Central nervous system efficacy of aumolertinib versus gefitinib in patients with untreated, EGFR-mutated, advanced non-small cell lung cancer: data from a randomized phase III trial (AENEAS).

BACKGROUND: The initial randomized, double-blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study. METHODS: Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological-BICR). The primary endpoint for this subgroup analysis was CNS progression-free survival (PFS). RESULTS: Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological-BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17-0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11-0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed. CONCLUSIONS: These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03849768.

Intrauterine hyperglycaemia during late gestation caused mitochondrial dysfunction in skeletal muscle of male offspring through CREB/PGC1A signaling.

BACKGROUND: Maternal diabetes mellitus can influence the development of offspring. Gestational diabetes mellitus (GDM) creates a short-term intrauterine hyperglycaemic environment in offspring, leading to glucose intolerance in later life, but the long-term effects and specific mechanism involved in skeletal muscle dysfunction in offspring remain to be clarified. METHODS: Pregnant mice were divided into two groups: The GDM group was intraperitoneally injected with 100 mg/kg streptozotocin on gestational days (GDs) 6.5 and 12.5, while the control (CTR) group was treated with vehicle buffer. Only pregnant mice whose random blood glucose level was higher than 16.8 mmol/L beginning on GD13.5 were regarded as the GDM group. The growth of the offspring was monitored, and the glucose tolerance test was performed at different time points. Body composition analysis and immunohistochemical methods were used to evaluate the development of lean mass at 8 weeks. The exercise capacity and grip strength of the male mouse offspring were assessed at the same period. Transmission electron microscopy was used to observe the morphology inside skeletal muscle at 8 weeks and as a foetus. The genes and proteins associated with mitochondrial biogenesis and oxidative metabolism were investigated. We also coanalyzed RNA sequencing and proteomics data to explore the underlying mechanism. Chromatin immunoprecipitation and bisulfite-converted DNA methylation detection were performed to evaluate this phenomenon. RESULTS: Short-term intrauterine hyperglycaemia inhibited the growth and reduced the lean mass of male offspring, leading to decreased endurance exercise capacity. The myofiber composition of the tibialis anterior muscle of GDM male offspring became more glycolytic and less oxidative. The morphology and function of mitochondria in the skeletal muscle of GDM male offspring were destroyed, and coanalysis of RNA sequencing and proteomics of foetal skeletal muscle showed that mitochondrial elements and lipid oxidation were consistently impaired. In vivo and in vitro myoblast experiments also demonstrated that high glucose concentrations impeded mitochondrial organisation and function. Importantly, the transcription of genes associated with mitochondrial biogenesis and oxidative metabolism decreased at 8 weeks and during the foetal period. We predicted Ppargc1α as a key upstream regulator with the help of IPA software. The proteins and mRNA levels of Ppargc1α in the skeletal muscle of GDM male offspring were decreased as a foetus (CTR vs. GDM, 1.004 vs. 0.665, p = 0.002), at 6 weeks (1.018 vs. 0.511, p = 0.023) and 8 weeks (1.006 vs. 0.596, p = 0.018). In addition, CREB phosphorylation was inhibited in GDM group, with fewer activated pCREB proteins binding to the CRE element of Ppargc1α (1.042 vs. 0.681, p = 0.037), Pck1 (1.091 vs. 0.432, p = 0.014) and G6pc (1.118 vs. 0.472, p = 0.027), resulting in their decreased transcription. Interestingly, we found that sarcopenia and mitochondrial dysfunction could even be inherited by the next generation. CONCLUSIONS: Short-term intrauterine hyperglycaemia significantly reduced lean mass in male offspring at 8 weeks, resulting in decreased exercise endurance and metabolic disorders. Disrupted organisation and function of the mitochondria in skeletal muscle were also observed among them. Foetal exposure to hyperglycaemia decreased the ratio of phosphorylated CREB and reduced the transcription of Ppargc1α, which inhibited the transcription of downstream genes involving in mitochondrial biogenesis and oxidative metabolism. Abnormal mitochondria, which might be transmitted through aberrant gametes, were also observed in the F2 generation.

The impact of co-exposure to polystyrene microplastics and norethindrone on gill histology, antioxidant capacity, reproductive system, and gut microbiota in zebrafish (Danio rerio).

