Energy Dissipation and Toughening of Covalent Networks via a Sacrificial Conformation Approach.

Covalent polymer networks find wide utility in diverse engineering applications owing to their desirable stiffness and resilience. However, the rigid covalent chemical structure between crosslinking points imposes limitations on enhancing their toughness. Although the incorporation of sacrificial chemical bonds has shown promise in improving toughness through energy dissipation, composite networks struggle to maintain both rapid recovery and stiffness. Consequently, a significant challenge persists in achieving a covalent network that combines high strength, stiffness, toughness, and fast recovery performance. To address this challenge, we propose a novel sacrificial structure termed "sacrificial conformation." In this approach, ß-cyclodextrin is covalently embedded into the network skeleton as the sacrificial conformation element.  Compared to traditional covalent networks (LCN), well-designed cyclodextrin-embedded covalent network (CCN) exhibit a 100-fold increase in Young's modulus and a 60-fold increase in toughness. Importantly, CCN maintains excellent elasticity, ensuring swift recovery after deformation. This sacrificial conformational strategy enables efficient energy dissipation without necessitating the rupture of chemical bonds, thereby overcoming the limitations of traditional approaches. This advancement holds great promise for the design and fabrication of advanced elastomers and hydrogels with superior mechanical properties and dynamic behavior.

Sex differences in the metabolic activation of and platelet response to vicagrel in mice: Androgen as a key player.

As a biological variable, sex influences the metabolism of and/or response to certain drugs. Vicagrel is being developed as an investigational new drug in China; however, it is unknown whether sex could affect its metabolic activation and platelet responsiveness. This study aimed to determine whether such differences could exist, and to elucidate the mechanisms involved. Orchiectomized (ORX) or ovariectomized (OVX) mouse models were used to investigate the effects of androgens or estrogens on the metabolic activation of and platelet response to vicagrel. Plasma vicagrel active metabolite H4 concentrations, platelet inhibition of vicagrel, and protein levels of intestinal hydrolases Aadac and Ces2 were measured, respectively. Further, p38-MAPK signaling pathway was enriched, whose role was determined using SB202190. Results showed that female mice exhibited significantly elevated systemic exposure of H4 and enhanced platelet responses to vicagrel than males, and that protein expression levels of Aadac and Ces2 differed by sex. OVX mice exhibited less changes than sham mice. ORX mice exhibited increases in protein levels of intestinal hydrolases, systemic exposure of H4, and platelet inhibition of vicagrel, but dihydrotestosterone (DHT) reversed these changes in ORX mice and suppressed these changes in OVX mice. Phosphorylated p38 levels were reduced in female or ORX mice but increased in ORX mice by DHT. SB202190 reversed DHT-induced changes observed in ORX mice. We concluded that sex differences exist in metabolic activation of and platelet response to vicagrel in mice through elevation of p38 phosphorylation by androgens, suggesting sex-based vicagrel dosage adjustments for patient care.

The gut microbiota: emerging biomarkers and potential treatments for infertility-related diseases.

Infertility is a disease of impaired fertility. With socioeconomic development, changes in human lifestyles, and increased environmental pollution, the problem of low human fertility has become increasingly prominent. The incidence of global infertility is increasing every year. Many factors lead to infertility, and common female factors include tubal factors, ovulation disorders, endometriosis, and immune factors. The gut microbiota is involved in many physiological processes, such as nutrient absorption, intestinal mucosal growth, glycolipid metabolism, and immune system regulation. An altered gut flora is associated with female infertility disorders such as polycystic ovary syndrome (PCOS), endometriosis (EMs), and premature ovarian failure (POF). Dysbiosis of the gut microbiota directly or indirectly contributes to the development of female infertility disorders, which also affect the homeostasis of the gut microbiota. Identifying the etiology and pathogenesis of infertility in patients is the focus of reproductive medicine physicians. We studied the developmental mechanism between the gut microbiota and PCOS, EMs, and POF from a new perspective, providing new ideas for diagnosing and treating female infertility diseases and specific reference values for eugenics.

Evaluating the predictive efficacy of real-time 3D echocardiography in cardiac resynchronization therapy.

