Bevacizumab induces ferroptosis and enhances CD8+ T cell immune activity in liver cancer via modulating HAT1 and increasing IL-9.

Bevacizumab is a recombinant humanized monoclonal immunoglobulin (Ig) G1 antibody of VEGF, and inhibits angiogenesis and tumor growth in hepatocellular carcinoma (HCC). Ferroptosis, a new form of regulated cell death function independently of the apoptotic machinery, has been accepted as an attractive target for pharmacological intervention; the ferroptosis pathway can enhance cell immune activity of anti-PD1 immunotherapy in HCC. In this study we investigated whether and how bevacizumab regulated ferroptosis and immune activity in liver cancer. Firstly, we performed RNA-sequencing in bevacizumab-treated human liver cancer cell line HepG2 cells, and found that bevacizumab significantly altered the expression of a number of genes including VEGF, PI3K, HAT1, SLC7A11 and IL-9 in liver cancer, bevacizumab upregulated 37 ferroptosis-related drivers, and downregulated 17 ferroptosis-related suppressors in particular. We demonstrated that bevacizumab triggered ferroptosis in liver cancer cells by driving VEGF/PI3K/HAT1/SLC7A11 axis. Clinical data confirmed that the expression levels of VEGF were positively associated with those of PI3K, HAT1 and SLC7A11 in HCC tissues. Meanwhile, we found that bevacizumab enhanced immune cell activity in tumor immune-microenvironment. We identified that HAT1 up-regulated miR-143 targeting IL-9 mRNA 3'UTR in liver cancer cells; bevacizumab treatment resulted in the increase of IL-9 levels and its secretion via VEGF/PI3K/HAT1/miR-143/IL-9 axis, which led to the inhibition of tumor growth in vivo through increasing the release of IL-2 and Granzyme B from activated CD8+ T cells. We conclude that in addition to inhibiting angiogenesis, bevacizumab induces ferroptosis and enhances CD8+ T cell immune activity in liver cancer. This study provides new insight into the mechanisms by which bevacizumab synergistically modulates ferroptosis and CD8+ T cell immune activity in liver cancer.

Cardiolipin oxidized by ROS from complex II acts as a target of gasdermin D to drive mitochondrial pore and heart dysfunction in endotoxemia.

Cardiac dysfunction, an early complication of endotoxemia, is the major cause of death in intensive care units. No specific therapy is available at present for this cardiac dysfunction. Here, we show that the N-terminal gasdermin D (GSDMD-N) initiates mitochondrial apoptotic pore and cardiac dysfunction by directly interacting with cardiolipin oxidized by complex II-generated reactive oxygen species (ROS) during endotoxemia. Caspase-4/11 initiates GSDMD-N pores that are subsequently amplified by the upregulation and activation of NLRP3 inflammation through further generation of ROS. GSDMD-N pores form prior to BAX and VDAC1 apoptotic pores and further incorporate into BAX and VDAC1 oligomers within mitochondria membranes to exacerbate the apoptotic process. Our findings identify oxidized cardiolipin as the definitive target of GSDMD-N in mitochondria of cardiomyocytes during endotoxin-induced myocardial dysfunction (EIMD), and modulation of cardiolipin oxidation could be a therapeutic target early in the disease process to prevent EIMD.

Transcriptomic analysis of epicardial adipose tissue reveals the potential crosstalk genes and immune relationship between type 2 diabetes mellitus and atrial fibrillation.

