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The risk of severe disease caused by co-infection with SARS-CoV-2 and influenza virus (IAV) raises an annual concern for global public health. Extracellular vesicles (EV) derived from mesenchymal stem cells (MSC) possess anti-inflammatory properties that can attenuate the inflammatory cytokine levels induced by viral infection. However, the effects of MSC-EV treatment on SARS-CoV-2 and IAV co-infection have not been elucidated. In the present study, we co-induced lung epithelial cells (EpiC) with SARS-CoV-2 Spike protein (S) and H1N1 influenza viral HA protein (HA) and found robust upregulation of inflammatory cytokines in comparison to those induced by either S or HA protein. Consequently, treatment of lung endothelial cells (EC) with conditioned medium from EpiC co-induced by both S and HA proteins resulted in increased apoptosis and impaired angiogenic ability, suggesting the effects of co-induction on epithelial-endothelial crosstalk. In addition, lung EpiC co-induced by both S and HA proteins showed paracrine effects on the recruitment of immune cells, including monocytes, macrophages and neutrophils. Of Note, EV derived from Wharton Jelly's MSC (WJ-EV) transferred miR-146a to recipient lung EpiC, which impaired TRAF6 and IRAK1, resulting in the downregulation of NF-κB pathway and secretion of inflammatory cytokines, rescuing the epithelial-endothelial crosstalk, and reducing the elevation of immune cell recruitment. Moreover, the anti-inflammatory properties of WJ-EV are affected by type 2 Diabetes Mellitus. WJ-EV derived from donors with type 2 Diabetes Mellitus contained less miR-146a and showed impaired ability to downregulate the NF-κB pathway and inflammatory cytokines in recipient cells. Taken together, our findings demonstrate the role of miR-146a in targeting the NF-κB pathway in the anti-inflammatory abilities of WJ-EV, which is a promising strategy to rescue the epithelial-endothelial crosstalk altered by co-infection with SARS-CoV-2 and IAV. [ABSTRACT FROM AUTHOR]

Aims: The aim of the study is to report the clinical and pharmacological observations from a pregnant patient treated with erlotinib in the second and third trimesters of pregnancy. Methods: Maternal and neonatal blood levels and safety of erlotinib and its metabolites were evaluated. Child development was monitored for 6 years. Results: A 31‐year‐old woman with stage IV lung adenocarcinoma with EGFR exon19 deletion began treatment with erlotinib 150 mg/day at 17 weeks of gestation. Although foetal growth retardation and oligohydramnios were observed at several times during the pregnancy, treatment was continued due to the severity of the maternal presentation, with ongoing foetal monitoring. The foetus seemed to tolerate and recover well without specific interventions. A healthy baby boy was delivered at 37 weeks gestation. The child grew and developed without any obvious issues. At last follow‐up, at age 6 years, he was attending school at a grade appropriate for his age without health or developmental problems. Blood levels of erlotinib were 397–856 ng/mL at 18–37 weeks of gestation and 1190 ng/mL at 8 weeks postpartum. The blood concentration ratios of OSI‐413‐to‐erlotinib ranged from 0.167 to 0.253 at 18–37 weeks of gestation, excluding 24 weeks, and 0.131 at 8 weeks postpartum. The maternal‐to‐foetal transfer rate of erlotinib, OSI‐420 and OSI‐413 were 24.5, 34.8 and 20.3%, respectively. Conclusion: Erlotinib use during the second and third trimester of pregnancy did not seem to cause any untoward effects on the developing foetus, or any long‐lasting effects that could be detected during 6 years of follow‐up of the child. [ABSTRACT FROM AUTHOR]

