Pharmacokinetics, pharmacodynamics, and safety of fesomersen, a novel antisense inhibitor of factor XI, in healthy Chinese, Japanese, and Caucasian volunteers.

The inhibition of coagulation factor XI (FXI) presents an attractive approach for anticoagulation as it is not expected to increase the risk of clinically relevant bleeding and is anticipated to be at least as effective as currently available anticoagulants. Fesomersen is a conjugated antisense oligonucleotide that selectively inhibits the expression of FXI. The article describes three clinical studies that investigated the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of fesomersen after subcutaneous (s.c.) injection to healthy participants. The studies included participants from diverse ethnic backgrounds (Caucasian, Japanese, and Chinese). Fesomersen demonstrated good safety and tolerability in all three studies. No major bleeding events were observed. After single-dose s.c. injection, fesomersen was rapidly absorbed into the systemic circulation, with maximum fesomersen-equivalent (fesomersen-eq) concentrations (Cmax) in plasma observed within a few hours. After reaching Cmax, plasma fesomersen-eq concentrations declined in a biphasic fashion. The PD analyses showed that the injection of fesomersen led to dose-dependent reductions in FXI activity and increases in activated partial thromboplastin time (aPTT). The maximum observed PD effects were reached between Day 15 and 30, and FXI activity and aPTT returned to near-baseline levels by Day 90 after a single dose. The PK/PD profiles after a single injection were similar among the various ethnic groups. Collectively, the study results suggest that fesomersen has a favorable safety profile and predictable and similar PK and PD profiles across Chinese, Japanese, and Caucasian participants.

Synthesis and biological evaluation of novel benzothiazole derivatives as potential anticancer and antiinflammatory agents.

Introduction: Cancer, a significant global health concern, necessitates innovative treatments. The pivotal role of chronic inflammation in cancer development underscores the urgency for novel therapeutic strategies. Benzothiazole derivatives exhibit promise due to their distinctive structures and broad spectrum of biological effects. This study aims to explore new anti-tumor small molecule drugs that simultaneously anti-inflammatory and anticancer based on the advantages of benzothiazole frameworks. Methods: The compounds were characterized by nuclear magnetic resonance (NMR), liquid chromatograph-mass spectrometer (LC-MS) and high performance liquid chromatography (HPLC) for structure as well as purity and other related physicochemical properties. The effects of the compounds on the proliferation of human epidermoid carcinoma cell line (A431) and human non-small cell lung cancer cell lines (A549, H1299) were evaluated by MTT method. The effect of compounds on the expression levels of inflammatory factors IL-6 and TNF-α in mouse monocyte macrophages (RAW264.7) was assessed using enzyme-linked immunosorbent assay (ELISA). The effect of compounds on apoptosis and cell cycle of A431 and A549 cells was evaluated by flow cytometry. The effect of compounds on A431 and A549 cell migration was evaluated by scratch wound healing assay. The effect of compounds on protein expression levels in A431 and A549 cells was assessed by Western Blot assay. The physicochemical parameters, pharmacokinetic properties, toxicity and drug similarity of the active compound were predicted using Swiss ADME and admetSAR web servers. Results: Twenty-five novel benzothiazole compounds were designed and synthesized, with their structures confirmed through spectrogram verification. The active compound 6-chloro-N-(4-nitrobenzyl) benzo[d] thiazol-2-amine (compound B7) was screened through a series of bioactivity assessments, which significantly inhibited the proliferation of A431, A549 and H1299 cancer cells, decreased the activity of IL-6 and TNF-α, and hindered cell migration. In addition, at concentrations of 1, 2, and 4 µM, B7 exhibited apoptosis-promoting and cell cycle-arresting effects similar to those of the lead compound 7-chloro-N-(2, 6-dichlorophenyl) benzo[d] thiazole-2-amine (compound 4i). Western blot analysis confirmed that B7 inhibited both AKT and ERK signaling pathways in A431 and A549 cells. The prediction results of ADMET indicated that B7 had good drug properties. Discussion: This study has innovatively developed a series of benzothiazole derivatives, with a focus on compound B7 due to its notable dual anticancer and anti-inflammatory activities. B7 stands out for its ability to significantly reduce cancer cell proliferation in A431, A549, and H1299 cell lines and lower the levels of inflammatory cytokines IL-6 and TNF-α. These results position B7B7 as a promising candidate for dual-action cancer therapy. The study's mechanistic exploration, highlighting B7's simultaneous inhibition of the AKT and ERK pathways, offers a novel strategy for addressing both the survival mechanisms of tumor cells and the inflammatory milieu facilitating cancer progression.

Estimating the prevalence of depression in people with acute coronary syndromes: A systematic review and meta-analysis.