BACKGROUND: The aim of this study is to assess the predictive efficacy of real-time three-dimensional echocardiography (RT-3DE) and QRS wave duration in determining the response to cardiac resynchronization therapy (CRT) and assessing left ventricular systolic function pre- and post-CRT device implantation. METHOD: A total of 51 patients with heart failure undergoing CRT at the Second Affiliated Hospital of Nantong University between January 1, 2013, and October 31, 2020, were enrolled in this study. Traditional two-dimensional echocardiography and RT-3DE were performed pre and post-CRT, with QRS wave width data from electrocardiograms and additional clinical information collected. Patients were categorized into CRT responder (n = 36) and CRT non-responder (n = 15) groups based on their response to CRT device implantation. Comparative analyses were conducted on the general characteristics of both groups, as well as the predictive efficacy of RT-3DE and QRS wave width for CRT responsiveness and left ventricular systolic function. Data on the standard deviation (Tmsv16-SD, Tmsv12-SD, Tmsv6-SD) and maximum difference (Tmsv16-Dif, Tmsv12-Dif, Tmsv6-Dif) of left ventricular end-systolic volume (LVESV) at segments 16, 12, and 6, as well as QRS wave width, were collected and analyzed. RESULTS: The indicators Tmsv6-Dif, Tmsv12-Dif, Tmsv16-Dif, Tmsv6-SD, Tmsv12-SD, Tmsv16-SD, and QRS wave width exhibited significantly higher values in the CRT responder group when compared to the CRT non-responder group (P < 0.05). Among these, Tmsv16-SD demonstrated superior predictive performance for post-CRT response, with a sensitivity of 88.9%, specificity of 80.0%, and a diagnostic cut-off value of 6.19%. This predictive capability exceeded that of the conventional indicator, QRS wave width. CONCLUSION: RT-3DE enables accurate prediction of post-CRT patient response and significantly facilitates quantitative assessment of CRT therapy efficacy.

Perioperative chemotherapy improves survival of patients with locally advanced diffuse gastric cancer.

BACKGROUND: Whether patients with diffuse gastric cancer, which is insensitive to chemotherapy, can benefit from neoadjuvant or adjuvant chemotherapy has long been controversial. AIM: To investigate whether perioperative chemotherapy can improve survival of patients with locally advanced diffuse gastric cancer. METHODS: A total of 2684 patients with locally advanced diffuse gastric cancer from 18 population-based cancer registries in the United States were analyzed. RESULTS: Compared with surgery alone, perioperative chemotherapy improved the prognosis of patients with locally advanced gastric cancer. Before stabilized inverse probability of treatment weighting (IPTW), the median overall survival (OS) times were 40.0 months and 13.0 months (P < 0.001), respectively. After IPTW, the median OS times were 33.0 months and 17.0 months (P < 0.001), respectively. Neoadjuvant chemotherapy did not improve the prognosis of patients with locally advanced gastric cancer compared with adjuvant chemotherapy after IPTW. After IPTW, the median OS times were 38.0 months in the neoadjuvant chemotherapy group and 42.0 months in the adjuvant chemotherapy group (P = 0.472). CONCLUSION: Patients with diffuse gastric cancer can benefit from perioperative chemotherapy. There was no significant difference in survival between patients who received neoadjuvant chemotherapy and those who received adjuvant chemotherapy.

Magnetic Resonance Imaging-Based Vertebral Bone Quality Score for Prediction of Cage Subsidence and Screw Loosening in Patients Undergoing Degenerative Lumbar Surgery: A Meta-analysis.