Aim: Pulmonary embolism remains a leading cause of maternal mortality in developed countries despite developments in venous thromboembolism prophylaxis strategies. This study aimed to evaluate the effectiveness of our approach involving risk‐scoring, D‐dimer level assessment, and ultrasonography for obstetric venous thromboembolism. Methods: This retrospective cohort study included women who delivered at 22–41 weeks of gestation in The University of Tsukuba Hospital, Japan between January and December 2020. Venous thromboembolism risk (determined according to Japanese guidelines) and D‐dimer levels were evaluated within 20 weeks of gestation, 30–34 weeks of gestation, and during the pre‐delivery period (36 weeks of gestation or any time before preterm delivery). Compression and color Doppler ultrasonography for lower extremity deep vein thrombosis were performed if D‐dimer levels were ≥3.2 μg/mL (for those undergoing cesarean delivery, 1.0 μg/mL). Results: Of 1026 women, 6 women had deep vein thrombosis during pregnancy and 1 during the puerperium period. Pulmonary embolism was not observed. The D‐dimer screening result was positive for 8 women (2%) within 20 weeks of gestation (deep vein thrombosis was confirmed in 3 of them), 87 women (10%) (no deep vein thrombosis) at 30–34 weeks of gestation, and 367 women (36%) during the pre‐delivery period (asymptomatic deep vein thrombosis in one). Based on the Japanese guidelines, 1%, 11%, 33%, and 55% of women had high, intermediate, low, and no postpartum risk factors, respectively. Conclusions: Our approach appears useful for antenatal venous thromboembolism screening in the first trimester. For postpartum prophylaxis, more cost‐effective strategies are needed. [ABSTRACT FROM AUTHOR]

Triple negative breast cancer (TNBC) is associated with worse outcomes and results in high mortality; therefore, great efforts are required to find effective treatment. In the present study, we suggested a novel strategy to treat TNBC using mesenchymal stem cell (MSC)-derived extracellular vesicles (EV) to transform the behaviors and cellular communication of TNBC cells (BCC) with other non-cancer cells related to tumorigenesis and metastasis. Our data showed that, BCC after being internalized with EV derived from Wharton's Jelly MSC (WJ-EV) showed the impaired proliferation, stemness properties, tumorigenesis and metastasis under hypoxic conditions. Moreover, these inhibitory effects may be involved in the transfer of miRNA-125b from WJ-EV to BCC, which downregulated the expression of HIF1α and target genes related to proliferation, epithelial-mesenchymal transition, and angiogenesis. Of note, WJ-EV-internalized BCC (wBCC) showed transformed behaviors that attenuated the in vivo development and metastatic ability of TNBC, the angiogenic abilities of endothelial cells and endothelial progenitor cells and the generation of cancer-associated fibroblasts from MSC. Furthermore, wBCC generated a new EV with modified functions that contributed to the inhibitory effects on tumorigenesis and metastasis of TNBC. Taken together, our findings suggested that WJ-EV treatment is a promising therapy that results in the generation of wBCC to interrupt the cellular crosstalk in the tumor environment and inhibit the tumor progression in TNBC. [ABSTRACT FROM AUTHOR]

To compare n-butyl cyanoacrylate (NBCA) and gelatine sponge (GS) as embolic materials for prophylactic pelvic arterial embolisation during caesarean hysterectomy for placenta accreta spectrum (PAS). This retrospective study comprised 12 women (age range, 23–42 years; mean, 34.1 years) who underwent caesarean hysterectomy for PAS. Following caesarean delivery, bilateral uterine and non-uterine parasitic arteries were embolized with GS in the first four cases (GS group) and primarily with NBCA mixed with iodized oil in the subsequent eight cases (NBCA group). Procedure time for embolisation and hysterectomy and total blood loss were compared between the two groups using Welch's t-test. Although procedure time for embolisation tended to be longer in the NBCA group than in the GS group (111 ± 47 min versus 71 ± 32 min, p=.11), that for hysterectomy was significantly reduced in the NBCA group when compared to the GS group (158 ± 42 min versus 236 ± 39 min, p=.02). Total blood loss was significantly lower in the NBCA group than in the GS group (1375 ± 565 mL versus 2668 ± 587 mL, p=.01). Procedure time for hysterectomy and total blood loss during caesarean hysterectomy can be reduced by using NBCA instead of GS in prophylactic pelvic arterial embolisation for PAS. [ABSTRACT FROM AUTHOR]