BACKGROUND: The epidemic of acute coronary syndromes (ACS) poses a great challenge to depression. However, the prevalence of depression among ACS patients has not been fully determined. This meta-analysis aimed to provide an estimation of the global prevalence of depression among ACS patients (ACS depression). METHODS: Online databases including PubMed, Cochrane Library, Web of Science, and Scopus were searched for all relevant studies that reported the prevalence of ACS depression through March 2023. Pooled prevalence of ACS depression with 95% confidence interval (CI) was estimated by the random-effect model. All statistical analyses were performed using comprehensive meta-analysis software. This review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (identifier CRD42023409338). RESULTS: A total of 28 studies (17 cohort studies, 9 cross-sectional studies, and 2 case-control studies) were included. The overall pooled prevalence of depression in ACS, derived from 28 studies, was 28.5% (95% CI: 0.28-0.29, P = .000, I2 = 99%). 21 included studies showed a prevalence of 20.3% (95% CI: 0.20-0.21, P = .000, I2 = 96%) in men, and the prevalence in women was 13.6% (95% CI: 0.13-0.14, P = .000, I2 = 95%). Subgroup analysis showed the lowest prevalence in Europe (20.7%, 95% CI: 0.20-0.22, P = .000, I2 = 98%); On different diagnostic criteria, the diagnostic and statistical manual of mental disorders (DSM-IV) (36.8%, 95% CI: 0.35-0.38, P = .000, I2 = 96%) has the highest prevalence. In terms of end year of data collection, the prevalence of ACS depression was lower for studies that ended data collection after 2012 (25.7%, 95% CI: 0.25-0.27, P = .000, I2 = 99%) than in studies before 2012 (30%, 95% CI: 0.29-0.31, P = .000, I2 = 98%). CONCLUSION SUBSECTIONS: This systematic review and meta-analysis suggest high global prevalence of depression among ACS patients, underlining the necessity of more preventive interventions among ACS patients especially in Asian and North American regions.

Multi-organ developmental toxicity and its characteristics in fetal mice induced by dexamethasone at different doses, stages, and courses during pregnancy.

Dexamethasone is widely used in pregnant women at risk of preterm birth to reduce the occurrence of neonatal respiratory distress syndrome and subsequently reduce neonatal mortality. Studies have suggested that dexamethasone has developmental toxicity, but there is a notable absence of systematic investigations about its characteristics. In this study, we examined the effects of prenatal dexamethasone exposure (PDE) on mother/fetal mice at different doses (0.2, 0.4, or 0.8 mg/kg b.i.d), stages (gestational day 14-15 or 16-17) and courses (single- or double-course) based on the clinical practice. Results showed that PDE increased intrauterine growth retardation rate, and disordered the serum glucose, lipid and cholesterol metabolic phenotypes, and sex hormone level of mother/fetal mice. PDE was further discovered to interfere with the development of fetal lung, hippocampus and bone, inhibits steroid synthesis in adrenal and testis, and promotes steroid synthesis in the ovary and lipid synthesis in the liver, with significant effects observed at high dose, early stage and double course. The order of severity might be: ovary > lung > hippocampus/bone > others. Correlation analysis revealed that the decreased serum corticosterone and insulin-like growth factor 1 (IGF1) levels were closely related to PDE-induced low birth weight and abnormal multi-organ development in offspring. In conclusion, this study systematically confirmed PDE-induced multi-organ developmental toxicity, elucidated its characteristics, and proposed the potential "glucocorticoid (GC)-IGF1" axis programming mechanism. This research provided an experimental foundation for a comprehensive understanding of the effect and characteristics of dexamethasone on fetal multi-organ development, thereby guiding the application of "precision medicine" during pregnancy.

Fear of childbirth and influencing factors of expectant fathers in China: a cross-sectional study.

Fear of childbirth not only brings negative psychological experiences to expectant fathers and affect their ability to prepare for parenthood but can even affect children's emotional and cognitive development. It is essential to identify men with a more severe fear of birth and its related risk factors for the better transition of fathers' role. The objective of this study was to investigate the prevalence of fear of childbirth among Chinese expectant fathers, identify its contributing factors and explore the association among fear of childbirth, resilience and dyadic coping. A cross-sectional survey was conducted in the obstetric department of two tertiary hospitals in Wuhan, China. The socio-demographic questionnaire, the father's version of the Wijma Delivery Expectancy/Experience Questionnaire version A (W-DEQ A), the Connor-Davidson Resilience Scale-10 (CD-RISC), and the Dyadic Coping Inventory (DCI) were used to explore the correlation of fear of childbirth, resilience and dyadic coping of participants. Ultimately, a total of 1176 expectant fathers were included in this study. The prevalence of fear of childbirth was 32.1%. Gestational weeks of pregnant women, monthly income, adverse birth experience, gravidity and parity of pregnant women were considered risk factors for the expectant fathers with fear of childbirth. Furthermore, there was a weak negative correlation between fear of childbirth and resilience and dyadic coping. In conclusion, the prevalence of fear of childbirth in expectant fathers in China was high. Adequate identification of factors influencing the fear of childbirth among expectant fathers is necessary to reduce the fear of childbirth and to develop appropriate interventions in preparing fathers for their new parenting role.

