Endothelial Cell Transcription Modulation in Cerebral Aneurysms After Endovascular Flow Diversion.

PURPOSE: Flow diverting stents (FDS) are used to treat cerebral aneurysms, by promoting thrombosis and occlusion of the aneurysm sac. However, retreatment is required in some cases, and the biologic basis behind treatment outcome is not known. The goal of this study was to understand how changes in hemodynamic flow after FDS placement affect aneurysmal endothelial cell (EC) activity. METHODS: Three-dimensional models of patient-specific aneurysms were created to quantify the EC response to FDS placement. Computational fluid dynamic simulations were used to determine the hemodynamic impact of FDS. Two identical models were created for each patient; into one a FDS was inserted. Each model was then populated with human carotid ECs and subjected to patient-specific pulsatile flow for 24 h. ECs were isolated from aneurysm dome from each model and bulk RNA sequencing was performed. RESULTS: Paired untreated and treated models were created for four patients. Aneurysm dome EC analysis revealed 366 (2.6%) significant gene changes between the untreated and FDS conditions, out of 13909 total expressed genes. Gene set enrichment analysis of the untreated models demonstrated enriched gene ontology terms related to cell adhesion, growth/tensile activity, cytoskeletal organization, and calcium ion binding. In the FDS models, enriched terms were related to cellular proliferation, ribosomal activity, RNA splicing, and protein folding. CONCLUSION: Treatment of cerebral aneurysms with FDS induces significant EC gene transcription changes related to aneurysm hemodynamics in patient-specific in vitro 3D-printed models subjected to pulsatile flow. Further investigation is needed into the relationship between transcriptional change and treatment outcome.

Correlation between retinal vascular geometric parameters and pathologically diagnosed type 2 diabetic nephropathy.

Background: Diabetic nephropathy (DN) and diabetic retinopathy (DR) are common microvascular complications of diabetes. The purpose of this study was to investigate the correlation between retinal vascular geometric parameters and pathologically diagnosed type 2 DN and to determine the capacity of retinal vascular geometric parameters in differentiating DN from non-diabetic renal disease (NDRD). Methods: The study participants were adult patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease who underwent a renal biopsy. Univariate and multivariable regression analyses were performed to evaluate associations between retinal vessel geometry parameters and pathologically diagnosed DN. Multivariate binary logistic regression analyses were performed to establish a differential diagnostic model for DN. Results: In total, 403 patients were examined in this cross-sectional study, including 152 (37.7%) with DN, 157 (39.0%) with NDRD and 94 (23.3%) with DN combined with NDRD. After univariate logistic regression, total vessel fractal dimension, arteriolar fractal dimension and venular fractal dimension were all found to be associated with DN. In multivariate analyses adjusting for age, sex, blood pressure, diabetes, DR and other factors, smaller retinal vascular fractal dimensions were significantly associated with DN (P < .05). We developed a differential diagnostic model for DN combining traditional clinical indicators and retinal vascular geometric parameters. The area under the curve of the model established by multivariate logistic regression was 0.930. Conclusions: Retinal vessel fractal dimension is of great significance for the rapid and non-invasive differentiation of DN. Incorporating retinal vessel fractal dimension into the diagnostic model for DN and NDRD can improve the diagnostic efficiency.

Time-resolved scRNA-seq reveals transcription dynamics of polarized macrophages with influenza A virus infection and antigen presentation to T cells.

