16/106) of the laparotomy cases which means no significant difference of lymphocyst (p = 1.00). The median size of symptomatic lymphocyst was significantly larger in laparotomy group than in laparoscopy group (4.8 cm v.s. 2.8 cm, median) (p = 0.04). Symptomatic lymphocysts were more common in laparotomy [7/90 (7.8%) vs 14/106 (13.2%) (p = 0.253)]. CONCLUSIONS: In a retrospective analysis with a strict diagnostic criteria, we could find no statistical difference in lymphocyst occurrence between laparoscopy and laparotomy. The median size of the lymphocyst was bigger and lymphocyst was likely to be symptomatic in the laparotomy group.

Atypical preeclampsia without underlying disease and elevated sFlt-1/PlGF ratio.

Atypical preeclampsia before 20 weeks of gestation without an underlying disease is very rare; however, the soluble Fms-like tyrosine kinase 1/placental growth factor (sFlt-1/PlGF) ratios remain unknown. Four pregnant women with no underlying disease, except for a history of childhood IgA vasculitis, developed preeclampsia at 13, 14, 17, and 18 weeks of gestation with sFlt-1/PlGF ratios of 1589, 1183, 500, and 1460 pg/mL, respectively. Their pregnancies were terminated, and they delivered within 2 weeks. All previously abnormal clinical findings normalized within 3 months. The sFlt-1/PlGF ratios were elevated in the four patients with atypical preeclampsia without underlying disease before 20 weeks of gestation. A high sFlt-1/PlGF ratio may be indicative of preeclampsia when no underlying disease is present in pregnancies of less than 20 weeks of gestation.

Diagnosis, Management, and Therapy of Fetal Ovarian Cysts Detected by Prenatal Ultrasonography: A Report of 36 Cases and Literature Review.

BACKGROUND: Fetal ovarian cysts are the most frequently diagnosed intra-abdominal cysts; however, the evidence for perinatal management remains controversial. METHODS: We retrospectively reviewed cases of fetal ovarian cysts diagnosed by prenatal ultrasonography at our institution between January 2010 and January 2020. The following were investigated: gestational age at diagnosis, cyst size, appearance, prenatal ultrasound findings, and postnatal outcomes. Prior to 2018, expectant management was applied in all cases; after 2018, in utero aspiration (IUA) of simple cysts ≥40 mm was performed. RESULTS: We diagnosed 29 and seven simple and complex cysts, respectively. Fourteen patients had simple cysts with a maximum diameter <40 mm, and two of them progressed to complex cysts during follow-up; however, when the diameter was limited to <35 mm, no cases showed progression to complex cyst. Fifteen of the simple cysts were ≥40 mm; three progressed to complex cysts, and two of them were confirmed to be ovarian necrosis. In four patients who underwent IUA, the ovaries could be preserved. CONCLUSIONS: IUA is a promising therapy for preserving ovaries with simple cysts ≥40 mm in diameter; however, the indications for fetal surgery and the appropriate timing of intervention require further study.

Atypical preeclampsia with systemic lupus erythematosus and elevated soluble fms-like tyrosine kinase 1/placental growth factor ratio.

While systemic lupus erythematosus is often complicated by preeclampsia, it is difficult to differentiate between its exacerbation and preeclampsia. The soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio is unknown in systemic lupus erythematosus with preeclampsia before 20 weeks of gestation. Three nulliparous women with systemic lupus erythematosus developed preeclampsia at 13, 13, and 17 weeks of gestation with sFlt-1/PlGF ratios of 427, 865, and 525, respectively. Two patients terminated their pregnancies and delivered within 2 weeks, while one experienced intrauterine fetal death 4 weeks after the measurements. Their symptoms gradually improved, and all patients were discharged within 3 months. The sFlt-1/PlGF ratio may be used in the differential diagnosis of preeclampsia and systemic lupus erythematosus exacerbation before 20 weeks of gestation.

A systematic review and meta-analysis of obstetric and maternal outcomes after prior uterine artery embolization.