BACKGROUND: The complex relationship between atrial fibrillation (AF) and type 2 diabetes mellitus (T2DM) suggests a potential role for epicardial adipose tissue (EAT) that requires further investigation. This study employs bioinformatics and experimental approaches to clarify EAT's role in linking T2DM and AF, aiming to unravel the biological mechanisms involved. METHOD: Bioinformatics analysis initially identified common differentially expressed genes (DEGs) in EAT from T2DM and AF datasets. Pathway enrichment and network analyses were then performed to determine the biological significance and network connections of these DEGs. Hub genes were identified through six CytoHubba algorithms and subsequently validated biologically, with further in-depth analyses confirming their roles and interactions. Experimentally, db/db mice were utilized to establish a T2DM model. AF induction was executed via programmed transesophageal electrical stimulation and burst pacing, focusing on comparing the incidence and duration of AF. Frozen sections and Hematoxylin and Eosin (H&E) staining illuminated the structures of the heart and EAT. Moreover, quantitative PCR (qPCR) measured the expression of hub genes. RESULTS: The study identified 106 DEGs in EAT from T2DM and AF datasets, underscoring significant pathways in energy metabolism and immune regulation. Three hub genes, CEBPZ, PAK1IP1, and BCCIP, emerged as pivotal in this context. In db/db mice, a marked predisposition towards AF induction and extended duration was observed, with HE staining verifying the presence of EAT. Additionally, qPCR validated significant changes in hub genes expression in db/db mice EAT. In-depth analysis identified 299 miRNAs and 33 TFs as potential regulators, notably GRHL1 and MYC. GeneMANIA analysis highlighted the hub genes' critical roles in stress responses and leukocyte differentiation, while immune profile correlations highlighted their impact on mast cells and neutrophils, emphasizing the genes' significant influence on immune regulation within the context of T2DM and AF. CONCLUSION: This investigation reveals the molecular links between T2DM and AF with a focus on EAT. Targeting these pathways, especially EAT-related ones, may enable personalized treatments and improved outcomes.

Causal relationship between type 2 diabetes mellitus and aortic dissection: insights from two-sample Mendelian randomization and mediation analysis.

Objective: Some evidence suggests a reduced prevalence of type 2 diabetes mellitus (T2DM) in patients with aortic dissection (AD), a catastrophic cardiovascular illness, compared to general population. However, the conclusions were inconsistent, and the causal relationship between T2DM and AD remains unclear. Methods: In this study, we aimed to explore the causal relationship between T2DM and AD using bidirectional Mendelian randomization (MR) analysis. Mediation MR analysis was conducted to explore and quantify the possible mediation effects of 1400 metabolites in T2DM and AD. Results: The results of 26 datasets showed no causal relationship between T2DM and AD (P>0.05). Only one dataset (ebi-a-GCST90006934) showed that T2DM was a protective factor for AD (I9-AORTDIS) (OR=0.815, 95%CI: 0.692-0.960, P=0.014), and did not show horizontal pleiotropy (P=0.808) and heterogeneity (P=0.525). Vanillic acid glycine plays a mediator in the causal relationship between T2DM and AD. The mediator effect for vanillic acid glycine levels was -0.023 (95%CI: -0.066-0.021). Conclusion: From the perspective of MR analysis, there might not be a causal relationship between T2DM and AD, and T2DM might not be a protective factor for AD. If a causal relationship does exist between T2DM and AD, with T2DM serving as a protective factor, vanillic acid glycine may act as a mediator and enhance such a protective effect.

Unlocking the Future of Periodontal Regeneration: An Interdisciplinary Approach to Tissue Engineering and Advanced Therapeutics.

Periodontal defects present a significant challenge in dentistry, necessitating innovative solutions for comprehensive regeneration. Traditional restoration methods have inherent limitations in achieving complete and functional periodontal tissue reconstruction. Tissue engineering, a multidisciplinary approach integrating cells, biomaterials, and bioactive factors, holds tremendous promise in addressing this challenge. Central to tissue engineering strategies are scaffolds, pivotal in supporting cell behavior and orchestrating tissue regeneration. Natural and synthetic materials have been extensively explored, each offering unique advantages in terms of biocompatibility and tunable properties. The integration of growth factors and stem cells further amplifies the regenerative potential, contributing to enhanced tissue healing and functional restoration. Despite significant progress, challenges persist. Achieving the seamless integration of regenerated tissues, establishing proper vascularization, and developing biomimetic scaffolds that faithfully replicate the natural periodontal environment are ongoing research endeavors. Collaborative efforts across diverse scientific disciplines are essential to overcoming these hurdles. This comprehensive review underscores the critical need for continued research and development in tissue engineering strategies for periodontal regeneration. By addressing current challenges and fostering interdisciplinary collaborations, we can unlock the full regenerative potential, paving the way for transformative advancements in periodontal care. This research not only enhances our understanding of periodontal tissues but also offers innovative approaches that can revolutionize dental therapies, improving patient outcomes and reshaping the future of periodontal treatments.

