Understanding patients’ underlying pathologies is essential for appropriate treatment during postpartum hemorrhage (PPH) management. The objective of this study is to develop an algorithm that quantitatively classifies the underlying pathologies in PPH using clinical parameters. A multicenter case series study involving nine perinatal centers in Japan was conducted on patients with severe PPH (blood loss > 2000 mL) excluding placental abruption, and placental abruption irrespective of blood loss spanning August 2020 to June 2024. The primary outcome was the development of an algorithm for classifying the underlying pathologies in PPH, based on bleeding rate, fibrinogen, and fibrin/fibrinogen degradation products (FDP). We used collected data to develop an algorithm by which cases with abnormally high bleeding rate (≥ 61 mL/min) were classified as whole blood loss with high bleeding rate (WBLH). Of cases with bleeding rate < 61 mL/min, those with fibrinogen ≥ 237 mg/dL were classified as non-coagulopathy (NCP). Of cases with fibrinogen < 237 mg/dL, those with FDP < 2 mg/dL and FDP ≥ 2 mg/dL were classified as whole blood loss with low bleeding rate (WBLL) and coagulation factor consumption (CFC), respectively. In CFC cases, a predictive formula distinguished between disseminated intravascular coagulation (DIC) from locally initiated and progressive consumptive coagulopathy for hemostasis (LIPC). We used the Mann–Whitney test and Fisher’s exact test for the statistical analysis. Among 171 participants, comprising 131 severe PPH cases and 40 placental abruption cases, the algorithm classified cases into WBLH (n = 9), NCP (n = 88), WBLL (n = 12), and CFC (n = 62). Of the CFC cases, 3 had DIC and 59 had LIPC. FDP levels did not differ between WBLH (median, 1.19 mg/dL) and WBLL (median, 0.91 mg/dL). Hemoglobin (median, 6.3 g/dL) in WBLL and fibrinogen (median, 168.5 mg/dL) in CFC were significantly lower than for the other three categories (P < 0.05). Coagulation-fibrinolytic activation in DIC was significantly increased compared with LIPC cases. Our algorithm, using bleeding rate, fibrinogen, and FDP as clinical parameters, classified PPH cases into four underlying pathologies. This pilot study provides a foundation for pathophysiology-based clinical management of PPH.

Background: No randomized controlled trial has directly compared the efficacy of pemafibrate to that of fenofibrate, or evaluated the dose–response relationship of pemafibrate in metabolic dysfunction–associated steatotic liver disease (MASLD). Therefore, we compared the efficacy and safety of high- and low-dose pemafibrate versus fenofibrate over 48 weeks in patients with MASLD and hypertriglyceridemia. Methods: This multicenter, open-label, randomized controlled trial included 360 patients with MASLD and hypertriglyceridemia at 29 sites in Japan. Participants were randomly assigned (1:1:1) to high-dose pemafibrate (0·4 mg/day; PEM-H), low-dose pemafibrate (0·2 mg/day; PEM-L), or fenofibrate (53·3-106·6 mg/day; FENO) groups. The primary endpoint was change in alanine aminotransferase (ALT) levels at Week 24. Secondary endpoints included liver fibrosis markers, renal parameters, magnetic resonance elastography (MRE), and adverse events. Findings: At Week 24, PEM-H and PEM-L produced significantly greater ALT reductions than FENO (p < 0·001 and p = 0·015, respectively). Exploratory comparison revealed greater reduction for PEM-H than PEM-L (p = 0·018, Holm adjustment), suggesting a dose-dependent effect. Higher baseline ALT levels and lean phenotypes were independently associated with ALT response. At Week 48, Mac-2 binding protein glycosylation isomer decreased significantly in PEM-H and PEM-L compared with a modest reduction in FENO (p < 0·001 and p < 0·001, respectively). MRE demonstrated significant decreases in liver stiffness in PEM-H and PEM-L compared with FENO (p < 0·05 and p = 0·02, respectively). Percentage change in serum creatinine levels was lower in PEM-H and PEM-L than in FENO. No treatment-related serious adverse events were observed in any of the three groups. Interpretations: Pemafibrate demonstrated greater reductions in ALT levels than fenofibrate, with a clear dose–response relationship and favorable safety profile, suggesting its therapeutic potential for patients with MASLD and hypertriglyceridemia.