Changes in Concentrations of Polyfluoroalkyl Substances in Human Milk Over Lactation Time and Effects of Maternal Exposure via Analysis of Matched Samples.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are potentially related to many adverse health outcomes and could be transferred from maternal blood to human milk, which is an important exposure source for infants during a long-term period. In this study, the maternal blood of 76 women after delivery and their matched human milk samples obtained at 0.5, 1, and 3 months were analyzed by solid-phase extraction method with metal-organic framework/polymer hybrid nanofibers as the sorbents and ultrahigh-performance liquid chromatography-negative electrospray ionization mass spectrometric for quantitative analysis of 31 PFAS. The perfluorooctanoic acid, perfluorooctane sulfonate, and N-methyl perfluorooctane sulfonamido acetic acid (N-MeFOSAA) contributed to more than approximately 50% of the total PFAS concentrations in blood and human milk, while N-MeFOSAA (median: 0.274 ng/mL) was the highest PFAS in human milk at 3 months. The transfer efficiencies for PFAS from maternal blood to human milk at 0.5 months were generally lower, with medians ranging from 0.20% to 16.9%. The number of PFAS species detected in human milk increased as the lactation time went on from 0.5 to 3 months, and the concentrations of 10 PFAS displayed an increasing trend as the prolongation of lactation time (p < 0.05).

Novel 3D morphological characteristics for congenital biliary dilatation diagnosis: a case-control study.

BACKGROUND: Congenital biliary dilatation (CBD) necessitates the timely removal of dilated bile ducts. Accurate differentiation between CBD and secondary biliary dilatation (SBD) is crucial for treatment decisions, and identification of CBD with intrahepatic involvement is vital for surgical planning and supportive care. This study aimed to develop quantitative models based on bile duct morphology to distinguish CBD from SBD and further identify CBD with intrahepatic involvement. MATERIALS AND METHODS: The retrospective study included 131 CBD and 209 SBD patients between December 2014 and December 2021 for model development, internal validation, and testing. A separate cohort of 15 CBD and 34 SBD patients between January 2022 and December 2022 was recruited for temporally-independent validation. Quantitative shape-based (Shape) and diameter-based (Diam) morphological characteristics of bile ducts were extracted to build a CBD diagnosis model to distinguish CBD from SBD and an intrahepatic involvement identification model to classify CBD with/without intrahepatic involvement. The diagnostic performance of the models was compared with that of experienced hepatobiliary surgeons. RESULTS: The CBD diagnosis model using clinical, Shape, and Diam characteristics showed good performance with an AUROC of 0.942 (95% CI: 0.890-0.994), AUPRC of 0.917 (0.855-0.979), accuracy of 0.891, sensitivity of 0.950, and F1-score of 0.864. The model outperformed two experienced surgeons in accuracy, sensitivity, and F1-score. The intrahepatic involvement identification model using clinical, Shape, and Diam characteristics yielded outstanding performance with an AUROC of 0.944 (0.879-1.000), AUPRC of 0.982 (0.947-1.000), accuracy of 0.932, sensitivity of 0.971, and F1-score of 0.957. The models demonstrated generalizable performance on the temporally-independent validation cohort. CONCLUSIONS: This study developed two robust quantitative models for distinguishing CBD from SBD and identifying CBD with intrahepatic involvement, respectively, based on morphological characteristics of the bile ducts, showing great potential in risk stratification and surgical planning of CBD.

Efficacy of early clinical interventions for children with global developmental delay.

OBJECTIVE: To evaluate the efficacy of early clinical interventions for children with global developmental delay. METHODS: A total of 127 initial subjects with GDD met the complete inclusion criteria. Seven cases were excluded due to withdrawal or refusal for follow-up. Eventually, the remaining 120 children were divided into two groups based on different treatment regimens: an experimental group and a control group. Ninety children received individualized treatment in the experimental group, while 30 children, due to various reasons, did not receive inpatient treatment and only underwent home-based intervention therapy in the control group. The developmental progress under different intervention methods was compared, and their clinical effectiveness was analyzed. RESULTS: Both groups of patients showed no significant differences in general characteristics such as gender and age (p > 0.05), demonstrating comparability. The initial comparison of developmental quotient scores in all patients before treatment revealed no significant differences. Post-treatment, there was improvement observed in both groups. However, children in the experimental group exhibited significantly higher scores in gross motor skills, fine motor skills, adaptability, language, and personal-social skills compared to those in the control group (p < 0.05). Additionally, the clinical effective rate in the experimental group was notably higher than that in the control group (p < 0.05). CONCLUSION: The combined use of acupuncture with home-based intervention therapy demonstrates favorable therapeutic outcomes in young children with comprehensive developmental delays. This approach has the potential to enhance gross motor skills, fine motor skills, cognition, language, and overall intellectual development in affected children.