This study aimed to review the obstetric complications during subsequent pregnancies after uterine artery embolization (UAE) for postpartum hemorrhage (PPH) by exploring the relationship between prior UAE and obstetric complications through a meta-analysis. We conducted a systematic literature review through March 31, 2021, using PubMed, Scopus, and the Cochrane Central Register of Controlled Trials in compliance with the PRISMA guidelines and determined the effect of prior UAE for PPH on the rate of placenta accreta spectrum (PAS), PPH, placenta previa, hysterectomy, fetal growth restriction (FGR), and preterm birth (PTB). Twenty-three retrospective studies (2003-2021) met the inclusion criteria. They included 483 pregnancies with prior UAE and 320,703 pregnancies without prior UAE. The cumulative results of all women with prior UAE indicated that the rates of obstetric complications PAS, hysterectomy, and PPH were 16.3% (34/208), 6.5% (28/432), and 24.0% (115/480), respectively. According to the patient background-matched analysis based on the presence of prior PPH, women with prior UAE were associated with higher rates of PAS (odds ratio [OR] 20.82; 95% confidence interval [CI] 3.27-132.41) and PPH (OR 5.32, 95% CI 1.40-20.16) but not with higher rates of hysterectomy (OR 8.93, 95% CI 0.43-187.06), placenta previa (OR 2.31, 95% CI 0.35-15.22), FGR (OR 7.22, 95% CI 0.28-188.69), or PTB (OR 3.00, 95% CI 0.74-12.14), compared with those who did not undergo prior UAE. Prior UAE for PPH may be a significant risk factor for PAS and PPH during subsequent pregnancies. Therefore, at the time of delivery, clinicians should be more attentive to PAS and PPH when women have undergone prior UAE. Since the number of women included in the patient background-matched study was limited, further investigations are warranted to confirm the results of this study.

The association of endometriosis with placenta previa and postpartum hemorrhage: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to review the effect of endometriosis on the prevalence of placenta previa and postpartum hemorrhage in pregnant patients and the surgical outcomes of pregnant patients with endometriosis developing placenta previa. DATA SOURCES: In compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic review of the literature was conducted on December 31, 2020, using PubMed, Scopus, and the Cochrane Library. STUDY ELIGIBILITY CRITERIA: Comparative studies between pregnant women with and without endometriosis and studies that investigated the surgical outcomes of patients with and without endometriosis developing placenta previa were included. METHODS: Here, 2 reviewers independently screened the titles and abstracts, completed data extraction, and assessed the reporting quality using the Risk of Bias in Nonrandomized Studies of Interventions tool. RESULTS: Overall, 19 studies (from 2010 to 2020) met the inclusion criteria (98,463 pregnancies with endometriosis and 7,184,313 pregnancies without endometriosis). In the adjusted pooled analysis, endometriosis was associated with a higher rate of placenta previa (adjusted odds ratio, 3.17; 95% confidence interval, 2.58-3.89), whereas the incidence of postpartum hemorrhage was similar between pregnant women with and without endometriosis (adjusted odds ratio, 1.15; 95% confidence interval, 0.99-1.34). When the analysis was restricted to histologically confirmed endometriosis cases, the relationship of endometriosis with placenta previa (adjusted odds ratio, 4.23; 95% confidence interval, 1.74-10.30) and postpartum hemorrhage (adjusted odds ratio, 1.29; 95% confidence interval, 0.50-3.34) was consistent with results from the nonrestricted analysis. There was no study that examined the surgical outcomes of patients with endometriosis developing placenta previa patients. However, there are 3 studies that examined the effect of endometriosis on surgical outcomes during cesarean delivery: 1 study showing that endometriosis was associated with increased intraoperative bleeding during emergent cesarean delivery; the other study showing that endometriosis was associated with an increased incidence of postpartum hemorrhage during cesarean delivery (adjusted odds ratio, 1.1; 95% confidence interval, 1.0-1.2), especially in primiparous women with singleton pregnancies (adjusted odds ratio, 1.7; 95% confidence interval, 1.5-2.0); and another study suggesting a significantly higher rate of hysterectomy (7.1%) and bladder injury (7.1%) in patients with endometriosis than in those without endometriosis. CONCLUSION: Endometriosis can potentially be associated with adverse surgical outcomes during cesarean delivery. Although there is a correlation between endometriosis and increased rate of placenta previa, the surgical outcomes of patients with endometriosis developing placenta previa remain understudied.

