Dietary supplements in polycystic ovary syndrome-current evidence.

Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder in women of reproductive age, and presents a significant challenge to the global population. This review provides comprehensive evidence of interventions, including food and dietary supplements, aimed at reversing PCOS and improving fertility outcomes. Various dietary supplements are known to cause metabolic changes and hormonal regulation and have a potential impact on increasing pregnancy rates. Although some biochemical alterations have been observed, these metabolic changes do not directly reverse the disorder. Moreover, the lack of sufficient evidence does not convince clinicians to standardize dietary supplements as alternatives to medical or pharmacological interventions. This calls for a study of women with PCOS taking dietary supplements. In addition, unbiased studies of combinations of treatment options for supplements, including large cohort clinical trials, will lead to evidence-based medicine.

Functionalized composite nanofiber membranes for selective steroid hormone micropollutants uptake from water: Role of cyclodextrin type.

Cyclodextrins (CD) entrapped in nanofiber composite membranes are potential selective adsorbing materials to remove steroid hormone (SHs) micropollutants from water. This study aims to elucidate the role of CD macrocyclic host type on the SHs inclusion complexation and uptake in filtration. Three CD types (α, ß, and γ) are cross-linked with epichlorohydrin to form polymers (αCDP, ßCDP and γCDP) and entrapped into a nanofiber composite membrane by electrospinning. TGA analysis confirmed the CD entrapment into the nanofiber without loss of CD molecules during filtration. The CD type plays a dominant role in controlling the removal of different SHs. A similar removal (range 33 to 50 %) was observed with αCDP, irrespective of the SH type. In contrast, removal and uptake dependent on SH type were observed for ß and γCDP, with the highest removal of 74 % for progesterone, followed by estradiol (46 %) and estrone (27 %) and the lowest removal of 3 % for testosterone. Molecular dynamic (MD) simulation revealed a stronger and more stable complex formed with ßCDP, as demonstrated by: i) the closer spatial distribution of SH molecules from the ßCDP cavity and, ii) the quantum chemistry calculations of the lower de-solvation energy (+6.0 kcal/mol), which facilitates the release of water molecules from interacting interface of CD molecule and hormone. Regarding γCDP, the highest de-solvation energy (+8.3 kcal/mol) poses an energetic barrier, which hinders the formation of the inclusion complex. In the case of αCDP, a higher interaction energy (-8.9 kcal/mol) compared to ßCDP (-4.9 kcal/mol) was obtained, despite the broader spatial distribution observed from the MD simulation attributed to a dominant hydrogen bonding interaction with the OH primary groups on the external surface cavity. The findings highlight the relevance of the CD type in designing selective adsorbing membranes for steroid hormone micropollutant uptake. Experimental results and MD simulation suggest that ßCD is the most suitable CD type for steroid hormone uptake, due to a more stable and stronger inclusion complexation than α and γCD.

Porcine reproductive and respiratory syndrome virus activates lipid synthesis through a ROS-dependent AKT/PCK1/INSIG/SREBPs axis.

The porcine reproductive and respiratory syndrome virus (PRRSV) is a highly contagious pathogen in pigs. This study aimed to investigate the impact of PRRSV infection on cellular metabolism, particularly focusing on lipid metabolism to understand its role in promoting viral replication. We conducted a metabolic analysis on MARC-145 cells before and after PRRSV infection. Our results demonstrated that the most significant alterations in cellular metabolism, accounting for 40.8 % of total changes, were related to lipid metabolism. These changes were primarily driven by the activation of sterol regulatory-element binding proteins (SREBPs), critical regulators of lipid biosynthesis. To understand the mechanisms behind SREBPs activation by PRRSV, we investigated the involvement of upstream effectors, specifically protein kinase B (AKT) and phosphoenolpyruvate carboxykinase 1 (PCK1). Our findings indicated that PRRSV infection triggered AKT activation, leading to the subsequent activation of PCK1. Activated PCK1 then phosphorylated insulin-induced genes (INSIGs), resulting in their degradation. This degradation facilitated the translocation of SREBPs from the endoplasmic reticulum to the nucleus. Additionally, we observed that PRRSV infection stimulated the production of reactive oxygen species (ROS), which played a critical role in activating AKT. Collectively, our findings demonstrate that PRRSV enhances lipid synthesis through a ROS-dependent AKT/PCK1/INSIG/SREBPs signaling axis, which provides new insights into the metabolic strategies employed by PRRSV.

