The association between PM2.5 components and blood pressure changes in late pregnancy: A combined analysis of traditional and machine learning models.

BACKGROUND: PM2.5 is a harmful mixture of various chemical components that pose a challenge in determining their individual and combined health effects due to multicollinearity issues with traditional linear regression models. This study aimed to develop an analytical methodology combining traditional and novel machine learning models to evaluate PM2.5's combined effects on blood pressure (BP) and identify the most toxic components. METHODS: We measured late-pregnancy BP of 1138 women from the Heshan cohort while simultaneously analyzing 31 PM2.5 components. We utilized multiple linear regression modeling to establish the relationship between PM2.5 components and late-pregnancy BP and applied Random Forest (RF) and generalized Weighted Quantile Sum (gWQS) regression to identify the most toxic components contributing to elevated BP and to quantitatively evaluate the cumulative effect of the PM2.5 component mixtures. RESULTS: The results revealed that 16 PM2.5 components, such as EC, OC, Ti, Fe, Mn, Cu, Cd, Mg, K, Pb, Se, Na+, K+, Cl-, NO3-, and F-, contributed to elevated systolic blood pressure (SBP), while 26 components, including two carbon components (EC, OC), fourteen metallics (Ti, Fe, Mn, Cr, Mo, Co, Cu, Zn, Cd, Na, Mg, Al, K, Pb), one metalloid (Se), and nine water-soluble ions (Na+, K+, Mg2+, Ca2+, NH4+, Cl-, NO3-, SO42-, F-), contributed to elevated diastolic blood pressure (DBP). Mn and Cr were the most toxic components for elevated SBP and DBP, respectively, as analyzed by RF and gWQS models and verified against each other. Exposure to PM2.5 component mixtures increased SBP by 1.04 mmHg (95% CI: 0.33-1.76) and DBP by 1.13 mmHg (95% CI: 0.47-1.78). CONCLUSIONS: Our study highlights the effectiveness of combining traditional and novel models as an analytical strategy to quantify the health effects of PM2.5 constituent mixtures.

Effect and safety of electroacupuncture on weight loss in obese patients with pre-diabetes: study protocol of a randomised controlled trial.

INTRODUCTION: Obesity has been identified as a significant risk factor for several chronic conditions, including diabetes, tumours and cardiovascular disease, and has been associated with increased mortality rates. Despite the well-established clinical practice of electroacupuncture (EA) as a potential treatment option for obesity, its efficacy remains questionable, primarily due to the paucity of empirical evidence supporting its therapeutic benefits. METHODS AND ANALYSIS: The present study aims to investigate the efficacy and safety of EA for weight loss in obese individuals with pre-diabetes, using a randomised, placebo-controlled clinical trial design. A total of 256 eligible patients will be randomly assigned to one of two groups: EA (comprising EA treatment with health education) or superficial acupuncture (SA) (comprising SA treatment with health education). The intervention will be administered three times per week for the initial 12 weeks, two times per week for the subsequent 8 weeks and one time per week for the final 4 weeks, with a 24-week follow-up period. The primary outcome measure will be the percentage of patients who achieve a reduction of 10% or more in their body weight at week 24. Secondary outcome measures will include changes in body weight and body mass index, blood test results, data collected by the body composition analyser, size of adipose tissue scanned by MRI of the abdomen and the Impact of Weight on Quality of Life, the 21-item Three-Factor Eating Questionnaire-Revised and the Food Craving Questionnaire-Trait. The Treatment Emergent Symptom Scale will be employed to monitor every adverse reaction from baseline to follow-up. ETHICS AND DISSEMINATION: This trial has received ethical clearance from the Ethics Committee of Shanghai Municipal Hospital of Traditional Chinese Medicine under the registration number 2021SHL-KY-74. All participants will provide their written informed consent prior to their enrolment. The findings of this investigation will be disseminated through peer-reviewed publications and scholarly conferences. TRIAL REGISTRATION NUMBER: NCT05237089.

Assessment of blood one-carbon metabolism indexes during mid-to-late pregnancy in 397 Chinese pregnant women.

