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Previous studies have shown that interpregnancy weight fluctuations impact perinatal outcomes. In order to examine this in Japanese women, we analyzed the data of 2,861 women in their first and second pregnancies who delivered singletons between 2000 and 2022. We compared the second pregnancy perinatal outcomes of women whose interpregnancy body mass index (BMI) change was -1 to 1 unit with those of women whose BMI change was < -1 or ≥ 1 unit. An interpregnancy BMI change ≥ 1 unit was associated with an increased risk of developing gestational diabetes mellitus (adjusted odds ratio [aOR], 1.51; 95% confidence interval [CI], 1.18–1.95) and delivering a large for gestational age neonate (aOR, 1.67; 95% CI, 1.15–2.42) but a decreased risk of preterm birth (aOR, 0.66; 95% CI, 0.46–0.95). An interpregnancy BMI change < -1 unit was associated with a decreased risk of developing gestational diabetes mellitus (aOR, 0.51; 95% CI, 0.31–0.85). In a subgroup analysis of three groups divided according to prepregnancy BMI, interpregnancy BMI changes ≥ 1 unit in women with a BMI of < 18.5 kg/m2 before their first pregnancy were associated with a remarkable risk reduction of developing preterm birth (aOR, 0.30; 95% CI, 0.11–0.81). Interpregnancy BMI changes < -1 unit in women with a BMI of ≥ 25 kg/m 2 before their first pregnancy were associated with a remarkable risk reduction of developing gestational diabetes mellitus (aOR, 0.33; 95% CI, 0.12–0.88). Weight gain during interpregnancy period was related to an increased risk of gestational diabetes mellitus and delivery of a large-for-gestational-age neonate, whereas weight loss was related to a decreased risk of developing gestational diabetes mellitus. These results indicate the importance of interpregnancy weight control as part of preconception care; therefore, women considering additional pregnancies should be educated on the importance of maintaining a healthy weight.

An increase in cervical cancer incidence has been reported in Japan. The Ministry of Health, Labor, and Welfare of Japan has resumed the active recommendation of regular HPV vaccines in 2022. In Japan, the preventive effect of CIN3+ in the real world has not yet been demonstrated in age‐adjusted cohort or case–control studies. This study aimed to estimate the effect of the HPV vaccine against CIN3+ in Japanese women. This nationwide case–control study from April 2013 to March 2020 targeted women aged 20–26 years old at the time of cervical screening. We compared HPV vaccination exposure between those with abnormal and those with normal cytology. Abnormal cytology was classified into cervical intraepithelial neoplasia (CIN)1+, CIN2+, and CIN3+. We calculated the odds ratio (OR) and 95% confidence interval (CI) of the above endpoints and vaccination exposure using the conditional logistic regression model and estimated vaccine effectiveness using the formula (1 −OR) × 100. A total of 2790 cases and 13,990 controls (one‐to‐five matching) were eligible in 37 municipalities in Japan. In this study, 61 CIN3 (2.2%) and 10 squamous cell carcinomas (SCC) (0.4%) were found. The OR for CIN3+ versus controls was 0.14 (95% CI, 0.03–0.75), equating to a vaccine effectiveness of 86%. Of the 10 patients who had SCC none were vaccinated. This nationwide case–control study in Japan demonstrated a substantial risk reduction in CIN3+ among women who did versus those who did not receive HPV vaccination. This nationwide case‐control study in Japan aimed to estimate the effectiveness of the HPV vaccine against CIN3+ in Japanese women and demonstrated that HPV vaccination reduces the risk of CIN3+ by 86%.