Spinal cord perfusion is associated with microstructural damage in cervical spondylotic myelopathy patients who underwent cervical laminoplasty.

OBJECTIVES: To investigate the association between spinal cord perfusion and microstructural damage in CSM patients who underwent cervical laminoplasty using MR dynamic susceptibility contrast (DSC), diffusion tensor imaging (DTI), and neurite orientation dispersion and density imaging (NODDI) techniques. METHODS: A follow-up cohort study was conducted with 53 consecutively recruited CSM patients who had undergone cervical laminoplasty 12-14 months after the surgery from April 2016 to December 2016. Twenty-one aged-matched healthy volunteers were recruited as controls. For each patient, decompressed spinal cord levels were imaged on a 3.0-T MRI scanner by diffusion and DSC sequences to quantify the degrees of microstructural damage and perfusion conditions, respectively. The diffusion data were analyzed by DTI and NODDI models to produce diffusion metrics. Classic indicator dilution model was used to quantify the DSC metrics. Mann-Whitney U test was performed for comparison of diffusion metrics between patients and healthy controls. Pearson correlation was used to explore the associations between the metrics of spinal cord perfusion and microstructural damage. RESULTS: DTI metrics, neurite density, and isotropic volume fraction had significant differences between postoperative patients and healthy controls. Pearson correlation test showed that SCBV was significantly positively correlated with RD, MD, and ODI, and negatively correlated with FA and NDI. SCBF was found to be significantly positively correlated with RD and MD, and negatively correlated with FA. CONCLUSIONS: Increased spinal cord perfusion quantified by DSC is associated with microstructural damage assessed by diffusion MRI in CSM patients who underwent cervical laminoplasty. CLINICAL RELEVANCE STATEMENT: This study found that the spinal cord perfusion is associated with microstructural damage in postoperative cervical spondylotic myelopathy patients, indicating that high perfusion may play a role in the pathophysiological process of cervical spondylotic myelopathy and deserves more attention. KEY POINTS: • Spinal cord microstructural damage can be persistent despite the compression had been relieved 12-14 months after the cervical laminoplasty in cervical spondylotic myelopathy (CSM) patients. • Spinal cord perfusion is associated with microstructural damage in CSM patients after the cervical laminoplasty. • Inflammation in the decompressed spinal cord may be a cause of increased perfusion and is associated with microstructural damage during the recovery period of CSM.

Comparative efficacy and safety of different doses of ponatinib versus other tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia: a systematic review and network meta-analysis.

OBJECTIVE: Ponatinib was recommended with caution because of its high risk of causing arterial occlusion events in chronic myeloid leukemia (CML) patients. The purpose of this study was to understand the efficacy and safety of different doses of ponatinib in the treatment of CML, and to compare it with other tyrosine kinase inhibitors (TKIs). METHOD: A network meta-analysis (NMA) was conducted by searching randomized controlled trials (RCTs) of ponatinib in patients with CML to compare the efficacy and safety of ponatinib, and ranked under the cumulative ranking curve (SUCRA) to evaluate the optimal treatment. RESULTS: A total of seven articles with eight RCTs were included in this study, involving 45 mg, 30 mg and 15 mg ponatinib doses. Seven outcome indexes were analyzed. The results showed that 45 mg ponatinib was superior to other doses of ponatinib and other TKIs in CCyR, MCyR and CHR, but the incidence of SAEs and AOEs was significantly higher than other treatment regimens. CONCLUSION: Ponatinib, with an initial dosage of 45 mg and a gradual reduction to 15 mg, may be a more favorable option for patients with CML at all stages of disease progression, rather than just those in the chronic phase of CML.

Assessment of the CYP3A4 Induction Potential by Carbamazepine: Insights from Two Clinical DDI Studies and PBPK Modeling.