Evaluation of a miniature mass spectrometer based point-of-care-test method for direct analysis of amlodipine and benazepril in whole blood.

A miniature mass spectrometer (mMS) based point-of-care testing (POCT) method was evaluated for on-site detecting the hypertension drugs, amlodipine and benazepril. The instrument parameters, including voltage, ISO1, ISO2, and CID, were optimized, under which the target compounds could be well detected in MS2. When these two drugs were injected simultaneously, the mutual ionization inhibition and mutual reduction between amlodipine and benazepril were evaluated. This phenomenon was severe on the precursor ions but had a small impact on the product ions, thus making this POCT method suitable for analysis using product ions. Finally, the method was validated and applied. The blood samples from patients were tested one hour after oral administration of the drugs (20 mg), and the benazepril was quantitatively analyzed using a standard curve, with detected concentrations ranging from 190.6 to 210 µg L-1 and a relative standard deviation (RSD) of 8.6 %. In summary, amlodipine has low sensitivity and can only be detected at higher concentrations, while benazepril has high sensitivity, good linearity, and even meets semi-quantitative requirements. The research results of this study are of great clinical significance for monitoring blood drug concentrations during hypertension medication, predicting drug efficacy, and customizing individualized medication plans.

Postovulatory Aging of Mouse Oocytes Impairs Offspring Behavior by Causing Oxidative Stress and Damaging Mitochondria.

Information on long-term effects of postovulatory oocyte aging (POA) on offspring is limited. Whether POA affects offspring by causing oxidative stress (OS) and mitochondrial damage is unknown. Here, in vivo-aged (IVA) mouse oocytes were collected 9 h after ovulation, while in vitro-aged (ITA) oocytes were obtained by culturing freshly ovulated oocytes for 9 h in media with low, moderate, or high antioxidant potential. Oocytes were fertilized in vitro and blastocysts transferred to produce F1 offspring. F1 mice were mated with naturally bred mice to generate F2 offspring. Both IVA and the ITA groups in low antioxidant medium showed significantly increased anxiety-like behavior and impaired spatial and fear learning/memory and hippocampal expression of anxiolytic and learning/memory-beneficial genes in both male and female F1 offspring. Furthermore, the aging in both groups increased OS and impaired mitochondrial function in oocytes, blastocysts, and hippocampus of F1 offspring; however, it did not affect the behavior of F2 offspring. It is concluded that POA caused OS and damaged mitochondria in aged oocytes, leading to defects in anxiety-like behavior and learning/memory of F1 offspring. Thus, POA is a crucial factor that causes psychological problems in offspring, and antioxidant measures may be taken to ameliorate the detrimental effects of POA on offspring.

PTPRO inhibition ameliorates spinal cord injury through shifting microglial M1/M2 polarization via the NF-κB/STAT6 signaling pathway.