In recent years, studies have focused on the combined ecological risks posed by microplastics and other organic pollutants. Although both microplastics and progestin residues are frequently detected in the aquatic environments, their ecological implications remain unknown. Adult zebrafish were exposed to polystyrene microplastics (PS, 200 nm, 200 µg/L), norethindrone (NET, 69.6 ng/L), and their mixture (200 µg/L PS + 63.1 ng/L NET) for 30 days. The results demonstrated that exposure to PS and NET resulted in gill damage. Notably, the PS and PS+NET exhibited a significant decrease in glutathione (GSH) and oxidized glutathione (GSSG) content, as well as reduced antioxidase activity in the gills. The oxidative stress in PS+NET primarily originated from PS. The PS, NET, or their mixture resulted in a decrease in testosterone (T) and estradiol (E2) levels in female. Furthermore, compared to NET, the PS+NET showed a significant reduction in E2 levels, thereby augmenting the inhibitory effect on reproductive ability mediated by NET. However, males showed an increase in 11-ketodihydrotestosterone (11-KT) content, accompanied by a significant decrease in spermatogonia (Sg) and increase in spermatocytes (Sc). Consequently, it can be inferred that PS enhances the androgenic effect of NET. In female fish brain, NET alone resulted in transcriptional down-regulation of partial hormone receptors; however, co-administration of PS effectively mitigated the interference effects. Furthermore, transcriptional downregulation of 17-alpha-hydroxylase (cyp17), hydroxysteroid 3-beta dehydrogenase (hsd3b), estrogen receptor 1 (esr1), and estrogen receptor 2a (esr2b) genes in the ovary was found to be associated with the androgenic activity induced by NET. Moreover, in comparison to PS or NET alone, PS+NET resulted in a notable decrease in Cetobacterium abundance and an increase in Aeromonas population, suggesting that the co-exposure of PS+NET may exacerbate intestinal burden. The findings highlight the importance of studying the combined toxicity of PS and NET.

Safety of embryo cryopreservation: insights from mid-term placental transcriptional changes.

BACKGROUND: In recent years, with benefits from the continuous improvement of clinical technology and the advantage of fertility preservation, the application of embryo cryopreservation has been growing rapidly worldwide. However, amidst this growth, concerns about its safety persist. Numerous studies have highlighted the elevated risk of perinatal complications linked to frozen embryo transfer (FET), such as large for gestational age (LGA) and hypertensive disorders during pregnancy. Thus, it is imperative to explore the potential risk of embryo cryopreservation and its related mechanisms. METHODS: Given the strict ethical constraints on clinical samples, we employed mouse models in this study. Three experimental groups were established: the naturally conceived (NC) group, the fresh embryo transfer (Fresh-ET) group, and the FET group. Blastocyst formation rates and implantation rates were calculated post-embryo cryopreservation. The impact of FET on fetal growth was evaluated upon fetal and placental weight. Placental RNA-seq was conducted, encompassing comprehensive analyses of various comparisons (Fresh-ET vs. NC, FET vs. NC, and FET vs. Fresh-ET). RESULTS: Reduced rates of blastocyst formation and implantation were observed post-embryo cryopreservation. Fresh-ET resulted in a significant decrease in fetal weight compared to NC group, whereas FET reversed this decline. RNA-seq analysis indicated that the majority of the expression changes in FET were inherited from Fresh-ET, and alterations solely attributed to embryo cryopreservation were moderate. Unexpectedly, certain genes that showed alterations in Fresh-ET tended to be restored in FET. Further analysis suggested that this regression may underlie the improvement of fetal growth restriction in FET. The expression of imprinted genes was disrupted in both FET and Fresh-ET groups. CONCLUSION: Based on our experimental data on mouse models, the impact of embryo cryopreservation is less pronounced than other in vitro manipulations in Fresh-ET. However, the impairment of the embryonic developmental potential and the gene alterations in placenta still suggested it to be a risky operation.

Changes in Posttreatment Spleen Volume Associated with Immunotherapy Outcomes for Advanced Hepatocellular Carcinoma.

Purpose: We investigated whether spleen volume (SV) changes were associated with treatment outcomes in advanced hepatocellular carcinoma (HCC) patients who received immunotherapy or first-line sorafenib. Patients and Methods: Patients with advanced HCC who underwent immunotherapy or first-line sorafenib at our institute were retrospectively analyzed. CT was used to measure SV before and within 3 months of treatment initiation. Tumor assessment followed Response Evaluation Criteria in Solid Tumors version 1.1. The association between SV change and tumor response or progression-free survival (PFS) was analyzed. The inverse probability of treatment weighting (IPTW) was used to adjust for differences in baseline characteristics. Results: The immunotherapy group comprised 143 patients (124 men, mean age, 59.8 years ± 11.2 [standard deviation]), while the sorafenib group had 57 (47 men, mean age, 59.6 years ± 9.9). SV increased in 108 (75.5%) immunotherapy and 21 (36.8%) sorafenib patients. In the immunotherapy group, patients with increased SV were more likely than those with decreased SV to have a higher disease control rate (76.9% vs 57.1%, p = 0.024) and durable clinical benefit (52.8% vs 25.7%, p = 0.005). It was also associated with extended PFS in the immunotherapy group in both the univariate (p = 0.028) and multivariate (p = 0.014) analysis. By contrast, in the sorafenib group, an increased in SV was not associated with treatment response but was presumably associated with reduced PFS (p = 0.072) in the multivariate analysis. After IPTW adjustment, the increase in SV remained a significant predictor for DCB and PFS in the immunotherapy group. Conclusion: Most patients exhibited an increase in SV after the initiation of immunotherapy, which may be used to predict response and prognosis. However, this association was not observed in patients who received sorafenib.