In Japan, recommendations for HPV vaccines were suspended in 2013 due to unfounded safety fears. Although vaccine opponents claim modifying sexual behavior can prevent cervical cancer, no comprehensive data exist on sexual behavior and the risk of high-grade cervical disease in a Japanese population. This study investigates sexual behavior and the risk of HPV infection and cervical disease in 3968 women aged 20–41 yrs undergoing cervical screening between April 2014 and March 2016. Mean age at first intercourse was 18.4 yrs ± 2.8 and 32% of women reported ≥ 6 lifetime sexual partners. In regression analyses, number of partners was a significant risk factor for HPV infection. However, for high-grade disease (CIN2+), when HPV genotype was adjusted for, number of partners was not statistically significant. The greatest risk factor was an HPV16/18 infection (adjusted odds ratio 113.7, 95% CI: 40.8–316.9). In conclusion, we found that having an HPV16/18 infection and not sexual behavior was the most significant risk factor for high grade cervical disease in young Japanese women. These infections can be prevented by a highly effective vaccine and we recommend that the Japanese government resume proactive recommendations for the HPV vaccine immediately.

Cancer tissues generally have molecular oxygen and serum component deficiencies because of poor vascularization. Recently, we revealed that ICAM1 is strongly activated through lipophagy in ovarian clear cell carcinoma (CCC) cells in response to starvation of long‐chain fatty acids and oxygen and confers resistance to apoptosis caused by these harsh conditions. CD69 is a glycoprotein that is synthesized in immune cells and is associated with their activation through cellular signaling pathways. However, the expression and function of CD69 in nonhematological cells is unclear. Here, we report that CD69 is induced in CCC cells as in ICAM1. Mass spectrometry analysis of phosphorylated peptides followed by pathway analysis revealed that CD69 augments CCC cell binding to fibronectin (FN) in association with the phosphorylation of multiple cellular signaling molecules including the focal adhesion pathway. Furthermore, CD69 synthesized in CCC cells could facilitate cell survival because the CD69–FN axis can induce epithelial–mesenchymal transition. Experiments with surgically removed tumor samples revealed that CD69 is predominantly expressed in CCC tumor cells compared with other histological subtypes of epithelial ovarian cancer. Overall, our data suggest that cancer cell‐derived CD69 can contribute to CCC progression through FN. We provided a novel concept that CD69 is strongly expressed in epithelial, nonhematological ovarian clear cell carcinoma (CCC) cells. CD69 protein induced in response to fatty acid and oxygen starvation is responsible for fibronectin‐driven epithelial–mesenchymal transition, potentially contributing to the poor prognosis of CCC patients.

Background\\n\\nAcute liver failure (ALF) is a life-threatening disease with a high mortality rate. However, there are limited treatments or devices available for ALF therapy. Here, we aimed to develop a new strategy for ALF treatment by transplanting functional liver organoids (LOs) generated from single donor-derived human induced pluripotent stem cell (hiPSC) endoderm, endothelial cells (ECs), and mesenchymal cells (MCs).\\nMethods\\n\\nFirst, we isolated ECs and MCs from a single donor umbilical cord (UC) through enzyme digestion and characterized the UC-ECs and UC-MCs by flow cytometry. Second, using a nonviral reprogramming method, we generated same donor-derived hiPSCs from the UC-ECs and investigated their hepatic differentiation abilities. Finally, we simultaneously plated EC-hiPSC endoderm, UC-ECs, and UC-MCs in a three-dimensional (3D) microwell culture system, and generated single donor cell-derived differentiated LOs for ALF mouse treatment.\\nResults\\n\\nWe obtained ECs and MCs from a single donor UC with high purity, and these cells provided a multicellular microenvironment that promoted LO differentiation. hiPSCs from the same donor were generated from UC-ECs, and the resultant EC-hiPSCs could be differentiated efficiently into pure definitive endoderm and further into hepatic lineages. Simultaneous plating of EC-hiPSC endoderm, UC-ECs, and UC-MCs in the 3D microwell system generated single donor cell-derived LOs (SDC-LOs) that could be differentiated into functional LOs with enhanced hepatic capacity as compared to that of EC-hiPSC-derived hepatic-like cells. When these functional SDC-LOs were transplanted into the renal subcapsules of ALF mice, they rapidly assumed hepatic functions and improved the survival rate of ALF mice.\\nConclusion\\n\\nThese results demonstrate that functional LOs generated from single donor cells can improve the condition of ALF mice. Functional SDC-LO transplantation provides a promising novel approach for ALF therapy.