Dose rate in the highest irradiation area of the rectum correlates with late rectal complications in patients treated with high-dose-rate computed tomography-based image-guided brachytherapy for cervical cancer.

The purpose of this study was to evaluate the effect of dose rate to the rectum on late rectal complications in patients treated with computed tomography (CT)-based image-guided brachytherapy (IGBT) for cervical cancer. The subjects were 142 patients with cervical cancer who underwent Ir-192 high-dose-rate (HDR)-IGBT between March 2012 and January 2018. The dose rate to the rectum was calculated using in-house software. The minimum, mean and maximum effective dose rate (EDR) was calculated for voxels of the rectal volume covered by cumulative doses >D0.1cc, >D2cc, and > D5cc. The average EDR of three to four brachytherapy sessions was calculated (EDR for patients; EDRp). The total dose of the rectum was calculated as the biologically equivalent dose in 2-Gy fractions (EQD2). The associations between EDRp for D0.1cc, D2cc, and D5cc and the respective rectal EQD2 values with late rectal complications were then analyzed. The median follow-up period was 40 months. Patients with rectal complications of ≥Grade 1 received a significantly higher mean EDRp for D0.1cc-5cc and had a greater EQD2 for D0.1cc-5cc. Multivariate analysis was performed using the mean EDRp for D2cc, EQD2 for D2cc, heavy smoking and BMI. Of these four variables, mean EDRp for D2cc (HR = 3.38, p = 0.004) and EQD2 for D2cc (HR = 2.59, p = 0.045) emerged as independent predictors for late rectal complications. In conclusion, mean EDRp and EQD2 were associated with late rectal complications in patients treated with HDR CT-based IGBT for cervical cancer.

Disparity of Cervical Cancer Risk in Young Japanese Women: Bipolarized Status of HPV Vaccination and Cancer Screening.

Women born between 1994 and 1999 achieved high vaccination rates for human papillomavirus (HPV); they are now reaching the age of cervical cancer screening programs in Japan. In this study, we aimed to investigate the health awareness of HPV-vaccinated and unvaccinated women and to create tailored leaflets recommending cervical cancer screening for each. Surveys on the cancer screening rates for HPV-vaccinated and unvaccinated women aged 20 and 21 have demonstrated that the rate was significantly higher (p < 0.01) in vaccinated (6.2%) than in unvaccinated women (3.1%). Next, interviews and Internet questionnaires clarified that there was a trend that vaccinated women have a better health consciousness than the unvaccinated ones, and that in unvaccinated women, their willingness to receive cervical cancer screening was significantly enhanced by the fear of developing cancer. Finally, in a prospective study, the increase in the screening rate for both vaccinated and unvaccinated groups after they read tailored leaflets, from 6.4% to 7.4% and from 3.9% to 5.1%, respectively, was not statistically significant compared to the groups provided with a standard reminder letter. Cervical cancer control measures might be enhanced by recommending cervical cancer screening in ways better tailored to HPV vaccination status.

Antenatal diagnosis of placenta accreta spectrum after in vitro fertilization-embryo transfer: a systematic review and meta-analysis.

Increasing evidence suggests a relationship between in vitro fertilization-embryo transfer (IVF-ET) and placenta accreta spectrum (PAS). Some studies have reported a lower rate of antenatal diagnosis of PAS after IVF-ET compared to PAS with spontaneous conception. This study aimed to review the diagnostic accuracy of PAS after IVF-ET and to explore the relationship between IVF-ET pregnancy and PAS. According to the PRISMA guidelines, a comprehensive systematic review of the literature was conducted through August 31, 2020 to determine the effects of IVF-ET on PAS. In addition, a meta-analysis was conducted to explore the relationship between IVF-ET pregnancy and PAS. Twelve original studies (2011-2020) met the inclusion criteria. Among these, 190,139 IVF-ET pregnancies and 248,534 spontaneous conceptions met the inclusion criteria. In the comparator analysis between PAS after IVF-ET and PAS with spontaneous conception (n = 2), the antenatal diagnosis of PAS after IVF-ET was significantly lower than that of PAS with spontaneous conception (22.2% versus 94.7%, P < 0.01; < 12.9% versus 46.9%, P < 0.01). The risk of PAS was significantly higher in women who conceived with IVF-ET than in those with spontaneous conception (odds ratio [OR]: 5.03, 95% confidence interval [CI]: 3.34-7.56, P < 0.01). In the sensitivity analysis accounting for the type of IVF-ET, frozen ET was associated with an increased risk of PAS (OR: 4.60, 95%CI: 3.42-6.18, P < 0.01) compared to fresh ET. Notably, frozen ET with hormone replacement cycle was significantly associated with the prevalence of PAS compared to frozen ET with normal ovulatory cycle (OR: 5.76, 95%CI 3.12-10.64, P < 0.01). IVF-ET is associated with PAS, and PAS after IVF-ET was associated with a lower rate of antenatal diagnosis. Therefore, clinicians can pay more attention to the presence of PAS during antenatal evaluation in women with IVF-ET, especially in frozen ET with hormone replacement cycle.

