Evaluation of Confocal Laser Scanning Microscopy in Histological Classification and Photodynamic Therapy of Low-risk Basal Cell Carcinoma.

BACKGROUND: Confocal laser scanning microscopy (CLSM) is noninvasive technique utilized for identification and analysis skin malignancies. Several studies have applied CLSM in monitoring the therapeutic effects of basal cell carcinoma (BCC). OBJECTIVE: To investigate the diagnostic value of CLSM in low-risk BCC and the evaluation of photodynamic therapy (PDT). METHODS: We have diagnosed 149 patients with BCC using CLSM and histopathological examination. Based on histopathology, we summarized the classification information of low-risk BCC along with imaging features observed through CLSM. Thirty-four low-risk BCC patients underwent PDT treatment, and we used CLSM to evaluate its efficacy. RESULTS: Out of 149 participants were diagnosed with BCC by CLSM, 52 were pigmented type, 87 were nodular type and 10 were superficial type. After histopathological examination, 44 out of 52 were pigmented type, five were nodular type and three were superficial type. The results of CLSM were consistent with those of 87 nodular type and 10 superficial type. The CLSM features of nodular were observed in the tissue fissures around the tumor, the pigment mass was the CLSM characteristic of pigmented type. The simultaneous occurrence of inflammation and increased vasculature were characteristics of superficial. The effective rate of PDT was 100%, and the cure rate was 67.6%. At 12 months follow up, the recurrence rate of PDT was 11.8%, 15.0% for nodule type, 10.0% for pigmented type and 0% for superficial type. CONCLUSION: The tissue classification of CLSM for low-risk BCC was consistent with histopathology. CLSM can be used to monitor the efficacy of PDT for low-risk BCC.

The mechanism and therapeutic potential of lncRNA MIR497HG/miR-16-5p axis in breast cancer.

BACKGROUND: Breast cancer has become a major public health problem in the current society, and its incidence rate ranks the first among Chinese female malignant tumors. This paper once again confirmed the efficacy of lncRNA in tumor regulation by introducing the mechanism of the diagnosis of breast cancer by the MIR497HG/miR-16-5p axis. METHODS: The abnormal expression of MIR497HG in breast cancer was determined by RT-qPCR method, and the correlation between MIR497HG expression and clinicopathological characteristics of breast cancer patients was analyzed via Chi-square test. To understand the diagnostic potential of MIR497HG in breast cancer by drawing the receiver operating characteristic curve (ROC). The overexpressed MIR497HG (pcDNA3.1-MIR497HG) was designed and constructed to explore the regulation of elevated MIR497HG on biological function of BT549 and Hs 578T cells through Transwell assays. Additionally, the luciferase gene reporter assay and Pearson analysis evaluated the targeting relationship of MIR497HG to miR-16-5p. RESULTS: MIR497HG was decreased in breast cancer and had high diagnostic function, while elevated MIR497HG inhibited the migration and invasion of BT549 and Hs 578T cells. In terms of functional mechanism, miR-16-5p was the target of MIR497HG, and MIR497HG reversely regulated the miR-16-5p. miR-16-5p mimic reversed the effects of upregulated MIR497HG on cell biological function. CONCLUSIONS: In general, MIR497HG was decreased in breast cancer, and the MIR497HG/miR-16-5p axis regulated breast cancer tumorigenesis, providing effective insights for the diagnosis of patients.

Optically Mediated Nonvolatile Resistive Memory Device Based on Metal-Organic Frameworks.

Metal-organic frameworks (MOFs), characterized by tunable porosity, high surface area, and diverse chemical compositions, offer unique prospects for applications in optoelectronic devices. However, the prevailing research on thin-film devices utilizing MOFs has predominantly focused on aspects such as information storage and photosensitivity, often neglecting the integration of the advantages inherent in both photonics and electronics to enhance optical memory. This work demonstrates a light-mediated resistive memory device based on a highly oriented porphyrin-based MOFs film, in which the resistance state of the memristor is modulated by light, realizing the integration of the perception and storage of optical information. The memristor shows excellent performance with a wide light range of 405-785 nm and a persistent photoconductivity phenomenon up to 8.3 × 103 s. Further mechanistic studies have revealed that the resistive switching effect in the memristor is primarily associated with the reversible formation and annihilation of Ag conductive filaments.