Analysis of computed tomography venography for the diagnosis and endovascular treatment of iliac venous compression syndrome with venous leg ulcers: a retrospective study.

Iliac vein compression syndrome (IVCS) is a clinical condition defined as obstruction of the iliac vein caused by chronic compression imposed by various causes. Currently, the clinical role of computed tomography venography (CTV) in the diagnosis of IVCS is unclear. Accurately diagnosing IVCS using CTV may enhance the understanding of the pathological anatomy of iliac veins, which may lead to better treatment outcomes, especially for recalcitrant venous leg ulcers (VLU). We aimed to investigate diagnostic criteria, contributing clinical factors, and stenting for IVCS with VLU in this study. CTV, digital subtraction angiography (DSV), and Doppler ultrasound (DUS) data were obtained from the medical and imaging records of 62 patients. Additionally, contributing factors and stenting for IVCS were analysed. Patients (100%) had clinical, aetiological, anatomic, or pathological C6 disease. CTV reduced the procedure time and contrast medium dose and provided more information than DSV. Risk factors for IVCS with VLU included female sex (P = 0.036) and advanced age (P = 0.014). The rate of ulcer healing was lower in the IVCS group without stent implantation (P = 0.020). Significant improvements were noted in venous clinical severity scores (P < 0.001) and chronic venous insufficiency questionnaire-20 scores (P < 0.001) after stenting for IVCS with C6 ulcers. CTV provides a more accurate diagnosis than DUS and DSV and allows detection of possible causes of IVCS. Female sex and advanced age were potential contributing factors for IVCS. Satisfactory outcomes were observed with stenting in the treatment of IVCS with C6 ulcers.

The Innovative Role of Nuclear Receptor Interaction Protein in Orchestrating Invadosome Formation for Myoblast Fusion.

BACKGROUND: Nuclear receptor interaction protein (NRIP) is versatile and engages with various proteins to execute its diverse biological function. NRIP deficiency was reported to cause small myofibre size in adult muscle regeneration, indicating a crucial role of NRIP in myoblast fusion. METHODS: The colocalization and interaction of NRIP with actin were investigated by immunofluorescence and immunoprecipitation assay, respectively. The participation of NRIP in myoblast fusion was demonstrated by cell fusion assay and time-lapse microscopy. The NRIP mutants were generated for mechanism study in NRIP-null C2C12 (termed KO19) cells and muscle-specific NRIP knockout (NRIP cKO) mice. A GEO profile database was used to analyse NRIP expression in Duchenne muscular dystrophy (DMD) patients. RESULTS: In this study, we found that NRIP directly and reciprocally interacted with actin both in vitro and in cells. Immunofluorescence microscopy showed that the endogenous NRIP colocalized with components of invadosome, such as actin, Tks5, and cortactin, at the tips of cells during C2C12 differentiation. The KO19 cells were generated and exhibited a significant deficit in myoblast fusion compared with wild-type C2C12 cells (3.16% vs. 33.67%, p < 0.005). Overexpressed NRIP in KO19 cells could rescue myotube formation compared with control (3.37% vs. 1.00%, p < 0.01). We further confirmed that NRIP directly participated in cell fusion by using a cell-cell fusion assay. We investigated the mechanism of invadosome formation for myoblast fusion, which depends on NRIP-actin interaction, by analysing NRIP mutants in NRIP-null cells. Loss of actin-binding of NRIP reduced invadosome (enrichment ratio, 1.00 vs. 2.54, p < 0.01) and myotube formation (21.82% vs. 35.71%, p < 0.05) in KO19 cells and forced NRIP expression in KO19 cells and muscle-specific NRIP knockout (NRIP cKO) mice increased myofibre size compared with controls (over 1500 µm2, 61.01% vs. 20.57%, p < 0.001). We also found that the NRIP mRNA level was decreased in DMD patients compared with healthy controls (18 072 vs. 28 289, p < 0.001, N = 10 for both groups). CONCLUSIONS: NRIP is a novel actin-binding protein for invadosome formation to induce myoblast fusion.

