Lipoprotein apheresis: an established therapeutic modality for homozygous familial hypercholesterolemia patients refractory to PCSK9 inhibitors: a case report and literature review.

Homozygous familial hypercholesterolemia (HoFH), is a rare genetic disorder characterized by dual mutations in the low-density lipoprotein receptor (LDLR) gene, leading to dysfunctional or absent LDLRs, often accompanied by severe premature Atherosclerotic Cardiovascular Disease (ASCVD) and exhibiting refractoriness to aggressive pharmacological interventions. Double filtration plasmapheresis (DFPP), a form of lipoprotein apheresis (LA), has been effectively utilized as an adjunctive treatment modality to reduce serum LDL-C levels in refractory cases of HoFH. Here, we report a case of a 36-year-old female with HoFH who developed xanthomas on her limbs and waist at age 7. Despite maximum-tolerated doses of statins from age 32, combined with ezetimibe and evolocumab, her LDL-C levels remained critically elevated at 12-14 mmol/L. Her genetic testing confirmed a homozygous LDLR mutation. At 35 years old, she experienced exertional chest pain, and percutaneous coronary intervention revealed severe calcific left main stenosis, necessitating stent implantation. Subsequently, she initiated once every 1-2 months DFPP. Pre-DFPP, her LDL-C and total cholesterol (TC) levels were 13.82 ± 3.28 and 15.45 ± 0.78 mmol/L, respectively. Post-DFPP, her LDL-C and TC levels significantly decreased to 2.43 ± 0.33 mmol/L (81.76 ± 4.11% reduction) and 3.59 ± 0.41 mmol/L (76.76 ± 2.75% reduction), respectively. Lipoprotein (a) and triglycerides also decreased by 89.10 ± 1.39% and 42.29 ± 15.68%,respectively. Two years later, there was no progression of coronary artery disease, and her symptoms and xanthomas regressed significantly. Collectively, DFPP effectively reduces LDL-C levels in refractory cases of HoFH and contributes to delaying ASCVD progression, representing an efficacious adjunctive therapeutic modality.

Research progress of exosomes from different sources in myocardial ischemia.

Ischemic heart disease refers to the imbalance between the supply and demand of myocardial blood; it has various causes and results in a class of clinical diseases characterized by myocardial ischemia (MI). In recent years, the incidence of cardiovascular disease has become higher and higher, and the number of patients with ischemic heart disease has also increased year by year. Traditional treatment methods include drug therapy and surgical treatment, both of which have limitations. The former maybe develop risks of drug resistance and has more significant side effects, while the latter may damage blood vessels and risk infection. At this stage, a new cell-free treatment method needs to be explored. Many research results have shown that exosomes from different cell sources can protect the ischemic myocardium via intercellular action methods, such as promoting angiogenesis, inhibiting myocardial fibrosis, apoptosis and pyroptosis, and providing a new basis for the treatment of MI. In this review, we briefly introduce the formation and consequences of myocardial ischemia and the biology of exosomes, and then focus on the role and mechanism of exosomes from different sources in MI. We also discuss the role and mechanism of exosomes pretreated with Chinese and Western medicines on myocardial ischemia. We also discuss the potential of exosomes as diagnostic markers and therapeutic drug for MI.

C/EBPδ deficiency delays infection-induced preterm birth.

BACKGROUND: Parturition is an inflammation process. Exaggerated inflammatory reactions in infection lead to preterm birth. Although nuclear factor kappa B (NF-κB) has been recognized as a classical transcription factor mediating inflammatory reactions, those mediated by NF-κB per se are relatively short-lived. Therefore, there may be other transcription factors involved to sustain NF-κB-initiated inflammatory reactions in gestational tissues in infection-induced preterm birth. METHODS: Cebpd-deficient mice were generated to investigate the role of CCAAT enhancer-binding protein δ (C/EBPδ) in lipopolysaccharide (LPS)-induced preterm birth, and the contribution of fetal and maternal C/EBPδ was further dissected by transferring Cebpd-/- or WT embryos to Cebpd-/- or WT dams. The effects of C/EBPδ pertinent to parturition were investigated in mouse and human myometrial and amnion cells. The interplay between C/EBPδ and NF-κB was examined in cultured human amnion fibroblasts. RESULTS: The mouse study showed that LPS-induced preterm birth was delayed by Cebpd deficiency in either the fetus or the dam, with further delay being observed in conceptions where both the dam and the fetus were deficient in Cebpd. Mouse and human studies showed that the abundance of C/EBPδ was significantly increased in the myometrium and fetal membranes in infection-induced preterm birth. Furthermore, C/EBPδ participated in LPS-induced upregulation of pro-inflammatory cytokines as well as genes pertinent to myometrial contractility and fetal membrane activation in the myometrium and amnion respectively. A mechanistic study in human amnion fibroblasts showed that C/EBPδ, upon induction by NF-κB, could serve as a supplementary transcription factor to NF-κB to sustain the expression of genes pertinent to parturition. CONCLUSIONS: C/EBPδ is a transcription factor to sustain the expression of gene initiated by NF-κB in the myometrium and fetal membranes in infection-induced preterm birth. Targeting C/EBPδ may be of therapeutic value in the treatment of infection-induced preterm birth.