The study provides significant evidence that an increase in spleen volume is associated with better treatment outcomes in advanced hepatocellular carcinoma patients undergoing immunotherapy. These findings offer oncologists a new potential biomarker for optimizing treatment strategies. Specifically, increased spleen volume could be used to predict higher rates of disease control and durable clinical benefits, allowing for more personalized care.

Pretreatment with or without GnRH-agonist before frozen-thawed embryo transfer in patients with PCOS: a systematic review and meta-analysis.

PURPOSE: This study was aimed to systematically evaluate the efficacy of artificial cycle-prepared frozen-thawed embryo transfer (FET) with or without gonadotrophin-releasing hormone agonist (GnRH-a) pretreatment for women with polycystic ovary syndrome (PCOS). METHODS: The analysis was carried out by searching the PubMed, EMBASE, and CNKI databases with a combination of keywords before October 2021. The available studies of the effects of GnRH-a pretreatment or no pretreatment on FET in PCOS patients were considered. The risk ratios (RRs) or standardized mean differences (SMD) with 95% confidence intervals (CIs) were calculated with using subgroups and sensitivity analysis. The quality evaluation for this analysis was followed. RESULTS: Seventeen studies including 3646 women were analyzed. GnRH-a pretreatment was significantly associated with a higher implantation rate (RR = 1.12, 95%CI: 1.00-1.24) and clinical pregnancy rate (RR = 1.19, 95%CI: 1.08-1.32) than the placebo. Moreover, in the GnRH-a pretreatment group, significant differences were detected for increasing the endometrium thickness among PCOS patients (SMD = 0.56, 95%CI: 0.20-0.92). However, for RCTs subgroup, no differences were observed, even after sensitivity analyses. In addition, the miscarriage rates, ectopic pregnancy rates, multiple pregnancy rates, and live birth rates were similar in both two groups. CONCLUSIONS: Endometrial preparation using GnRH agonist pretreatment prior to FET seems to be the better choice for PCOS patients. However, well-designed RCTs are required for confirmation.

Assessment of causal relationships between omega-3 and omega-6 polyunsaturated fatty acids in autoimmune rheumatic diseases: a brief research report from a Mendelian randomization study.

Background: Currently, the association between the consumption of polyunsaturated fatty acids (PUFAs) and the susceptibility to autoimmune rheumatic diseases (ARDs) remains conflict and lacks substantial evidence in various clinical studies. To address this issue, we employed Mendelian randomization (MR) to establish causal links between six types of PUFAs and their connection to the risk of ARDs. Methods: We retrieved summary-level data on six types of PUFAs, and five different types of ARDs from publicly accessible GWAS statistics. Causal relationships were determined using a two-sample MR analysis, with the IVW approach serving as the primary analysis method. To ensure the reliability of our research findings, we used four complementary approaches and conducted multivariable MR analysis (MVMR). Additionally, we investigated reverse causality through a reverse MR analysis. Results: Our results indicate that a heightened genetic predisposition for elevated levels of EPA (ORIVW: 0.924, 95% CI: 0.666-1.283, P IVW = 0.025) was linked to a decreased susceptibility to psoriatic arthritis (PsA). Importantly, the genetically predicted higher levels of EPA remain significantly associated with an reduced risk of PsA, even after adjusting for multiple testing using the FDR method (P IVW-FDR-corrected = 0.033) and multivariable MR analysis (P MV-IVW < 0.05), indicating that EPA may be considered as the risk-protecting PUFAs for PsA. Additionally, high levels of LA showed a positive causal relationship with a higher risk of PsA (ORIVW: 1.248, 95% CI: 1.013-1.538, P IVW = 0.037). It is interesting to note, however, that the effects of these associations were weakened in our MVMR analyses, which incorporated adjustment for lipid profiles (P MV-IVW > 0.05) and multiple testing using the FDR method (P IVW-FDR-corrected = 0.062). Moreover, effects of total omega-3 PUFAs, DHA, EPA, and LA on PsA, were massively driven by SNP effects in the FADS gene region. Furthermore, no causal association was identified between the concentrations of other circulating PUFAs and the risk of other ARDs. Further analysis revealed no significant horizontal pleiotropy and heterogeneity or reverse causality. Conclusion: Our comprehensive MR analysis indicated that EPA is a key omega-3 PUFA that may protect against PsA but not other ARDs. The FADS2 gene appears to play a central role in mediating the effects of omega-3 PUFAs on PsA risk. These findings suggest that EPA supplementation may be a promising strategy for preventing PsA onset. Further well-powered epidemiological studies and clinical trials are warranted to explore the potential mechanisms underlying the protective effects of EPA in PsA.