Labor patterns of spontaneous first-stage labor in Chinese women with normal neonatal outcomes.

BACKGROUND: Friedman's standards, developed almost 50 years ago, may no longer align with the needs of today's obstetric population and current pregnancy management practices. This study aims to analyze contemporary labor patterns and estimate labor duration in China, focusing on first-stage labor data from Chinese parturients with a spontaneous onset of labor. METHODS: This retrospective observational study utilized data from electronic medical records of a tertiary hospital in Changsha, Hunan. Out of a total of 2,689 parturients, exclusions were made for multiple gestations, preterm, post-term, or stillbirth, cesarean delivery, non-vertex presentation, and neonatal intensive care unit admission. Average labor curves were constructed by parity using repeated-measure analysis, and labor duration was estimated through interval-censored regression, stratified by cervical dilation at admission. We performed an analysis to assess the impact of oxytocin augmentation and amniotomy on labor progression and conducted a sensitivity analysis using women with complicated outcomes. RESULTS: Nulliparous women take over 180 minutes for cervical dilation from 3 to 4 cm, and the duration from 5 to 6 cm exceeds 145 minutes. Multiparous women experience shorter labor durations than nulliparous. Labor acceleration is observed after 5 cm in nulliparous, but no distinct inflection point is evident in the average labor curve. In the second stage of labor, the 95th percentile for nulliparous, with and without epidural analgesia, is 142 minutes and 127 minutes, respectively. CONCLUSIONS: These findings provide valuable insights for the reassessment of labor and delivery processes in contemporary obstetric populations, including current Chinese obstetric practice.

BHBA attenuates endoplasmic reticulum stress-dependent neuroinflammation via the gut-brain axis in a mouse model of heat stress.

BACKGROUND: Heat stress (HS) commonly occurs as a severe pathological response when the body's sensible temperature exceeds its thermoregulatory capacity, leading to the development of chronic brain inflammation, known as neuroinflammation. Emerging evidence suggests that HS leads to the disruption of the gut microbiota, whereas abnormalities in the gut microbiota have been demonstrated to affect neuroinflammation. However, the mechanisms underlying the effects of HS on neuroinflammation are poorly studied. Meanwhile, effective interventions have been unclear. ß-Hydroxybutyric acid (BHBA) has been found to have neuroprotective and anti-inflammatory properties in previous studies. This study aims to explore the modulatory effects of BHBA on neuroinflammation induced by HS and elucidate the underlying molecular mechanisms. METHODS: An in vivo and in vitro model of HS was constructed under the precondition of BHBA pretreatment. The modulatory effects of BHBA on HS-induced neuroinflammation were explored and the underlying molecular mechanisms were elucidated by flow cytometry, WB, qPCR, immunofluorescence staining, DCFH-DA fluorescent probe assay, and 16S rRNA gene sequencing of colonic contents. RESULTS: Heat stress was found to cause gut microbiota disruption in HS mouse models, and TM7 and [Previotella] spp. may be the best potential biomarkers for assessing the occurrence of HS. Fecal microbiota transplantation associated with BHBA effectively reversed the disruption of gut microbiota in HS mice. Moreover, BHBA may inhibit microglia hyperactivation, suppress neuroinflammation (TNF-α, IL-1ß, and IL-6), and reduce the expression of cortical endoplasmic reticulum stress (ERS) markers (GRP78 and CHOP) mainly through its modulatory effects on the gut microbiota (TM7, Lactobacillus spp., Ruminalococcus spp., and Prevotella spp.). In vitro experiments revealed that BHBA (1 mM) raised the expression of the ERS marker GRP78, enhanced cellular activity, and increased the generation of reactive oxygen species (ROS) and anti-inflammatory cytokines (IL-10), while also inhibiting HS-induced apoptosis, ROS production, and excessive release of inflammatory cytokines (TNF-α and IL-1ß) in mouse BV2 cells. CONCLUSION: ß-Hydroxybutyric acid may be an effective agent for preventing neuroinflammation in HS mice, possibly due to its ability to inhibit ERS and subsequent microglia neuroinflammation via the gut-brain axis. These findings lay the groundwork for future research and development of BHBA as a preventive drug for HS and provide fresh insights into techniques for treating neurological illnesses by modifying the gut microbiota.