In the past, rifampicin was well-established as strong index CYP3A inducer in clinical drug-drug interaction (DDI) studies. However, due to identified potentially genotoxic nitrosamine impurities, it should not any longer be used in healthy volunteer studies. Available clinical data suggest carbamazepine as an alternative to rifampicin as strong index CYP3A4 inducer in clinical DDI studies. Further, physiologically-based pharmacokinetic (PBPK) modeling is a tool with increasing importance to support the DDI risk assessment of drugs during drug development. CYP3A4 induction properties and the safety profile of carbamazepine were investigated in two open-label, fixed sequence, crossover clinical pharmacology studies in healthy volunteers using midazolam as a sensitive index CYP3A4 substrate. Carbamazepine was up-titrated from 100 mg twice daily (b.i.d.) to 200 mg b.i.d., and to a final dose of 300 mg b.i.d. for 10 consecutive days. Mean area under plasma concentration-time curve from zero to infinity (AUC(0-∞)) of midazolam consistently decreased by 71.8% (ratio: 0.282, 90% confidence interval (CI): 0.235-0.340) and 67.7% (ratio: 0.323, 90% CI: 0.256-0.407) in study 1 and study 2, respectively. The effect was adequately described by an internally developed PBPK model for carbamazepine which has been made freely available to the scientific community. Further, carbamazepine was safe and well-tolerated in the investigated dosing regimen in healthy participants. The results demonstrated that the presented design is appropriate for the use of carbamazepine as alternative inducer to rifampicin in DDI studies acknowledging its CYP3A4 inductive potency and safety profile.

Effectiveness of a breastfeeding promotion intervention model based on Society ecosystems Theory for maternal women: a study protocol of randomized controlled trial.

BACKGROUND: Breastfeeding is recognized internationally as the most scientific and effective way to feed infants and young children. According to the World Health Organization in 2022, the exclusive breastfeeding rate within 6 months is 34.1% in China, which is still far from the goal of "more than 60% exclusive breastfeeding rate of infants within 6 months" by 2030 required by China's State Council. It is necessary to promote breastfeeding and provide maternal breastfeeding guidance to increase exclusive breastfeeding. Factors influencing breastfeeding can be explained by the society ecosystems theory, distributed in macro, mezzo and micro systems. The interventions focused on breastfeeding promotion are mainly carried out in the health systems and services, home and family environment, community environment, work environment, policy environment or a combination of these facilities. But there is sparse research on integrating resources in the macro, mezzo and micro systems of maternal breastfeeding processes to promote breastfeeding behavior. A randomized controlled trial will test the effect of a breastfeeding promotion intervention model based on the society ecosystems theory versus usual prenatal and postnatal care on maternal and infant health and the exclusive breastfeeding rate at 6 months. METHODS/DESIGN: The study is a single-blind, parallel design, randomized controlled trial with an intervention group (n = 109) and a control group (n = 109) that compares the effect of a breastfeeding promotion intervention model based on the society ecosystems theory with usual prenatal and postnatal care. The intervention covers macro- (policy, culture), mezzo- (family-hospital-community) and micro- (biological, psychological and social) systems of the maternal breastfeeding process. Infant feeding patterns, neonatal morbidity and physical and mental health of antenatal and postpartum women will be collected at baseline (28 to 35 weeks of gestation), 1-, 4-, and 6-month postpartum. DISCUSSION: This is a multifaceted, multifactorial, and multi-environmental breastfeeding promotion strategy to help mothers and their families learn breastfeeding knowledge and skills. The study provides a new modality for adding breastfeeding interventions to prenatal and postnatal care for healthcare providers in the hospital and the community. TRIAL REGISTRATION: Chinese Clinical Trial Registry at www.chictr.org.cn , ChiCTR2300075795.

Maternal education and support during breastfeeding can increase maternal breastfeeding self-efficacy, promote breastfeeding behaviors, and improve maternal and infant health outcomes. The interventions focused on breastfeeding promotion are mainly carried out in the health systems and services, home and family environment, community environment, work environment, policy environment or a combination of any of these facilities. But there is sparse research on integrating in multifaceted, multifactorial, and multi-environmental resources of maternal breastfeeding processes to help pregnant women and their families learn breastfeeding knowledge and skills. The current study optimizes the existing breastfeeding promotion intervention program and construct a breastfeeding promotion intervention program to correct the public's perception of breastfeeding, increase breastfeeding self-efficacy and improve breastfeeding behavior, thus increasing the breastfeeding duration and improving maternal and infant outcomes. The program includes presenting breastfeeding-related policies and support facilities; prenatal educational sessions combined with theories and skills on breastfeeding, development of lactation, infants feeding and cares for maternal families; postnatal hands-on instruction and WeChat group peer support from hospital; home visits, group counseling and experience sharing from community and one-on-one personalized counseling throughout the intervention. The present study will be conducted to evaluate the effect of breastfeeding promotion intervention including prenatal and postnatal care on the breastfeeding duration, breastfeeding attitudes, knowledge, and self-efficacy, maternal and infant health.

Gadolinium-enhanced intracranial aneurysm wall imaging and risk of aneurysm growth and rupture: a multicentre longitudinal cohort study.