Aim: Post‐partum hematomas are a serious obstetrical complication. Choosing treatments for post‐partum hematomas is difficult, and the application of transcatheter arterial embolization remains unclear. We aimed to clarify the clinical characteristics, identify the treatment indications and create a treatment algorithm for post‐partum hematomas. Methods: Fifty‐four patients with post‐partum hematomas were enrolled. Hematomas were categorized according to location: upper vaginal, lower vaginal and vulvar. Blood loss, treatment methods and other clinical data were collected from the patients' medical records and analyzed retrospectively. Results: Five, 19 and 30 patients had upper vaginal wall, lower vaginal wall and vulvar hematomas, respectively. All upper vaginal wall hematomas required transcatheter arterial embolization to control bleeding, and the average blood loss was 2473 ± 1689 mL. Most lower vaginal wall hematomas were treated surgically; however, two patients required transcatheter arterial embolization, and the average blood loss in these patients was much higher (2010 ± 1145 mL) than that in patients with lower vaginal wall hematomas (395 ± 316 mL). No patient with vulvar hematomas was treated with transcatheter arterial embolization. Two and four patients with vulvar and lower vaginal wall hematomas, respectively, were managed with observation. Conclusion: We created an algorithm for post‐partum hematoma management. Post‐partum hematoma location should guide treatment selection. Transcatheter arterial embolization should be selected for upper vaginal wall hematomas. Most lower vaginal wall hematomas are treatable with surgery, but transcatheter arterial embolization should be considered for hemostasis in difficult cases. Management with observation may also be possible for lower vaginal wall and vulvar hematomas. [ABSTRACT FROM AUTHOR]

Background and Aim Liver dysfunction with decreased antithrombin (AT) activity and/or thrombocytopenia is life threatening in pregnant women. Whether AT is clinically useful for prediction of liver dysfunction remains unclear. Methods A total of 541 women were registered prospectively at gestational week 34.7 (20.0-41.4) with available data on antenatal AT and platelet count (PLC). Results Liver dysfunction defined as serum aspartate aminotransferase > 45 IU/L concomitant with lactate dehydrogenase > 400 IU/L occurred in five women antenatally (≤ 2 weeks before delivery) and in 17 women post-partum (within 1 week post-partum). Median (5th-95th) antenatal value was 85 (62-110)% for AT and 202 (118-315) × 109/L for PLC in the 541 women and was significantly lower in women with than without perinatal liver dysfunction; 75 (51-108) versus 86 (62-110)% and 179 (56-244) versus 203 (121-316) × 109/L, respectively. Nineteen (86%) women with liver dysfunction showed AT ≤ 62% or thrombocytopenia (PLC ≤ 118 × 109/L) perinatally, but five lacked thrombocytopenia throughout the perinatal period. The best cut-off (AT, 77%; PLC, 139 × 109/L) suggested by receiver operating characteristic curve gave antenatal AT and PLC sensitivity of 59% and 41% with positive predictive value of 8.6% and 14%, respectively, and combined use of AT and PLC improved sensitivity to 73% (16/22) with positive predictive value of 9.2% for prediction of perinatal liver dysfunction. Conclusions Reduced AT not accompanied by thrombocytopenia can precede liver dysfunction. Clinical introduction of AT may enhance the safety of pregnant women. [ABSTRACT FROM AUTHOR]