The Role of the Intestinal Flora and Its Derivatives in Neurocognitive Disorders: A Narrative Review from Surgical Perspective.

Perioperative neurocognitive dysfunction is a significant concern for population health, impacting postoperative recovery and increasing the financial burden on patients. With an increasing number of surgical procedures being performed, the prevention and management of perioperative neurocognitive dysfunction have garnered significant attention. While factors such as age, lifestyle, genetics, and education are known to influence the development of cognitive dysfunction, recent research has highlighted the role of the gut microbiota in neurological health. An increased abundance of pro-inflammatory gut microbiota can trigger and worsen neuroinflammation, neuronal cell damage, and impaired cellular autophagy. Moreover, the inflammation-promoting gut microbiota can disrupt immune function, impair neuroautophagy, and affect the production and circulation of extracellular vesicles and neurotransmitters. These factors collectively play a role in the onset and advancement of cognitive impairment. This narrative review delves into the molecular mechanisms through which gut microbiota and their derivatives contribute to cognitive impairment, focusing on the impact of anesthesia surgery, changes in gut microbial populations, and perioperative cognitive impairment associations. The study suggests that alterations in the abundance of various bacterial species and their metabolites pre- and post-surgery may be linked to postoperative cognitive impairment. Furthermore, the potential of probiotics or prebiotics in addressing cognitive impairment is discussed, offering a promising avenue for investigating the treatment of perioperative neurocognitive disorders.

Cross-linked Sodium Hyaluronate Gel with PLLA-b-PEG Microsphere for Facial Contouring in Chinese: A Retrospective Study.

BACKGROUND: In Asia, the demand for cosmetic facial treatments has surged due to technological advancements, increased social acceptability, and affordability. Poly-L-lactic acid (PLLA) fillers, known for their biocompatibility and biodegradability, have emerged as a popular choice for facial contouring, yet studies specifically addressing their use in Asian populations are scarce. METHODS: This retrospective study examined 30 Chinese patients who underwent facial contouring with PLLA fillers, focusing on product composition, injection techniques, and safety measures. A comprehensive clinical evaluation was performed, including the Global Aesthetic Improvement Scale (GAIS) and Global Impression of Change Scale (GICS) for effectiveness and patient satisfaction, respectively. RESULTS: No significant difference in GAIS scores was observed between injectors and blinded evaluators over a 12-month period, indicating consistent effectiveness. Patient satisfaction remained high, with GICS scores reflecting positive outcomes. The safety profile was favorable, with no serious adverse events reported. The study highlighted the importance of anatomical knowledge to avoid complications, particularly in areas prone to blindness. CONCLUSIONS: PLLA fillers offer a safe, effective option for facial contour correction in the Asian population, achieving high patient satisfaction and maintaining results over time. The study underscores the need for tailored approaches in cosmetic procedures for Asians, considering their unique facial structures and aesthetic goals. Further research with larger, multicenter cohorts is recommended to validate these findings and explore long-term effects. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Zebrafish as a Model for Lipidomics and Similar Investigations.

Zebrafish (Danio rerio) has emerged as a pivotal model organism in vertebrate development research over several decades. Beyond its contributions to developmental biology, zebrafish have increasingly played a crucial role in the field of lipidomics. Lipidomics, a comprehensive analysis of lipids within biological systems, offers profound insights into lipid metabolism and signaling pathways. This chapter explores the zebrafish's unique attributes that make it an ideal candidate for lipidomics studies. With a genome sharing numerous genetic similarities with humans, zebrafish serve as a powerful model for dissecting lipid metabolism and unraveling the complexities of lipid mediator-related diseases. In this chapter, we delve into specific protocols tailored for utilizing zebrafish in lipidomics research and similar investigations. Through a comprehensive exploration of zebrafish as a model organism, this chapter aims to provide researchers with valuable insights and methodologies for advancing lipidomics studies using zebrafish.

Effects of a Laparotomy on Targeted Lipidomics Profiles in a Mouse Model of Surgical Stress During Aging.