Proteomics analysis of immune response-related proteins in Guillain-Barré Syndrome (GBS) and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP).

The objective is to characterize differentially expressed proteins (DEPs) in Guillain-Barré Syndrome (GBS) and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) through high-throughput analysis. Sera from 11 healthy controls (HCs), 21 GBS and 19 CIDP patients were subjected to Olink Proteomics Analysis. In the comparison between CIDP and GBS groups, up-regulation of ITM2A and down-regulation of NTF4 were observed. Comparing GBS with HCs revealed 18 up-regulated and 4 down-regulated proteins. Comparing CIDP with the HCs identified 15 up-regulated and 4 down-regulated proteins. Additionally, the correlation between clinical characteristics and DEPs were uncovered. In conclusion, the DEPs have significant potential to advance our understanding of the pathogenesis in these debilitating neurological disorders.

Vagus nerve stimulation (VNS) preventing postoperative cognitive dysfunction (POCD): two potential mechanisms in cognitive function.

Postoperative cognitive dysfunction (POCD) impacts a significant number of patients annually, frequently impairing their cognitive abilities and resulting in unfavorable clinical outcomes. Aimed at addressing cognitive impairment, vagus nerve stimulation (VNS) is a therapeutic approach, which was used in many mental disordered diseases, through the modulation of vagus nerve activity. In POCD model, the enhancement of cognition function provided by VNS was shown, demonstrating VNS effect on cognition in POCD. In the present study, we primarily concentrates on elucidating the role of the VNS improving the cognitive function in POCD, via two potential mechanisms: the inflammatory microenvironment and epigenetics. This study provided a theoretical support for the feasibility that VNS can be a potential method to enhance cognition function in POCD.

The anti-rheumatoid arthritic activity of Artemisia ordosica Krasch. (traditional Chinese/Mongolian medicine) extract in collagen-induced arthritis in rats.

OBJECTIVES: Rheumatoid arthritis (RA) seriously affects the daily life of people. The whole plant of Artemisia ordosica Krasch. (AOK) has been used in folk medicine. This study aimed to investigate the in vivo anti-RA effects of AOK extract (AOKE) on collagen-induced arthritis in rats. METHODS: AOKE (400, 200, or 100 mg/kg) was administered orally to animals for 30 days. Body weight, paw swelling, arthritis index, thymus, and spleen indices, and pathological changes were assessed for effects of AOKE on RA. Furthermore, the inflammatory cytokines in rat serum were detected. In addition, the expressions of STAT3, Caspase-3, Galectin-3, and S100A9 in synovial tissue were researched using immunohistochemistry. KEY FINDINGS: The AOKE significantly reduced the arthritis indices, paw swelling, spleen, and thymus indices. Meanwhile, AOKE (400 mg/kg) decreased the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-17A, and increased the level of IL-10 in rat serum. Histopathological examination showed that AOKE reduced inflammatory cell infiltration and cartilage erosion. Then, AOKE decreased the expressions of STAT3, Galectin-3, S100A9, and increased the expression of Caspase-3. CONCLUSION: AOKE had interesting anti-RA activity in rats, which deserved further research for the development and clinical use of this medicinal resource.

Impact of Pulmonary Ventilation Dysfunction on Prognosis of Patients with Coronary Artery Disease: A Single-Center, Observational Study.