Background: Neoadjuvant chemotherapy is increasingly used to reduce the size of lesions with anticancer drugs. In patients with breast cancer, tumor shrinkage increases the feasibility of breast-conserving surgery, which may help reduce psychological stress. It is important to maintain the relative dose intensity above a certain level to maximize the efficacy of chemotherapy. Active Hexose Correlated Compound (AHCC), a standardized extract of cultured Lentinula edodes mycelia, has been reported to reduce chemotherapy-related adverse events in patients with various cancers receiving different chemotherapy regimens. However, the effects of AHCC in breast cancer patients receiving FEC75 (fluorouracil 500 mg/m2 + epirubicin 75 mg/m2 + cyclophosphamide 500 mg/m2) treatment as neoadjuvant chemotherapy have not been well established. Objective: The purpose of this study was to explore the effects of AHCC on chemotherapy-related adverse events, including bone marrow suppression, in breast cancer patients receiving FEC75 as a neoadjuvant chemotherapy. Methods: Sixty breast cancer patients who were scheduled to receive neoadjuvant chemotherapy with the "paclitaxel followed by FEC75" regimen participated in this study. They took either placebo or AHCC (2.0 g/day) for 13 weeks, including the FEC75 treatment period. Results: AHCC significantly reduced the incidence of Common Terminology Criteria for Adverse Events (CTCAE) grade 3–4 neutropenia on Cycle 3 Day 1 of FEC75 treatment. In addition, the dyspnea score on the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire version 3.0 (EORTC QLQ-C30) was significantly lower in the AHCC group than in the placebo group after completion of FEC75 treatment. The diarrhea score also tended to be lower in the AHCC group than in the placebo group. Conclusion: These findings suggest that AHCC reduces the incidence of CTCAE grade 3–4 neutropenia on Cycle 3 Day 1 of FEC75 treatment in breast cancer patients. Novelty of the Study: This randomized, double-blind, placebo-controlled exploratory study provides new clinical evidence on the effects of AHCC supplementation (2.0 g/day) in breast cancer patients receiving FEC75 as part of neoadjuvant chemotherapy. The study specifically demonstrates a significant reduction in the incidence of CTCAE grade 3–4 neutropenia on Cycle 3 Day 1 in the AHCC group compared with placebo, while also identifying potential improvements in selected chemotherapy-related quality-of-life symptoms. These findings extend previous research on AHCC by evaluating its potential supportive role in a defined breast cancer population receiving a specific neoadjuvant chemotherapy regimen. Keywords: AHCC; neoadjuvant chemotherapy; breast cancer; adverse event; leukopenia; QOL

Non-invasive prenatal testing (NIPT) is a screening method that detects fetal chromosomal trisomies from cell-free DNA in maternal blood. Because NIPT uses whole-genome sequencing with next-generation sequencing for data processing, it can also detect maternal genomic information. Although most copy number variations (CNVs) are benign, some have been reported to be associated with pathological phenotypes and are attracting increasing attention. However, most CNV studies have been conducted in Western populations, and large-scale studies in Japanese cohorts remain scarce. This study represents the first multicenter, large-scale cohort investigation of maternal CNVs in Japanese pregnant women. We analyzed 46,082 participants to establish a reliable threshold for maternal CNV detection and to evaluate their clinical significance. Maternal CNVs were validated using array comparative genomic hybridization, and receiver operating characteristic curve analysis identified 0.8 Mbp as the minimum threshold achieving 100