Laparotomy (EL) is one of the most common procedures performed among surgical specialties. Previous research demonstrates that surgery is associated with an increased inflammatory response. Low psoas muscle mass and quality markers are associated with increased mortality rates after emergency laparotomy. Analysis of lipid mediators in serum and muscle by using liquid chromatography-mass spectrometry (LC-MS)-based lipidomics has proven to be a sensitive and precise technique. In this chapter, we describe an LC-MS/MS protocol for the profiling and quantification of signaling lipids formed from Eicosapentaenoic Acid (EPA) and Eicosatetranoic acid (ETA) by 5, 12, or 15 lipoxynases. This protocol has been developed for and validated in serum and muscle samples in a mouse model of surgical stress caused by laparotomy.

Quantitative parameters of dual-layer spectral detector computed tomography for evaluating differentiation grade and lymphovascular and perineural invasion in colorectal adenocarcinoma.

PURPOSE: To explore the predictive value of dual-layer spectral detector CT (SDCT) quantitative parameters for determining differentiation grade, lymphovascular invasion (LVI) and perineural invasion (PNI) in colorectal adenocarcinoma (CRAC) patients. METHODS: A total of 106 eligible patients with CRAC were included in this study. Spectral parameters, including CT values at 40 and 100 keV, the effective atomic number (Zeff), the iodine concentration (IC), the slope of the spectral Hounsfield unit (HU) curve (λHU), and the normalized iodine concentration (NIC) in the arterial phase (AP) and venous phase (VP), were compared according to the differentiation grade and the status of LVI and PNI. The diagnostic accuracies of the quantitative parameters with statistical significance were determined via receiver operating characteristic (ROC) curves, and the area under the curve (AUC) was calculated. RESULTS: There were 57 males and 49 females aged 43-86 (69 ± 10) years. The measured values of the spectral quantitative parameters of the CRAC were consistent within the observer (ICC range: 0.800-0.926). The 40 keV-AP, IC-AP, NIC-AP, 40 keV-VP, and IC-VP were significantly different among the different differentiation grades in the CRAC (P = 0.040, AUC = 0.673; P = 0.035, AUC = 0.684; P = 0.031, AUC = 0.639; P = 0.044, AUC = 0.663 and P = 0.035, AUC = 0.666, respectively). A statistically significant difference was observed in 40 keV-VP, 100 keV-VP, Zeff-VP, IC-VP, and λHU-VP between LVI-positive and LVI-negative patients (P = 0.003, AUC = 0.688; P = 0.015, AUC = 0.644; P = 0.001, AUC = 0.688; P = 0.001, AUC = 0.703 and P = 0.003, AUC = 0.677, respectively). There were no statistically significant differences in the values of the spectral parameters of the PNI state of patients with CRAC (P > 0.05). CONCLUSION: The quantitative parameters of SDCT had good diagnostic efficacy in differentiating between different grades and statuses of LVI in patients with CRAC; however, SDCT did not have value for identifying the state of PNI.

Tumor suppressor KEAP1 promotes HSPA9 degradation, controlling mitochondrial biogenesis in breast cancer.

The oxidative-stress-related protein Kelch-like ECH-associated protein 1 (KEAP1) is a substrate articulator of E3 ubiquitin ligase, which plays an important role in the ubiquitination modification of proteins. However, the function of KEAP1 in breast cancer and its impact on the survival of patients with breast cancer remain unclear. Our study demonstrates that KEAP1, a positive prognostic factor, plays a crucial role in regulating cell proliferation, apoptosis, and cell cycle transition in breast cancer. We investigate the underlying mechanism using human tumor tissues, high-throughput detection technology, and a mouse xenograft tumor model. KEAP1 serves as a key regulator of cellular metabolism, the reprogramming of which is one of the hallmarks of tumorigenesis. KEAP1 has a significant effect on mitochondrial biogenesis and oxidative phosphorylation by regulating HSPA9 ubiquitination and degradation. These results suggest that KEAP1 could serve as a potential biomarker and therapeutic target in the treatment of breast cancer.

The feasibility and safety of laparoscopic transcystic common bile duct exploration after prior gastrectomy.