BackgroundTissue factor pathway inhibitor 2 (TFPI2) is a novel serum biomarker that discriminates ovarian clear cell carcinoma (CCC) from borderline ovarian tumors (BOTs) and non-clear cell epithelial ovarian cancers (EOCs). Here, we examined the performance of TFPI2 for preoperative diagnosis of CCC.MethodsSerum samples were obtained preoperatively from patients with ovarian masses, who needed surgical treatment at five hospitals in Japan. The diagnostic powers of TFPI2 and cancer antigen 125 (CA125) serum levels to discriminate CCC from BOTs, other EOCs, and benign lesions were compared.ResultsA total of 351 patients including 69 CCCs were analyzed. Serum TFPI2 levels were significantly higher in CCC patients (mean ± SD, 508.2 ± 812.0 pg/mL) than in patients with benign lesions (154.7 ± 46.5), BOTs (181 ± 95.5) and other EOCs (265.4 ± 289.1). TFPI2 had a high diagnostic specificity for CCC (79.5%). In patients with benign ovarian endometriosis, no patient was positive for TFPI2, but 71.4% (15/21) were CA125 positive. TFPI2 showed good performance in discriminating stage II–IV CCC from BOTs and other EOCs (AUC 0.815 for TFPI2 versus 0.505 for CA125) or endometriosis (AUC 0.957 for TFPI2 versus 0.748 for CA125). The diagnostic sensitivity of TFPI2 to discriminate CCC from BOTs and other EOCs was improved from 43.5 to 71.0% when combined with CA125.ConclusionsHigh specificity of TFPI2 for preoperative detection of CCC was verified with the defined cutoff level of TFPI2 in clinical practice. TFPI2 and CA125 may contribute substantially to precise prediction of intractable CCC.

ObjectivesTo estimate uptake of the 75 g oral glucose tolerance test (OGTT) at 6–12 weeks postpartum among women with gestational diabetes mellitus (GDM) in Japan, and to explore the demographic and clinical characteristics associated with screening uptake.DesignRetrospective cohort study using administrative claims data.SettingData from a nationwide employees’ health insurance claims database (Japan Medical Data Center; JMDC) during the fiscal years 2012–2020 were assessed.Participants2282 women with GDM in the JMDC claims database (April 2012–January 2021), ascertained using the International Classification of Diseases 10th revision (ICD-10) codes cross-validated with a high-risk GDM management fee.Primary and secondary outcome measuresPrimary outcome: completion of a 75 g OGTT at 6–12 weeks postpartum. Secondary outcomes: completion of a 75 g OGTT at 4–12 weeks postpartum and cumulative completion up to 1 year postpartum.ResultsWe included 2282 women in the analysis. The overall screening rate was 28.7% (654/2282) from 2012 to 2020. Even in 2020, the year with the highest reported screening rate, it remained low at 33.2% (181/546). After expanding the range to include 4 weeks to ≤1 year postpartum, the cumulative screening rate reached 64.9% by 1 year postpartum. The screening rate was lower when childbirth and GDM were managed at different facilities than when both were managed within the same facility.ConclusionsWe report suboptimal screening rates for women with a GDM history in Japan. This study highlights the need for continuous monitoring and the development of effective strategies for early screening and intervention in this high-risk group. These strategies should include system-level improvements in screening methods and enhance patient awareness through antenatal education prior to delivery.