Twelve-Month Outcomes of Three Episcleral Surgeries in Treatment of Rhegmatogenous Retinal Detachment.

INTRODUCTION: The aim of this study was to compare the long-term outcomes of conventional scleral buckling (CSB), modified scleral buckling (MSB), and scleral encircling (SE) in the treatment of rhegmatogenous retinal detachment and identify factors influencing the outcomes. METHODS: This comparative, retrospective cohort study assigned patients to CSB, MSB, and SE groups. The follow-up was 12 months, and the reattachment rate, complication rate, visual acuity, number of newly discovered tears during surgery, and changes in diopters were compared among the three surgeries. Influential factors on anatomical and functional reattachment were identified. RESULTS: There were no significant differences in the primary reattachment rate, overall complication rate, or best corrected visual acuity at 6 or 12 months among the three groups. The MSB group had a higher number of newly discovered tears during surgery compared with the other two groups. At 12 months of post-surgery, the SE group displayed the greatest change of diopter, whereas the MSB group showed the least change. The surgical approach did not influence the primary reattachment rate. Long-term visual outcomes were influenced by factors including sex, preoperative visual acuity, macular status, and duration of symptoms. CONCLUSION: MSB is an effective method for treating rhegmatogenous retinal detachment. Its advantages include the ability to identify smaller tears and induce minimal changes in diopter.

The involvement of SigmaR1K142 degradation mediated by ERAD in neural senescence linked with CdCl2 exposure.

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Due to its uncertain pathogenesis, there is currently no treatment available for AD. Increasing evidences have linked cellular senescence to AD, although the mechanism triggering cellular senescence in AD requires further exploration. To investigate the involvement of cellular senescence in AD, we explored the effects of cadmium chloride (CdCl2) exposure, one of the potential environmental risk factors for AD, on neuron senescence in vivo and in vitro. ß-amyloid (Aß) and tubulin-associated protein (tau) pathologies were found to be enhanced by CdCl2 exposure in the in vitro models, while p53/p21/Rb cascade-related neuronal senescence pathways were activated. Conversely, the use of melatonin, a cellular senescence inhibitor, or a cadmium ion chelator suppressed CdCl2-induced neuron senescence, along with the Aß and tau pathologies. Mechanistically, CdCl2 exposure activated the suppressor enhancer Lin-12/Notch 1-like (SEL1L)/HMG-CoA reductase degradation 1 (HRD1)-regulated endoplasmic reticulum-associated degradation (ERAD), which enhanced the ubiquitin degradation of sigma-1 receptor (SigmaR1) by specifically recognizing its K142 site, resulting in the activation of the p53/p21/Rb pathway via the induction of Ca2+ dyshomeostasis and mitochondrial dysfunction. In the in vivo models, the administration of the SigmaR1 agonist ANAVEX2-73 rescues neurobehavioral inhibition and alleviates cellular senescence and AD-like pathology in the brain tissue of CdCl2-exposed mice. Consequently, the present study revealed a novel senescence-associated regulatory route for the SEL1L/HRD1/SigmaR1 axis that affects the pathological progression of CdCl2 exposure-associated AD. CdCl2 exposure activated SEL1L/HRD1-mediated ERAD and promoted the ubiquitinated degradation of SigmaR1, activating p53/p21/Rb pathway-regulated neuronal senescence. The results of the present study suggest that SigmaR1 may function as a neuroprotective biomarker of neuronal senescence, and pharmacological activation of SigmaR1 could be a promising intervention strategy for AD therapy.

Differentiation of bone marrow mesenchymal stem cells into Leydig-like cells with testicular extract liquid in vitro.