OBJECTIVE: Poor bone quality is a risk factor for postoperative complications after degenerative lumbar fusion surgery. The magnetic resonance imaging-based vertebral bone quality (VBQ) score is a good tool for assessing bone quality, and this is the first meta-analysis performed to summarize the predictive value of the VBQ score for cage subsidence and screw loosening in patients undergoing degenerative lumbar surgery. METHODS: Studies were comprehensively searched in electronic databases. The quality of the studies was assessed. The pooled sensitivity, specificity and summary receiver operating characteristic curve were calculated. Publication bias was assessed and meta-regression was conducted. RESULTS: We ultimately included 9 studies with a total of 1,404 patients with a mean age of 60.4 years and a percentage of females of 57.0%. According to the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) tool to assess methodological quality, the quality of the included studies was relatively low and risks of bias might exist. Results showed that a high VBQ was significantly associated with cage subsidence and screw loosening, and risk factor analysis revealed that the merged odds ratio was 5.37 for cage subsidence and 3.87 for screw loosening. With a VBQ cutoff value of 3.34±0.45, the pooled sensitivity and specificity for the diagnosis of postoperative complications were 0.75 and 0.75, respectively, and the area under the curve was 0.82 (95% confidence interval, 0.78-0.85). CONCLUSION: A high VBQ was associated with a high risk of cage subsidence and screw loosening in patients who underwent degenerative lumbar surgery. The VBQ score could be considered for identifying high-risk patients for further evaluation.

Acute toxicity of salicylic acid and its derivatives on the diatom Phaeodactylum tricornutum: Physico-Biochemical and transcriptomic insights.

Salicylate pollutants (SAs) poses a serious threat to marine ecosystems as emerging contaminants. However, the toxic effects of SAs on marine phytoplankton, as well as the potential mechanisms and their ecological risks linked with them, are remain largely unknown. In this study, we aimed to evaluate the toxic effects of salicylic acid (SA) and its 5-substituted derivatives (5-sSA) on the marine diatom Phaeodactylum tricornutum, as well as the potential molecular mechanism involved in the toxicity. Physiological assays conducted on P. tricornutum revealed significant changes in photosynthetic pigments, chlorophyll fluorescence parameters, and antioxidant enzyme activities. The results showed that exposure of P. tricornutum to SAs caused a significant decline in chlorophyll contents and damage to the photosystem II (PSII) core resulting in the decline of photosynthesis. Although the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) were enhanced, oxidative damage occurred. Transcriptome analysis showed that a large number of differentially expresses genes (DEGs) were significantly enriched in metabolic pathways such as porphyrin metabolism, terpenoid backbone biosynthesis, and carbon fixation in photosynthetic organisms after SA and 5-BrSA treatments. In addition, key genes in transcriptomic metabolic pathways were further analyzed and validated using weighted correlation network analysis (WGCNA) and real-time fluorescence quantitative PCR (qPCR). Considering the above results, SAs mainly inhibit the processes of photosynthesis by repressing the expression of genes involved in secondary metabolite synthesis and photosynthetic carbon sequestration pathways, thus exerting toxic effects on algal cells. The results of the study will provide key data for understanding the ecological risk and toxicity mechanisms of SA pollutants.

Neuritin attenuates neuroinflammation and apoptosis in early brain injury after subarachnoid hemorrhage via endoplasmic reticulum stress-related inflammatory pathways.

Neuroinflammation is a key destructive pathophysiological process in early brain injury (EBI) following subarachnoid hemorrhage (SAH). Recent studies have discovered that endoplasmic reticulum stress-related inflammatory pathways include the IRE1α-TRAF2-NF-κB pathway, PERK-eIF2α-NF-κB pathway, and ATF6-AKT -NF-κB pathway leading to neuroinflammatory response. Neuritin is a neurotrophin that is involved in neuronal plasticity and regeneration. Studies have suggested that Neuritin has a vital role in reducing neuroinflammation, and can also decrease the expression of proteins related to endoplasmic reticulum stress following SAH. This suggests that Neuritin could be a potential therapeutic target for SAH and other neurological conditions. However, the regulatory mechanisms of Neuritin in ER stress-related inflammatory pathways after SAH are not yet fully understood. In this work, we discovered that the activation of ER stress-related inflammatory pathways leads to neuroinflammation, which further aggravates neuronal apoptosis after SAH. Our findings indicate that Neuritin overexpression play a neuroprotective role by inhibiting IRE1α-TRAF2-NF-κB pathway, PERK-eIF2α-NF-κB pathway, and ATF6-AKT-NF-κB pathway associated with endoplasmic reticulum stress. These inhibitory effects on neuroinflammation ultimately reduce nerve cell apoptosis.