Spinal cord injury (SCI) induces severe neuroinflammation, and subsequently neurological dysfunction. Activated microglia are critical for modulation of neuroinflammation. Protein tyrosine phosphatase receptor type O (PTPRO), a member of protein tyrosine phosphatases (PTPs), exerts a pro-inflammatory role in multiple human diseases; however, its role in SCI remains unclarified. Here, a T7 spinal cord compression injury model was established in Sprague-Dawley (SD) rats, and PTPRO expression was upregulated in injured spinal cord and microglia after SCI. Microglia M1 and M2 polarization in vitro were induced using LPS/IFN-γ and IL-4, respectively. PTPRO expression was elevated in M1-polarized microglia, and PTPRO downregulation mediated by PTPRO shRNA (shPTPRO) decreased CD86+ cell proportion, iNOS, TNF-α, IL-1ß, and IL-6 levels, and p65 phosphorylation. PTPRO was downregulated in M2 microglia, and PTPRO upregulation by PTPRO overexpression plasmid (OE-PTPRO) reduced CD206+ cell percentage, Arg-1, IL-10, and TGF-ß1 levels and STAT6 phosphorylation. Mechanistically, the transcription factor SOX4 elevated PTPRO expression and its promoter activity. SOX4 overexpression enhanced M1 polarization and p65 phosphorylation, while its knockdown promoted M2 polarization and STAT6 phosphorylation. PTPRO might mediate the function of SOX4 in BV2 microglia polarization. Furthermore, lentivirus-mediated downregulation of PTPRO following SCI improved locomotor functional recovery, demonstrated by elevated BBB scores, incline angle, consistent hindlimb coordination, and reduced lesion area and neuronal apoptosis. PTPRO downregulation promoted microglia M2 polarization, NF-κB inactivation and STAT6 activation after injury. In conclusion, PTPRO inhibition improves spinal cord injury through facilitating M2 microglia polarization via the NF-κB/STAT6 signaling pathway, which is probably controlled by SOX4.

Differences in attentional function between experienced mindfulness meditators and non-meditators.

Introduction: Attentional enhancement has often been identified as the central cognitive mechanism underlying the benefits of mindfulness meditation. However, the extent to which this enhancement is observable in the neural processes underlying long-term meditation is unclear. This current study aimed to examine differences in attentional performance between meditators and controls (non-meditators) using a visual oddball task with concurrent electroencephalography (EEG) recordings. Methods: Thirty-four participants were recruited, including 16 meditators and 18 healthy controls, who were non-meditators. The participants completed a visual oddball task, using visual stimuli, and EEG recording. Results: Self-reports revealed that meditators had higher mindful attention scores than did the control group. The behavioral results showed that the meditators demonstrated faster reaction times than the non-meditators did. Neural findings indicated a higher P2 amplitude in the meditators than in the controls. The meditators demonstrated a significantly higher P3 in the target trials than in the distractor trials, which was not observed in the controls. Additionally, the time-frequency analysis demonstrated that the delta and theta powers in the meditators were significantly higher than those in the controls. Conclusions: The study suggests the meditators exhibited greater attentional performance than the controls did, as revealed by EEG and behavioral measures. This study extends previous research on the effects of mindfulness meditation on attention and adds to our understanding of the effects of long-term mindfulness meditation.

The Effect of SiO2 Particle Size on Crystallization Behavior and Space Charge Properties for SiO2/MMT/LDPE Composites.

The matrix material used in this paper was low-density polyethene (LDPE), and the added particles selected were silicon oxide (SiO2) particles and montmorillonite (MMT) particles. The sizes of the SiO2 particles were 1 µm, 30 nm, and 100 nm, respectively; three kinds of SiO2/MMT/LDPE multi-component composites were prepared based on MMT/LDPE composites doped with MMT particles. The effect of the SiO2 particle size on the crystallization behavior and space charge properties of SiO2/MMT/LDPE composites was studied. The crystalline behaviors and crystallinity of the materials were analyzed. At the same time, the changes in the relative dielectric constant εr and loss factor tanδ for each material with the influence of frequency were studied, and the space charge accumulation, residual characteristics, and apparent charge mobility of each material were explored. The results show that the smaller the size of the added particles, the smaller the grain size and the clearer the grain outline for the multi-composite material. After adding 30 nm SiO2 particles, the crystallinity of the material increases significantly. The microstructure formed by the addition of 100 nm SiO2 particles effectively restricts molecular chain movement and makes it difficult to establish the polarization of the composite. The incorporation of large-size particles can reduce the proportion of the crystalline structure for the material as a whole, resulting in the formation of a new structure to promote charge transfer. Among the three kinds of SiO2 particles, the addition of 30 nm SiO2 particles can effectively suppress the space charge, and the composite material has the lowest residual space charge after depolarization. The addition of 100 nm SiO2 particles can cause the accumulation of many homopolar charges near the anode.