Background/Objectives: We define severe postpartum hemorrhage (PPH) with macroscopic hematuria as clinical disseminated intravascular coagulation (DIC), a life-threatening condition. We also report a methodology using machine learning, a subtype of artificial intelligence, for developing the boundary criterion for predicting hematuria on the fibrinogen–fibrin/fibrinogen degradation product (FDP) plane. A positive FDP–fibrinogen/3–60 (mg/dL) value indicates hematuria; otherwise, non-hematuria is observed. We aimed to validate this criterion using severe placental abruption (PA), and to examine the activation of the coagulation–fibrinolytic system in clinical DIC. Methods: Of 17,285 deliveries across nine perinatal centers in Japan between 2020 and 2024, 13 had severe PA without hematuria, 18 had severe PPH without hematuria, and 3 had severe PPH with hematuria, i.e., clinical DIC. We calculated the values of the criterion formula for 13 cases of severe PA to validate the boundary criterion and compared the laboratory tests for coagulation–fibrinolytic activation among the three groups. Results: The calculated values using the criterion for the 13 PA without hematuria ranged from −108.91 to −5.87 and all were negative. In cases of clinical DIC, fibrinogen levels (median, 62 mg/dL) were lower (p < 0.05), while levels of FDP (96 mg/dL), the thrombin–antithrombin complex (120 ng/mL), and the plasmin-α2–plasmin inhibitor complex (28.4 μg/mL) were significantly higher than in the other two groups. Conclusions: This study demonstrated the validity of the boundary criterion for predicting hematuria using severe PA. The coagulation–fibrinolytic test results suggested that PPH cases with hematuria were assumed to have clinical DIC, indicating that this criterion may be considered for diagnosing DIC during delivery. However, further additional patient data are needed to confirm the usefulness of this criterion because of the very low number of hematuria cases.

Noninvasive prenatal testing diagnoses fetal aneuploidies in singleton pregnancies with trisomy 21, 18, or 13 accurately. However, clinical data on noninvasive prenatal testing in women with twin or vanishing twin pregnancies are limited. We report on the accuracy and prenatal and neonatal outcomes of noninvasive prenatal testing in twin and vanishing twin pregnancies. This retrospective study was conducted at 22 facilities belonging to the Noninvasive Prenatal Testing Consortium, part of a nationwide project in Japan, visited by women with twin or vanishing twin pregnancies between January 2015 and March 2022. This study investigated the accuracy and perinatal and neonatal outcomes of noninvasive prenatal testing using massively parallel sequencing in twin or vanishing twin pregnancies. Of 1013 women with twin pregnancies, 986 (97.3%) had negative; 13 (1.3%), positive; and 14 (1.4%), non-reportable noninvasive prenatal testing results. Of 225 women with vanishing twins, 203 (90.2%) had negative; 11 (4.9%), positive; and 11 (4.9%), non-reportable results. Among 1693 fetuses (77.3%) excluding 497 unknowns were available for follow-up, 1476 were from twin pregnancies, and 134 were from vanishing twin pregnancies, totaling 1610 babies has born. No false negatives were observed in the cases followed. These results indicate that noninvasive prenatal testing is useful for vanishing twin pregnancies and provide reassurance for pregnant women with twins and vanishing twins.

OBJECTIVE:This study aimed to investigate the association between fetal fraction (FF) on non-invasive prenatal testing (NIPT) and pregnancy-related complications using a large sample to support improved prenatal management. METHODS:This retrospective cohort study included women with singleton pregnancies and negative NIPT results between January 2015 and March 2022 as part of the Japan Multicenter Study. Chi-square tests and binary logistic regression analyses were used to assess the association between FF and pregnancy-related complications. RESULTS:A total of 40,716 responses were analyzed. No significant association was found between FF and placental abruption (χ2 (1) = 2.84, p = 0.09). Women in the low FF group (FF < 10.27%, < 25th percentile) had higher risks of fetal demise, adjusted OR = 1.79, 95% CI [1.31, 2.43]), preterm birth (adjusted OR = 1.63, 95% CI [1.30, 2.06]), fetal growth restriction (FGR) (adjusted OR = 1.50, 95% CI [1.10, 2.05]), and hypertensive disorders of pregnancy (HDP) (adjusted OR = 1.44, 95% CI [1.24, 1.66]). No significant differences were observed for gestational diabetes mellitus (GDM) (adjusted OR = 1.13, 95% CI [0.99, 1.30], p = 0.081). CONCLUSION:Low FF on NIPT is associated with an increased risk of several pregnancy complications, highlighting the need for careful management.