Inhibition of HIF-2α expression in cardiomyocytes attenuates PCB126-induced cardiotoxicity associated with decreased apoptosis through the PI3K/Akt and p53 signaling pathways.

PCB126, a type of polychlorinated biphenyl (PCB), is a persistent pollutant found in both biotic and abiotic environments and poses significant public health risks due to its potential to cause cardiac damage with prolonged exposure. Hypoxia-inducible factor-2α (HIF-2α) is part of the hypoxia-inducible factor (HIF) transcription complex family. Previous studies have shown that knocking out or inhibiting HIF-2α expression can ameliorate pulmonary hypertension and right ventricular dysfunction. This study aimed to investigate whether cardiac-specific knockout of HIF-2α can alleviate the cardiotoxicity caused by PCB126. In this study, cardiac-specific knockout mice and wild-type mice were orally administered PCB126 or corn oil (50 µg/kg/week) for eight weeks. Our findings indicated that PCB126 induces cardiotoxicity and myocardial injury, as evidenced by elevated cardiac enzyme levels and increased cardiac collagen fibers. RNA sequencing revealed that PCB126-induced cardiotoxicity involves the PI3K/Akt and p53 signaling pathways, which was confirmed by western blot analysis. Notably, cardiac-specific knockout of HIF-2α mitigated the damage caused by PCB126, reducing the expression of cardiac enzymes, inflammatory cytokines, and myocardial collagen fibers. Under normal conditions, conditional knockout (CKO) of the HIF-2α gene in cardiomyocytes did not affect the morphology or function of the mouse heart. However, HIF-2α CKO in the heart reduced the cardiotoxic effects of PCB126 by decreasing apoptosis through the PI3K/Akt and p53 signaling pathways. In conclusion, inhibiting HIF-2α expression in cardiomyocytes attenuated PCB126-induced cardiotoxicity by modulating apoptosis through these signaling pathways.

The clinical prognostic risk stratification system for HIV infected hepatocellular carcinoma.

BACKGROUND: Patients with human immunodeficiency virus (HIV) are more susceptible to liver cancer because of their compromised immune system. There is no specific prognostic model for HIV-infected hepatocellular carcinoma (HCC) patients. METHODS: Clinical data of 85 patients with HIV-infected HCC was divided into a 7:3 ratio for training and internal validation sets, while the data of 23 patients with HIV-infected HCC was served as the external validation set. Data of 275 HIV-negative HCC patients was considered as external HIV-negative validation set. Variables associated with overall survival (OS) in the training set were used to develop the HIV-infected HCC prognosis (HIHP) model. The model was tested in the internal and external validation sets. The predictive accuracy of the model was assessed with conventional HIV-negative HCC prognostic scoring systems. RESULTS: In the training set, variables independently associated with OS in multivariable analysis were organ involvement and tumor number. The HIHP model demonstrated a significant association with OS in the training set, with a median OS of 13 months for low risk, 7 months for medium risk, and 3 months for high risk (p < 0.001). The HIHP model showed a significant association with OS, and exhibited greater discriminative abilities compared to conventional HIV-negative HCC prognostic models both in the internal and external validation sets. In the external HIV-negative validation set, the HIHP model did not show better discrimination than conventional HIV-negative HCC scores. CONCLUSION: The new model presented in the work provided a more accurate prognostic prediction of OS in HIV-infected HCC patients. However, the model is not applicable to patients with HIV-negative HCC.

In-Hospital Mortality and Treatment in Patients With Acute Coronary Syndrome With and Without Standard Modifiable Cardiovascular Risk Factors: Findings From the CCC-ACS Project.