Associations of vaginal microbiota with the onset, severity, and type of symptoms of genitourinary syndrome of menopause in women.

Introduction: Genitourinary syndrome of menopause (GSM) describes the symptoms and signs resulting from the effect of estrogen deficiency on the female genitourinary tract, including genital, urinary, and sexual symptoms. However, besides estrogen deficiency, little is known about the etiology of GSM. The objective of this study was to investigate the effects of vaginal microbiota dysbiosis on the occurrence and development of GSM in perimenopausal and postmenopausal women. Methods: In total, 96 women were enrolled in this cross-sectional study and clinical data were collected. GSM symptoms were divided into three types: genital, urological, and sexual symptoms. Full-length 16S rRNA gene sequencing using the third-generation PacBio sequencing technology was performed to analyze the vaginal microbiome using vaginal swabs of non-GSM and GSM women with different types of GSM symptoms. Live Lactobacillus Capsule for Vaginal Use (LLCVU) treatment was used to verify the effects of Lactobacillus on GSM symptoms. Results: We found that 83.58% (56/67) of women experienced GSM symptoms in the perimenopausal and postmenopausal stages. Among these women with GSM, 23.21% (13/56), 23.21% (13/56), and 53.57% (30/56) had one type, two types, and three types of GSM symptoms, respectively. The richness and diversity of vaginal microbiota gradually increased from reproductive to postmenopausal women. There were significant differences in vaginal microbial community among non-GSM women and GSM women with different types of symptoms. Lactobacillus was found to be negatively associated with the onset, severity, and type of GSM while some bacteria, such as Escherichia-shigella, Anaerococcus, Finegoldia, Enterococcus, Peptoniphilus_harei, and Streptococcus, were found to be positively associated with these aspects of GSM, and these bacteria were especially associated with the types of genital and sexual symptoms in GSM women. LLCVU significantly relieved genital symptoms and improved the sexual life of GSM women in shortterm observation. Conclusions: The onset, severity, and type of GSM symptoms may be associated with changes in vaginal microbiota in perimenopausal and postmenopausal women. Vaginal microbiota dysbiosis probably contributes to the occurrence and development of GSMsymptoms, especially vaginal and sexual symptoms. Lactobacillus used in the vagina may be a possible option for non-hormonal treatment of GSM women with genital and sexual symptoms. Clinical Trial Registration: https://www.chictr.org.cn/indexEN.html, identifier ChiCTR2100044237.

The hemostatic activity and Mechanistic roles of glucosyloxybenzyl 2-isobutylmalate extract (BSCE) from Bletilla striata (Thunb.) Rchb.f. in Inhibiting pulmonary hemorrhage.