The increased incidence of gallstones can be linked to previous gastrectomy (PG). However, the success rate of endoscopic retrograde cholangiopan-creatography after gastrectomy has significantly reduced. In such cases, laparoscopic transcystic common bile duct exploration (LTCBDE) may be an alternative. In this study, LTCBDE was evaluated for its safety and feasibility in patients with PG. We retrospectively evaluated 300 patients who underwent LTCBDE between January 2015 and June 2023. The subjects were divided into 2 groups according to their PG status: PG group and No-PG group. The perioperative data from the 2 groups were compared. The operation time in the PG group was longer than that in the No-PG group (184.69 ±â€…20.28 minutes vs 152.19 ±â€…26.37 minutes, P < .01). There was no significant difference in intraoperative blood loss (61.19 ±â€…41.65 mL vs 50.83 ±â€…30.47 mL, P = .087), postoperative hospital stay (6.36 ±â€…1.94 days vs 5.94 ±â€…1.36 days, P = .125), total complication rate (18.6 % vs 14.1 %, P = .382), stone clearance rate (93.2 % vs 96.3 %, P = .303), stone recurrence rate (3.4 % vs 1.7 %, P = .395), and conversion rate (6.8 % vs 7.0 %, P = .941) between the 2 groups. No deaths occurred in either groups. A history of gastrectomy may not affect the feasibility and safety of LTCBDE, because its perioperative results are comparable to those of patients with a history of No-gastrectomy.

Clinical value of serum neuron-specific enolase in sepsis-associated encephalopathy: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to investigate the serum levels of neuron-specific enolase (NSE) in sepsis-associated encephalopathy (SAE) and perform a meta-analysis to assess the diagnostic and prognostic potential of serum NSE in SAE patients. METHODS: We searched English and Chinese databases for studies related to SAE that reported serum NSE levels until November 2023. We extracted information from these studies including the first author and year of publication, the number of samples, the gender and age of patients, the collection time of blood samples in patients, the assay method of serum NSE, the study methods, and the levels of serum NSE with units of ng/mL. The quality assessment of diagnostic accuracy studies 2 (QUADAS-2) tool was used to evaluate the study quality. A meta-analysis was performed using Review Manager version 5.3, employing either a random effects model or a fixed effects model. RESULTS: A total of 17 studies were included in the final meta-analysis, including 682 SAE patients and 946 NE patients. The meta-analysis demonstrated significantly higher serum NSE levels in SAE patients compared to NE patients (Z = 5.97, P < 0.001, MD = 7.79, 95%CI 5.23-10.34), irrespective of the method used for serum NSE detection (Z = 6.15, P < 0.001, mean difference [MD] = 7.75, 95%CI 5.28-10.22) and the study methods (Z = 5.97, P < 0.001, MD = 7.79, 95%CI 5.23-10.34). Furthermore, sepsis patients with a favorable outcome showed significantly lower levels of serum NSE compared to those with an unfavorable outcome (death or adverse neurological outcomes) (Z = 5.44, P < 0.001, MD = - 5.34, 95%CI - 7.26-3.42). CONCLUSION: The Serum level of NSE in SAE patients was significantly higher than that in septic patients without encephalopathy. The higher the serum NSE level in SAE patients, the higher their mortality rate and incidence of adverse neurological outcomes.

Drug delivery particles for targeted imaging-guided photothermal/chemotherapy synergy cancer therapy.

The early stage of pancreatic cancer is asymptomatic and the treatment effect is not ideal. The progression to the advanced stage leads to a close relationship between mortality and morbidity. Therefore, there is an urgent need to develop precise and efficient therapeutic strategies to combat pancreatic cancer. In this study, we introduce a near-infrared (NIR) targeted drug delivery nanoparticle for ultrasound (US) imaging to guide magnetothermal/chemotherapy synergistic treatment of pancreatic cancer. Carboxylated polylactic acid (PLGA-PEG-COOH) serves as the structure of the nanoparticles, specifically binding the RGD cyclic peptide for pancreatic cancer targeting activity and promoting tumor aggregation of the nanoparticles. NIR-induced superparamagnetic iron oxide (SPIO) nanoparticles convert near-infrared light into thermal energy, triggering vaporization of perfluoropentane (PFH) droplets to generate PFH bubbles that enhance US imaging and help load doxorubicin (DOX), which are released from nanoparticles. SPIO can also be used for thermal ablation of tumors to improve therapeutic effect in treating pancreatic cancer. The results show that the targeted particles mediated by NIR have the characteristics of targeted drug delivery imaging. The microspheres exhibit strong acoustic and near-infrared responsiveness. Cell proliferation experiments showed that IR-mediated PFH-DOX@PLGA/SPIO-RGD NPs (RNPs) had a higher inhibitory effect on cell proliferation. Animal experiments have shown that RNPS can accumulate highly in the tumor area and show good therapeutic effect. In conclusion, this nanotherapeutic particle is a very promising targeted image-guided photothermal/chemotherapeutic synergistic tumor therapy strategy.