BACKGROUND: Patients with acute coronary syndrome without standard modifiable cardiovascular risk factors (SMuRFs; hypertension, smoking, dyslipidemia, diabetes) have not been well studied, with little known about their characteristics, quality of care, or outcomes. We sought to systematically analyze patients with ACS without SMuRFs, especially to evaluate the effectiveness of guideline-directed medical therapy for these patients. METHODS AND RESULTS: In the CCC-ACS (Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome) project (2014-2019), we examined the presence and absence of SMuRFs and features among 89 462 patients with initial acute coronary syndrome. The main outcome was in-hospital all-cause mortality. Among eligible patients, 11.0% had none of the SMuRFs (SMuRF-less). SMuRF-less patients had higher in-hospital mortality (unadjusted hazard ratio [HR], 1.49 [95% CI, 1.19-1.87]). After adjustment for clinical characteristics and treatments, the associations between SMuRF status and in-hospital mortality persisted (adjusted HR, 1.35 [95% CI, 1.07-1.70]). Guideline-directed optimal medical therapy (receiving angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, ß-blockers, and statins) was not associated with lower mortality (adjusted HR, 0.98 [95% CI, 0.58-1.67]) in SMuRF-less patients, unlike the association in patients with SMuRFs (adjusted HR, 0.80 [95% CI, 0.66-0.98]). Sensitivity analyses were consistent with these results. CONCLUSIONS: SMuRF-less patients were associated with an increased risk of in-hospital mortality. Guideline-directed medical therapy was less effective in SMuRF-less patients than in patients with SMuRFs. Dedicated studies are needed to confirm the optimal therapy for SMuRF-less patients. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02306616.

The characteristic activity of regulatory B cells during the occurrence and development of insulin resistance.

PURPOSE: To investigate the aberrant distribution and clinical relevance of regulatory B cells (Bregs) subsets in the peripheral blood of individuals with different levels of insulin resistance (IR). METHODS: A cohort of 124 subjects were divided into five groups according to their insulin resistance index (HOMA-IR) and diabetes diagnosis. The groups comprised Group 1 (IR- with good glycemic control) and Group 2 (IR- with poor glycemic control) at HOMA-IR < 3, Group 3 (IR+ without T2DM) and Group 4 (IR+ with T2DM), at 3 ≤ HOMA-IR < 6, and Group 5 (IR++ with T2DM) at HOMA-IR ≥ 6. Peripheral blood samples were collected from each group, the percentages of CD19+CD24+CD27+ and CD19+CD24+CD38+ Bregs and the levels of IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α, IFN-γ were detected by flow cytometry and flow microsphere matrix method. Additionally, the cytokines levels were validated through ELISA. The activation of Bregs and the production of IL-10 among different groups were analyzed. Spearman correlation analysis was used to analyze the correlation between Bregs activation rate and IR degree. RESULTS: The results showed that the levels of CD19+CD24+CD27+ and CD19+CD24+CD38+ cells were increased whether in IR+ without or with type 2 diabetes mellitus (T2DM) groups compared to the IR- groups, with the most significant increase observed in Group 5. Moreover, the plasma levels of IL-6, IL-10, IL-17, TNF-α and IFN-γ in the IR+ group were higher than those in the IR- group. The expression and activation level of Bregs were positively correlated with the severity of IR in T2DM. CONCLUSION: These results suggest that the increase level of Bregs is closely related to the severity of IR, highlighting the potential significance of Bregs in the clinical progression of T2DM and its associated insulin resistance.

Inhibitory impact of a mesoporous silica nanoparticle-based drug delivery system on Porphyromonas gingivalis-induced bone resorption.

Controlling and reducing plaque formation plays a pivotal role in preventing and treating periodontal disease, often utilizing antibacterial drugs to enhance therapeutic outcomes. Mesoporous silica nanoparticles (MSN), an FDA-approved inorganic nanomaterial, possess robust physical and chemical properties, such as adjustable pore size and pore capacity, easy surface modification, and high biosafety. Numerous studies have exploited MSN to regulate drug release and facilitate targeted delivery. This study aimed to synthesize an MSN-tetracycline (MSN-TC) complex and investigate its inhibitory potential on Porphyromonas gingivalis (P. gingivalis)-induced bone resorption. The antibacterial efficacy of MSN-TC was evaluated through bacterial culture experiments. A P. gingivalis-induced bone resorption model was constructed by subcutaneously injecting P. gingivalis around the cranial bone of rats. Micro-computed tomography was employed to assess the inhibitory impact of MSN and MSN-TC on bone resorption. Furthermore, the influence of MSN and MSN-TC on osteoclast differentiation was examined in vitro. The MSN exhibited optimal pore size and particle dimensions for effective loading and gradual release of TC. MSN-TC demonstrated significant bacteriostatic activity against P. gingivalis. MSN-TC-treated rats showed significantly reduced cranial bone tissue destruction compared to MSN or TC-treated rats. Additionally, both MSN and MSN-TC exhibited inhibitory effects on the receptor activator of nuclear factor kappa-Β ligand-mediated osteoclast differentiation. The MSN-TC complex synthesized in this study demonstrated dual efficacy by exerting antibacterial effects on P. gingivalis and by resisting osteoclast differentiation, thereby mitigating bone resorption induced by P. gingivalis.