Objectives: One-carbon metabolism (OCM) significantly influences fetal growth and neurodevelopment through transferring methyl group to biomolecules, during which folate, methionine, choline and betaine function as methyl donor nutrients, while vitamin B2, B6, B12 function as enzyme cofactors, and homocysteine (Hcy) and S-adenosyl methionine (SAM) are functional metabolites. This study aimed to assess blood OCM index levels and explore their relationships among Chinese pregnant women. Methods: Data were obtained from the baseline of the Mother-Child Nutrition and Health Cohort Study. Pregnant women, voluntarily recruited from September 2020 to June 2022 during antenatal examinations in five Chinese cities at 24-32 gestational weeks, provided fasting venous blood samples. Measurements included RBC and serum folate, serum vitamin B2, B6, B12, choline, betaine, methionine, total Hcy (tHcy), and plasma SAM. Sociodemographic characteristics and pregnancy-related conditions were collected via a self-designed questionnaire. Results: Of 397 participants, 82.6% were in mid-pregnancy (24-27 gestational weeks) and 17.4% were in late-pregnancy (28-32 gestational weeks). Serum folate, vitamin B6, and B12 deficiencies were 2.5, 1.3, and 8.3%, respectively. Elevated tHcy (≥10 µmol/L) was observed in 1.8% of pregnant women. Elderly pregnant women (aged 35 and above) exhibited significantly lower serum methionine levels (p < 0.05), while multiparous women had lower RBC folate levels (p < 0.05), and lower serum methionine and vitamin B12 levels (p < 0.10, not statistically significant). Partial correlation analysis revealed positive associations between RBC folate and cofactor vitamin B12 (r = 0.244, p < 0.05) in the folate cycle, as well as significant correlations between two methyl donor paths [serum folate was significantly related to serum choline (r = 0.172) and betaine (r = 0.193)]. As functional biomarkers of OCM, serum tHcy exhibited negative associations with RBC folate (ß = -0.330, p < 0.05) and vitamin B6 (ß = -0.317, p < 0.05), and plasma SAM displayed a positive association with serum betaine (ß = 0.610, p < 0.05), while negatively associated with serum vitamin B6 (ß = -0.181, p < 0.05). Conclusion: The blood OCM exhibited imbalances during mid-to-late pregnancy, characterized by lower levels of folate, vitamin B6, and B12, alongside elevated tHcy levels. Adequate folate and vitamin B6 emerged as significant predictors of lower tHcy levels. Additionally, serum betaine showed a positive correlation with plasma SAM. This suggests the importance of not only ensuring sufficient folate but also optimizing other OCM-related nutrients throughout pregnancy.

Cost-effectiveness analysis of dostarlimab plus carboplatin-paclitaxel as first-line treatment for advanced endometrial cancer.

Background: A recent phase III clinical trial (NCT03981796) evaluated the efficacy and safety of dostarlimab combined with carboplatin-paclitaxel (DOS-CP) compared to placebo combined with carboplatin-paclitaxel (PLB-CP) as a first-line treatment for advanced endometrial cancer (EC). The NCT03981796 trial demonstrated that DOS-CP significantly improved progression-free survival and overall survival of patients with advanced EC while maintaining an acceptable safety profile. However, DOS-CP is expensive and its cost-effectiveness has not been evaluated. This study aims to evaluate the cost-effectiveness of DOS-CP compared to PLB-CP as a first-line treatment for advanced EC from the perspective of the Chinese healthcare system. Methods: A Markov model with three health states was developed to evaluate the cost-effectiveness of DOS-CP as a first-line treatment for advanced EC. Clinical efficacy data were derived from the NCT03981796 trial, and drug costs were determined based on national tender prices. Other costs and utility values were obtained from published literature. The outcomes assessed included total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). The robustness of the model was assessed through one-way sensitivity analysis and probabilistic sensitivity analysis. Results: In comparison to PLB-CP, the ICER of DOS-CP was $98,276.61/QALY for the overall population, $53,063.61/QALY for the dMMR subgroup, and $124,088.56/QALY for the pMMR subgroup. All of these ICER values were higher than the willingness-to-pay threshold of $38,201 per QALY. The most important variable that affected the results of the model was the discount rate, the cost of dostarlimab, and the utility value for progressive disease. Conclusion: From the perspective of the Chinese healthcare system, DOS-CP is unlikely to be a cost-effective first-line treatment option for advanced EC.

Land use change alters carbon and nitrogen dynamics mediated by fungal functional guilds within soil aggregates.