Background: Hemorrhagic events cause numerous deaths annually worldwide, highlighting the urgent need for effective hemostatic drugs. The glucosyloxybenzyl 2-isobutylmalates Control Extract (BSCE) from the orchid plant Bletilla striata (Thunb.) Rchb.f. has demonstrated significant hemostatic activity in both in vitro and in vivo studies. However, the effect and mechanism of BSCE on non-traumatic bleeding remain unclear. Methods: Pulmonary hemorrhage was induced in 40 Sprague-Dawley rats by administering Zingiber officinale Roscoe. for 14 days. These rats were then randomly divided into five groups: model (Mod), positive control (YNBY), and BSCE low, medium, and high-dose groups. An additional 8 rats served as the control group (Con). The BSCE groups received different doses of BSCE for 10 days, while the YNBY group received Yunnan Baiyao suspension. The effects on body weight, food and water intake, red blood cell count (RBC), hemoglobin concentration (HGB), lung tissue pathology, platelet count, coagulation parameters, and fibrinolytic system markers were evaluated. Network pharmacology and molecular docking analyses were also conducted to identify potential targets and pathways involved in BSCE's effects. Results: BSCE treatment significantly improved body weight, food intake, and water consumption in rats with pulmonary hemorrhage. RBC and HGB levels increased significantly in the BSCE medium and high-dose groups compared to the Mod group (P < 0.05). Pathological examination revealed that BSCE reduced lung tissue hemorrhage and inflammation, with improvements in alveolar structure. BSCE also positively affected platelet count, thrombin time (TT), activated partial thromboplastin time (APTT), fibrinogen (FIB) levels, and fibrinolytic markers (D-dimer, PAI-1, and t-PA). Network pharmacology and molecular docking identified key targets such as MMPs, CASPs, and pathways including IL-17 and TNF signaling, suggesting BSCE's involvement in hemostasis and anti-inflammatory processes. Conclusions: BSCE exhibits significant hemostatic and protective effects on Z.officinale-induced pulmonary hemorrhage in rats by improving hematological parameters, reducing lung tissue damage, and modulating the coagulation and fibrinolytic systems. The study provides evidence supporting the potential of BSCE as a therapeutic agent for hemorrhagic diseases, with its efficacy linked to multi-target and multi-pathway interactions.

Upgrading Isoquercitrin Concentration via Submerge Fermentation of Mulberry Fruit Extract with Edible Probiotics to Suppress Gene Targets for Controlling Kidney Cancer and Inflammation.

In recent years, kidney cancer has become one of the most serious medical issues. Kidney cancer is treated with a variety of active compounds that trigger genes that cause cancer. We identified in our earlier research that isoquercitrin (IQ) can activate PIK3CA, IGF1R, and PTGS2. However, it has a very low bioavailability because of its lower solubility in water. So, we utilized sub-merge fermentation technology with two well-known probiotics, Lactobacillus acidophilus and Bacillus subtilis, as a microbial source and mulberry fruit extract as a substrate, which has a high IQ level to improve IQ yield. Furthermore, we compared the total phenolic, flavonoid, and antioxidant contents of fermented and non-fermented samples, and we found that the fermented samples had greater levels than non-fermented sample. In addition, the high-performance liquid chromatography (HPLC) results showed that the fermented mulberry fruit extract from B. subtilis and L. acidophilus showed higher IQ values (190.73 ± 0.004 µg/ml and 220.54 ± 0.007 µg/ml, respectively), compared to the non-fermented samples, which had IQ values (80.12 ± 0.002 µg/ml). Additionally, at 62.5 µg/ml doses of each sample, a normal kidney cell line (HEK 293) showed higher cell viability for fermented and non-fermented samples. Conversely, at the same doses, the fermented samples of L. acidophilus and B. subtilis in a kidney cancer cell line (A498) showed an inhibition of cell growth around 36% and 31%, respectively. Finally, we performed RT and qRT PCR assay, and we found a significant reduction in the expression of the PTGS2, PIK3CA, and IGF1R genes. We therefore can conclude that the fermented samples have a higher concentration of isoquercitrin, and also can inhibit the expression of the genes PTGS2, PIK3CA, and IGF1R, which in turn regulates kidney cancer and inflammation.

Association Between Extreme Heat and Outpatient Visits for Mental Disorders: A Time-Series Analysis in Guangzhou, China.

Previous evidence on heatwaves' impact on mental health outpatient visits is limited, especially uncertainty on how different heatwave definitions affect this relationship. In this time-series study, we assessed the association between heatwaves and outpatient visits for mental disorders in Guangzhou, China. Daily outpatient visits for mental disorders and its specific categories (schizophrenia, mood, and neurotic disorders) were sourced from the Urban Resident-based Basic Medical Insurance (URBMI) and the Urban Employee-based Basic Medical Insurance (UEBMI) claims databases in Guangzhou from 2010 to 2014. The study employed nine heatwave definitions, based on combinations of three daily mean temperature thresholds (90th, 92.5th, and 95th percentiles) and durations (2, 3, and 4 days). Using quasi-Poisson generalized linear models (GLMs), we estimated the risks (at lag 0 day) and cumulative effects (lag 0-10 days) of heatwaves on mental disorder outpatient visits. Age, gender, types of medical insurance were considered as potential effect modifiers. We observed a positive association between heatwaves and increased total outpatient visits for mental disorders, both at lag 0 day and during lag 0-10 days. The impact of heatwave was significant at lag 0 day for schizophrenia, mood and neurotic disorders visits, it remained significant for neurotic and mood disorders visits during lag 0-10 days. Heatwave durations lasting more than 4 days were associated with higher relative risks of mental disorders at lag 0 day. Older adults had relatively higher effect estimations than younger individuals. This research highlights the effects of extreme heat on mental health.