[Effect of Pterostilbene Regulating Nuclear Factor E2-Related Factor 2 on Apoptosis of Colon Cancer Cells in Vitro].

Objective To investigate the effects of pterostilbene on human colon cancer LoVo cells and study the regulatory mechanism of nuclear factor E2-related factor 2 (Nrf2) in the process of pterostilbene acting on LoVo cells. Methods LoVo cells were treated with different concentrations (5,10,20,40,60,80,100 µmol/L) of pterostilbene.Cell viability,migration,invasion,and apoptosis were examined by CCK-8,scratch,Transwell,and TUNEL assays,respectively.The mitochondrial membrane potential was measured by the mitochondrial membrane potential assay kit with JC-1.The reactive oxygen species level was measured by 2',7'-dichlorofluorescein diacetate.The protein levels of Nrf2,phosphorylated Nrf2,heme oxygenase 1,and apoptotic proteins (Bcl2 and Bax) were determined by Western blotting.In addition,cell viability,Nrf2 expression,and apoptosis rate were determined after co-application of the Nrf2-specific agonist sulforaphane. Results Compared with the control group,40,60,80,100 µmol/L pterostilbene reduced the viability of LoVo cells (P=0.014,P<0.001,P<0.001,P<0.001).Pterostilbene at 5,10,20 µmol/L did not show effects on cell viability but inhibited cell migration (P=0.008,P<0.001,P<0.001) and invasion (all P<0.001).Pterostilbene at 40,60,80 µmol/L increased apoptosis (P=0.014,P<0.001,P<0.001),promoted mitochondrial membrane potential depolarization (P=0.026,P<0.001,P<0.001) and reactive oxygen species accumulation (all P<0.001),and down-regulated the expression of phosphorylated Nrf2 (P=0.030,P<0.001,P<0.001),heme oxygenase 1 (P=0.015,P<0.001,P<0.001),and Bcl2 (P=0.039,P<0.001,P<0.001) in LoVo cells.Pterostilbene at 60,80 µmol/L down-regulated Nrf2 expression (P=0.001,P<0.001) and up-regulated Bax expression (both P<0.001).The application of sulforaphane reversed the effects of pterostilbene on cell viability (P<0.001),apoptosis (P<0.001),and Nrf2 expression (P=0.022). Conclusion Pterostilbene is a compound that can effectively inhibit colon cancer cells by inhibiting the Nrf2 pathway.

Structure-Based Discovery of Symmetric Disulfides from Garlic Extract as Pseudomonas aeruginosa Quorum Sensing Inhibitors.

Microorganisms are the most common cause of food spoilage. Pseudomonas aeruginosa is a common foodborne pathogen that causes food spoilage and poses a serious threat to food safety. As a crucial target in antitoxicity strategies, the quorum sensing (QS) system shows promising potential for further development. The garlic extract diallyl disulfide exhibits inhibitory activity against the QS system of P. aeruginosa, with disulfide bonds serving as the active component. However, the biological activity of other symmetric disulfides has not been investigated in this capacity. The study synthesized 39 disulfide bond-containing analogs and evaluated their activity as quorum sensing inhibitors (QSIs). The results showed that p-hydroxyphenyl substitution can replace the allyl groups while maintaining strong biological activity. The virulence factors production was reduced by compound 2i, with the strongest inhibitory effect being observed on elastase production. Synergistic inhibition was observed in the presence of antibiotics like ciprofloxacin and tobramycin. 2i successfully inhibited P. aeruginosa infection in the Galleria mellonella larvae model. Primary mechanism studies using transcriptome, surface plasmon resonance and molecular docking suggested that 2i inhibits the QS system by targeting the LasR protein. Thus, compound 2i could be used in developing QSIs for the control of P. aeruginosa infections.