Background: Patients with coronary artery disease (CAD) often experience pulmonary ventilation dysfunction following their initial event. However, there is insufficient research exploring the relationship between this dysfunction and CAD prognosis. Methods: To address this gap, a retrospective observational study was conducted involving 3800 CAD patients without prior pulmonary ventilation disease who underwent cardiopulmonary exercise testing (CPET) during hospitalization between November 2015 and September 2021. The primary endpoint was a composite of major adverse cardiovascular events (MACE), such as death, myocardial infarction (MI), repeat revascularization, and stroke. Propensity score matching (PSM) was used to minimize selection bias between the two groups, with a subgroup analysis stratified by smoking status. Results: The results showed that patients were divided into normal (n = 2159) and abnormal (n = 1641) groups based on their pulmonary ventilation function detected by CPET, with 1469 smokers and 2331 non-smokers. The median follow-up duration was 1237 (25-75% interquartile range 695-1596) days. The primary endpoint occurred in 390 patients (10.26%). 1472 patients in each of the two groups were enrolled in the current analysis after PSM, respectively. However, pulmonary function was not associated with MACE before (hazard ratio (HR) 1.20, 95% confidence interval (95% CI) 0.99-1.47; Log-rank p = 0.069) or after PSM (HR 1.07, 95% CI 0.86-1.34; Log-rank p = 0.545) among the entire population. Nonetheless, pulmonary ventilation dysfunction was significantly associated with an increased risk of MACE in smoking patients (HR 1.65, 95% CI 1.25-2.18; p < 0.001) but not in non-smoking patients (HR 0.81, 95% CI 0.60-1.09; p = 0.159). In addition, there was a significant interaction between current smoking status and pulmonary ventilation dysfunction on MACE (p for interaction < 0.001). Conclusions: Pulmonary ventilation dysfunction identified through CPET was independently associated with long-term poor prognosis in smoking patients with CAD but not in the overall population.

Heterostructure g-C3N4/Bi2MoO6 PVDF nanofiber composite membrane for the photodegradation of steroid hormone micropollutants.

Photocatalytic membrane reactors (PMRs) are a promising technology for micropollutant removal. Sunlight utilization and catalyst surface sites limit photodegradation. A poly(vinylidene fluoride) (PVDF) nanofiber composite membrane (NCM) with immobilized visible-light-responsive g-C3N4/Bi2MoO6 (BMCN) were developed. Photodegradation of steroid hormones with the PVDF-BMCN NCM was investigated with varying catalyst properties, operating conditions, and relevant solution chemistry under solar irradiation. Increasing CN ratio (0-65 %) enhanced estradiol (E2) degradation from 20 ± 10 to 75 ± 7 % due to improved sunlight utilization and photon lifetime. PVDF nanofibers reduced self-aggregation of catalysts. Hydraulic residence time and light intensity enhanced the photodegradation. With the increasing pH value, the E2 removal decreased from 84 ± 4 to 67 ± 7 % owing to electrical repulsion and thus reduced adsorption between catalysts and E2. A removal of 96 % can be attained at environmentally relevant feed concentration (100 ng.L-1) with a flux of 60 L.m-2.h-1, irradiance of 100 mW.cm-2, and 1 mg.cm-2 BMCN65 loading. This confirmed that heterojunction photocatalysts can enhance micropollutants degradation in PMRs.

Squamous cell carcinoma of ear and temporal bone: A retrospective study on clinicopathological predictors.