AbstractThroughout history, the influenza A virus has caused numerous devastating global pandemics. Macrophages, as pivotal innate immune cells, exhibit a wide range of immune functions characterized by distinct polarization states, reflecting their intricate heterogeneity. In this study, we employed the time-resolved single-cell sequencing technique coupled with metabolic RNA labelling to elucidate the dynamic transcriptional changes in distinct polarized states of bone marrow-derived macrophages (BMDMs) upon infection with the influenza A virus. Our approach not only captures the temporal dimension of transcriptional activity, which is lacking in conventional scRNA-seq methods, but also reveals that M2-polarized Arg1_macrophages is the sole state supporting successful replication of influenza A virus. Furthermore, we identified distinct antigen presentation capabilities to CD4+ T and CD8+ T cells across diverse polarized states of macrophages. Notably, the M1 phenotype, exhibited by both bone marrow-derived macrophages (BMDMs) and murine alveolar macrophages (AMs), demonstrated superior conventional and cross-presentation abilities for exogenous antigens, with a particular emphasis on cross-presentation capacity. Additionally, as CD8+ T cell differentiation progressed, M1 polarization exhibited an enhanced capacity for cross-presentation. All three phenotypes of BMDMs, including M1, demonstrated robust presentation of CD4+ regulatory T cells, while displaying limited ability to present naive CD4+ T cells. These findings offer novel insights into the immunological regulatory mechanisms governing distinct polarized states of macrophages, particularly their roles in restricting the replication of influenza A virus and modulating antigen-specific T cell responses through innate immunity.

Functional and aesthetic results of the Z-shaped and straight lower lip-splitting incision: a randomized clinical trial.

The lip-splitting approach enables excellent access to all areas of the mouth and pharynx to remove tumors; however, traditional lower lip-splitting incisions produce an unsatisfactory scar. To achieve better functional and aesthetic results, we used a Z-shaped incision and compared the functional and aesthetic outcomes of the straight and Z-shaped incisions. Sixty patients who fulfilled the inclusion criteria were randomly divided into two groups and underwent lip-splitting between March 2021 and September 2023. Eventually, 77 patients were reviewed within 6 months and evaluated using the lip function assessment scale, patient and observer scar assessment scale, naïve observer scar assessment scale, and a clinical examination. The Z-shaped incision group performed better in terms of the lip pout movement at 3 months and in the subjective overall opinion, color, irregularity, and pigmentation at 6 months. The Z-shaped incision group had a lower incidence of notched vermilion. In conclusion, Z-shaped lower lip-splitting incisions have better functional and aesthetic outcomes than traditional straight incisions.Trial registration: Public title: Difference between the effect of Z-shaped and vertical incisions of labiobuccal flap on the recovery of lower lip scars. Registration date: 09/03/2021. Registration number: ChiCTR2100044084. Registry URL: http://www.chictr.org.cn .

Macrophages: A missing key in cardiac tissue engineering for sustained vascularization.

Macrophages regulate angiogenesis, repair, conduction, and homeostasis in heart tissue. Landau et al.1 demonstrate that incorporating primitive macrophages into engineered heart tissues significantly promotes long-term vascularization and cardiac maturation. This advance demonstrates the importance of resident immune-vascular microenvironments in cardiac tissue engineering, marking an important step forward for heart-on-chip technologies.

Electrocatalysts for Urea Synthesis from CO2 and Nitrogenous Species: from CO2 and N2/NOx Reduction to urea synthesis.

The traditional industrial synthesis of urea relies on the energy-intensive and polluting process, namely the Haber-Bosch method for ammonia production, followed by the Bosch-Meiser process for urea synthesis. In contrast, electrocatalytic C-N coupling from carbon dioxide (CO2) and nitrogenous species presents a promising alternative for direct urea synthesis under ambient conditions, bypassing the need for ammonia production. This review provides an overview of recent progress in the electrocatalytic coupling of CO2 and nitrogen sources for urea synthesis. It focuses on the role of intermediate species and active site structures in promoting urea synthesis, drawing from insights into reactants' adsorption behavior and interactions with catalysts tailored for CO2 reduction, nitrogen reduction, and nitrate reduction. Advanced electrocatalyst design strategies for urea synthesis from CO2 and nitrogenous species under ambient conditions are explored, providing insights for efficient catalyst design. Key challenges and prospective directions are presented in the conclusion. Mechanistic studies elucidating the C-N coupling reaction and future development directions are discussed. The review aims to inspire further research and development in electrocatalysts for electrochemical urea synthesis.

EasyNAT MTC Assay: a Rapid Method to Detect Mycobacterium Tuberculosis in Respiratory Specimens.