Angiopoietin-like 4 is a potential biomarker for diabetic kidney disease in type 2 diabetes patients.

AIMS/INTRODUCTION: The association between serum angiopoietin-like 4 (ANGPTL4) levels and the severity of diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus remains unclear. METHODS: A total of 1,115 type 2 diabetes mellitus patients were analyzed in this cross-sectional study. DKD index included DKD stages defined by estimated glomerular filtration rate, the albuminuria grades and DKD risk management grades. Serum levels of ANGPTL4 and other biomarkers were detected. Multivariable-adjusted linear and logistic analyses were used to study the association between ANGPTL4 and DKD. The protein levels of ANGPTL4 were assessed in the kidney. Renal tubular cells were stimulated with glucose to study ANGPTL4 expression. RESULTS: Compared with the participants in the third or fourth quantile of ANGPTL4, those in the first or second quantile of ANGPTL4 were younger, with lower glycated hemoglobin, triglycerides and urinary albumin creatinine ratio (all P < 0.05). There was a negative nonlinear relationship between ANGPTL4 and estimated glomerular filtration rate in type 2 diabetes mellitus patients. One standard deviation increased serum ANGPTL4 levels, the odds ratio of having DKD was 1.40 (95% confidence interval 1.08-1.80). The mediation analysis showed that triglycerides did not mediate the association between ANGPTL4 and DKD. Furthermore, ANGPTL4 could be the strongest among multiple panels of biomarkers in its association of DKD. Compared with mice at 8 weeks-of-age, db/db mice at 18 weeks-of-age had increased ANGPTL4 expression in glomeruli and tubular segments. In vitro, glucose could stimulate ANGPTL4 expression in tubular cells in a dose-dependent manner. CONCLUSIONS: ANGPTL4 could be a potential marker and therapeutic target for DKD treatment.

Prevalence, Characteristics, and Treatment Strategy of Different Types of Heart Failure in Patients With Nonvalvular Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia in patients with heart failure (HF). Epidemiological data regarding HF in patients with AF are lacking. We describe the epidemiology, clinical features, treatment strategies, and in-hospital outcomes in patients with AF and HF. METHODS AND RESULTS: Patients with HF and nonvalvular AF in the Improving Care for Cardiovascular Disease in China-AF cohort from February 2015 to December 2019 were included. Patients were stratified by left ventricular ejection fraction into HF with reduced EF, HF with mildly reduced EF, and HF with preserved EF groups. The primary outcome was the occurrence of hospitalization for major adverse cardiovascular events, including death, cardiogenic shock, cardiac arrest, and stroke. Overall, 16 562 patients with AF and HF were included (mean age: 72.35±11.07 years; 46.1% female). HF with preserved EF (63.1%) accounted for the largest proportion, followed by HF with mildly reduced EF (19.0%) and HF with reduced EF (17.9%). Different HF subtypes in patients with AF had unique baseline demographic and clinical characteristics after multinomial logistic regression analysis. Compared with the HF with preserved EF group, hospitalization for major adverse cardiovascular events was increased in the HF with mildly reduced EF group (odds ratio=1.55 [95% CI, 1.18-2.03]) and HF with reduced EF group (odds ratio 1.60 [95% CI, 1.21-2.13]) after adjusting for confounders. CONCLUSIONS: In this large Chinese AF registry, the distribution of HF differed from the non-AF population. Patients with AF with different types of HF have unique demographic and clinical characteristics. Occurrence rates of in-hospital outcomes were higher in patients with HF with mildly reduced EF and patients with HF with reduced EF compared with the HF with preserved EF group. REGISTRATION: URL: http://www.clinicaltrials.gov; Unique identifier: NCT02309398.

The relationship between Geriatric Nutritional Risk Index (GNRI) and in-hospital mortality in critically ill patients with Acute Kidney Injury (AKI).