Land use change is one of the greatest threats to soil biodiversity and ecological functions; however, how such a transition affects soil carbon (C) and nitrogen (N) dynamics driven by fungal communities at the aggregate level remains unclear. Here, we explored the variation in soil C and N pools, specific enzyme activities and fungal communities and functional guilds within three aggregate sizes (megaaggregates, > 2 mm; macroaggregates, 0.25-2 mm; microaggregates, < 0.25 mm) in a natural forest, 12- and 24-year-old rubber monocultures and corresponding agroforestry systems in tropical China. Tropical forest conversion to rubber monocultures generally reduced C and N pools in all aggregates, while agroforestry systems decreased microbial biomass C and N. Carbon- and N-degrading enzyme activities responded differently to forest conversion and were enhanced in agroforestry systems. The levels of C and N pools and their related enzyme activities increased as the aggregate size decreased. Moreover, fungal compositional shifts in dominance from copiotrophic Ascomycota and Basidiomycota (r-strategists) into oligotrophic Zygomycota (K-strategists) were noted following forest conversion, resulting in more pathogenic fungi at the expense of saprotrophic and arbuscular mycorrhizal fungi. Pathogenic fungi were greatly inhibited due to abundant Mortierella after the establishment of 12-year-old agroforestry systems. The diversity of saprotrophic fungi was the highest in microaggregates. Regardless of land use type, aggregate-associated C and N pools, especially DOC, MBC, NO3--N and DON in microaggregates, were interactively mediated by functional guilds of fungi, which was primarily driven by soil pH. These results highlight the importance of fungal functional guilds in determining C and N dynamics at the aggregate level and provide insights into the sustainable management of cash tree plantations.

Detection of MET Polysomy by Next-generation Sequencing and Its Clinical Relevance for MET Inhibitors.

Next-generation sequencing (NGS) has failed to detect mesenchymal epithelial transition factor gene (MET) polysomy in previous studies. We included three non-small cell lung cancer (NSCLC) cohorts in this retrospective study to establish new criteria for detecting MET polysomy and to explore the clinical relevance of MET polysomy. Cohort 1 included 53 patients whose tissues were available for both FISH and NGS assays. Paired plasma and tissue samples were obtained from 261 patients with NSCLC as cohort 2. Cohort 3 included 46 patients with metastatic NSCLC, who presented with MET copy-number gain assessed by NGS. ROC analysis demonstrated that a cut-off point of 2.3 copies achieved the maximum Youden index in discriminating polysomy from normal copy number. Compared with the FISH test for MET polysomy, the sensitivity, specificity, and agreement of NGS were 90%, 90%, and 96.2%, respectively. Following optimization using maximum somatic allele frequency, the sensitivity and specificity of NGS for defining polysomy using plasma samples according to different circulating tumor DNA mutation frequencies were 42% and 63%. The concordance rate between tissue and plasma samples for detecting polysomy was 85%. Regarding the response to MET inhibitor, the median progression-free survival (PFS) of the MET amplification group was significantly higher than that of the polysomy group. The median PFS was similar between the polysomy and normal groups. Our results indicated that NGS may serve as an alternative method for detecting MET polysomy in NSCLC tissues. Moreover, patients with MET polysomy may not benefit from MET inhibitors. Significance: In this study, we established a methodology to differentiate polysomy from normal copy numbers and amplification using NGS. Moreover, this study suggests that it is critical to discriminate MET polysomy from amplification, for the former may dilute the clinical benefit of MET inhibitors.

Ultra-stable perovskite quantum dot composites encapsulated with mesoporous SiO2 and PbBr(OH) for white light-emitting diodes.

Lead halide perovskite quantum dots (QDs) with high fluorescence efficiency and high color purity have a broad application prospect in the field of backlight display, but poor stability has been a key factor limiting their commercialization. Herein, we successfully synthesized CsPbBr3 QDs-KIT-6 (CsPbBr3 -K6) composite by using KIT-6 molecular sieve as the limited template with a simple high temperature solid-phase method. Further, the semi-protected CsPbBr3 QDs in KIT-6 frame will spontaneously hydrolyze when encountering water, and finally the double-encapsulated CsPbBr3 QDs-KIT-6@PbBr(OH) (CsPbBr3 -K6@PbBr(OH)) composite are obtained. CsPbBr3 -K6@PbBr(OH) composite shows excellent green emission properties, including a photoluminescence quantum yield (PLQY) (~73%) and a narrow emission linewidth of 25 nm. It is interesting that, the composite has excellent stability, including water stability without attenuation of fluorescence intensity after soaking in water for 60 days, thermal stability of 120°C heating-cooling cycle, and excellent optical stability without attenuation under continuous ultraviolet irradiation.

Chitosan@Puerarin hydrogel for accelerated wound healing in diabetic subjects by miR-29ab1 mediated inflammatory axis suppression.

Wound healing is one of the major global health concerns in patients with diabetes. Overactivation of pro-inflammatory M1 macrophages is associated with delayed wound healing in diabetes. miR-29ab1 plays a critical role in diabetes-related macrophage inflammation. Hence, inhibition of inflammation and regulation of miR-29 expression have been implicated as new points for skin wound healing. In this study, the traditional Chinese medicine, puerarin, was introduced to construct an injectable and self-healing chitosan@puerarin (C@P) hydrogel. The C@P hydrogel promoted diabetic wound healing and accelerated angiogenesis, which were related to the inhibition of the miR-29 mediated inflammation response. Compared to healthy subjects, miR-29a and miR-29b1 were ectopically increased in the skin wound of the diabetic model, accompanied by upregulated M1-polarization, and elevated levels of IL-1ß and TNF-α. Further evaluations by miR-29ab1 knockout mice exhibited superior wound healing and attenuated inflammation. The present results suggested that miR-29ab1 is essential for diabetic wound healing by regulating the inflammatory response. Suppression of miR-29ab1 by the C@P hydrogel has the potential for improving medical approaches for wound repair.