M2DC: A Meta-Learning Framework for Generalizable Diagnostic Classification of Major Depressive Disorder.

Psychiatric diseases are bringing heavy burdens for both individual health and social stability. The accurate and timely diagnosis of the diseases is essential for effective treatment and intervention. Thanks to the rapid development of brain imaging technology and machine learning algorithms, diagnostic classification of psychiatric diseases can be achieved based on brain images. However, due to divergences in scanning machines or parameters, the generalization capability of diagnostic classification models has always been an issue. We propose Meta-learning with Meta batch normalization and Distance Constraint (M2DC) for training diagnostic classification models. The framework can simulate the train-test domain shift situation and promote intra-class cohesion, as well as inter-class separation, which can lead to clearer classification margins and more generalizable models. To better encode dynamic brain graphs, we propose a concatenated spatiotemporal attention graph isomorphism network (CSTAGIN) as the backbone. The network is trained for the diagnostic classification of major depressive disorder (MDD) based on multi-site brain graphs. Extensive experiments on brain images from over 3261 subjects show that models trained by M2DC achieve the best performance on cross-site diagnostic classification tasks compared to various contemporary domain generalization methods and SOTA studies. The proposed M2DC is by far the first framework for multi-source closed-set domain generalizable training of diagnostic classification models for MDD and the trained models can be applied to reliable auxiliary diagnosis on novel data.

The complete chloroplast genome of Dryas octopetala var. asiatica (Dryadoideae, Rosaceae) and phylogenetic analysis.

Dryas octopetala L. var. asiatica (Nakai) Nakai 1918 is a dwarf shrub that mainly grow in alpine and arctic zones of the Northern Hemisphere, representing an endemic variety in Asia. In the present study, the complete chloroplast (cp) genome of D. octopetala var. asiatica was first characterized and used for its phylogenetic analysis. The cp genome span 158,271 bp with an overall GC content of 36.5%. A total of 129 genes were identified, including 84 protein-coding genes (PCGs), 37 tRNA genes, and 8 rRNA genes. In addition, repetitive sequences and microsatellites were detected within this species. Phylogenetic analysis involving 39 cp genomes from Rosaceae family indicated that D. octopetala var. asiatica was sister to the clade of Amygdaloideae. This study contributes fundamental insights into the cp genome of Dryas octopetala var. asiatica, which will have expanded its use in photosynthesis and evolutionary study.

Integrating clinical and biochemical markers: a novel nomogram for predicting lacunes in cerebral small vessel disease.

Background: Lacunes, a characteristic feature of cerebral small vessel disease (CSVD), are critical public health concerns, especially in the aging population. Traditional neuroimaging techniques often fall short in early lacune detection, prompting the need for more precise predictive models. Methods: In this retrospective study, 587 patients from the Neurology Department of the Affiliated Hospital of Hebei University who underwent cranial MRI were assessed. A nomogram for predicting lacune incidence was developed using LASSO regression and binary logistic regression analysis for variable selection. The nomogram's performance was quantitatively assessed using AUC-ROC, calibration plots, and decision curve analysis (DCA) in both training (n = 412) and testing (n = 175) cohorts. Results: Independent predictors identified included age, gender, history of stroke, carotid atherosclerosis, hypertension, creatinine, and homocysteine levels. The nomogram showed an AUC-ROC of 0.814 (95% CI: 0.791-0.870) for the training set and 0.805 (95% CI: 0.782-0.843) for the testing set. Calibration and DCA corroborated the model's clinical value. Conclusion: This study introduces a clinically useful nomogram, derived from binary logistic regression, that significantly enhances the prediction of lacunes in patients undergoing brain MRI for various indications, potentially advancing early diagnosis and intervention. While promising, its retrospective design and single-center context are limitations that warrant further research, including multi-center validation.