Inhibition of USP7 enhances CD8+ T cell activity in liver cancer by suppressing PRDM1-mediated FGL1 upregulation.

Lymphocyte activation gene 3 (LAG3), an immune checkpoint molecule expressed on activated T cells, functions as a negative regulator of immune responses. Persistent antigen exposure in the tumor microenvironment results in sustained LAG3 expression on T cells, contributing to T cell dysfunction. Fibrinogen-like protein 1 (FGL1) has been identified as a major ligand of LAG3, and FGL1/LAG3 interaction forms a novel immune checkpoint pathway that results in tumor immune evasion. In addition, ubiquitin-specific peptidase 7 (USP7) plays a crucial role in cancer development. In this study we investigated the role of USP7 in modulation of FGL1-mediated liver cancer immune evasion. We showed that knockdown of USP7 or treatment with USP7 inhibitor P5091 suppressed liver cancer growth by promoting CD8+ T cell activity in Hepa1-6 xenograft mice and in HepG2 or Huh7 cells co-cultured with T cells, whereas USP7 overexpression produced the opposite effect. We found that USP7 upregulated FGL1 in HepG2 and Huh7 cells by deubiquitination of transcriptional factor PR domain zinc finger protein 1 (PRDM1), which transcriptionally activated FGL1, and attenuated the CD8+ T cell activity, leading to the liver cancer growth. Interestingly, USP7 could be transcriptionally stimulated by PRDM1 as well in a positive feedback loop. P5091, an inhibitor of USP7, was able to downregulate FGL1 expression, thus enhancing CD8+ T cell activity. In an immunocompetent liver cancer mouse model, the dual blockade of USP7 and LAG3 resulted in a superior antitumor activity compared with anti-LAG3 therapy alone. We conclude that USP7 diminishes CD8+ T cell activity by a USP7/PRDM1 positive feedback loop on FGL1 production in liver cancer; USP7 might be a promising target for liver cancer immunotherapy.

Effect of lower urinary tract conditions on surgical outcomes of different suburethral sling procedures for female stress urinary incontinence.

PURPOSE: The suburethral sling procedure has been widely used as the first-line treatment for female stress urinary incontinence (SUI). This study retrospectively compared the long-term surgical outcomes and complications between retropubic and transobturator suburethral sling procedures. METHODS: From 2010 to 2022, a total of 533 women with SUI underwent retropubic pubovaginal sling (PVS) or transobturator tape (TOT) procedures using a synthetic polypropylene mesh with or without concomitant anterior colporrhaphy. All patients underwent preoperative videourodynamic studies, Valsalva leak point pressure (VLPP), and voiding efficiency (VE). The success rate, postoperative complications, overactive bladder symptoms, transvaginal urethrolysis, and repeat procedures were compared among different surgical procedures. RESULTS: Among the patients, PVS was performed in 251 (47.1%) patients and with colporrhaphy in 58 (10.9%), TOT in 174 (32.6%) and with colporrhaphy in 50 (9.4%). The success rate was 87.4% in the PVS group and 75.4% in the TOT group, with or without colporrhaphy (p = 0.001). Urethrolysis was performed in 4.7% of the patients, and repeat suburethral sling procedures were performed in 8.3%. The overall success rate was significantly lower in TOT group, either with high or low VLPP, or with high or low VE. The rate of persistent OAB was significantly higher in TOT group regardless of VLPP or VE, whereas patients with VE < 90% at baseline had a significantly higher rate of postoperative dysuria. CONCLUSION: TOT procedures had an inferior long-term success rate than PVS procedures for female SUI. Additionally, no differences in the success rate were observed between patients with different bladder functions, high or low VLPP, and high or low VE.