Introduction: Some pregnant women develop significant proteinuria in the absence of hypertension. However, clinical significance of isolated gestational proteinuria (IGP) is not well understood. This study aimed to determine the prevalence of IGP in singleton pregnancies and the proportion of women with IGP who subsequently developed preeclampsia (IGP-PE) among all PE cases.Material and Methods: This was an observational study of 6819 women with singleton pregnancies at 12 centers, including 938 women with at least once determination of protein-to-creatinine ratio (P/Cr). Significant proteinuria in pregnancy (SPIP) was defined as P/Cr (mg/mg) level >0.27. IGP was defined as SPIP in the absence of hypertension. Gestational hypertension (GH) preceding preeclampsia (GH-PE) was defined as preeclampsia (PE) in which GH preceded SPIP. Simultaneous PE (S-PE) was defined as PE in which both SPIP and hypertension occurred simultaneously.Results: IGP and PE were diagnosed in 130 (1.9%) and 158 (2.3%) of 6819 women, respectively. Of 130 women with IGP, 32 (25%) progressed to PE and accounted for 20% of all women with PE. Hence, women with IGP had a relative risk of 13.1 (95% CI; 9.2-18.5) for developing PE compared with those without IGP [25% (32/130) vs. 1.9% (126/6689)]. At diagnosis of SPIP, P/Cr levels already exceeded 1.0 more often in women with S-PE than in those with IGP-PE [67% (33/49) vs. 44% (14/32), respectively, p = 0.031].Conclusions: IGP is a risk factor for PE, and IGP-PE accounts for a considerable proportion (20%) of all PE. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to determine effective predictive factors for primary postpartum hemorrhage (PPH) among clinical blood parameters associated with coagulation and fibrinolysis and demographic characteristics. Methods: We retrospectively studied 1032 women who underwent determinations of clinical blood parameters at gestational week (GW) 29-32 and GW 35-37 and gave birth to singleton infants at our hospital between January 2011 and December 2013. PPH was defined as estimated blood loss ≥700 mL. Multivariate logistic regression analyses were used to determine independent risk factors and odds ratios (OR) for PPH. Results: PPH occurred in 104 of 1032 women (10%). Three blood variables, fibrinogen level <4.0 g/L (OR [95% CI], 1.96 [1.18-3.27]), antithrombin activity <85% of normal activity level (1.84 [1.05-3.21]), and D-dimer level >2.7 μg/mL (2.03 [1.29-3.19]) at GW 35-37, and three demographic characteristics, maternal age ≥35 years (1.75 [1.15-2.68]), BMI >28.2 kg/m2 on admission for childbirth (1.95 [1.20-3.16]), and previous cesarean delivery (2.77 [1.31-5.83]), were identified as independent risk factors for PPH. Conclusion: Among blood parameters, higher D-dimer levels and lower levels of antithrombin activity and fibrinogen in late gestation were independent risk factors for PPH. [ABSTRACT FROM AUTHOR]

Aim: We aimed to assess the efficacy and safety of midtrimester termination of pregnancy using gemeprost in combination with laminaria in women who had previously undergone cesarean section and in women who had not. Methods: Between January 1999 and December 2006, we carried out a retrospective study of termination of pregnancy at 12–21 weeks of gestation at the University of Tsukuba Hospital. Termination of pregnancy was carried out by three-step uterine cervical dilation using laminaria followed by vaginal administration of 1 mg gemeprost every 3 h for up to four doses over 24 h. Results: A total of 173 women underwent midtrimester termination of pregnancy. The women were categorized into two groups: those who had previously undergone cesarean section ( n = 26) (previous cesarean section group) and those who had not ( n = 147) (control group). Seven women had undergone cesarean section at least twice. The gemeprost dose administered was 2.8 ± 1.4 mg for the previous cesarean section group and 2.4 ± 1.6 mg for the control group (difference in doses not significant). Although abnormal vaginal bleeding (>500 mL) was more likely to occur in the previous cesarean section group than in the control group (odds ratio, 2.61; 95% confidence interval, 0.63–10.82), none of the woman required blood transfusion. Uterine rupture and failed abortion were not observed. Conclusion: The efficacy and safety of our laminaria-gemeprost protocol for termination of pregnancy during the midtrimester are similar for women who have previously undergone cesarean section and those who have not. [ABSTRACT FROM AUTHOR]