Effect of radiofrequency combined with magnetic stimulation on mild and moderate pelvic organ prolapse. / å°„é¢‘è”åˆç£åˆºæ¿€æ²»ç–—å¯¹è½»ä¸­åº¦ç›†è ”å™¨å®˜è„±åž‚çš„ç–—æ•ˆ.

OBJECTIVES: The efficacy of using a single electrical or magnetic stimulation for treating pelvic floor dysfunction is limited. This study aims to investigate the efficacy of radiofrequency combined with magnetic stimulation treatment for mild to moderate pelvic organ prolapse. METHODS: Patients who completed the treatment in the Third Xiangya Hospital, Central South University were screened, and were divided into 2 groups based on different treatment plans. There were 28 patients who completed magnetic stimulation therapy (the magnetic stimulation therapy group) and 21 patients who completed radiofrequency combined with magnetic stimulation therapy (the combined treatment group). The pelvic organ prolapse quantitation (POP-Q), pelvic floor muscle strength, and pelvic floor ultrasound results were analyzed to assess the efficacy before and after the treatment in both groups, and the POP-Q results of 3 months after the treatment were used to evaluate the maintenance effect of the treatment mode. RESULTS: The POP-Q evaluation results of Aa, Ap, and C points after the treatment in both groups were better than those before the treatment, with statistical significance (all P<0.05). The Aa point POP-Q result of the combined treatment group was better than that of the magnetic stimulation therapy group, with statistical significance (P<0.05). Pelvic floor ultrasound evaluation showed that the bladder neck position during the valsalva maneuver in the combined treatment group was higher than that in the magnetic stimulation treatment group, with statistical significance (P<0.05). The persistence effect of the combined treatment group was long better than that of the magnetic stimulation treatment group, with significant statistical significance (P<0.01). CONCLUSIONS: The combined treatment is more effective and has a longer lasting effect than single magnetic stimulation treatment.

The Influence of Airborne Particulate Matter on the Risk of Gestational Diabetes Mellitus: A Large Retrospective Study in Chongqing, China.

Emerging research findings suggest that airborne particulate matter might be a risk factor for gestational diabetes mellitus (GDM). However, the concentration-response relationships and the susceptible time windows for different types of particulate matter may vary. In this retrospective analysis, we employ a novel robust approach to assess the crucial time windows regarding the prevalence of GDM and to distinguish the susceptibility of three GDM subtypes to air pollution exposure. This study included 16,303 pregnant women who received routine antenatal care in 2018-2021 at the Maternal and Child Health Hospital in Chongqing, China. In total, 2482 women (15.2%) were diagnosed with GDM. We assessed the individual daily average exposure to air pollution, including PM2.5, PM10, O3, NO2, SO2, and CO based on the volunteers' addresses. We used high-accuracy gridded air pollution data generated by machine learning models to assess particulate matter per maternal exposure levels. We further analyzed the association of pre-pregnancy, early, and mid-pregnancy exposure to environmental pollutants using a generalized additive model (GAM) and distributed lag nonlinear models (DLNMs) to analyze the association between exposure at specific gestational weeks and the risk of GDM. We observed that, during the first trimester, per IQR increases for PM10 and PM2.5 exposure were associated with increased GDM risk (PM10: OR = 1.19, 95%CI: 1.07~1.33; PM2.5: OR = 1.32, 95%CI: 1.15~1.50) and isolated post-load hyperglycemia (GDM-IPH) risk (PM10: OR = 1.23, 95%CI: 1.09~1.39; PM2.5: OR = 1.38, 95%CI: 1.18~1.61). Second-trimester O3 exposure was positively correlated with the associated risk of GDM, while pre-pregnancy and first-trimester exposure was negatively associated with the risk of GDM-IPH. Exposure to SO2 in the second trimester was negatively associated with the risk of GDM-IPH. However, there were no observed associations between NO2 and CO exposure and the risk of GDM and its subgroups. Our results suggest that maternal exposure to particulate matter during early pregnancy and exposure to O3 in the second trimester might increase the risk of GDM, and GDM-IPH is the susceptible GDM subtype to airborne particulate matter exposure.