BACKGROUND: Ear and temporal bone squamous cell carcinoma (ETBSCC) is a rare and aggressive malignant tumor with minimal clinicopathological studies. The object of this study was to retrospectively evaluate the predictive effect of clinicopathological variables on the 5-year overall survival (OS) rate of ETBSCC patients in a single tertiary medical center in Tianjin, China. METHODS: A cohort of 44 patients with diagnosed ETBSCC from December 2012 to August 2022 were retrospectively studied. Univariate and multivariate analysis were, respectively, performed for the assessment of clinicopathological predictors, including sex, age, history of chronic suppurative otitis media (CSOM), lesion side, diameter, the choice of surgical approach, parotidectomy, neck dissection, adjuvant therapies, T stage, lymph node metastasis, tumor grade, margin, perineural invasion (PNI), and Ki-67 index. RESULTS: Seventeen females and 27 males were included, with the mean age of 65 years old, ranging from 36 to 89 years. The 5-year OS rate was 43% (mean 51 months, 95% confidence interval [CI] = 39-64). Significant prediction of a worse prognosis for 5-year OS rate was observed under univariate analysis for advanced T stage, positive margin, identified PNI, and higher Ki-67 index, respectively. Advanced T stage was confirmed to be an independent prognostic factor strongly affecting 5-year OS rate among this cohort of patients using a multivariate cox proportional hazard model. CONCLUSION: We found that clinicopathological parameters, especially postoperative pathological parameters, play a critical role in predicting the prognosis of ETBSCC patients.

ICU Nurses' Perception of Sensitive Indicators of Quality of Care for ECMO Patients in Guizhou Province, China: A Cross-Sectional Study.

Purpose: This study aimed to investigate the cognitive evaluation level of ICU nurses in Guizhou Province, China, on the sensitivity indicators of nursing quality for ECMO patients. Patients and Methods: This was a cross-sectional observational study conducted in Guizhou Province, China, from May to July 2023, 259 ICU nurses were surveyed. Objective sampling method was used to select the participants from 10 hospitals in Guizhou Province that carried out ECMO. Data were collected through questionnaire survey. Two researchers checked and recorded Epidata 3.1. SPSS 25.0 was used for statistical analysis of the data, and frequency, mean and component ratio were used for descriptive statistical analysis. The importance rating was used to reflect the degree of nurses' agreement with the indicators. Results: The results of this study showed that 79.1% of the 253 ICU nurses in Guizhou Province, China, had not participated in training and courses related to indicators of quality of care evaluation for ECMO patients. The main way for ICU nurses to acquire knowledge related to indicators of quality of care sensitivity for ECMO patients was departmental training, which accounted for 87.4%. And the other ways, in descending order, were public, the matic lectures or academic conferences, journals and magazines; their evaluation scores of the importance of most of the quality of care sensitivity indicators for ECMO patients was moderate, with the scores ranging from 73 to 150. Among them, the range of importance evaluation scores for each indicator was 4.01 ~ 4.48. Conclusion: The overall cognitive evaluation of ICU nurses in Guizhou Province, China, on most sensitivity indicators of quality of care for ECMO patients was moderate, and there is a general lack of systematic courses and training on the knowledge related to ECMO care quality sensitive indicators.

A Novel Frameshift Variant of the ELF4 Gene in a Patient with Autoinflammatory Disease: Clinical Features, Transcriptomic Profiling and Functional Studies.

We described the diagnosis and treatment of a patient with autoinflammatory disease, named "Deficiency in ELF4, X-linked (DEX)". A novel ELF4 variant was discovered and its pathogenic mechanism was elucidated. The data about clinical, laboratory and endoscopic features, treatment, and follow-up of a patient with DEX were analyzed. Whole exome sequencing and Sanger sequencing were performed to identify potential pathogenic variants. The mRNA and protein levels of ELF4 were analyzed by qPCR and Western blotting, respectively. The association of ELF4 frameshift variant with nonsense-mediated mRNA decay (NMD) in the pathogenesis DEX was examined. Moreover, RNA-seq was performed to identify the key molecular events triggered by ELF4 variant. The relationship between ELF4 and IFN-ß activity was validated using a dual-luciferase reporter assay and a ChIP-qPCR assay. An 11-year-old boy presented with a Behçet's-like phenotype. The laboratory abnormality was the most obvious in elevated inflammatory indicators. Endoscopy revealed multiple ileocecal ulcers. Intestinal histopathology showed inflammatory cell infiltrations. The patient was treated with long-term immunosuppressant and TNF-α blocker (adalimumab), which reaped an excellent response over 16 months of follow-up. Genetic analysis identified a maternal hemizygote frameshift variant (c.1022del, p.Q341Rfs*30) in ELF4 gene in the proband. The novel variant decreased the mRNA level of ELF4 via the NMD pathway. Mechanistically, insufficient expression of ELF4 disturbed the immune system, leading to immunological disorders and pathogen susceptibility, and disrupted ELF4-activating IFN-ß responses. This analysis detailed the clinical characteristics of a Chinese patient with DEX who harbored a novel ELF4 frameshift variant. For the first time, we used patient-derived cells and carried out transcriptomic analysis to delve into the mechanism of ELF4 variant in DEX.