Differentiation of Leydig cells plays a key role in male reproductive function. Bone marrow mesenchymal stem cells (BMSCs) have emerged as a potential cell source for generating Leydig-like cells due to their multipotent differentiation capacity and accessibility. This study aimed to investigate the morphological and genetic expression changes of BMSCs during differentiation into Leydig-like cells. Testicular extract liquid, which simulates the microenvironment in vivo, induced the third passage BMSCs differentiated into Leydig-like cells. Changes in cell morphology were observed by microscopy, the formation of lipid droplets of androgen precursor was identified by Oil Red Staining, and the expression of testicular specific genes 3ß-HSD and SF-1 in testicular stromal cells was detected by RT-qPCR. BMSCs isolated from the bone marrow of Sprague-Dawley (SD) rats were cultured for 3 generations and identified as qualified BMSCs in terms of morphology and cell surface markers. After 14 days of induction with testicular tissue lysate, lipid droplets appeared in the cytoplasm of P3 BMSCs by Oil Red O staining. RT-qPCR detection was performed on BMSCs on the 3rd, 7th, 14th, and 21st day after induction. Relative expression levels of 3ß-HSD mRNA significantly increased after 14 days of induction, while the relative expression of SF-1 mRNA increased after 14 days of induction but was not significant. BMSCs can differentiate into testicular interstitial cells with reserve androgen precursor lipid droplets after induction by testicular tissue lysate. The differentiation ability of BMSCs provides the potential to reconstruct the testicular microenvironment and is expected to fundamentally improve testicular function and provide new treatment options for abnormal spermatogenesis diseases.

Intraoperative Intraocular Lens Waste: Incidence, Cost and Reasons.

PURPOSE: To evaluate the incidence and cost of intraocular lens(IOL) waste during IOL implantation, as well as the reasons for it. METHODS: A retrospective analysis was conducted on the data of 485 patients from the IOL waste registers of a single tertiary eye hospital in China during 2016-2020. The primary outcomes were the incidence, cost, and reasons for different IOL properties. Cases were examined to ascertain IOL material, design, procedural details, and causes of waste. RESULTS: IOL waste occurred in 485 (6.62‰) of the 73,246 IOL implantations during the study period. The total cost of IOL waste was 429, 850.26 Chinese Yuan (CNY) related to waste with an average cost of 2, 442.33 CNY per procedure during the study period. Comparisons between IOL properties showed that polymethyl methacrylate (PMMA) material (39, 2.05%), three-piece design (142, 1.49%), and secondary IOL implantation (26, 2.16%) were associated with IOL wastage, and the difference was statistically significant. The causes of IOL waste were damage (107, 60.80%), patient reasons (37, 21.26%), aseptic errors (22, 12.50%), IOL quality problems (8, 4.55%), and loss (2, 1.14%). CONCLUSIONS: The incidence of IOL waste is low, but still leads to a significant cost burden due to a large number of cataract surgeries. PMMA material, three-piece design, and secondary implantation were identified as factors increasing IOL waste. Damage emerged as the primary reason for waste, largely attributed to human error. Therefore, the development of strategies to mitigate IOL waste is imperative.

Effects of glycopyrrolate and atropine for oral secretions and perioperative hemodynamics in children undergoing tonsillectomy and adenoidectomy: a prospective, single-center, randomized, double-blind, controlled trial.

Introduction: Glycopyrrolate is commonly researched as a preoperative medication or in conjunction with cholinesterase inhibitors to counteract the lingering muscarinic effects of non-depolarizing muscarinic agents. However, studies have yielded inconsistent results regarding the superiority of glycopyrrolate over other anti-cholinergic drugs, such as atropine, particularly its effect on heart rate, blood pressure (BP), and glandular secretions. This study aimed to evaluate the differences in perioperative oral secretions, hemodynamics, and recovery quality with glycopyrrolate versus those with atropine before anesthesia induction in children undergoing tonsillectomy and adenoidectomy. Methods: In this prospective, single-center, randomized, double-blind, controlled trial, a total of 103 children were randomly assigned to group A (n = 51, glycopyrrolate 0.005 mg/kg) or B (n = 52, atropine 0.01 mg/kg). The follow-up anesthetic induction and maintenance protocols were the same in both groups. Vital signs, duration of surgery, extubation time, degree of wetness around the vocal cords during tracheal intubation, weight of oral secretions, and perioperative complications were recorded. Results: No significant differences were observed in the degree of wetness around the vocal cords during tracheal intubation, as well as in the weight of oral secretions, duration of surgery, or extubation time, between the two groups. The intraoperative and postoperative heart rates were lower in group A than in group B (110.18 ± 10.58 vs. 114.94 ± 11.14, p = 0.028; 96.96 ± 10.81 vs. 103.38 ± 10.09, p = 0.002). The differences observed in the intraoperative and preoperative heart rates were lower in group A than in group B (23.84 ± 9.62 vs. 29.65 ± 8.75, p = 0.002). The differences observed in the postoperative and preoperative heart rates were lower in group A than in group B (10.63 ± 9.97 vs. 18.09 ± 9.39, p = 0.000). Conclusion: Glycopyrrolate showed a smoother change in heart rate than atropine during and after tonsillectomy and adenoidectomy, with no effect on BP or recovery quality, and did not increase oral secretions. The findings indicate that glycopyrrolate can serve as an alternative to atropine to prevent secretions in anesthesia induction for tonsillectomy and adenoidectomy in children. Trial registration: This study was registered with the Chinese Clinical Trial Registry (Registration Number: ChiCTR2200063578; Date of Registration: 12/09/2022).