Complement activation by an angiogenic imbalance leads to systemic vascular endothelial dysfunction: A new proposal for the pathophysiology of preeclampsia.

The underlying mechanism of preeclampsia by which an angiogenic imbalance results in systemic vascular endothelial dysfunction remains unclear. Complement activation directly induces endothelial dysfunction and is known to be involved in preeclampsia; nevertheless, the association between complement activation and angiogenic imbalance has not been established. This study aimed to evaluate whether angiogenic imbalance affects the expression and secretion of inhibitory complement factor H (CFH) in endothelial cells, resulting in complement activation and systemic vascular endothelial dysfunction. Viability of human umbilical vein endothelial cells (HUVECs) was assessed upon CFH knockdown by targeted-siRNA, and were incubated with complement factors. HUVECs were also treated with placental growth factor (PlGF) and/or soluble fms-like tyrosine kinase 1 (sFlt1), and CFH expression and secretion were measured. These cells were evaluated by cell viability assay and cell surface complement activation was quantified by immunocytochemical assessment of C5b-9 deposition. HUVECs transfected with CFH-siRNA had significantly lower viability than that of control cells. Moreover, the expression and secretion of CFH were significantly increased upon PlGF treatment compared with PlGF + sFlt1 combo. HUVECs treated with PlGF had less C5b-9 deposition and higher viability than HUVECs treated with PlGF + sFlt1. In summary, CFH was found to be essential for endothelial cell survival by inhibiting complement activation. An angiogenic imbalance, including decreased PlGF and increased sFlt1, suppresses CFH expression and secretion, resulting in complement activation on the surface of endothelial cells and systemic vascular endothelial dysfunction.

Hypertensive Disorders of Pregnancy in Relation to Coffee and Tea Consumption: The Japan Environment and Children's Study.

BACKGROUND: The association between coffee/tea intake and hypertensive disorders of pregnancy (HDP) remains unclear. This study aimed to investigate the association of caffeine, coffee, and tea intake during pregnancy with the risk of HDP. METHODS: We assessed this association in 85,533 singleton pregnant women with live births in the Japan Environment and Children's Study, a prospective cohort in Japan that included women from early pregnancy onward. Caffeinated and decaffeinated coffee and tea (green, oolong, and black) consumption during pregnancy was assessed using a validated food frequency questionnaire conducted at mid-pregnancy, and caffeine intake was calculated based on coffee and tea consumption. Multivariable logistic regression was used to assess the association with the risk of HDP. RESULTS: HDP developed in 2222 women (2.6%). Caffeine intake was weakly associated with increased risk of HDP; the multivariable odds ratio of HDP for the highest versus the lowest quartile was 1.26 (95% confidence interval: 1.11, 1.43). Coffee drinkers of two or more cups per day showed a decreased risk compared with non-drinkers (multivariable odds ratio 0.79; 0.62, 0.99) even after adjustment for total caffeine intake. Tea consumption was not associated with the risk of HDP. CONCLUSIONS: Our study suggests that higher caffeine intake may increase HDP risk, while coffee drinkers had a lower risk. Further high-quality studies are needed to replicate these findings, and to elucidate if other substances in coffee may be protective against HDP.

Controlled induction of immune tolerance by mesenchymal stem cells transferred by maternal microchimerism.