Therapeutic effect of proprioception training combined with pelvic floor electrical stimulation biofeedback on postpartum pelvic floor dysfunction. / æœ¬ä½“æ„Ÿè§‰è®­ç»ƒè”åˆç›†åº•ç”µåˆºæ¿€ç”Ÿç‰©åé¦ˆå¯¹äº§åŽç›†åº•åŠŸèƒ½éšœç¢æ€§ç–¾ç— çš„æ²»ç–—æ•ˆæžœ.

OBJECTIVES: Pelvic floor tendons, fascia, and ligaments are rich in proprioceptors. Proprioceptive training can stimulate local proprioceptors to increase neuromuscular responses and promote the recovery of muscle and fascial ligament functions. This study aims to observe the therapeutic effect of proprioception training combined with pelvic floor electrical stimulation biofeedback on postpartum pelvic floor dysfunction (PFD), and to provide evidence for the treatment of postpartum PFD. METHODS: A total of 108 puerpera with postpartum PFD were selected and divided into a control group ( n =50) and an experimental group ( n =58). Puerpera in the control group received pelvic floor electrical stimulation biofeedback treatment. Puerpera in the experimental group received proprioception training combined with pelvic floor electrical stimulation biofeedback treatment. After one course of treatment, the pelvic floor muscle strength, muscle endurance, repetitive contraction ability, rapid contraction ability, percentage of normal vaginal posterior wall elevation, percentage of normal lower abdominal muscle synergistic contraction, percentage of normal reflex contraction during coughing, incidence of stress urinary incontinence (SUI), and staging of pelvic organ prolapse (POP) were compared before and after treatment between the 2 groups. RESULTS: After treatment, all indexes of the 2 groups were better than those before treatment; the pelvic floor muscle strength, muscular endurance, repetitive contraction ability, and rapid contraction ability of the experimental group were better than those of the control group (all P <0.05); the percentage of normal lower abdominal muscle synergistic contraction and percentage of normal reflex contraction during coughing of the experimental group were higher than those of the control group (both P <0.05); the incidence of SUI in the experimental group was lower than that in the control group ( P <0.05); the percentage of POP staging II in the experimental group was significantly lower than that in the control group ( P <0.05). There was no significant difference in the percentage of normal posterior vaginal wall elevation after treatment between the 2 groups ( P >0.05). CONCLUSIONS: Proprioception training combined with pelvic floor electrical stimulation biofeedback could improve the rehabilitation effect of postpartum pelvic floor dysfunction and promote the recovery of pelvic floor function, which possesses important clinical application value.

Risk Stratification in Acute Coronary Syndrome by Comprehensive Morphofunctional Assessment With Optical Coherence Tomography.

Background: Artificial intelligence enables simultaneous evaluation of plaque morphology and computational physiology from optical coherence tomography (OCT). Objectives: This study sought to appraise the predictive value of major adverse cardiovascular events (MACE) by combined plaque morphology and computational physiology. Methods: A total of 604 patients with acute coronary syndrome who underwent OCT imaging in ≥1 nonculprit vessel during index coronary angiography were retrospectively enrolled. A novel morphologic index, named the lipid-to-cap ratio (LCR), and a functional parameter to evaluate the physiologic significance of coronary stenosis from OCT, namely, the optical flow ratio (OFR), were calculated from OCT, together with classical morphologic parameters, like thin-cap fibroatheroma (TCFA) and minimal lumen area. Results: The 2-year cumulative incidence of a composite of nonculprit vessel-related cardiac death, cardiac arrest, acute myocardial infarction, and ischemia-driven revascularization (NCV-MACE) at 2 years was 4.3%. Both LCR (area under the curve [AUC]: 0.826; 95% CI: 0.793-0.855) and OFR (AUC: 0.838; 95% CI: 0.806-0.866) were superior to minimal lumen area (AUC: 0.618; 95% CI: 0.578-0.657) in predicting NCV-MACE at 2 years. Patients with both an LCR of >0.33 and an OFR of ≤0.84 had significantly higher risk of NCV-MACE at 2 years than patients in whom at least 1 of these 2 parameters was normal (HR: 42.73; 95% CI: 12.80-142.60; P < 0.001). The combination of thin-cap fibroatheroma and OFR also identified patients at higher risk of future events (HR: 6.58; 95% CI: 2.83-15.33; P < 0.001). Conclusions: The combination of LCR with OFR permits the identification of a subgroup of patients with 43-fold higher risk of recurrent cardiovascular events in the nonculprit vessels after acute coronary syndrome.

Mechanism of Electroacupuncture Analgesia on Nicotine Withdrawal-Induced Hyperalgesia in a Rat Model.