Clinical application of two types of Hook-Wire needle localization procedures for pulmonary small nodule biopsy.

BACKGROUND: With the widespread use of low-dose spiral computed tomography (LDCT) and increasing awareness of personal health, the detection rate of pulmonary nodules is steadily rising. OBJECTIVE: To evaluate the success rate and safety of two different models of Hook-Wire needle localization procedures for pulmonary small nodule biopsy. METHODS: Ninety-four cases with a total of 97 pulmonary small nodules undergoing needle localization biopsy were retrospectively analyzed. The cases were divided into two groups: Group A, using breast localization needle steel wire (Bard Healthcare Science Co., Ltd.); Group B, using disposable pulmonary nodule puncture needle (SensCure Biotechnology Co., Ltd.). All patients underwent video-assisted thoracoscopic surgery (VATS) for nodule removal on the same day after localization and biopsy. The puncture localization operation time, success rate, complications such as pulmonary hemorrhage, pneumothorax, hemoptysis, and postoperative comfort were observed and compared. RESULTS: In Group A, the average localization operation time for 97 nodules was 15.47 ± 5.31 minutes, with a success rate of 94.34%. The complication rate was 71.69% (12 cases of pneumothorax, 35 cases of pulmonary hemorrhage, 2 cases of hemoptysis), and 40 cases of post-localization discomfort were reported. In Group B, the average localization operation time was 25.32 ± 7.83 minutes, with a 100% success rate. The complication rate was 29.55% (3 cases of pneumothorax, 15 cases of pulmonary hemorrhage, 0 cases of hemoptysis), and 3 cases reported postoperative discomfort. According to the data analysis in this study, Group B had a lower incidence of puncture-related complications than Group A, along with a higher success rate and significantly greater postoperative comfort. CONCLUSIONS: The disposable pulmonary nodule puncture needle is safer and more effective in pulmonary small nodule localization biopsy, exhibiting increased comfort compared to the breast localization needle. Additionally, the incidence of complications is significantly lower.

Immune checkpoint inhibitor-associated gastritis: Patterns and management.

Immune checkpoint inhibitors (ICIs) are widely used due to their effectiveness in treating various tumors. Immune-related adverse events (irAEs) are defined as adverse effects resulting from ICI treatment. Gastrointestinal irAEs are a common type of irAEs characterized by intestinal side effects, such as diarrhea and colitis, which may lead to the cessation of ICIs. Although irAE gastritis is rarely reported, it may lead to serious complications such as gastrorrhagia. Furthermore, irAE gastritis is often difficult to identify early due to its diverse symptoms. Although steroid hormones and immunosuppressants are commonly used to reverse irAEs, the best regimen and dosage for irAE gastritis remains uncertain. In addition, the risk of recurrence of irAE gastritis after the reuse of ICIs should be considered. In this editorial, strategies such as early identification, pathological diagnosis, management interventions, and immunotherapy rechallenge are discussed to enable clinicians to better manage irAE gastritis and improve the prognosis of these patients.

Aflatoxin B1-exposed hepatocyte-derived extracellular vesicles: Initiating hepatic stellate cell-mediated liver fibrosis through a p53-Parkin-dependent mitophagy pathway.

Environmental aflatoxin B1 (AFB1) exposure has been proposed to contribute to hepatocellular carcinoma by promoting liver fibrosis, but the potential mechanisms remain to be further elucidated. Extracellular vesicles (EVs) were recognized as crucial traffickers for hepatic intercellular communication and play a vital role in the pathological process of liver fibrosis. The AFB1-exposed hepatocyte-derived EVs (AFB1-EVs) were extracted, and the functional effects of AFB1-EVs on the activation of hepatic stellate cells (HSCs) were explored to investigate the molecular mechanism of AFB1 exposure-induced liver fibrogenesis. Our results revealed that an environment-level AFB1 exposure induced liver fibrosis via HSCs activation in mice, while the AFB1-EVs mediated hepatotoxicity and liver fibrogenesis in vitro and in vivo. AFB1 exposure in vitro increased PINK1/Parkin-dependent mitophagy in hepatocytes, where upregulated transcription of the PARK2 gene via p53 nuclear translocation and mitochondrial recruitment of Parkin, and promoted AFB1-EVs-mediated mitochondria-trafficking communication between hepatocytes and HSCs. The knockdown of Parkin in HepaRG cells reversed HSCs activation by blocking the mitophagy-related AFB1-EVs trafficking. This study further revealed that the hepatic fibrogenesis of AFB1 exposure was rescued by genetic intervention with siPARK2 or p53's Pifithrin-α (PFTα) inhibitors. Furthermore, AFB1-EVs-induced HSCs activation was relieved by GW4869 pharmaceutic inhibition of EVs secretion. These results revealed a novel mechanism that AFB1 exposure-induced p53-Parkin signal axis regulated mitophagy-dependent hepatocyte-derived EVs to mediate the mitochondria-trafficking intercellular communication between hepatocytes and HSCs in the local hepatotoxic microenvironment to promote the activated HSCs-associated liver fibrogenesis. Our study provided insight into p53-Parkin-dependent pathway regulation and promised an advanced strategy targeting intervention to EVs-mediated mitochondria trafficking for preventing xenobiotics-induced liver fibrosis.