Feto-maternal immune tolerance is established during pregnancy; however, its mechanism and maintenance remain underexplored. Here, we investigated whether mesenchymal stem/stromal cells (MSCs) as non-inherited maternal antigens (NIMAs) transferred by maternal microchimerism could induce immune tolerance. We showed that MSCs had a potential equivalent to hematopoietic stem and progenitor cells (HSPCs) to induce immune tolerance and that MSCs were essential to induce tolerance to MSC-specific antigens. Furthermore, we demonstrated that MSCs as NIMAs transferred by maternal microchimerism could induce robust immune tolerance that can be further enhanced using a drug. Our data shed light on induction of immune tolerance and serve as a foundation to develop new therapies using maternally derived cells for autoimmune or genetic diseases.

Placenta previa with posterior extrauterine adhesion: clinical features and management practice.

BACKGROUND: A diagnostic sign on magnetic resonance imaging, suggestive of posterior extrauterine adhesion (PEUA), was identified in patients with placenta previa. However, the clinical features or surgical outcomes of patients with placenta previa and PEUA are unclear. Our study aimed to investigate the clinical characteristics of placenta previa with PEUA and determine whether an altered management strategy improved surgical outcomes. METHODS: This single institution retrospective study examined patients with placenta previa who underwent cesarean delivery between 2014 and 2019. In June 2017, we recognized that PEUA was associated with increased intraoperative bleeding; thus, we altered the management of patients with placenta previa and PEUA. To assess the relationship between changes in practice and surgical outcomes, a quasi-experimental method was used to examine the difference-in-difference before (pre group) and after (post group) the changes. Surgical management was modified as follows: (i) minimization of uterine exteriorization and adhesion detachment during cesarean delivery and (ii) use of Nelaton catheters for guiding cervical passage during Bakri balloon insertion. To account for patient characteristics, propensity score matching and multivariate regression analyses were performed. RESULTS: The study cohort (n = 141) comprised of 24 patients with placenta previa and PEUA (PEUA group) and 117 non-PEUA patients (control group). The PEUA patients were further categorized into the pre (n = 12) and post groups (n = 12) based on the changes in surgical management. Total placenta previa and posterior placentas were more likely in the PEUA group than in the control group (66.7% versus 42.7% [P = 0.04] and 95.8% versus 63.2% [P < 0.01], respectively). After propensity score matching (n = 72), intraoperative blood loss was significantly higher in the PEUA group (n = 24) than in the control group (n = 48) (1515 mL versus 870 mL, P < 0.01). Multivariate regression analysis revealed that PEUA was a significant risk factor for intraoperative bleeding before changes were implemented in practice (t = 2.46, P = 0.02). Intraoperative blood loss in the post group was successfully reduced, as opposed to in the pre group (1180 mL versus 1827 mL, P = 0.04). CONCLUSIONS: PEUA was associated with total placenta previa, posterior placenta, and increased intraoperative bleeding in patients with placenta previa. Our altered management could reduce the intraoperative blood loss.

Correlation Between the Transient Elevation of Peripheral Eosinophil Count During Radiotherapy and Acute Diarrhea.

Background/Aim: This study aimed to evaluate the association between the change in peripheral eosinophil count during postoperative pelvic radiotherapy and gastrointestinal (GI) toxicities in patients with cervical cancer. Patients and Methods: The medical records of 163 patients with cervical cancer who underwent postoperative concurrent chemoradiotherapy between 2000 and 2016 were analyzed. Results: Among the peripheral blood cell counts, transient elevation of the eosinophil count was observed during radiotherapy. Of the 163 patients, 117 developed grade ≥2 diarrhea during radiotherapy, and 25 patients developed grade ≥2 late GI toxicities. In multivariate analysis, the maximum eosinophil count and age emerged as independent predictors of grade ≥2 acute diarrhea during radiotherapy, while bowel bag V 40 Gy and age were predictive of grade ≥2 late GI toxicities. Conclusion: Early detection of transient elevation of eosinophil may facilitate early treatment of acute diarrhea during radiotherapy.

Potency of Tokishakuyakusan in treating preeclampsia: Drug repositioning method by in vitro screening of the Kampo library.