Deoxypodophyllotoxin Mediates Autophagy Death through Inhibition of GRP78 in Human Osteosarcoma.

BACKGROUND: Glucose-regulated protein 78 (GRP78), as a chaperone protein, can protect the endoplasmic reticulum of cells and is expressed to influence chemoresistance and prognosis in cancer. Deoxypodophyllotoxin (DPT) is a compound with antitumor effects on cancers. DPT inhibits the proliferation of osteosarcoma by inducing apoptosis, necrosis, or cell cycle arrest. OBJECT: This study was performed to demonstrate the molecular mechanism by which DPT attenuates osteosarcoma progression through GRP78. METHODS: Natural compound libraries and western blot (WB) were used to screen the inhibitors of osteosarcoma GRP78. The expression of mitochondria-related genes in cancer cells of the treatment group was detected by quantitative real-time PCR (qPCR) and WB. 3-(4,5)- Dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) and 5-ethynyl-2'- deoxyuridine (EDU) were used to discover the activity and proliferation of osteosarcoma cells treated with DPT. We constructed an in vivo mouse model of DPT drug therapy and carried out immunohistochemical detection of xenografts. The treated osteosarcoma cells were analyzed using bioinformatics and electron microscopy. The data were analyzed finally. RESULTS: DPT inhibited osteosarcoma cell survival and the growth of tumor xenografts. It promoted up-regulation of BCL2-associated X protein (Bax) and B-cell CLL/lymphoma 2 (Bcl-2), which serves to mediate and attenuate, respectively, the killing activities of DPT through mitochondria dysfunction. The effect of DPT against cancer cells could be attenuated by the overexpression of GRP78, characterized by the inactivation of the caspase cascade. The loss of GRP78 in osteosarcoma cells negatively mediated the basal level of autophagyassociated genes. DPT stimulated autophagy via the phosphoinositide 3-kinase (PI3K)-v-akt murine thymoma viral oncogene homolog (AKT), a mechanistic target of rapamycin (mTOR) axis. The autophagy caused by DPT played an active role in the osteosarcoma of humans and blocked the apoptotic cascade. CONCLUSION: Combination treatment with the GRP78 inhibitor DPT and pharmacological autophagy inhibitors will be a meaningful method of obviating osteosarcoma cells.

Highly sensitive detection platform-based diagnosis of oesophageal squamous cell carcinoma in China: a multicentre, case-control, diagnostic study.