Revealing Fermi surface evolution and Berry curvature in an ideal type-II Weyl semimetal.

In type-II Weyl semimetals (WSMs), the tilting of the Weyl cones leads to the coexistence of electron and hole pockets that touch at the Weyl nodes. These electrons and holes experience the Berry curvature generated by the Weyl nodes, leading to an anomalous Hall effect that is highly sensitive to the Fermi level position. Here we have identified field-induced ferromagnetic MnBi2-xSbxTe4 as an ideal type-II WSM with a single pair of Weyl nodes. By employing a combination of quantum oscillations and high-field Hall measurements, we have resolved the evolution of Fermi-surface sections as the Fermi level is tuned across the charge neutrality point, precisely matching the band structure of an ideal type-II WSM. Furthermore, the anomalous Hall conductivity exhibits a heartbeat-like behavior as the Fermi level is tuned across the Weyl nodes, a feature of type-II WSMs that was long predicted by theory. Our work uncovers a large free carrier contribution to the anomalous Hall effect resulting from the unique interplay between the Fermi surface and diverging Berry curvature in magnetic type-II WSMs.

Application of machine learning in prediction of Pb2+ adsorption of biochar prepared by tube furnace and fluidized bed.

Data mining by machine learning (ML) has recently come into application in heavy metals purification from wastewater, especially in exploring lead removal by biochar that prepared using tube furnace (TF-C) and fluidized bed (FB-C) pyrolysis methods. In this study, six ML models including Random Forest Regression (RFR), Gradient Boosting Regression (GBR), Support Vector Regression (SVR), Kernel Ridge Regression (KRR), Extreme Gradient Boosting (XGB), and Light Gradient Boosting Machine (LGBM) were employed to predict lead adsorption based on a dataset of 1012 adsorption experiments, comprising 422 TF-C groups from our experiments and 590 FB-C groups from literatures. The XGB model showed superior accuracy and predictive performance for adsorption, achieving R2 values for TF-C (0.992) and FB-C (0.981), respectively. Contrasting inferior results were observed in other models, including RF (0.962 and 0.961), GBR (0.987 and 0.975), SVR (0.839 and 0.763), KRR (0.817 and 0.881), and LGBM (0.975 and 0.868). Additionally, a hybrid dataset combining both biochars in Pb adsorption also indicated high accuracy (0.972) as obtained from XGB model. The investigation revealed that the influence of char characteristics and adsorption conditions on Pb adsorption differs between the two biochar. Specific char characteristics, particularly nitrogen content, significantly influence lead adsorption in both biochar. Interestingly, the influence of pyrolysis temperature (PT) on lead adsorption is found to be greater for TF-C than for FB-C. Consequently, careful consideration of PT is crucial when preparing TF-C biochar. These findings offer practical guidance for optimizing biochar preparation conditions during heavy metal removal from wastewater.

Protective Effect of Silibinin on Lipopolysaccharide-Induced Endotoxemia by Inhibiting Caspase-11-Dependent Cell Pyroptosis.