Silver Nanoparticles Encapped by Dihydromyricetin: Optimization of Green Synthesis, Characterization, Toxicity, and Anti-MRSA Infection Activities for Zebrafish (Danio rerio).

To achieve the environmentally friendly and rapid green synthesis of efficient and stable AgNPs for drug-resistant bacterial infection, this study optimized the green synthesis process of silver nanoparticles (AgNPs) using Dihydromyricetin (DMY). Then, we assessed the impact of AgNPs on zebrafish embryo development, as well as their therapeutic efficacy on zebrafish infected with Methicillin-resistant Staphylococcus aureus (MRSA). Transmission electron microscopy (TEM) and dynamic light-scattering (DLS) analyses revealed that AgNPs possessed an average size of 23.6 nm, a polymer dispersity index (PDI) of 0.197 ± 0.0196, and a zeta potential of -18.1 ± 1.18 mV. Compared to other published green synthesis products, the optimized DMY-AgNPs exhibited smaller sizes, narrower size distributions, and enhanced stability. Furthermore, the minimum concentration of DMY-AgNPs required to affect zebrafish hatching and survival was determined to be 25.0 µg/mL, indicating the low toxicity of DMY-AgNPs. Following a 5-day feeding regimen with DMY-AgNP-containing food, significant improvements were observed in the recovery of the gills, intestines, and livers in MRSA-infected zebrafish. These results suggested that optimized DMY-AgNPs hold promise for application in aquacultures and offer potential for further clinical use against drug-resistant bacteria.

[Analysis of 41 cases of non-metastatic Ewing's sarcoma in children]. / 儿童非转移性尤文肉瘤41例分析.

OBJECTIVES: To summarize the clinical characteristics, treatment outcomes, and prognostic factors of children with non-metastatic Ewing's sarcoma (ES). METHODS: A retrospective analysis was conducted on the clinical data of 41 children with non-metastatic ES diagnosed and treated at the Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine from January 2010 to December 2018. All patients underwent chemotherapy based on the RMS-2009 protocol of the center, and local treatment such as surgery and/or radiotherapy was performed according to risk grouping. The Kaplan-Meier method was used to calculate the overall survival (OS) and event-free survival (EFS) rates. Univariate prognostic analysis was performed using the log-rank test, and multivariate analysis was conducted with Cox regression. RESULTS: Of the 41 children, 21 were male and 20 were female. The median age at diagnosis was 7.7 years (range: 1.2-14.6 years). The median follow-up time for patients with event-free survival was 68.1 months (range: 8.1-151.7 months). As of the last follow-up, 33 patients were in complete remission, and the overall 5-year EFS and OS rates were (78±6)% and (82±6)%, respectively. Univariate analysis by the log-rank test showed that a tumor diameter ≥8 cm, time from diagnosis to start of local treatment ≥16 weeks, and incomplete surgical resection were associated with poor prognosis (P<0.05). Multivariate Cox regression analysis indicated that incomplete surgical resection (HR=8.381, 95%CI: 1.681-41.801, P=0.010) was an independent risk factor for poor prognosis in children with ES. Secondary tumors occurred in 2 cases. CONCLUSIONS: A comprehensive treatment strategy incorporating chemotherapy, surgery, and radiotherapy can improve the prognosis of children with ES. Poor prognosis is associated with an initial tumor diameter ≥8 cm, while complete surgical resection and early initiation of local treatment can improve outcomes.