Type 1 fimbriae of Escherichia coli mediate mannose-specific adhesion to host epithelial surfaces and consist of a major, antigenically variable pilin subunit, FimA, and a minor, structurally conserved adhesive subunit, FimH, located on the fimbrial tip. We have analysed the variability of fimA and fimH in strains of vaginal and other origin that belong to one of the most prominent clonal groups of extraintestinal pathogenic E. coli, comprised of O1:K1-, O2:K1- and O18:K1-based serotypes. Multiple locus sequence typing (MLST) of this group revealed that the strains have identical (at all but one nucleotide position) eight housekeeping loci around the genome and belong to the ST95 complex defined by the publicly available E. coli MLST database. Multiple highly diverse fimA alleles have been introduced into the ST95 clonal complex via horizontal transfer, at a frequency comparable to that of genes defining the major O- and H-antigens. However, no further significant FimA diversification has occurred via point mutation after the transfers. In contrast, while fimH alleles also move horizontally (along with the fimA loci), they acquire point amino acid replacements at a higher rate than either housekeeping genes or fimA. These FimH mutations enhance binding to monomannose receptors and bacterial tropism for human vaginal epithelium. A similar pattern of rapid within-clonal structural evolution of the adhesive, but not pilin, subunit is also seen, respectively, in papG and papA alleles of the di-galactose-specific P-fimbriae. Thus, while structurally diverse pilin subunits of E. coli fimbriae are under selective pressure for frequent horizontal transfer between clones, the adhesive subunits of extraintestinal E. coli are under strong positive selection (Dn/Ds > 1 for fimH and papG) for functionally adaptive amino acid replacements. [ABSTRACT FROM AUTHOR]

Fimbrial (type 1, P, and S) and afimbrial adhesins, the unique virulence traits of uropathogenic Escherichia coli (UPEC), are well recognized for their role in the initial step of uropathogenesis. In this study, we investigated whether these adhesins are dispensable for UPEC in adherence and invasion of uroepithelial cells by using E. coli isolates (n=40) from cystitis patients and T-24 cells, the bladder carcinoma cell line. We found all isolates adherent to T-24 cells within 15 min of infection. In invasion assay, all isolates could invade T-24 cells to a variable degree; 22.5% of them were found highly invasive. About 33% of isolates that do not have any recognized adhesins were as invasive as other isolates. The amplitude of invasiveness was also independent of the adhesins. In conclusion, this study demonstrates that type 1 fimbriae, P fimbriae, S fimbriae, and afimbrial adhesin I are not required for UPEC to adhere to and invade uroepithelial cells. [Copyright &y& Elsevier]

We here report the first case of discordant Pena-Shokeir phenotype observed in monoamniotic twins. A 34-year-old woman, pregnant with twins, was referred at 10 weeks' gestation because one of the twins had increased nuchal translucency. Serial ultrasonographic examinations suggested that twin A may have had several other abnormalities, including pleural effusion at 21 weeks' gestation, decreased movement and contracted limbs at 24 weeks, and fetal growth restriction at 26 weeks. No abnormalities were observed in twin B. At 34 weeks of gestation, the twins were delivered by cesarean section. There were cord entanglements, and although the resuscitation of twin A was attempted, it proved difficult due to lockjaw. Twin A died during the second hour of life, and autopsy findings were consistent with the diagnosis of Pena-Shokeir phenotype. We suggest that cord entanglement during early gestation is a possible cause for the occurrence of Pena-Shokeir phenotype through an anoxic-ischemic mechanism. [ABSTRACT FROM AUTHOR]

We report a case of alveolar capillary dysplasia, wherein duodenal atresia was diagnosed during the third trimester. A 36-year-old mother was referred to our hospital for polyhydramnios at 31 weeks’ gestation. Duodenal atresia was suspected from the ultrasonographic findings, which showed gastric dilation. Other findings noted were enlarged, highly echogenic lungs, a spherical heart and an increased lung–thorax transverse area ratio.A male infantwas born at 37 weeks’ gestation. The findings of serial radiography of the infant’s upper gastrointestinal tract were compatible with the diagnosis of duodenal atresia; however, he developed persistent pulmonary hypertension of the newborn eight hours after birth and died at five days of age. The autopsy revealed alveolar capillary dysplasia and duodenal obstruction. We propose that the detection of duodenal atresia should prompt the physician to conduct a thorough ultrasonographic examination to rule out associated anomalies, such as alveolar capillary dysplasia, which can be detected by the presence of highly echogenic lungs. [ABSTRACT FROM AUTHOR]