Elucidation of spatial interactions between cancer and host cells is important for the development of new therapies against disseminated cancers. The aim of this study is to establish easy and useful method for elucidating spatial interactions. In this study, we developed a practical spatial analysis method using a gel-based embedding system and applied it to a murine model of cancer dissemination. After euthanization, every abdominal organ enclosed in the peritoneum was extracted en bloc. We injected agarose gel into the peritoneal cavities to preserve the spatial locations of the organs, including their metastatic niches, and then produced specimens when the gel had solidified. Preservation of the original spatial localization was confirmed by correlating magnetic resonance imaging results with the sectioned specimens. We examined the effects of spatial localization on cancer hypoxia using immunohistochemical hypoxia markers. Finally, we identified the mRNA expression of the specimens and demonstrated the applicability of spatial genetic analysis. In conclusion, we established a practical method for the in vivo investigation of spatial location-specific biological mechanisms in disseminated cancers. Our method can elucidate dissemination mechanisms, find therapeutic targets, and evaluate cancer therapeutic effects.

Abstract Background Proactive recommendations for human papillomavirus (HPV) vaccines in Japan have been suspended for 5 years because of safety concerns. While no scientific evidence exists to substantiate these concerns, one reason given for not reinstating recommendations is the lack of reliable vaccine effectiveness (VE) data in a Japanese population. This study reports the VE of the bivalent HPV vaccine in Japanese women aged 20–22 years. Methods During cervical screening between 2014 and 2016, women had Papanicolaou smears and HPV tests performed and provided data about their sexual history. Estimates of VE for vaccine-targeted HPV type 16 (HPV16) and 18 and cross-protection against other types were calculated. Results Overall, 2197 women were tested, and 1814 were included in the analysis. Of these, 1355 (74.6%) were vaccinated, and 1295 (95.5%) completed the 3-dose schedule. In women sexually naive at vaccination, the pooled VEs against HPV16 and 18 and for HPV31, 45, and 52 were 95.5% (P < .01) and 71.9% (P < .01), respectively. When adjusted for number of sex partners and birth year, pooled VEs were 93.9% (P = .01) and 67.7% (P = .01) for HPV16 and 18 and HPV31, 45, and 52, respectively. Conclusions The bivalent HPV vaccine is highly effective against HPV16 and 18. Furthermore, significant cross-protection against HPV31, 45, and 52 was demonstrated and sustained up to 6 years after vaccination. These findings should reassure politicians about the VE of bivalent HPV vaccine in a Japanese population. Proactive recommendations for human papillomavirus (HPV) vaccines in Japan have been suspended. In this study, bivalent HPV vaccine is highly effective against HPV types 16 (HPV16) and 18, and significant cross-protection against HPV31, 45, and 52 was demonstrated. These findings should reassure politicians of vaccine effectiveness in a Japanese population.

In 2009, the United States Institute of Medicine (IOM) reported the optimal gestational weight gain (GWG) during twin pregnancy based on the pre-pregnancy body mass index (BMI). However, there are ethnic variations in the relationship between GWG and pregnancy outcomes. We aimed to establish the criteria for optimal GWG during twin pregnancy in Japan. The study included cases of dichorionic diamniotic twin pregnancy registered in the Japan Society of Obstetrics and Gynecology Successive Pregnancy Birth Registry System between 2013 and 2017. We analyzed data for cases wherein both babies were appropriate for gestational age and delivered at term. Cases were classified into four groups based on the pre-pregnancy BMI: underweight (BMI <18.5 kg/m 2 ), normal weight (18.5 kg/m 2 ≤BMI< 25.0 kg/m 2 ), overweight (25.0 kg/m 2 ≤BMI< 30.0 kg/m 2 ), and obese (BMI ≥30.0 kg/m 2 ) and we calculated the 25 th –75 th percentile range for GWG for the cases. The 3,936 cases were included. The GWG ranges were 11.5–16.5 kg, 10.3–16.0 kg, 6.9–14.7 kg, and 2.2–11.7 kg in the underweight, normal weight, overweight, and obese groups, respectively. Thus, in the current study, the optimal GWG during twin pregnancy was lower than that specified by the IOM criteria. Factoring this in maternal management may improve the outcomes of twin pregnancies in Japan.