Chinese Guidelines for the Diagnosis and Management of Atrial Fibrillation.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, significantly impacting patients' quality of life and increasing the risk of death, stroke, heart failure, and dementia. Over the past two decades, there have been significant breakthroughs in AF risk prediction and screening, stroke prevention, rhythm control, catheter ablation, and integrated management. During this period, the scale, quality, and experience of AF management in China have greatly improved, providing a solid foundation for the development of guidelines for the diagnosis and management of AF. To further promote standardized AF management, and apply new technologies and concepts to clinical practice in a timely and comprehensive manner, the Chinese Society of Cardiology of the Chinese Medical Association and the Heart Rhythm Committee of the Chinese Society of Biomedical Engineering have jointly developed the Chinese Guidelines for the Diagnosis and Management of Atrial Fibrillation. The guidelines have comprehensively elaborated on various aspects of AF management and proposed the CHA2DS2-VASc-60 stroke risk score based on the characteristics of AF in the Asian population. The guidelines have also reevaluated the clinical application of AF screening, emphasized the significance of early rhythm control, and highlighted the central role of catheter ablation in rhythm control.

Ticagrelor with or without aspirin following percutaneous coronary intervention in high-risk patients with concomitant peripheral artery disease: A subgroup analysis of the TWILIGHT randomized clinical trial.

BACKGROUND: The optimal antiplatelet regimen after percutaneous coronary intervention (PCI) in patients with peripheral artery disease (PAD) is still debated. This analysis aimed to compare the effect of ticagrelor monotherapy versus ticagrelor plus aspirin in patients with PAD undergoing PCI. METHODS: In the TWILIGHT trial, patients at high ischemic or bleeding risk that underwent PCI were randomized after 3 months of dual antiplatelet therapy (DAPT) to aspirin or matching placebo in addition to open-label ticagrelor for 12 additional months. In this post-hoc analysis, patient cohorts were examined according to the presence or absence of PAD. The primary endpoint was Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding. The key secondary endpoint was a composite of all-cause death, myocardial infarction (MI), or stroke. Endpoints were assessed at 12 months after randomization. RESULTS: Among 7,119 patients, 489 (7%) had PAD and were older, more likely to have comorbidities, and multivessel disease. PAD patients had more bleeding or ischemic complications than no-PAD patients. Ticagrelor monotherapy compared to ticagrelor plus aspirin was associated with less BARC 2, 3, or 5 bleeding in PAD (4.6% vs 8.7%; HR 0.52; 95%CI 0.25-1.07) and no-PAD patients (4.0% vs 7.0%; HR 0.56; 95%CI 0.45-0.69; interaction P-value .830) and a similar risk of death, MI, or stroke in these 2 groups (interaction P-value .446). CONCLUSIONS: Despite their higher ischemic and bleeding risk, patients with PAD undergoing PCI derived a consistent benefit from ticagrelor monotherapy after 3 months of DAPT in terms of bleeding reduction without any relevant increase in ischemic events. CLINICAL TRIAL REGISTRY INFORMATION:: https://www. CLINICALTRIALS: gov/study/NCT02270242.

Microglial ApoD-induced NLRC4 inflammasome activation promotes Alzheimer's disease progression.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease with no effective therapies. It is well known that chronic neuroinflammation plays a critical role in the onset and progression of AD. Well-balanced neuronal-microglial interactions are essential for brain functions. However, determining the role of microglia-the primary immune cells in the brain-in neuroinflammation in AD and the associated molecular basis has been challenging. METHODS: Inflammatory factors in the sera of AD patients were detected and their association with microglia activation was analyzed. The mechanism for microglial inflammation was investigated. IL6 and TNF-α were found to be significantly increased in the AD stage. RESULTS: Our analysis revealed that microglia were extensively activated in AD cerebra, releasing sufficient amounts of cytokines to impair the neural stem cells (NSCs) function. Moreover, the ApoD-induced NLRC4 inflammasome was activated in microglia, which gave rise to the proinflammatory phenotype. Targeting the microglial ApoD promoted NSC self-renewal and inhibited neuron apoptosis. These findings demonstrate the critical role of ApoD in microglial inflammasome activation, and for the first time reveal that microglia-induced inflammation suppresses neuronal proliferation. CONCLUSION: Our studies establish the cellular basis for microglia activation in AD progression and shed light on cellular interactions important for AD treatment.