Background: 17α-Hydroxylase deficiency is a recessively inherited autosomal disease caused by mutations in the CYP17A1 gene. It is a rare disease and accounts for approximately 1% of congenital adrenal cortex hyperplasias. Inhibition of 17α-hydroxylase causes low levels of cortisol and high levels of adrenocorticotropic hormone in the blood as well as excessive levels of mineralocorticoids that lead to hypertension and hypokalemia. Usually, the female patients are diagnosed with abnormality of the genitalia or extra genitalia, primary amenorrhea, or hypertension in puberty. We report a case of a 29-year-old woman who had undergone gonadectomy in her childhood due to complete androgen insensitivity syndrome and was diagnosed with 17α-hydroxylase deficiency in adulthood.Case Presentation: Our patient was a Japanese female diagnosed with androgen insensitivity syndrome, and both gonadectomy and episioplasty were performed at the age of 11 years at the University of Tsukuba Hospital. Thereafter, she was transferred to our hospital at the age of 21 years for vaginoplasty. At the age of 25 years, she presented with hypertension followed by complicated hypokalemia at the age of 28 years. The captopril loading test and adrenocorticotropic hormone loading test of her adrenal steroidogenesis revealed primary aldosteronism. After sufficient genetic counseling, a genetic test was performed that identified her as having CYP17A1 gene mutation.Conclusions: The differential diagnosis of disorders of sex development can be difficult at a young age without complete expression of the phenotype. However, diagnosis at a later age would change the treatment and prognosis of the disease; therefore, a genetic examination should be considered. [ABSTRACT FROM AUTHOR]

Background: The dipstick test is widely used as a primary screening test for detection of significant proteinuria in pregnancy (SPIP). However, it often shows a false positive test result. This study was performed to determine which pregnant women should be recommended to undergo determination of urinary protein-to-creatinine ratio (mg/mg, P/Cr test) after dipstick test for confirmation of SPIP.Methods: This was a multicenter, prospective, and observational study of 2212 urine specimens from 1033 pregnant women who underwent simultaneous dipstick and P/Cr tests in the same spot urine samples at least once. SPIP was defined as P/Cr > 0.27. Preeclampsia was diagnosed in women with both hypertension and SPIP.Results: Preeclampsia, hypertension alone, and SPIP alone developed in 202 (20 %), 73 (7.1 %), and 120 (12 %) women, respectively. Creatinine concentration [Cr] varied greatly, ranging from 8.1 to 831 mg/dL in the 2212 urine samples. Rate of positive dipstick test results increased with increasing [Cr], while SPIP prevalence rate was lower in urine samples with higher [Cr], yielding higher false positive rates in samples with higher [Cr]. Postpartum urine samples had significantly lower [Cr] compared to those obtained antepartum (60 [8.7-297] vs. 100 [10-401] mg/dL, respectively). At the first P/Cr test among women with similar dipstick test results, the risk of having SPIP was consistently and significantly higher for hypertensive women than for normotensive women at any dipstick test result: 18 % (14/77) vs. 3.2 % (8/251), 47 % (26/55) vs. 8.7 % (37/425), 91 % (82/90) vs. 59 % (44/75) for negative/equivocal, 1+, and ≥ 2+ test results, respectively. The risk of SPIP was 16 % (9/55) for normotensive women when two successive antenatal urine samples showed a dipstick test result of 1 + .Conclusions: For prediction of SPIP, the dipstick test was more likely to show a false positive result in concentrated urine samples with higher [Cr]. Hypertensive women with ≥ 1+ as well as normotensive women with ≥ 2+ on dipstick test should be advised to undergo the P/Cr test. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented with regards to possible risk factor for vaginal/anorectal colonization by Group B Streptococcus (GBS) due to impaired glucose tolerance during pregnancy.