OBJECTIVES: In patients with an unruptured intracranial aneurysm, gadolinium enhancement of the aneurysm wall is associated with growth and rupture. However, most previous studies did not have a longitudinal design and did not adjust for aneurysm size, which is the main predictor of aneurysm instability and the most important determinant of wall enhancement. We investigated whether aneurysm wall enhancement predicts aneurysm growth and rupture during follow-up and whether the predictive value was independent of aneurysm size. MATERIALS AND METHODS: In this multicentre longitudinal cohort study, individual patient data were obtained from twelve international cohorts. Inclusion criteria were as follows: 18 years or older with ≥ 1 untreated unruptured intracranial aneurysm < 15 mm; gadolinium-enhanced aneurysm wall imaging and MRA at baseline; and MRA or rupture during follow-up. Patients were included between November 2012 and November 2019. We calculated crude hazard ratios with 95%CI of aneurysm wall enhancement for growth (≥ 1 mm increase) or rupture and adjusted for aneurysm size. RESULTS: In 455 patients (mean age (SD), 60 (13) years; 323 (71%) women) with 559 aneurysms, growth or rupture occurred in 13/194 (6.7%) aneurysms with wall enhancement and in 9/365 (2.5%) aneurysms without enhancement (crude hazard ratio 3.1 [95%CI: 1.3-7.4], adjusted hazard ratio 1.4 [95%CI: 0.5-3.7]) with a median follow-up duration of 1.2 years. CONCLUSIONS: Gadolinium enhancement of the aneurysm wall predicts aneurysm growth or rupture during short-term follow-up, but not independent of aneurysm size. CLINICAL RELEVANCE STATEMENT: Gadolinium-enhanced aneurysm wall imaging is not recommended for short-term prediction of growth and rupture, since it appears to have no additional value to conventional predictors. KEY POINTS: • Although aneurysm wall enhancement is associated with aneurysm instability in cross-sectional studies, it remains unknown whether it predicts risk of aneurysm growth or rupture in longitudinal studies. • Gadolinium enhancement of the aneurysm wall predicts aneurysm growth or rupture during short-term follow-up, but not when adjusting for aneurysm size. • While gadolinium-enhanced aneurysm wall imaging is not recommended for short-term prediction of growth and rupture, it may hold potential for aneurysms smaller than 7 mm.

A model to predict delivery time following induction of labor at term with a dinoprostone vaginal insert: a retrospective study.

BACKGROUND: Dinoprostone vaginal insert is the most common pharmacological method for induction of labor (IOL); however, studies on assessing the time to vaginal delivery (DT) following dinoprostone administration are limited. AIMS: We sought to identify the primary factors influencing DT in women from central China, at or beyond term, who underwent IOL with dinoprostone vaginal inserts. METHODS: In this retrospective observational study, we analyzed the data of 1562 women at 37 weeks 0 days to 41 weeks 6 days of gestation who underwent dinoprostone-induced labor between January 1st, 2019, and December 31st, 2021. The outcomes of interest were vaginal or cesarean delivery and factors influencing DT, including maternal complications and neonatal characteristics. RESULTS: Among the enrolled women, 71% (1109/1562) delivered vaginally, with median DT of 740.50 min (interquartile range 443.25 to 1264.50 min). Of the remaining 29% (453/1562), who delivered by cesarean section, 11.9% (54/453) were multiparous. Multiple linear regression analysis showed that multiparity, advanced maternal age, fetal macrosomia, premature rupture of membranes (PROM), and daytime insertion of dinoprostone were the factors that significantly influenced DT. Time to vaginal delivery increased with advanced maternal age and fetal macrosomia and decreased with multiparity, PROM, and daytime insertion of dinoprostone. A mathematical model was developed to integrate these factors for predicting DT: Y = 804.478 - 125.284 × multiparity + 765.637 × advanced maternal age + 411.511 × fetal macrosomia-593.358 × daytime insertion of dinoprostone - 125.284 × PROM. CONCLUSIONS: Our findings may help obstetricians estimate the DT before placing a dinoprostone insert, which may improve patient management in busy maternity wards and minimize potential risks.

The Degree of Prepregnancy Vitamin D Deficiency Is Not Associated With Gestational Diabetes in Women Undergoing ART.

Context: Gestational diabetes mellitus (GDM) is a common pregnancy complication, particularly in women undergoing assisted reproductive technology (ART). An association of GDM with vitamin D in women conceiving naturally has been described; however, studies have yielded heterogeneous results. Objective: To analyze the association between prepregnancy total and free vitamin D and GDM incidence in women undergoing ART. Methods: Post hoc analysis of a prospective study at the Reproductive and Genetic Hospital of CITIC-Xiangya in Changsha, China. Total and free vitamin D were measured 1 day before embryo transfer. The patients were screened for GDM using the oral glucose tolerance test. Results: A total of 1593 women were included in the study, among whom 256 (16.1%) developed GDM. According to international guidelines for total 25-hydroxyvitamin D [25(OH)D], 47 (2.9%) patients had sufficient (≥30 ng/mL) levels, while 696 (43.7%) were insufficient (20 to <30 ng/mL) and 850 (54.4%) were deficient (<20 ng/mL). Comparing GDM and non-GDM patients, there was no significant difference in total nor free vitamin D levels (P = .340 and .849). Similarly, analysis of GDM rates by quintiles of total and free 25(OH)D showed no significant association in one-way ANOVA (P = .831 and .799). Multivariate logistic regression, considering age, BMI, and fasting glucose, also did not show a significant influence of the 2 vitamin D forms on GDM incidence (P = .266 and .123 respectively). Conclusion: In this relatively vitamin D deficient/insufficient ART cohort, the degree of neither total nor free vitamin D deficiency before pregnancy was associated with the occurrence of GDM.