Purpose: This study aimed to investigate the analgesic effect and mechanism of electroacupuncture (EA) in nicotine withdrawal-induced hyperalgesia rats. Methods: Behavioral testing was conducted twice a week for 7 weeks during nicotine administration using von Frey filaments. Electroacupuncture at the bilateral "Zusanli" and "Taichong" points was applied daily for 3 days during nicotine withdrawal. Western blot analysis and immunohistology were used to determine expression levels of pain-related factors in the spinal cord and midbrain periaqueductal gray (PAG). Results: Behavioral tests showed that electroacupuncture had a significant analgesic effect on nicotine withdrawal-induced hyperalgesic rats. Western blot results demonstrated that, in hyperalgesic rats, the expressions of nicotinic acetylcholine receptors (subunits: nAChR α7, α4, or ß2) decreased in the spinal cord, nAChR α7, and ß2 decreased in PAG. The proinflammatory factor cyclooxygenase 2 (COX2) and the activated microglia (ionized calcium-binding adaptor molecule 1, Iba1 positive cells) increased in the spinal cord and PAG compared to controls. After electroacupuncture treatment, nAChR α7 and nAChR ß2 expressions increased significantly, and COX2 and Iba1 expressions decreased in the spinal cord. Compared with the nonelectroacupuncture nicotine withdrawal group, electroacupuncture stimulation increased the expression of nAChR α7 and nAChR α4 in the PAG of rats with electroacupuncture. Immunohistochemical results confirmed that electroacupuncture reversed nicotine withdrawal-induced changes in nAChR α7 positive neurons and Iba1-positive microglia in the dorsal horn of the spinal cord. Conclusion: Electroacupuncture treatment has an analgesic effect on nicotine withdrawal-induced pain in nicotine-dependent rats. The mechanism of analgesia of the electroacupuncture treatment relates to the increased expression of nAChR α7 and nAChR ß2 proteins in the spinal cord, nAChR α7 in the PAG, and decreased expression of Iba1 and COX2 protein in the spinal cord.

PDGFD switches on stem cell endothelial commitment.

The critical factors regulating stem cell endothelial commitment and renewal remain not well understood. Here, using loss- and gain-of-function assays together with bioinformatic analysis and multiple model systems, we show that PDGFD is an essential factor that switches on endothelial commitment of embryonic stem cells (ESCs). PDGFD genetic deletion or knockdown inhibits ESC differentiation into EC lineage and increases ESC self-renewal, and PDGFD overexpression activates ESC differentiation towards ECs. RNA sequencing reveals a critical requirement of PDGFD for the expression of vascular-differentiation related genes in ESCs. Importantly, PDGFD genetic deletion or knockdown increases ESC self-renewal and decreases blood vessel densities in both embryonic and neonatal mice and in teratomas. Mechanistically, we reveal that PDGFD fulfills this function via the MAPK/ERK pathway. Our findings provide new insight of PDGFD as a novel regulator of ESC fate determination, and suggest therapeutic implications of modulating PDGFD activity in stem cell therapy.

Sleep Quality is an Independent Predictor of Blood Glucose and Gestational Diabetes Mellitus: A Longitudinal Study of 4550 Chinese Women.

Purpose: To investigate whether pregnant women's subjective sleep quality during the first trimester independently predicted blood glucose and gestational diabetes mellitus (GDM). Methods: A total of 4550 pregnant women in the first trimester were enrolled in Chongqing Health Center for Women and Children, China, from January to October 2020.The Pittsburgh Sleep Quality Index (PSQI) was used to measure subjective sleep quality. Depression symptoms and anxiety were measured with the Patient Health Questionnaire-9 (PHQ-9) and General Anxiety Disorder-7 (GAD-7). Oral glucose tolerance tests (OGTT) and blood glucose area under the curve (AUC) were used for estimation of blood glucose and diagnosis of GDM during the second trimester. Linear, mixed model, and logistic regression were used to analyze the association between PSQI and blood glucose as well as GDM. Results: 946/4550 were diagnosed with GDM (20.8%). In the mixed model analysis, the blood glucose level of the highest-scoring group (PSQI score = 18) was 1.94 (95% CI: 0.45~3.43, P = 0.011) mmol/L higher than that of the lowest-scoring group (PSQI score = 0). After adjusting for potential confounders, a one-point PSQI score increase was associated with a 0.014 (95% CI: 0.001~0.027, P = 0.039) mmol/L increase in blood glucose level. Blood glucose AUC was also positively associated with PSQI scores (ß = 0.034, 95% CI: 0.003~0.064, P = 0.030). The results for the logistic regression model showed that PSQI was marginal positively correlated with GDM (OR = 1.146, 95% CI: 0.995~1.321, P = 0.059) when age and BMI were not controlled for. When investigating the association between PSQI and the GDM-diagnosed time window, the 1-h diagnosed GDM had a borderline positive correlation with PSQI (OR = 1.182, 95% CI: 0.993~1.405, P = 0.060). Conclusion: Sleep quality during the first trimester may be a risk factor for elevated blood glucose and GDM later in gestation.