BACKGROUND: This study aimed to effectively evaluate the diagnostic performance of the EasyNAT Mycobacterium tuberculosis complex (MTC) assay for tuberculosis (TB) detection from sputum. METHODS: The retrospectively analyzed data was collected from September 1, 2021, to November 1, 2023, in our hospital. RESULTS: Forty EasyNAT-positive sputum specimens were simultaneously detected using the GeneXpert MTB/ rifampicin (RIF) assay. The concordance rate between the EasyNAT and GeneXpert MTB/RIF assays was 100%. CONCLUSIONS: Because of the complexity of detecting RIF resistance data information, the rapid EasyNAT system used in conjunction with GeneXpert might be a better choice for the detection of TB in hospitals.

Adequacy of the Dosing and Infusion Time of Ceftazidime/Avibactam for the Treatment of Gram-Negative Bacterial Infections: A PK/PD Simulation Study.

Introduction: Recent studies suggested the potential benefits of extended infusion times to optimize the treatment efficacy of ceftazidime/avibactam, which indicated that the current pharmacokinetic/pharmacodynamic (PK/PD) target may not be sufficient, especially for severe infections. The purpose of this study is to assess the adequacy of dosing strategies and infusion durations of ceftazidime/avibactam when applying higher PK/PD targets. Methods: This study utilized published PK parameters to conduct Monte Carlo simulations. Different dosages including the recommended regimen based on renal function were simulated and evaluated by the probability of target attainment (PTA) and cumulative fraction of response (CFR). Different PK/PD targets were set for ceftazidime and avibactam. MIC distributions from various sources were used to calculate the CFR. Results: Multiple PK/PD targets have been set in this study, All recommended dosage could easily achieve the target of 50%fT ≥ MIC (ceftazidime) and 50%fT ≥ CT=1.0 mg/L (avibactam). However, for severe infection patients with normal renal function and augmented renal clearance at the recommended dosage (2000 mg/500 mg, every 8 hours), the infusion duration needs to be extended to 3 hours and 4 hours to achieve the targets of 100%fT ≥ MIC and 100%fT ≥ CT=1.0 mg/L. Only continuous infusion at higher dosages achieved 100%fT ≥ 4×MIC and 100%fT ≥ CT=4.0 mg/L targets to all currently recommended regimens. According to the varying MIC distributions, higher concentrations are needed for Pseudomonas aeruginosa, with the attainment rates vary across different regions. Conclusion: The current recommended dosing regimen of ceftazidime/avibactam is insufficient for severe infection patients, and continuous infusion is suggested.

An effective textured Novel Object Recognition Test (tNORT) for repeated measure of whisker sensitivity of rodents.

Rodents use their whisker system to discriminate surface texture. Whisker-based texture discrimination tasks are often used to investigate the mechanisms encoding tactile sensation. One such task is the textured Novel Object Recognition Test (tNORT). It takes advantage of a tendency of rodents to explore novel objects more than familiar ones and assesses the sensitivity of whiskers in discriminating different textures of objects. It requires little training of the animals and the equipment involved is a simple arena with typically two objects placed inside. The success of the test relies on rodents spending sufficient time exploring these objects. Animals may lose interests in such tasks when performed repetitively within a limited time frame. However, such repeated tests may be crucial when establishing a sensitivity threshold of the whisker system. Here we present an adapted rodent tNORT protocol designed to maintain sustained interest in the objects even with repeated testing. We constructed complex objects from three simple-shaped objects. Different textures were provided by sandpapers of varying grit sizes. To minimise olfactory clues, we used the sandy and the laminar side of the same sandpaper as the familiar and novel textures assigned at random. We subsequently conducted repeated tNORTs on eight rats in order to identify a critical threshold of the sandpaper grit size below which rats would be unable to discriminate the sandy from the laminar side. With an inter-test-interval of seven days and after five tNORTs, the protocol enabled us to successfully identify the threshold. We suggest that the proposed tNORT is a useful tool for investigating the sensitivity threshold of the whisker system of rodent, and for testing the effectiveness of an intervention by comparing sensitivity threshold pre- and post-intervention.

Significantly Increased Specific Discharge Capacitance at Carbon Fibers Created via Architected Ultramicropores.