BACKGROUND: Early detection and screening of oesophageal squamous cell carcinoma rely on upper gastrointestinal endoscopy, which is not feasible for population-wide implementation. Tumour marker-based blood tests offer a potential alternative. However, the sensitivity of current clinical protein detection technologies is inadequate for identifying low-abundance circulating tumour biomarkers, leading to poor discrimination between individuals with and without cancer. We aimed to develop a highly sensitive blood test tool to improve detection of oesophageal squamous cell carcinoma. METHODS: We designed a detection platform named SENSORS and validated its effectiveness by comparing its performance in detecting the selected serological biomarkers MMP13 and SCC against ELISA and electrochemiluminescence immunoassay (ECLIA). We then developed a SENSORS-based oesophageal squamous cell carcinoma adjunct diagnostic system (with potential applications in screening and triage under clinical supervision) to classify individuals with oesophageal squamous cell carcinoma and healthy controls in a retrospective study including participants (cohort I) from Sun Yat-sen University Cancer Center (SYSUCC; Guangzhou, China), Henan Cancer Hospital (HNCH; Zhengzhou, China), and Cancer Hospital of Shantou University Medical College (CHSUMC; Shantou, China). The inclusion criteria were age 18 years or older, pathologically confirmed primary oesophageal squamous cell carcinoma, and no cancer treatments before serum sample collection. Participants without oesophageal-related diseases were recruited from the health examination department as the control group. The SENSORS-based diagnostic system is based on a multivariable logistic regression model that uses the detection values of SENSORS as the input and outputs a risk score for the predicted likelihood of oesophageal squamous cell carcinoma. We further evaluated the clinical utility of the system in an independent prospective multicentre study with different participants selected from the same three institutions. Patients with newly diagnosed oesophageal-related diseases without previous cancer treatment were enrolled. The inclusion criteria for healthy controls were no obvious abnormalities in routine blood and tumour marker tests, no oesophageal-associated diseases, and no history of cancer. Finally, we assessed whether classification could be improved by integrating machine-learning algorithms with the system, which combined baseline clinical characteristics, epidemiological risk factors, and serological tumour marker concentrations. Retrospective SYSUCC cohort I (randomly assigned [7:3] to a training set and an internal validation set) and three prospective validation sets (SYSUCC cohort II [internal validation], HNCH cohort II [external validation], and CHSUMC cohort II [external validation]) were used in this step. Six machine-learning algorithms were compared (the least absolute shrinkage and selector operator regression, ridge regression, random forest, logistic regression, support vector machine, and neural network), and the best-performing algorithm was chosen as the final prediction model. Performance of SENSORS and the SENSORS-based diagnostic system was primarily assessed using accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). FINDINGS: Between Oct 1, 2017, and April 30, 2020, 1051 participants were included in the retrospective study. In the prospective diagnostic study, 924 participants were included from April 2, 2022, to Feb 2, 2023. Compared with ELISA (108·90 pg/mL) and ECLIA (41·79 pg/mL), SENSORS (243·03 fg/mL) showed 448 times and 172 times improvements, respectively. In the three retrospective validation sets, the SENSORS-based diagnostic system achieved AUCs of 0·95 (95% CI 0·90-0·99) in the SYSUCC internal validation set, 0·93 (0·89-0·97) in the HNCH external validation set, and 0·98 (0·97-1·00) in the CHSUMC external validation set, sensitivities of 87·1% (79·3-92·3), 98·6% (94·4-99·8), and 93·5% (88·1-96·7), and specificities of 88·9% (75·2-95·8), 74·6% (61·3-84·6), and 92·1% (81·7-97·0), respectively, successfully distinguishing between patients with oesophageal squamous cell carcinoma and healthy controls. Additionally, in three prospective validation cohorts, it yielded sensitivities of 90·9% (95% CI 86·1-94·2) for SYSUCC, 84·8% (76·1-90·8) for HNCH, and 95·2% (85·6-98·7) for CHSUMC. Of the six machine-learning algorithms compared, the random forest model showed the best performance. A feature selection step identified five features to have the highest performance to predictions (SCC, age, MMP13, CEA, and NSE) and a simplified random forest model using these five features further improved classification, achieving sensitivities of 98·2% (95% CI 93·2-99·7) in the internal validation set from retrospective SYSUCC cohort I, 94·1% (89·9-96·7) in SYSUCC prospective cohort II, 88·6% (80·5-93·7) in HNCH prospective cohort II, and 98·4% (90·2-99·9) in CHSUMC prospective cohort II. INTERPRETATION: The SENSORS system facilitates highly sensitive detection of oesophageal squamous cell carcinoma tumour biomarkers, overcoming the limitations of detecting low-abundance circulating proteins, and could substantially improve oesophageal squamous cell carcinoma diagnostics. This method could act as a minimally invasive screening tool, potentially reducing the need for unnecessary endoscopies. FUNDING: The National Key R&D Program of China, the National Natural Science Foundation of China, and the Enterprises Joint Fund-Key Program of Guangdong Province. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Maternal Hypertension and Fecundability: A Population-Based Cohort Study.

BACKGROUND: The association of hypertension and blood pressure control with fecundability among women is not yet elucidated. The purpose of this study was to evaluate the hypothesis that maternal preconception hypertension would be associated with reduced fecundability and that blood pressure control could reduce excess risk. METHODS: Using the National Free Preconception Checkup Projects in Guangdong Province, China, 1422 couples whose female partners had been diagnosed with hypertension and 997 703 reference couples whose female partners were without hypertension were included in this prospective cohort study. Fecundability was measured by time to pregnancy (TTP) and infertility (TTP >12 months). RESULTS: Compared with women without hypertension, those with controlled hypertension (time ratio, 1.47 [95% CI, 1.24-1.73]) or uncontrolled hypertension (time ratio, 1.59 [95% CI, 1.34-1.90]) were associated with prolonged TTP and increased risk of infertility (relative risk, 1.19 [95% CI, 1.09-1.31]; relative risk, 1.24 [95% CI, 1.14-1.34]). However, using instrumental variable analyses, there was no significant association between blood pressure control and TTP (time ratio, 0.68 [95% CI, 0.34-1.36]; P=0.270) or infertility (relative risk, 0.97 [95% CI, 0.70-1.34]; P=0.849) among women with hypertension. These results were consistent in the propensity score matching and inverse probability of treatment weighting analyses. CONCLUSIONS: Maternal hypertension, with or without controlled blood pressure, was independently associated with prolonged TTP and an increased risk of infertility. These findings may provide insights for the implementation of preconception hypertension screening and the design of future trials.