INTRODUCTION: Preeclampsia therapy has not been established, except for the termination of pregnancy. The aim of this study was to identify a potential therapeutic agent from traditional Japanese medicine (Kampo) using the drug repositioning method. MATERIALS AND METHODS: We screened a library of 74 Kampo to identify potential drugs for the treatment of preeclampsia. We investigated the angiogenic effects of these drugs using human umbilical vein endothelial cells (HUVECs). Enzyme-linked immunosorbent assays were performed to measure the levels of placental growth factor (PlGF) in conditioned media treated with 100 µg/mL of each drug. We assessed whether the screened drugs affected cell viability. We performed tube formation assays to evaluate the angiogenic effects of PlGF-inducing drugs. PlGF was measured after administering 10, 50, 100, and 200 µg/mL of the candidate drug in the dose correlation experiment, and at 1, 2, 3, 6, 12, and 24 h in the time course experiment. We also performed tube formation assays with the candidate drug and 100 ng/mL of soluble fms-like tyrosine kinase 1 (sFlt1). PlGF production by the candidate drug was measured in trophoblastic cells (BeWo and HTR-8/SVneo). The Mann-Whitney U test or one-way analyses of variance followed by the Newman-Keuls post-hoc test were performed. P-values < 0.05 were considered significant. RESULTS: Of the 7 drugs that induced PlGF, Tokishakuyakusan (TS), Shoseiryuto, and Shofusan did not reduce cell viability. TS significantly facilitated tube formation (P = 0.017). TS administration increased PlGF expression in a dose- and time-dependent manner. TS significantly improved tube formation, which was inhibited by sFlt1 (P = 0.033). TS also increased PlGF production in BeWo (P = 0.001) but not HTR-8/SVneo cells (P = 0.33). CONCLUSIONS: By using the drug repositioning method in the in vitro screening of the Kampo library, we identified that TS may have a therapeutic potential for preeclampsia. Its newly found mechanisms involve the increase in PlGF production, and improvement of the antiangiogenic state.

Evaluation of leucine-rich alpha-2 glycoprotein as a biomarker of fetal infection.

This study aimed to determine the association between umbilical cord leucine-rich alpha-2 glycoprotein (LRG) and fetal infection and investigate the underlying mechanism of LRG elevation in fetuses. We retrospectively reviewed the medical records of patients who delivered at Osaka University Hospital between 2012 and 2017 and selected those with histologically confirmed chorioamnionitis (CAM), which is a common pregnancy complication that may cause neonatal infection. The participants were divided into two groups: CAM with fetal infection (CAM-f[+] group, n = 14) and CAM without fetal infection (CAM-f[-] group, n = 31). Fetal infection was defined by the histological evidence of funisitis. We also selected 50 cases without clinical signs of CAM to serve as the control. LRG concentrations in sera obtained from the umbilical cord were unaffected by gestational age at delivery, neonatal birth weight, nor the presence of noninfectious obstetric complications (all, p > 0.05). Meanwhile, the LRG levels (median, Interquartile range [IQR]) were significantly higher in the CAM-f(+) group (10.37 [5.21-13.7] µg/ml) than in the CAM-f(-) (3.61 [2.71-4.65] µg/ml) or control group (3.39 [2.81-3.93] µg/ml; p < 0.01). The area under the receiver operating characteristic (ROC) curve of LRG for recognizing fetal infection was 0.92 (optimal cutoff, 5.08 µg/ml; sensitivity, 86%; specificity, 88%). In a mouse CAM model established by lipopolysaccharide administration, the fetal LRG protein in sera and LRG mRNA in the liver were significantly higher than those in phosphate-buffered saline (PBS)-administered control mice (p < 0.01). In vitro experiments using a fetal liver-derived cell line (WRL68) showed that the expression of LRG mRNA was significantly increased after interleukin (IL)-6, IL-1ß, and tumor necrosis factor- alpha (TNF-α) stimulation (p < 0.01); the induction was considerably stronger following IL-6 and TNF-α stimulation (p < 0.01). In conclusion, LRG is an effective biomarker of fetal infection, and fetal hepatocytes stimulated with inflammatory cytokines may be the primary source of LRG production in utero.