ADAMTS16 Suppression by MicroRNA-25 Leads to Oncogenic Properties in Renal Cell Carcinoma.

INTRODUCTION: Increasing evidence indicates that microRNAs (miRNAs) play a crucial role in modulating tumor growth. This study is centered on investigating the contribution of miR-25 to the progression of Renal Cell Carcinoma (RCC). METHODS: The investigators examined the expression levels of miR-25 and ADAMTS16 in RCC samples and cell lines. The association between miR-25 and ADAMTS16 was validated via a luciferase reporter assay. Cell viability, apoptosis, migration, and invasion were evaluated utilizing CCK-8 and flow cytometry techniques, while the expression levels of ADAMTS16, ß-catenin, GSK-3ß, and p-GSK-3ß were assessed through western blot analysis. RESULTS: The investigation revealed elevated expression levels of miR-25 in RCC tissues. Subsequently, ADAMTS16 was identified as a target of miR-25. Increased miR-25 levels were associated with decreased expression of ADAMTS16, resulting in enhanced cell viability and diminished apoptosis. Conversely, inhibition of miR-25 led to decreased cell viability, proliferation, and migration. Additionally, the researchers observed that miR-25 triggered the phosphorylation of GSK-3ß and ß-catenin while leaving the total GSK-3ß level unaffected. CONCLUSION: This study suggests that miR-25 regulates the expression of ADAMTS16 through the Wnt/ß-catenin signaling pathway, providing new insights into the cause and potential treatment of RCC.

Comparison of Polygonatum sibiricum Polysaccharides Found in Young and Mature Rhizomes.

The main active component of Polygonatum sibiricum (P. sibiricum) rhizome is Polygonatum sibiricum Polysaccharide (PsP) with antioxidant function. At present, only the mature rhizome of P. sibiricum is used to extract PsP, while the young rhizome of by-product is discarded directly as waste, resulting in significant wastage of P. sibiricum resources. We used ultrasound-assisted extraction-deep eutectic solvents (UAE-DESs) method to extract PsP of young and mature rhizomes, respectively. The extraction rate, structure composition and antioxidant ability of PsP between young and mature rhizomes were compared, so as to provide references for comprehensive utilization of P. sibiricum resources. The PsP extraction rate (33.88 ± 1.95%) of young rhizome was close to that (45.08 ± 1.92%) of mature rhizomes. The main component (PsP-2) of the PsP in young rhizome contained six kinds of monosaccharides, which belonged to acidic polysaccharides. The above characteristics of the PsP of young rhizome were similar to those of mature rhizome. The PsP of young rhizome also exhibited similar biological activity to that of the mature rhizome, which indicated even more advantages in DPPH free radical scavenging ability. The results of this study support the utility of the young rhizome, consequently helping to avoid unnecessary waste and provide reference for comprehensive utilization of P. sibiricum.

Body Mass Index and Hypertension as Mediators of the Association Between Age at Menarche and Subclinical Atherosclerosis: A Sex-Specific Mendelian Randomization Analysis.

BACKGROUND: Early age at menarche (AAM) has been associated with a higher risk of carotid artery intima-media thickness (cIMT), an indicator of subclinical vascular disease, albeit the mechanisms underlying this association remain elusive. A better understanding of the relationship between AAM, modifiable cardiometabolic risk factors, and subclinical atherosclerosis may contribute to improved primary prevention and cardiovascular disease treatment. We aimed to investigate the putative causal role of AAM on cIMT, and to identify and quantify the potentially mediatory effects of cardiometabolic risk factors underlying this relationship. METHODS AND RESULTS: We conducted linkage disequilibrium score regression analyses between our exposure of interest, AAM, our outcome of interest, cIMT and potential mediators of the AAM-cIMT association to gauge cross-trait genetic overlap. We considered as mediators the modifiable anthropometric risk factors body mass index (BMI), systolic blood pressure (SBP), lipid traits (total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), and glycemic traits (fasting glucose). We then leveraged the paradigm of Mendelian randomization to infer causality between AAM and cIMT, and to identify whether cardiometabolic risk factors served as potential mediators of this effect. Our analyses showed that genetically predicted AAM was inversely associated with cIMT, BMI, SBP, and triglycerides, and positively associated with high-density lipoprotein, low-density lipoprotein, and total cholesterol. We showed that the effect of genetically predicted AAM on cIMT may be partially mediated through BMI (20.1% [95% CI, 1.4% to 38.9%]) and SBP (13.5% [95% CI, 0.5%-26.6%]). Our cluster-specific Mendelian randomization revealed heterogeneous causal effect estimates of age at menarche on BMI and SBP. CONCLUSIONS: We highlight supporting evidence for a potential causal association between earlier AAM and cIMT, and almost one third of the effect of AAM on cIMT may be mediated by BMI and SBP. Early intervention aimed at lowering BMI and hypertension may be beneficial in reducing the risk of developing subclinical atherosclerosis due to earlier age at menarche.