Characteristic and health risk of per- and polyfluoroalkyl substances from cosmetics via dermal exposure.

In this work, 45 cosmetic samples were collected from China, and 27 target per- and polyfluoroalkyl substances (PFAS) were analyzed by ultrahigh-performance liquid chromatography-high resolution mass spectrometry. PFAS were found in all samples, including the products marketed for pregnant women, and the total concentrations of PFAS measured in each sample were in the range of 4.05 - 94.9 ng/g. Short-chain perfluorinated carboxylic acids were the dominant compounds contributing to over 60% of the total content. Perfluorobutanoic acid, with high placental transfer efficiency, was the major PFAS in cosmetics for pregnant women. Three emerging PFAS, 2-perfluorohexyl ethanoic acid, 3-perfluoropentyl propanoic acid (5:3) and perfluoro-2-propoxypropanoic acid, were also identified in the cosmetic samples at quantifiable levels. Significantly, positive correlations between individual PFAS were observed, indicating that there may be a common source for PFAS in these samples. Statistical analyses suggested that using plastic containers and precursor substances may be potential sources of PFAS in terminal products, and product aging may increase PFAS levels. From the PFAS analysis of the cosmetics, the margin of safety (MoS) and hazard quotient (HQ) were calculated to assess human health risks through dermal exposure by using these products. Although the MoS and HQ values obtained were deemed acceptable, the cumulative effect caused by composite and long-term exposure to these contaminants needs to be given greater attention by health authorities.

Automatic prediction of hepatic arterial infusion chemotherapy response in advanced hepatocellular carcinoma with deep learning radiomic nomogram.

OBJECTIVES: Hepatic arterial infusion chemotherapy (HAIC) using the FOLFOX regimen (oxaliplatin plus fluorouracil and leucovorin) is a promising option for advanced hepatocellular carcinoma (Ad-HCC). As identifying patients with Ad-HCC who would obtain objective response (OR) to HAIC preoperatively remains a challenge, we aimed to develop an automatic and non-invasive model for predicting HAIC response. METHODS: A total of 458 patients with Ad-HCC who underwent HAIC were retrospectively included from three hospitals (310 for training, 77 for internal validation, and 71 for external validation). The deep learning and radiomic features were extracted from the automatically segmented liver region on contrast-enhanced computed tomography images. Then, a deep learning radiomic nomogram (DLRN) was constructed by integrating deep learning scores, radiomic scores, and significant clinical variables with multivariate logistic regression. Model performance was assessed by AUC and Kaplan-Meier estimator. RESULTS: After automatic segmentation, only a few modifications were needed (less than 30 min for 458 patients). The DLRN achieved an AUC of 0.988 in the training cohort, 0.915 in the internal validation cohort, and 0.896 in the external validation cohort, respectively, outperforming other models in HAIC response prediction. Moreover, survival risk stratification was also successfully performed by the DLRN. The overall survival (OS) of the predictive OR group was significantly longer than that of the predictive non-OR group (median OS: 26.0 vs. 12.3 months, p < 0.001). CONCLUSIONS: The DLRN provided a satisfactory performance for predicting HAIC response, which is essential to identify Ad-HCC patients for HAIC and may potentially benefit personalized pre-treatment decision-making. CLINICAL RELEVANCE STATEMENT: This study presents an accurate and automatic method for predicting response to hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma, and therefore help in defining the best candidates for this treatment. KEY POINTS: • Deep learning radiomic nomogram (DLRN) based on automatic segmentation of CECT can accurately predict hepatic arterial infusion chemotherapy (HAIC) response of advanced HCC patients. • The proposed prediction model can perform survival risk stratification and is an easy-to-use tool for personalized pre-treatment decision-making for advanced HCC patients.

DppfCuBH4: new reducing agents for the synthesis of ferrocene-functionalized metal nanoclusters.