Managing RhD-negative pregnancies is vital for preventing hemolytic disease of the fetus and newborn, which occurs when RhD-negative mothers develop anti-D antibodies after exposure to RhD-positive fetal blood. This retrospective cohort study evaluated the proportion of RhD-negative pregnancies and newborns in Japan by assessing current management practices and outcomes. This study included RhD-negative pregnant women who delivered at 22 weeks or later at 47 Japanese facilities between April 2018 and March 2023. Pregnancies with unknown newborn RhD status were excluded. Data were obtained from medical records. Among the 1088 RhD-negative women, 1062 met the inclusion criteria. RhD-negative pregnancies comprised 0.71% of the total cohort, with 8.7% RhD-negative newborns. Anti-D immunoglobulin was administered in 96.5% of pregnancies, with a maternal spontaneous sensitization rate of 0.6% before 28 weeks and no sensitization detected from 28 weeks to postpartum. Sensitized RhD-negative women had higher cesarean section, preterm delivery, and neonatal hemolytic anemia rates than the non-sensitized group, leading to increased neonatal intensive care unit admissions. Despite the low incidence of RhD-negative pregnancies, this study underscores the need for tailored management strategies, suggesting that non-invasive prenatal diagnosis of fetal RhD status could prevent unnecessary anti-D immunoglobulin administration, improving outcomes and resource utilization in Japan.

Objective: Postpartum social problems, such as postpartum depression and bonding disorders, are important risk factors for child maltreatment. Mothers with such problems are known to need social support. The aim of this study was to develop and validate the Social Life Impact for Mother (SLIM) scale to identify mothers in Japan who need social support during postpartum. Design: A hospital-based prospective study. Setting: Obstetric clinics and hospitals in four populous prefectures in Japan. Sample: A total of 7462 pregnant women. Methods: The participants completed the SLIM scale at first trimester, and postpartum social problems (postpartum depression and bonding disorders) were assessed at one month after delivery (N=5768, follow-up rate: 77.3%). Multivariate logistic regression was applied to investigate the association between the SLIM scale and postpartum social problems. Main outcome measures: Postpartum social problems (postpartum depression and bonding disorders) at one month after delivery. Results: The SLIM scale predicted postpartum social problems in moderate accuracy (AUC=0.63, 95% confidence interval: 0.60-0.65). Further stratification by local clinic and tertiary hospital did not affect the estimates. Conclusion: The SLIM scale at prenatal checkup may be useful for obstetricians to detect mothers with postpartum social problems. Further intervention study using SLIM score is warranted.

(1) Background: The number of severely obese patients worldwide is rapidly increasing. Recently, novel therapeutic approaches, such as bariatric surgery or GLP-1 receptor agonists, have emerged, bringing about a paradigm shift in this field. However, these therapies sometimes face challenges, such as peri-surgical complications or supply shortages. Mazindol, which is an appetite suppressant approved decades ago in Japan, remains a valuable option. In this study, we investigated the effectiveness of mazindol in reducing body weight in 147 patients, and we examined the factors influencing said effectiveness. (2) Methods: The patients were divided into four groups based on the treatment cycles they underwent: 1 cycle, 2 cycles, 3–5 cycles, and over 6 cycles. We compared the changes in body weight before and after the treatment among these four groups. Additionally, we sought to identify the factors correlated to the effectiveness of mazindol. (3) Results: The change in body weight was more pronounced in the group which underwent 3–5 cycles compared to the groups which underwent 1 cycle and 2 cycles; this change was also more pronounced in the group which underwent over 6 cycles compared to those which underwent 1 cycle. Furthermore, we observed a significant correlation between the initial body weight and the extent of body weight change. (4) Conclusions: Mazindol demonstrated effectiveness in reducing the body weight of patients in a cycle-dependent manner.