Carbon is commonly used as an electrode material for supercapacitors operating on an electrical double-layer energy storage mechanism. However, the low specific capacitance limits its application. Increasing the specific surface area is by far the most common expansion method, and surprisingly, they are not always positively correlated. The overmuch specific surface will show the characteristics of nanoconfinement, and the potential synergistic enhancement mechanism of various key parameters is still controversial. In this work, carbon fiber electrodes with different ultramicropore structures were designed in order to improve the utilization rate and the discharge capacitance. It has been found that when the ultramicropore entrance's surface is too small, it will lead to the decrease of the external charge of the pore transport channel, and then, the selectivity of the opposite ions will decrease. The numerical simulation based on Poisson and Nernst-Planck equations also indicates that ions have difficulty diffusing into the micropores when their entrance surface decreases. Surface properties within the nanocontainment space become critical factors influencing ion transport and adsorption. The specific discharge capacitance of carbon fiber is increased from 3 to 1430 mF cm-2.

Is it time to recommend AUC-based vancomycin therapeutic drug monitoring only? A cross-sectional survey in China.

Background: The latest published therapeutic drug monitoring (TDM) guidelines for vancomycin recommend changing trough-based monitoring to area under the concentration-to-time curve (AUC)-based monitoring. This study aimed to evaluate the implementation status and perceptions of vancomycin AUC-based TDM in China and to determine the challenges in performing AUC-based TDM. Methods: A nationwide cross-sectional survey was conducted in China using an online questionnaire. The questionnaire comprised a total of 25 questions with open- and closed-ended answers to collect information about the current implementation of vancomycin TDM and the participants' perceptions of these practices. The questionnaire responses were collected via the Questionnaire Star platform and analyzed. Results: A total of 161 questionnaires were completed by 131 hospitals and were included. Approximately 59.5% (78/131) of the surveyed hospitals conducted vancomycin TDM; however, only 10.7% (14/131) of these hospitals performed AUC-based vancomycin TDM. Of the eligible participants, 58.4% (94/161) had experience with vancomycin TDM, and only 37 participants (37/161, 23.0%) had the ability to estimate the AUC, primarily through Bayesian simulation (33/161, 20.5%). The participants considered the following challenges to implementing AUC-based monitoring: (1) the high cost of AUC-based monitoring; (2) inadequate knowledge among pharmacists and/or physicians; (3) the complexity of AUC calculations; (4) difficulty obtaining AUC software; and (5) unclear benefit of AUC-based monitoring. Conclusion: The majority of surveyed hospitals have not yet implemented AUC-based vancomycin TDM. Multiple challenges should be addressed before wide implementation of AUC-based monitoring, and guidance for trough-based monitoring is still needed.

Paragonimiasis misdiagnosed as liver abscess: A case report.

BACKGROUND: Paragonimiasis is a typical food-borne zoonotic disease. Hosts acquire Paragonimus infection through the ingestion of raw or undercooked crayfish and crab. The clinical manifestations of the disease are varied, and it is often misdiagnosed or missed. The diagnosis of paragonimiasis should be considered comprehensively. Praziquantel is the first choice for treatment, and albendazole can be used in combination with repeated courses in severe cases. CASE SUMMARY: We report a case of liver paragonimiasis that was misdiagnosed as an abscess. The patient presented with fatigue and poor appetite for 2 months, and was diagnosed with liver abscess in the local hospital. After 6 months, the patient visited our hospital because of recurrent abdominal pain and was diagnosed with liver paragonimiasis based on epidemiological history, clinical presentations, and laboratory findings. He was treated with praziquantel (25 mg/kg) three times a day for 3 days; however, the symptoms still presented after treatment. He was treated with oral praziquantel and albendazole for one further course. Follow-up suggested that the treatment was effective and the symptoms improved. CONCLUSION: The combination of albendazole and praziquantel may improve the therapeutic efficacy of paragonimiasis.

Serum 5'-Nucleotidase as a Novel Predictor of Adverse Clinical Outcomes after Percutaneous Coronary Intervention in Patients with Coronary Artery Disease.