Comparison of oral aprepitant and intravenous fosaprepitant for prevention of chemotherapy-induced nausea and vomiting in pediatric oncology patients: a randomized phase III trial.

Background: Neurokinin-1 receptor antagonists have improved the management of chemotherapy-induced nausea and vomiting (CINV), but to date there has been no prospective comparison between oral aprepitant and intravenous fosaprepitant in pediatric oncology patients. Methods: Our study was a double-parallel study, and the distribution ratio was 1:1. Children aged 2-12 years who were undergoing moderate or highly emetogenic chemotherapy (MEC or HEC) were randomly assigned to receive ondansetron and dexamethasone combined with either a single dose of intravenous fosaprepitant (arm A), or 3 days of oral aprepitant (arm B). The primary outcome measure was the rate of complete response (CR) of CINV within the acute phase, defined as from the start through 24 hours after the last chemotherapy dose. Response during the delayed phase, overall response, and use of rescue antiemetics were also assessed. Results: We prospectively evaluated 108 eligible patients, including 55 receiving fosaprepitant. Study observations were made during a single cycle for each patient. The occurrence of CR in the acute phase was statistically higher for patients receiving fosaprepitant (95% vs. 79%, P=0.018<0.05). Modest differences were seen in CR rates during the delayed phase (71% vs. 66%, P=0.586), and overall response rate (69% vs. 57%, P=0.179). The use of antiemetic rescue medicines was similar between arms A (11%) and B (7%). Conclusions: Fosaprepitant produced more CRs of CINV in the acute phase than did aprepitant, although there were no statistical differences in delayed phase response, overall response, or use of rescue antiemetics. This study confirms the safety, efficacy, and potential advantages of fosaprepitant in reducing CINV in pediatric oncology patients. Trial Registration: ClinicalTrials.gov identifier: NCT04873284.

DsbA-L ameliorates renal aging and renal fibrosis by maintaining mitochondrial homeostasis.

Renal fibrosis is the final pathological change in renal disease, and aging is closely related to renal fibrosis. Mitochondrial dysfunction has been reported to play an important role in aging, but the exact mechanism remains unclear. Disulfide-bond A oxidoreductase-like protein (DsbA-L) is mainly located in mitochondria and plays an important role in regulating mitochondrial function and endoplasmic reticulum (ER) stress. However, the role of DsbA-L in renal aging has not been reported. In this study, we showed a reduction in DsbA-L expression, the disruption of mitochondrial function and an increase in fibrosis in the kidneys of 12- and 24-month-old mice compared to young mice. Furthermore, the deterioration of mitochondrial dysfunction and fibrosis were observed in DsbA-L-/- mice with D-gal-induced accelerated aging. Transcriptome analysis revealed a decrease in Flt4 expression and inhibition of the PI3K-AKT signaling pathway in DsbA-L-/- mice compared to control mice. Accelerated renal aging could be alleviated by an AKT agonist (SC79) or a mitochondrial protector (MitoQ) in mice with D-gal-induced aging. In vitro, overexpression of DsbA-L in HK-2 cells restored the expression of Flt4, AKT pathway factors, SP1 and PGC-1α and alleviated mitochondrial damage and cell senescence. These beneficial effects were partially blocked by inhibiting Flt4. Finally, activating the AKT pathway or improving mitochondrial function with chemical reagents could alleviate cell senescence. Our results indicate that the DsbA-L/AKT/PGC-1α signaling pathway could be a therapeutic target for age-related renal fibrosis and is associated with mitochondrial dysfunction.