Impact of coronary plaque morphology on the precision of computational fractional flow reserve derived from optical coherence tomography imaging.

Background: Computational fractional flow reserve (FFR) was recently developed to expand the use of physiology-guided percutaneous coronary intervention (PCI). Nevertheless, current methods do not account for plaque composition. It remains unknown whether the numerical precision of computational FFR is impacted by the plaque composition in the interrogated vessels. Methods: This study is an observational, retrospective, cross-sectional study. Patients who underwent both optical coherence tomography (OCT) and FFR prior to intervention between August 2011 and October 2018 at Wakayama Medical University Hospital were included. All frames from OCT pullbacks were analyzed using a deep learning algorithm to obtain coronary plaque morphology including thin-cap fibroatheroma (TCFA), lipidic plaque volume (LPV), fibrous plaque volume (FPV), and calcific plaque volume (CPV). The interrogated vessels were stratified into three subgroups: the overestimation group with the numerical difference between the optical flow ratio (OFR) and FFR >0.05, the reference group with the difference ≥-0.05 and ≤0.05, and the underestimation group with the difference <-0.05. Results: In total 230 vessels with intermediate coronary artery stenosis from 193 patients were analyzed. The mean FFR was 0.82±0.10. Among them, 21, 179, and 30 vessels were in the overestimation, the reference, and the underestimation group, respectively. TCFA was higher in the underestimation group (60%) compared with reference (36.3%) and overestimation group (19%). Besides, it was not associated with numerical difference between OFR and FFR (NDOF) after multilevel linear regression. LPV was associated with NDOF as OFR underestimated FFR with -0.028 [95% confidence interval (CI): -0.047, -0.009] for every 100 mm3 increase in LPV. Conclusions: High lipid burden underestimates FFR when OFR is used to assess the hemodynamic importance of intermediate coronary artery stenosis. TCFA, FPV, and CPV were not independent predictors of NDOF.

Satellite Cells are Activated in a Rat Model of Radiation-Induced Muscle Fibrosis.

Radiation-induced muscle fibrosis is a long-term side effect of radiotherapy that significantly affects the quality of life and even reduces the survival of cancer patients. We have demonstrated that radiation induces satellite cell (SC) activation at the molecular level; however, cellular evidence in a rat model of radiation-induced muscle fibrosis was lacking. In this study, we evaluated SC activation in vivo and investigated whether radiation affects the proliferation and differentiation potential of SCs in vitro. For in vivo studies, Sprague-Dawley rats were randomly divided into six groups (n = 6 per group): non-irradiated controls, 90 Gy/1 week-, 90 Gy/2 weeks-, 90 Gy/4 weeks-, 90 Gy/12 weeks- and 90 Gy/24 weeks-postirradiation groups. Rats received a single dose of radiation in the left groin area and rectus femoris tissues were collected in the indicated weeks. Fibrosis, apoptosis, and autophagy were evaluated by Masson's trichrome staining, TUNEL staining, and electron microscopy, respectively. SC activation and central nuclear muscle fibers were evaluated by immunofluorescence staining and hematoxylin and eosin staining. IL-1ß concentrations in serum and irradiated muscle tissue samples were determined by ELISA. For in vitro studies, SCs were isolated from rats with radiation-induced muscle fibrosis and their proliferation and differentiation were evaluated by immunofluorescence staining. In vivo, fibrosis increased over time postirradiation. Apoptosis and autophagy levels, IL-1ß concentrations in serum and irradiated skin tissues, and the numbers of SCs and central nuclear muscle fibers were increased in the irradiated groups when compared with the control group. In vitro, cultured SCs from irradiated muscle were positive for the proliferation marker Pax7, and differentiated SCs were positive for the myogenic differentiation marker MyHC. This study provided cellular evidence of SC activation and proliferation in rats with radiation-induced muscle fibrosis.

E2F transcription factor 1 (E2F1) enhances the proliferation, invasion and EMT of trophoblast cells by binding to Zinc Finger E-Box Binding Homeobox 1 (ZEB1).