Background: The correlation between 5 ' -Nucleotidase ( 5 ' -NT) and the clinical outcomes in coronary artery disease (CAD) patients following percutaneous coronary intervention (PCI) is not clear. This study aims to clarify this relationship. Methods: The PRACTICE study enrolled 15,250 patients between December 2016 and October 2021. After filtering out those without 5 ' -NT data, a total of 6555 patients were analyzed with a median follow-up of 24 months. Based on the receiver operating characteristic (ROC) curve analysis, a 5 ' -NT level of 5.57 U/L was selected as the optimal cutoff value. All research samples were divided into high-value ( ≥ 5.57 U/L, n = 2346) and low-value groups ( < 5.57 U/L, n = 4209). Key clinical outcomes included all-cause death (ACD), cardiovascular death (CD), major adverse cardiovascular events (MACE), and major adverse cardiovascular and cerebrovascular events (MACCE). After separating patients into high and low value groups, multivariate Cox regression analysis was used to correct for potential confounding variables. Finally, risk ratios and their 95% confidence intervals (CIs) were calculated. Results: During the follow-up period, 129 instances of ACD were recorded-49 cases (1.2%) in the low-value group and 80 cases (3.4%) in the high-value group. Similarly, 102 CDs occurred, including 42 low-value group cases (1.0%) and 60 high-value group cases (2.6%). A total of 363 MACE occurred, including 198 low-value group cases (4.7%) and 165 high-value group cases (7%). A total of 397 cases of MACCE occurred, including 227 low-value group cases (5.4%) and 170 high-value group cases (7.2%). As serum 5 ' -NT increased, the incidence of ACD, CD, MACE and MACCE increased. After multivariate Cox regression, high 5 ' -NT levels were linked with a 1.63-fold increase in ACD risk (hazard ratio [HR] = 2.630, 95% CI: [1.770-3.908], p < 0.001) when compared to low 5 ' -NT patients. Similarly, the risk of CD, MACE, and MACCE increased by 1.298-fold (HR = 2.298, 95% CI: [1.477-3.573], p < 0.001), 41% (HR = 1.410, 95% CI: [1.124-1.768], p = 0.003) and 30.5% (HR = 1.305, 95% CI: [1.049-1.623], p = 0.017), respectively. Conclusions: high serum 5 ' -NT levels were independently correlated with adverse clinical outcomes in CAD patients following PCI, affirming its potential as a prognostic indicator.

CCDC189 depletion leads to oligo-astheno-teratozoospermia and male infertility in mice.

In male reproductive system, proteins containing the coiled-coil domain (CCDC) are predominantly expressed in specific regions including the testis, epididymis, seminal vesicle, and prostate. They play a vital role in centriole formation, sperm motility and flagellar development in male gametes. Despite being highly expressed in the testis, the exact physiological function of the coiled-coil domain-containing 189 (Ccdc189) gene remain largely unclear. Our research provides a comprehensive and detailed investigation into the localization of CCDC189 protein within the testis seminiferous tubules. CCDC189 specifically expressed in spermatocytes, round spermatids and elongating spermatids in mouse testis. The deletion of Ccdc189 in mouse leads to male infertility, characterized by significantly reduced sperm counts and motility. Abnormally shaped spermatozoa with irregular tails, exhibiting shortened and twisted morphology, were observed in the seminiferous tubules. Electron microscopy revealed disordered and missing peripheral microtubule doublets (MTD) and outer dense fibers (ODF) in the sperm flagella, accompanied by a consistent absence of central pairs (CP). The knockout of Ccdc189 resulted in oligo-astheno-teratozoospermia, which is characterized by low sperm count and reduced sperm motility and abnormal morphology. Furthermore, we identified poly(A)-binding protein cytoplasmic 1 (PABPC1) and PABPC2 as interacting proteins with CCDC189. These proteins belong to the poly(A)-binding protein (PABP) family and are involved in regulating mRNA translational activity in spermatogenic cells by specifically binding to poly(A) tails at the 3' ends of mRNAs.