(1) Background: Although the diagnostic criteria for massive hemorrhage with organ dysfunction, such as disseminated intravascular coagulation associated with delivery, have been empirically established based on clinical findings, strict logic has yet to be used to establish numerical criteria. (2) Methods: A dataset of 107 deliveries with >2000 mL of blood loss, among 13,368 deliveries, was obtained from nine national perinatal centers in Japan between 2020 and 2023. Twenty-three patients had fibrinogen levels <170 mg/dL, which is the initiation of coagulation system failure, according to our previous reports. Three of these patients had hematuria. We used six machine learning methods to identify the borderline criteria dividing the fibrinogen/fibrin/fibrinogen degradation product (FDP) planes, using 15 coagulation fibrinolytic factors. (3) Results: The boundaries of hematuria development on a two-dimensional plane of fibrinogen and FDP were obtained. A positive FDP-fibrinogen/3-60 (mg/dL) value indicates hematuria; otherwise, the case is nonhematuria, as demonstrated by the support vector machine method that seemed the most appropriate. (4) Conclusions: Using artificial intelligence, the borderline criterion was obtained, which divides the fibrinogen/FDP plane for patients with hematuria that could be considered organ dysfunction in massive hemorrhage during delivery; this method appears to be useful.

Introduction Non-alcoholic fatty liver disease, now known as metabolic dysfunction-associated steatotic liver disease (MASLD), is a phenotype of the metabolic syndrome in the liver and is clearly associated with metabolic abnormalities such as hyperglycaemia and dyslipidaemia. Although the prevalence of MASLD is increasing worldwide, there is currently no consensus on the efficacy and safety of the drugs used to treat MASLD/metabolic dysfunction-associated steatohepatitis (MASH). Pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, was designed to have higher peroxisome proliferator-activated receptor alfa (PPARα) agonist activity and selectivity than existing PPARα agonists, and in development trials, without increasing creatinine levels, lipid parameters and alanine aminotransferase (ALT) were significantly improved. Thus, pemafibrate may effectively ameliorate the pathogenesis and metabolic abnormalities in MASLD/MASH. In this trial, we evaluated the efficacy and safety of pemafibrate in patients with MASLD/MASH.Methods and analysis This trial was designed as an open-label, three-arm, randomised controlled study. After obtaining informed consent, patients aged 20–80 years who met the selection criteria were enrolled. Patients were randomised to receive pemafibrate 0.4 mg/day, 0.2 mg/day or fenofibrate (n=120 per group). The duration of treatment was 48 weeks. The primary endpoint was a change in ALT levels after 24 weeks of administration. Secondary endpoints included changes from baseline in liver fibrosis markers (fibrosis-4 index, type IV collagen 7s, enhanced liver fibrosis and Mac-2 binding protein glycosylation isomer) at 48 weeks as well as changes in liver fat mass and liver stiffness measured by MRI and ultrasound (US) at centres equipped with MRI and US capabilities.Ethics and dissemination Ethical approval was obtained from the Yokohama City University Certified Institutional Review Board before participant enrolment (CRB20-014). The results of this study will be submitted for publication in international peer-reviewed journals and the key findings will be presented at international scientific conferences. Participants wishing to understand the results of this study will be contacted directly on data publication.Trial registration number This trial was registered in the Japan Registry of Clinical Trials (number: jRCTs031200280).Protocol version V.1.9, 23 November 2023

Obesity is closely associated with insulin resistance and establishes the leading risk factor for type 2 diabetes mellitus, yet the molecular mechanisms of this association are poorly understood(1). The c-Jun amino-terminal kinases (JNKs) can interfere with insulin action in cultured cells(2) and are activated by inflammatory cytokines and free fatty acids, molecules that have been implicated in the development of type 2 diabetes(3,4). Here we show that JNK activity is abnormally elevated in obesity. Furthermore, an absence of JNK1 results in decreased adiposity, significantly improved insulin sensitivity and enhanced insulin receptor signalling capacity in two different models of mouse obesity. Thus, JNK is a crucial mediator of obesity and insulin resistance and a potential target for therapeutics.