Research on the application of AHP-FAST-FBS in the design of home entrance disinfection devices in the post-pandemic era.

With the outbreak and continued spread of the COVID-19 pandemic, people's demand for daily disinfection products has increased rapidly, and its innovative design has received widespread attention. In this context, this study aims to propose a design methodology for home entrance disinfection devices based on AHP-FAST-FBS. Firstly, the design requirements of the home entrance disinfection device were collected and analyzed through in-depth interviews and the KJ method, and a hierarchical model of design demand indicators was constructed. Secondly, the Analytical Hierarchy Process (AHP) was employed to quantify these design demand indicators, and core design demands for home entrance disinfection devices were identified by weight calculations. On this basis, the Functional Analysis System Technique (FAST) method was combined to rationally transform the design demands into product functional indicators, constructing a functional system model for the home entrance disinfection device through systematic decomposition and categorization. Lastly, based on the Function-Behavior-Structure (FBS) theoretical model, the mapping of each function of the product to its structure was realized, the product structure modules were determined, and the comprehensive design and output of the innovative design scheme for the home entrance disinfection device were completed. The results of this study indicate that the design methodology combining AHP-FAST-FBS can effectively improve the scientific rigor and effectiveness of the home entrance disinfection device design, thereby generating an ideal product design scheme. This study provides systematic theoretical guidance and practical reference for designers of subsequent related disinfection products and also offers a new path for improving social health and safety.

Hydrogel Microneedle Patches Loaded with Stem Cell Mitochondria-Enriched Microvesicles Boost the Chronic Wound Healing.

Rescuing or compensating mitochondrial function represents a promising therapeutic avenue for radiation-induced chronic wounds. Adult stem cell efficacies are primarily dependent on the paracrine secretion of mitochondria-containing extracellular vesicles (EVs). However, effective therapeutic strategies addressing the quantity of mitochondria and mitochondria-delivery system are lacking. Thus, in this study, we aimed to design an effective hydrogel microneedle patch (MNP) loaded with stem cell-derived mitochondria-rich EVs to gradually release and deliver mitochondria into the wound tissues and boost wound healing. We, first, used metformin to enhance mitochondrial biogenesis and thereby increasing the secretion of mitochondria-containing EVs (termed "Met-EVs") in adipose-derived stem cells. To verify the therapeutic effects of Met-EVs, we established an in vitro and an in vivo model of X-ray-induced mitochondrial dysfunction. The Met-EVs ameliorated the mitochondrial dysfunction by rescuing mitochondrial membrane potential, increasing adenosine 5'-triphosphate levels, and decreasing reactive oxygen species production by transferring active mitochondria. To sustain the release of EVs into damaged tissues, we constructed a Met-EVs@Decellularized Adipose Matrix (DAM)/Hyaluronic Acid Methacrylic Acid (HAMA)-MNP. Met-EVs@DAM/HAMA-MNP can load and gradually release Met-EVs and their contained mitochondria into wound tissues to alleviate mitochondrial dysfunction. Moreover, we found Met-EVs@DAM/HAMA-MNP can markedly promote macrophage polarization toward the M2 subtype with anti-inflammatory and regenerative functions, which can, in turn, enhance the healing process in mice with skin wounds combined radiation injuries. Collectively, we successfully fabricated a delivery system for EVs, Met-EVs@DAM/HAMA-MNP, to effectively deliver stem cell-derived mitochondria-rich EVs. The effectiveness of this system has been demonstrated, holding great potential for chronic wound treatments in clinic.

Restoration of ARA metabolic disorders in vascular smooth muscle cells alleviates intimal hyperplasia.