Toward better understanding and management of chemobrain: the potential utilities of the MemTrax memory test.

OBJECTIVE: To study the effects of chemotherapy on cognitive function in breast cancer patients, and to investigate the relationship of MemTrax test of memory and related functions to the FACT-Cog functional self-assessment for the evaluation and management of chemobrain. METHODS: In this prospective cohort study, clinical information of pathologically confirmed female breast cancer patients who decided to receive chemotherapy were collected in a questionnaire which was developed for this study and provided as a supplementary file. The FACT-Cog self-assessment and MemTrax test were administered before and after the chemotherapy treatments. Patients with chemobrain were identified using published criteria based on FACT-Cog scores, and MemTrax scores from chemobrain patients were analyzed. RESULTS: Fifty-six patients participated in this study, of which 41 participants completed 4 or more cycles of chemotherapy and were included in the final analyses here. Using the reported high end of minimal clinical differences (10.6 points) of FACT-Cog before and after chemotherapy, 18 patients suffered from chemobrain in this study. In these 18 chemobrain patients, no cognitive impairments were detected by MemTrax, which paradoxically demonstrated an improvement in the normal cognitive range. CONCLUSION: The cognitive impairment induced by chemotherapy in breast cancer patients is detectable by the FACT-Cog in a Chinese cohort but is not detected by the MemTrax memory test. The fact that the more objective MemTrax could not detect the impairment could alleviate patients' concerns which in turn would be beneficial for patients' mental health.

Association between the C-Reactive Protein-Albumin-Lymphocyte (CALLY) Index and Adverse Clinical Outcomes in CAD Patients after PCI: Findings of a Real-World Study.

Background: The C-reactive protein-albumin-lymphocyte (CALLY) index is a novel inflammatory biomarker, and its association with the prognosis of coronary artery disease (CAD) after percutaneous coronary intervention (PCI) has not previously been studied. Therefore, this study aimed to investigate the effect of using the CALLY index on adverse outcomes in CAD patients undergoing PCI. Methods: From December 2016 to October 2021, we consecutively enrolled 15,250 CAD patients and performed follow-ups for primary endpoints consisting of all-cause mortality (ACM) and cardiac mortality (CM). The CALLY index was computed using the following formula: (albumin × lymphocyte)/(C-reactive protein (CRP) × 10 4 ). The average duration of the follow-up was 24 months. Results: A total of 3799 CAD patients who had undergone PCI were ultimately enrolled in the present study. The patients were divided into four groups according to the CALLY index quartiles: Q1 ( ≤ 0.69, n = 950), Q2 (0.69-2.44, n = 950), Q3 (2.44-9.52, n = 950), and Q4 ( > 9.52, n = 949). The low-Q1 group had a significantly higher prevalence of ACM (p < 0.001), CM (p < 0.001), major adverse cardiac events (MACEs) (p = 0.002), and major adverse cardiac and cerebrovascular events (MACCEs) (p = 0.002). Kaplan-Meier analysis revealed that a low CALLY index was significantly linked with adverse outcomes. After univariate and multivariate Cox regression analysis, the risk of ACM, CM, MACEs, and MACCEs decreased by 73.7% (adjust hazard risk [HR] = 0.263, 95% CI: 0.147-0.468, p < 0.001), 70.6% (adjust HR = 0.294, 95% CI: 0.150-0.579, p < 0. 001), 37.4% (adjust HR = 0.626, 95% CI: 0.422-0.929, p = 0.010), and 41.5% (adjust HR = 0.585, 95% CI: 0.401-0.856, p = 0.006), respectively, in the Q4 quartiles compared with the Q1 quartiles. Conclusions: This study revealed that a decreased CALLY index was associated with worse prognoses for CAD patients after PCI. The categorization of patients with a decreased CALLY index could provide valuable evidence for the risk stratification of adverse outcomes in CAD patients after PCI. Clinical Trial Registration: The details are available at http://www.chictr.org.cn (Identifier: NCT05174143).

Association between extremely high prognostic nutritional index and all-cause mortality in patients with coronary artery disease: secondary analysis of a prospective cohort study in China.