Preeclampsia (PE) is a serious pregnancy syndrome, which is mainly caused by attenuated trophoblast proliferation and invasion. It has been verified that E2F transcription factor 1 (E2F1) is lowly expressed in PE. It is identified that E2F1 binds to the promoter region of Zinc Finger E-Box Binding Homeobox 1 (ZEB1) in JASPAR datasets. ZEB1 is also a transforming factor that can facilitate EMT. The present work was designed to investigate the biological functions of E2F1 and ZEB1 on the proliferation, invasiveness and EMT of trophoblast cells and further explore the molecular mechanism underlying the participation of E2F1 and ZEB1 in the behaviors of trophoblast cells. Results revealed that upregulation of E2F1 reinforced the proliferation, invasiveness and EMT of trophoblast cells and downregulation of E2F1 exhibited opposite effects on trophoblast proliferation, invasion and EMT. It was confirmed that E2F1 bound to the promoter region of ZEB1 and two binding sites (E1 and E2) in ZEB1 promoter region to E2F1 was identified by CHIP assays. Luciferase reporter assay further verified the binding relationship between E2F1 and ZEB1. Overexpression of ZEB1 rescued the suppressing effects of E2F1 knockdown on proliferation, invasiveness and EMT of trophoblast cells. To conclude, E2F1 could promote trophoblast proliferation and invasion and strengthen EMT of trophoblast cells by enhancing ZEB1 expression.

Association of abnormal-glucose tolerance during pregnancy with exposure to PM2.5 components and sources.

Maternal exposure to PM2.5 has been associated with abnormal glucose tolerance during pregnancy, but little is known about which constituents and sources are most relevant to glycemic effects. We conducted a retrospective cohort study of 1148 pregnant women to investigate associations of PM2.5 chemical components with gestational diabetes mellitus (GDM) and impaired glucose tolerance (IGT) and to identify the most harmful sources in Heshan, China from January 2015 to July 2016. We measured PM2.5 using filter-based method and analyzed them for 28 constituents, including carbonaceous species, water-soluble ions and metal elements. Contributions of PM2.5 sources were assessed by positive matrix factorization (PMF). Logistic regression model was used to estimate composition-specific and source-specific effects on GDM/IGT. Random forest algorithm was applied to evaluate the relative importance of components to GDM and IGT. PM2.5 total mass and several chemical constituents were associated with GDM and IGT across the early to mid-gestation periods, as were the PM2.5 sources fossil fuel/oil combustion, road dust, metal smelting, construction dust, electronic waster, vehicular emissions and industrial emissions. The trimester-specific associations differed among pollutants and sources. The third and highest quartile of elemental carbon, ammonium (NH4+), iron (Fe) and manganese (Mn) across gestation were consistently associated with higher odds of GDM/IGT. Maternal exposures to zinc (Zn), titanium (Ti) and vehicular emissions during the first trimester, and vanadium (V), nickel (Ni), road dust and fossil fuel/oil combustion during the second trimester were more important for GDM/IGT. This study provides important new evidence that maternal exposure to PM2.5 components and sources is significantly related to elevated risk for abnormal glucose tolerance during pregnancy.

Artificial intelligence and optical coherence tomography for the automatic characterisation of human atherosclerotic plaques.

BACKGROUND: Intravascular optical coherence tomography (IVOCT) enables detailed plaque characterisation in vivo, but visual assessment is time-consuming and subjective. AIMS: This study aimed to develop and validate an automatic framework for IVOCT plaque characterisation using artificial intelligence (AI). METHODS: IVOCT pullbacks from five international centres were analysed in a core lab, annotating basic plaque components, inflammatory markers and other structures. A deep convolutional network with encoding-decoding architecture and pseudo-3D input was developed and trained using hybrid loss. The proposed network was integrated into commercial software to be externally validated on additional IVOCT pullbacks from three international core labs, taking the consensus among core labs as reference. RESULTS: Annotated images from 509 pullbacks (391 patients) were divided into 10,517 and 1,156 cross-sections for the training and testing data sets, respectively. The Dice coefficient of the model was 0.906 for fibrous plaque, 0.848 for calcium and 0.772 for lipid in the testing data set. Excellent agreement in plaque burden quantification was observed between the model and manual measurements (R2=0.98). In the external validation, the software correctly identified 518 out of 598 plaque regions from 300 IVOCT cross-sections, with a diagnostic accuracy of 97.6% (95% CI: 93.4-99.3%) in fibrous plaque, 90.5% (95% CI: 85.2-94.1%) in lipid and 88.5% (95% CI: 82.4-92.7%) in calcium. The median time required for analysis was 21.4 (18.6-25.0) seconds per pullback. CONCLUSIONS: A novel AI framework for automatic plaque characterisation in IVOCT was developed, providing excellent diagnostic accuracy in both internal and external validation. This model might reduce subjectivity in image interpretation and facilitate IVOCT quantification of plaque composition, with potential applications in research and IVOCT-guided PCI.