A facile synthesis of atomically precise metal nanoclusters, especially those decorated with functional groups, is the prerequisite for finding applications in special fields and studying structure-and-property relationships. The exploration of simple and efficient synthetic prototypes for introducing functional ligands (such as ferrocene) into cluster moieties is thus of high interest. In this work, a type of reducing agent of dppfCuBH4 (dppf is 1,1'-bis(diphenyphosphino)ferrocene) is introduced for the first time to prepare ferrocene-functionalized metal nanoclusters. Two new clusters of [Ag25Cu4(dppf)6(3-F-PhCC)12Cl6]3+ (1) and [Ag4(dppf)5Cl2]2+ (2) have been obtained from the simple synthetic method. The two compounds have been fully characterized by advanced techniques of electrospray ionization mass spectroscopy (ESI-MS), nuclear magnetic resonance (NMR), and ultraviolet-visible spectroscopy (UV-Vis). The total structure of the clusters, as determined by X-ray single-crystal diffraction, describes the Ag13@Ag12Cu4(dppf)6(3-F-PhCC)12Cl6 core-shell structure of 1 and [Ag2Cl(dppf)2]+-dppf-[Ag2Cl(dppf)2]+ polymeric structure of 2. This work opens the door to employing dppfCuBH4 as a functional reducing agent to discover many underlying metal nanoclusters and even other nanomaterials which feature ferrocene-groups.

Taurine alleviates heat stress-induced mammary inflammation and impairment of mammary epithelial integrity via the ERK1/2-MLCK signaling pathway.

Heat stress leads to milk production losses and mammary gland inflammation, which may be associated with mammary epithelium damage. Taurine is one of the most abundant free amino acids in mammals which has anti-inflammatory properties. This study aimed to explore the effect of taurine pretreatment on heat stress-induced mammary epithelial integrity disruption and inflammatory damage. In our first experiment on dairy cows our results showed that compared with animals under autumn thermoneutral condition (THI = 62.99 ± 0.71), summer heat stress (THI = 78.01 ± 0.39) significantly reduced milk yield and disrupted mammary epithelial integrity as revealed by increased concentrations of serotonin and lactose in plasma, and increased levels of SA and Na+/K+ in milk. In our second study, 36 lactating mice were randomly divided into three groups (n = 12) for a 9d experiment using a climate chamber to establish a heat stress model. Our findings suggest taurine pretreatment could attenuate heat stress-induced mammary histopathological impairment, inflammation response, and enhance mammary epithelium integrity, which was mainly achieved by promoting the secretion of ZO-1, Occludin, and Claudin-3 through inhibiting activation of the ERK1/2-MLCK signaling pathway in the mammary gland. Overall, our findings indicated that heat stress induced mammary epithelium dysfunction in dairy cows, and emphasized the protective effect of taurine on mammary health under heat stress conditions using a mouse model, which may be achieved by alleviating the mammary epithelium integrity damage and inflammation response.

Long-term fertilization coupled with rhizobium inoculation promotes soybean yield and alters soil bacterial community composition.

Microbial diversity is an important indicator of soil fertility and plays an indispensable role in farmland ecosystem sustainability. The short-term effects of fertilization and rhizobium inoculation on soil microbial diversity and community structure have been explored extensively; however, few studies have evaluated their long-term effects. Here, we applied quantitative polymerase chain reaction (qPCR) and amplicon sequencing to characterize the effect of 10-year fertilizer and rhizobium inoculation on bacterial communities in soybean bulk and rhizosphere soils at the flowering-podding and maturity stages. Four treatments were examined: non-fertilization control (CK), phosphorus and potassium fertilization (PK), nitrogen and PK fertilization (PK + N), and PK fertilization and Bradyrhizobium japonicum 5821 (PK + R). Long-term co-application of rhizobium and PK promoted soybean nodule dry weight by 33.94% compared with PK + N, and increased soybean yield by average of 32.25%, 5.90%, and 5.00% compared with CK, PK, and PK + N, respectively. The pH of PK + R was significantly higher than that of PK and PK + N at the flowering-podding stage. The bacterial abundance at the flowering-podding stage was positively correlated with soybean yield, but not at the maturity stage. The significant different class Gemmatimonadetes, and the genera Gemmatimonas, and Ellin6067 in soil at the flowering-podding stage were negatively correlated with soybean yield. However, the bacterial community at class and genus levels at maturity had no significant effect on soybean yield. The key bacterial communities that determine soybean yield were concentrated in the flowering-podding stage, not at maturity stage. Rhizosphere effect, growth period, and treatment synergies resulted in significant differences in soil bacterial community composition. Soil organic matter (OM), total nitrogen (TN), pH, and available phosphorus (AP) were the main variables affecting bacterial community structure. Overall, long-term co-application of rhizobium and fertilizer not only increased soybean yield, but also altered soil bacterial community structure through niche reconstruction and microbial interaction. Rhizobium inoculation plays key role in reducing nitrogen fertilizer application and promoting sustainable agriculture practices.