OBJECTIVES: Decreased prognostic nutritional index (PNI) was associated with adverse outcomes in many clinical diseases. This study aimed to evaluate the relationship between baseline PNI value and adverse clinical outcomes in patients with coronary artery disease (CAD). DESIGN: The Personalized Antiplatelet Therapy According to CYP2C19 Genotype in Coronary Artery Disease (PRACTICE) study, a prospective cohort study of 15 250 patients with CAD, was performed from December 2016 to October 2021. The longest follow-up period was 5 years. This study was a secondary analysis of the PRACTICE study. SETTING: The study setting was Xinjiang Medical University Affiliated First Hospital in China. PARTICIPANTS: Using the 50th and 90th percentiles of the PNI in the total cohort as two cut-off limits, we divided all participants into three groups: Q1 (PNI <51.35, n = 7515), Q2 (51.35 ≤ PNI < 59.80, n = 5958) and Q3 (PNI ≥ 59.80, n = 1510). The PNI value was calculated as 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (per mm3). PRIMARY OUTCOME: The primary outcome measure was mortality, including all-cause mortality (ACM) and cardiac mortality (CM). RESULTS: In 14 983 participants followed for a median of 24 months, a total of 448 ACM, 333 CM, 1162 major adverse cardiovascular events (MACE) and 1276 major adverse cardiovascular and cerebrovascular events (MACCE) were recorded. The incidence of adverse outcomes was significantly different among the three groups (p <0.001). There were 338 (4.5%), 77 (1.3%) and 33 (2.2%) ACM events in the three groups, respectively. A restricted cubic spline displayed a J-shaped relationship between the PNI and worse 5-year outcomes, including ACM, CM, MACE and MACCE. After adjusting for traditional cardiovascular risk factors, we found that only patients with extremely high PNI values in the Q3 subgroup or low PNI values in the Q1 subgroup had a greater risk of ACM (Q3 vs Q2, HR: 1.617, 95% CI 1.012 to 2.585, p=0.045; Q1 vs Q2, HR=1.995, 95% CI 1.532 to 2.598, p <0.001). CONCLUSION: This study revealed a J-shaped relationship between the baseline PNI and ACM in patients with CAD, with a greater risk of ACM at extremely high PNI values. TRIAL REGISTRATION NUMBER: NCT05174143.

Advanced nanomedicines and immunotherapeutics to treat respiratory diseases especially COVID-19 induced thrombosis.

Immunotherapy and associated immune regulation strategies gained huge attraction in order to be utilized for treatment and prevention of respiratory diseases. Engineering specifically nanomedicines can be used to regulate host immunity in lungs in the case of respiratory diseases including coronavirus disease 2019 (COVID-19) infection. COVID-19 causes pulmonary embolisms, thus new therapeutic options are required to target thrombosis, as conventional treatment options are either not effective due to the complexity of the immune-thrombosis pathophysiology. In this review, we discuss regulation of immune response in respiratory diseases especially COVID-19. We further discuss thrombosis and provide an overview of some antithrombotic nanoparticles, which can be used to develop nanomedicine against thrombo-inflammation induced by COVID-19 and other respiratory infectious diseases. We also elaborate the importance of immunomodulatory nanomedicines that can block pro-inflammatory signalling pathways, and thus can be recommended to treat respiratory infectious diseases.

Icariin Ameliorates D-galactose-induced Cell Injury in Neuron-like PC12 Cells by Inhibiting MPTP Opening.