Intimal hyperplasia (IH) is an innegligible issue for patients undergoing interventional therapy. The proliferation and migration of vascular smooth muscle cells (VSMCs) induced by platelet-derived growth factor-BB (PDGF-BB) are critical events in the development of IH. While the exact mechanism and effective target for IH needs further investigation. Metabolic disorders of arachidonic acid (ARA) are involved in the occurrence and progression of various diseases. In this study, we found that the expressions of soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) were significantly increased in the VSMCs during balloon injury-induced IH. Then, we employed a COX-2/sEH dual inhibitor PTUPB to increase the concentration of epoxyeicosatrienoic acids (EETs) while prevent the release of pro-inflammatory prostaglandins. Results showed that PTUPB treatment significantly reduced neointimal thickening induced by balloon injury in rats in vivo and inhibited PDGF-BB-induced proliferation and migration of VSMCs in vitro. Our results showed that PTUPB may reverse the phenotypic transition of VSMCs by inhibiting Pttg1 expression. In conclusion, we found that the dysfunction of ARA metabolism in VSMCs contributes to IH, and the COX-2/sEH dual inhibitor PTUPB attenuates IH progression by reversing the phenotypic switch in VSMC through the Sirt1/Pttg1 pathway.

Recent advances in pathogenesis, diagnosis, and therapeutic approaches for digestive system involvement in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the presence of large amounts of autoantibodies and immune complex formation. Because of their atypical clinical symptoms, SLE patients with digestive system involvement may not be recognized or treated precisely and extensively. Clinicians should pay close attention to SLE with digestive system involvement, as these conditions can easily worsen the condition and possibly endanger the patient's life. In this review we summarized the pathogenesis, pathological characteristics, clinical manifestations, diagnosis, and therapies for digestive system involvement in SLE.

Design, Synthesis, and Antifeedant Activity Evaluation of 13/14-Arylthioether Matrine Derivatives.

Introducing a sulfur atom into active agricultural molecules is an important strategy for pesticide development. Matrine, an environmentally friendly botanical pesticide, has the advantage of being easily degraded and has drawn attention in the agricultural field. To explore the novel matrine-type pesticides, in this study, we designed and synthesized 13/14-arylthioether matrine derivatives by introducing various aryl sulfide motifs into bioactive matrine. Most of the synthesized arylthioether matrines exhibited good antifeedant activity against Spodoptera exigua. Among them, compound 2q showed the best antifeedant effect with an EC50 value of 0.038 mg/mL, which is approximately 125-fold more activity than matrine and reached the activity level of commercial standard azadirachtin A. Furthermore, compound 2q exhibited an inhibitory effect on antifeedant-related enzyme carboxylesterase (CarE) from S. exigua. In short, the high activity of arylthioether matrines offers new insights into developing new antifeedants.

The dual role of glucocorticoid regeneration in inflammation at parturition.

Introduction: Fetal membrane inflammation is an integral event of parturition. However, excessive pro-inflammatory cytokines can impose threats to the fetus. Coincidentally, the fetal membranes express abundant 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1), which generates biologically active cortisol to promote labor through induction of prostaglandin synthesis. Given the well-recognized anti-inflammatory actions of glucocorticoids, we hypothesized that cortisol regenerated in the fetal membranes might be engaged in restraining fetus-hazardous pro-inflammatory cytokine production for the safety of the fetus, while reserving pro-labor effect on prostaglandin synthesis to ensure safe delivery of the fetus. Methods: The hypothesis was examined in human amnion tissue and cultured primary human amnion fibroblasts as well as a mouse model. Results: 11ß-HSD1 was significantly increased in the human amnion in infection-induced preterm birth. Studies in human amnion fibroblasts showed that lipopolysaccharide (LPS) induced 11ß-HSD1 expression synergistically with cortisol. Cortisol completely blocked NF-κB-mediated pro-inflammatory cytokine expression by LPS, but STAT3-mediated cyclooxygenase 2 expression, a crucial prostaglandin synthetic enzyme, remained. Further studies in pregnant mice showed that corticosterone did not delay LPS-induced preterm birth, but alleviated LPS-induced fetal organ damages, along with increased 11ß-HSD1, cyclooxygenase 2, and decreased pro-inflammatory cytokine in the fetal membranes. Discussion: There is a feed-forward cortisol regeneration in the fetal membranes in infection, and cortisol regenerated restrains pro-inflammatory cytokine expression, while reserves pro-labor effect on prostaglandin synthesis. This dual role of cortisol regeneration can prevent excessive pro-inflammatory cytokine production, while ensure in-time delivery for the safety of the fetus.