OBJECTIVE: To explore the protective effect and the underlying mechanism of silibinin (SIB), one of the active compounds from Silybum marianum (L.) Gaertn in endotoxemia. METHODS: Mouse peritoneal macrophage were isolated via intraperitoneally injection of BALB/c mice with thioglycolate medium. Cell viability was assessed using the cell counting kit-8, while cytotoxicity was determined through lactate dehydrogenase cytotoxicity assay. The protein expressions of interleukin (IL)-1 α, IL-1 ß, and IL-18 were determined by enzyme-linked immunosorbent assay. Intracellular lipopolysaccharide (LPS) levels were measured by employing both the limulus amoebocyte lysate assay and flow cytometry. Additionally, proximity ligation assay was employed for the LPS and caspase-11 interaction. Mice were divided into 4 groups: the control, LPS, high-dose-SIB (100 mg/kg), and low-dose-SIB (100 mg/kg) groups (n=8). Zebrafish were divided into 4 groups: the control, LPS, high-dose-SIB (200 εmol/L), and low-dose-SIB (100 εmol/L) groups (n=30 for survival experiment and n=10 for gene expression analysis). The expression of caspase-11, gasdermin D (GSDMD), and N-GSDMD was determined by Western blot and the expressions of caspy2, gsdmeb, and IL-1 ß were detected using quantitative real-time PCR. Histopathological observation was performed through hematoxylineosin staining, and protein levels in bronchoalveolar lavage fluid were quantified using the bicinchoninicacid protein assay. RESULTS: SIB noticeably decreased caspase-11 and GSDMD-mediated pyroptosis and suppressed the secretion of IL-1 α, IL-1 ß, and IL-18 induced by LPS (P<0.05). Moreover, SIB inhibited the translocation of LPS into the cytoplasm and the binding of caspase-11 and intracellular LPS (P<0.05). SIB also attenuated the expression of caspase-11 and N-terminal fragments of GSDMD, inhibited the relative cytokines, prolonged the survival time, and up-regulated the survival rate in the endotoxemia models (P<0.05). CONCLUSIONS: SIB can inhibit pyroptosis in the LPS-mediated endotoxemia model, at least in part, by inhibiting the caspase-11-mediated cleavage of GSDMD. Additionally, SIB inhibits the interaction of LPS and caspase-11 and inhibits the LPS-mediated up-regulation of caspase-11 expression, which relieves caspase-11-dependent cell pyroptosis and consequently attenuates LPS-mediated lethality.

Perioperative changes of serum orphanin in diabetic patients and its relationship with sympathetic nervous system.

The occurrence of cardiovascular events in diabetic patients during the perioperative period is related to the activation of sympathetic nerves. Basic research shows that serum nociceptin/orphanin FQ (N/OFQ) levels in diabetic neuropathy rats increased, and N/OFQ reduces the release of norepinephrine (NE). We hypothesize that N/OFQ will affect the sympathetic nervous system during perioperative myocardium of diabetic patients. 66 patients with unilateral knee arthroplasty were divided into diabetes group (D group) and non-diabetes group (N group). Measured blood glucose, serum NE, N/OFQ concentrations at the 30 min before anesthesia (T0), 1 h after surgery (T1), 24 h after surgery (T2) and the cardiac troponinI (cTnI) concentration at T0 and T2. Compared with N group, the concentration of blood glucose, N/OFQ and cTnI in D group was higher and the NE was lower at T0 (P < 0.05). At T1, the blood glucose, N/OFQ, NE concentrations of D group increased, only the blood glucose increased in N group (P < 0.05). Serum N/OFQ of D group from T0 to T1 was correlated with the change trend of blood glucose, NE concentration from T0 to T1 and cTnI from T0 to T2(r = 0.386, P = 0.027; r = 0.350, P = 0.046; r = 0.363, P = 0.038). The outcomes demonstrated that the preoperative serum N/OFQ concentration in diabetic patients was increased, and the increase in N/OFQ concentration during the operation was related to the increase in NE and cTnI concentrations, perioperative N/OFQ may mediate myocardial injury through sympathetic nervous system.

Subthreshold micropulse diode laser treatment in diabetic macular edema: biological impact, therapeutic effects, and safety.

PURPOSE: To introduce the treatment of diabetic macular edema (DME) with subthreshold micropulse diode laser (SMPL), to summarize the biological impact, therapeutic effects, and safety of this treatment, and to discuss the response to DME when SMPL is combined with anti-vascular endothelial growth factor (anti-VEGF) or steroid. METHODS: The literature search was performed on the PubMed database, with a selection of English-language articles published from 2000 to 2023 with the following combinations of search terms: diabetes macular (o) edema, micropulse laser or subthreshold micropulse laser, anti-vascular endothelial growth factor, and steroid. RESULTS: SMPL is a popular, invisible retinal laser phototherapy that is inexpensive, safe, and effective in the treatment of DME. It can selectively target the retinal pigment epithelium, reduce the expression of pro-inflammatory factors, promote the absorption of macular edema, and exert a similar and lasting clinical effect to traditional lasers. No significant difference was found in the therapeutic effects of SMPL between different wavelengths. However, HbA1c level and pretreatment central macular thickness (CMT) may affect the therapeutic outcomes of SMPL. CONCLUSION: SMPL has a slow onset and produces lasting clinical effects similar to conventional photocoagulation. It has been reported that SMPL combined with the intravitreal anti-VEGF injection can significantly reduce the number of injections without influencing the therapeutic effect, which is essential for clinical applications and research. Although 577 nm SMPL is widely used clinically, there are no standardized protocols for SMPL. Additionally, some important problems regarding the treatment of SMPL require further discussion and exploration.