BACKGROUND: The role of the geriatric nutritional risk index (GNRI) as a prognostic factor in intensive care unit (ICU) patients with acute kidney injury (AKI) remains uncertain. OBJECTIVES: The aim of this study was to investigate the impact of the GNRI on mortality outcomes in critically ill patients with AKI. METHODS: For this retrospective study, we included 12,058 patients who were diagnosed with AKI based on ICD-9 codes from the eICU Collaborative Research Database. Based on the values of GNRI, nutrition-related risks were categorized into four groups: major risk (GNRI < 82), moderate risk (82 ≤ GNRI < 92), low risk (92 ≤ GNRI < 98), and no risk (GNRI ≥ 98). Multivariate analysis was used to evaluate the relationship between GNRI and outcomes. RESULTS: Patients with higher nutrition-related risk tended to be older, female, had lower blood pressure, lower body mass index, and more comorbidities. Multivariate analysis showed GNRI scores were associated with in-hospital mortality. (Major risk vs. No risk: OR, 95% CI: 1.90, 1.54-2.33, P < 0.001, P for trend < 0.001). Moreover, increased nutrition-related risk was negatively associated with the length of hospital stay (Coefficient: -0.033; P < 0.001) and the length of ICU stay (Coefficient: -0.108; P < 0.001). The association between GNRI scores and the risks of in-hospital mortality was consistent in all subgroups. CONCLUSIONS: GNRI serves as a significant nutrition assessment tool that is pivotal to predicting the prognosis of critically ill patients with AKI.

High-order diffraction for optical superfocusing.

High-order diffraction (HOD) from optical microstructures is undesirable in many applications because of the accompanying ghosting patterns and loss of efficiency. In contrast to suppressing HOD with subwavelength structures that challenge the fabrication of large-scale devices, managing HOD is less developed due to the lack of an efficient method for independently manipulating HOD. Here, we report independent manipulation of HODs, which are unexploited for subdiffraction-limit focusing in diffractive lenses, through an analytical formula that correlates the diffraction order and the width of each zone. The large spatial frequencies offered by the HODs enable our lenses to reduce the lateral focal size down to 0.44 λ even without any subwavelength feature (indispensable in most high-NA diffractive lenses), facilitating large-scale manufacture. Experimentally, we demonstrate high-order lens-based confocal imaging with a center-to-center dry resolution of 190 nm, the highest among visible-light confocal microscopies, and laser-ablation lithography with achieved direct-writing resolution of 400 nm (0.385 λ).

Magnetic resonance imaging-based radiomics model for preoperative assessment of risk stratification in endometrial cancer.

BACKGROUND: Preoperative risk stratification is significant for the management of endometrial cancer (EC) patients. Radiomics based on magnetic resonance imaging (MRI) in combination with clinical features may be useful to predict the risk grade of EC. AIM: To construct machine learning models to predict preoperative risk stratification of patients with EC based on radiomics features extracted from MRI. METHODS: The study comprised 112 EC patients. The participants were randomly separated into training and validation groups with a 7:3 ratio. Logistic regression analysis was applied to uncover independent clinical predictors. These predictors were then used to create a clinical nomogram. Extracted radiomics features from the T2-weighted imaging and diffusion weighted imaging sequences of MRI images, the Mann-Whitney U test, Pearson test, and least absolute shrinkage and selection operator analysis were employed to evaluate the relevant radiomic features, which were subsequently utilized to generate a radiomic signature. Seven machine learning strategies were used to construct radiomic models that relied on the screening features. The logistic regression method was used to construct a composite nomogram that incorporated both the radiomic signature and clinical independent risk indicators. RESULTS: Having an accuracy of 0.82 along with an area under the curve (AUC) of 0.915 [95% confidence interval (CI): 0.806-0.986], the random forest method trained on radiomics characteristics performed better than expected. The predictive accuracy of radiomics prediction models surpassed that of both the clinical nomogram (AUC: 0.75, 95%CI: 0.611-0.899) and the combined nomogram (AUC: 0.869, 95%CI: 0.702-0.986) that integrated clinical parameters and radiomic signature. CONCLUSION: The MRI-based radiomics model may be an effective tool for preoperative risk grade prediction in EC patients.