OBJECTIVE: Icariin (ICA) has a good neuroprotective effect and can upregulate neuronal basal autophagy in naturally aging rats. Mitochondrial dysfunction is associated with brain aging-related neurodegenerative diseases. Abnormal opening of the mitochondrial permeability transition pore (mPTP) is a crucial factor in mitochondrial dysfunction and is associated with excessive autophagy. This study aimed to explore that ICA protects against neuronal injury by blocking the mPTP opening and down-regulating autophagy levels in a D-galactose (D-gal)-induced cell injury model. METHODS: A cell model of neuronal injury was established in rat pheochromocytoma cells (PC12 cells) treated with 200 mmol/L D-gal for 48 h. In this cell model, PC12 cells were pre-treated with different concentrations of ICA for 24 h. MTT was used to detect cell viability. Senescence associated ß-galactosidase (SA-ß-Gal) staining was used to observe cell senescence. Western blot analysis was performed to detect the expression levels of a senescence-related protein (p21), autophagy markers (LC3B, p62, Atg7, Atg5 and Beclin 1), mitochondrial fission and fusion-related proteins (Drp1, Mfn2 and Opa1), and mitophagy markers (Pink1 and Parkin). The changes of autophagic flow were detected by using mRFP-GFP-LC3 adenovirus. The intracellular ultrastructure was observed by transmission electron microscopy. Immunofluorescence was used to detect mPTP, mitochondrial membrane potential (MMP), mitochondrial reactive oxygen species (mtROS) and ROS levels. ROS and apoptosis levels were detected by flow cytometry. RESULTS: D-gal treatment significantly decreased the viability of PC12 cells, and markedly increased the SA-ß-Gal positive cells as compared to the control group. With the D-gal stimulation, the expression of p21 was significantly up-regulated. Furthermore, D-gal stimulation resulted in an elevated LC3B II/I ratio and decreased p62 expression. Meanwhile, autophagosomes and autolysosomes were significantly increased, indicating abnormal activation of autophagy levels. In addition, in this D-gal-induced model of cell injury, the mPTP was abnormally open, the ROS generation was continuously increased, the MMP was gradually decreased, and the apoptosis was increased. ICA effectively improved mitochondrial dysfunction to protect against D-gal-induced cell injury and apoptosis. It strongly inhibited excessive autophagy by blocking the opening of the mPTP. Cotreatment with ICA and an mPTP inhibitor (cyclosporin A) did not ameliorate mitochondrial dysfunction. However, the protective effects were attenuated by cotreatment with ICA and an mPTP activator (lonidamine). CONCLUSION: ICA inhibits the activation of excessive autophagy and thus improves mitochondrial dysfunction by blocking the mPTP opening.

Establishment of a SUMO pathway related gene signature for predicting prognosis, chemotherapy response and investigating the role of EGR2 in bladder cancer.

Background: Bladder cancer is a prevalent malignancy with significant clinical implications. Small Ubiquitin-like Modifier (SUMO) pathway related genes (SPRG) have been implicated in the development and progression of cancer. Methods: In this study, we conducted a comprehensive analysis of SPRG in bladder cancer. We analyzed gene expression and prognostic value of SPRG and developed a SPRG signature (SPRGS) prognostic model based on four genes (HDAC4, TRIM27, EGR2, and UBE2I) in bladder cancer. Furthermore, we investigated the relationship between SPRGS and genomic alterations, tumor microenvironment, chemotherapy response, and immunotherapy. Additionally, we identified EGR2 as a key SPRG in bladder cancer. The expression of EGR2 in bladder cancer was detected by immunohistochemistry, and the cell function experiment clarified the effect of knocking down EGR2 on the proliferation, invasion, and migration of bladder cancer cells. Results: Our findings suggest that SPRGS hold promise as prognostic markers and predictive biomarkers for chemotherapy response and immunotherapy efficacy in bladder cancer. The SPRGS prognostic model exhibited high predictive accuracy for bladder cancer patient survival. We also observed correlations between SPRG and genomic alterations, tumor microenvironment, and response to chemotherapy. Immunohistochemical results showed that EGR2 was highly expressed in bladder cancer tissues, and its overexpression was associated with poor prognosis. Knockdown of EGR2 inhibited bladder cancer cell proliferation, invasion, and migration. Conclusion: This study provides valuable insights into the landscape of SPRGS in bladder cancer and their potential implications for personalized treatment strategies. The identification of EGR2 as a key SPRG and its functional impact on bladder cancer cells further highlights its significance in bladder cancer development and progression. Overall, SPRGS may serve as important prognostic markers and predictive biomarkers for bladder cancer patients, guiding treatment decisions and improving patient outcomes.