PD-L1 expression and its correlation with tumor biomarkers in Chinese urothelial bladder cancer.

Data on prevalence of programmed death ligand-1 (PD-L1) expression and its correlation with tumor biomarkers in Chinese patients with muscle-invasive urothelial bladder cancer (MIUBC) are scarce. We investigated the prevalence of PD-L1 expression, PD-L1 expression in tumor cells (TC) and immune cells (IC), and its correlation with tumor biomarkers (CD8+ T cells and tumor mutation burden [TMB]) in Chinese patients with newly diagnosed MIUBC (NCT03433924). Of 248 patients enrolled, 229 with PD-L1 data available were analysed. High PD-L1 expression (≥ 25% of TC or IC with PD-L1 expression) was observed in 120 (52.4%) patients. 59 cases showed positive staining in ≥ 25% of TC, and 82 cases had positive staining in ≥ 25% of IC. High expression of CD8+ T cell and TMB (> 10 mutations/megabase) was observed in 44.5% and 54.1% patients, respectively. A positive correlation was observed between percentage of TC with membrane PD-L1 positivity and CD8+ T cells (0.34; P < 0.001) and between IC with membrane PD-L1 positivity and CD8+ T cells (0.44; P < 0.001). There is high prevalence of PD-L1 expression in Chinese patients with MIUBC, suggesting that a sizable subset of patients could benefit from immunotherapy. The correlation of PD-L1 expression with tumor biomarkers provide clues for mechanisms underlying the effects of biomarkers for predicting efficacy.

Comparison of the Efficacy and Safety of Sacubitril/Valsartan and Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers in Patients With Reduced Ejection Fraction Combined With Moderate-to-Severe Chronic Kidney Disease.

Background and Objectives: The efficacy and safety of a lower target dose of sacubitril/valsartan (angiotensin receptor neprilysin inhibitor [ARNI]) for treating heart failure with reduced ejection fraction (HFrEF) in Chinese patients with moderate-to-severe chronic kidney disease (CKD) remain unknown. We performed a retrospective study to compare the efficacy of ARNI with that of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) in patients with HFrEF and moderate-to-severe CKD. Methods: This retrospective study included 129 patients. An inverse probability of treatment weighting (IPTW) analysis was performed to compare the baseline characteristics and outcomes between the 2 groups. The incidence of death due to cardiovascular disease, rehospitalization due to heart failure after treatment, and improvement in cardiac function symptoms (New York Heart Association [NYHA]) were assessed after 12 months. Improvements of ejection fraction (EF), N-terminal pro-brain natriuretic peptide (NT-proBNP) level, left ventricular end-systolic diameter (LVESD), and left ventricular end-diastolic diameter (LVEDD) were compared. Results: Compared with the ACEI/ARB group, the ARNI group, with 90.77% (59/65) in the lower target dose group, showed a lower rate of death due to cardiovascular disease (6.6% vs 0.9% after IPTW) and a lower incidence of rehospitalization (46.5% vs 30.4% after IPTW). NYHA class, estimated glomerular filtration rate, EF, NT-ProBNP levels, LVEDD, and LVESD improved in the ARNI group. None of the patients withdrew from treatment because of adverse drug reactions. Conclusion: Our study showed that ARNI resulted in a greater improvement in heart failure than ACEIs/ARBs in patients with HFrEF and moderate-to-severe CKD.