Functionalized lipid nanoparticles modulate the blood-brain barrier and eliminate α-synuclein to repair dopamine neurons.

The challenge in the clinical treatment of Parkinson's disease lies in the lack of disease-modifying therapies that can halt or slow down the progression. Peptide drugs, such as exenatide (Exe), with potential disease-modifying efficacy, have difficulty in crossing the blood-brain barrier (BBB) due to their large molecular weight. Herein, we fabricate multi-functionalized lipid nanoparticles (LNP) Lpc-BoSA/CSO with BBB targeting, permeability-increasing and responsive release functions. Borneol is chemically bonded with stearic acid and, as one of the components of Lpc-BoSA/CSO, is used to increase BBB permeability. Immunofluorescence results of brain tissue of 15-month-old C57BL/6 mice show that Lpc-BoSA/CSO disperses across the BBB into brain parenchyma, and the amount is 4.21 times greater than that of conventional LNP. Motor symptoms of mice in Lpc-BoSA/CSO-Exe group are significantly improved, and the content of dopamine is 1.85 times (substantia nigra compacta) and 1.49 times (striatum) that of PD mice. α-Synuclein expression and Lewy bodies deposition are reduced to 51.85% and 44.72% of PD mice, respectively. Immunohistochemical mechanism studies show AKT expression in Lpc-BoSA/CSO-Exe is 4.23 times that of PD mice and GSK-3ß expression is reduced to 18.41%. Lpc-BoSA/CSO-Exe could reduce the production of α-synuclein and Lewy bodies through AKT/GSK-3ß pathway, and effectively prevent the progressive deterioration of Parkinson's disease. In summary, Lpc-BoSA/CSO-Exe increases the entry of exenatide into brain and promotes its clinical application for Parkinson's disease therapy.

Synthesis of Two-Dimensional Zeolite Nanosheets Applied to the Catalytic Cracking of a Waste Cooking Oil Model Compound to Produce Light Olefins.

Hierarchical zeolites can provide multidimensional spatial networks and, therefore, have significant potential as catalysts for the cracking of biomass to generate light olefins. The present work synthesized the diquaternary ammonium-type surfactant [C18H37-N+(CH3)2-(CH2)6-N+(CH3)2-C6H13]Br2, incorporating hydrophobic 18-carbon alkyl groups for usage as a structure-directing agent. This compound was subsequently used to prepare nanosheets of a hierarchical ZSM-5 two-dimensional zeolite (HNZSM-5) through a one-pot hydrothermal method. The crystal phase, morphology, and hierarchical structure of the HNZSM-5 were analyzed using various techniques, including X-ray diffraction, electron microscopy, and N2 adsorption/desorption. When applied to the catalytic cracking of a waste cooking oil model compound, the HNZSM-5 exhibited superior activity and stability compared with a conventional ZSM-5. This performance was attributed to the more accessible acid sites and unique lamellar structure of the former material. The HNZSM-5 also outlasted the conventional zeolite, showing deactivation after 45 h of reaction compared with 20 h, indicating exceptional stability and excellent resistance to coking.

Urine biomarker could be a useful tool for differential diagnosis of a lower urinary tract dysfunction.

A precision diagnosis of lower urinary tract dysfunctions (LUTD) such as bladder outlet obstruction, detrusor overactivity (DO), interstitial cystitis/bladder pain syndrome (IC/BPS), dysfunctional voiding (DV), or detrusor underactivity (DU) needs invasive videourodynamic study. Exploring non-invasive tools to help screening LUTD is necessary for clinicians in their daily practice. This article reviews recently clinical studies of using urinary inflammatory proteins and oxidative stress biomarkers in the identification of specific LUTD among men and women with lower urinary tract symptoms (LUTS). Some important findings have been reported: (1) Using urine chemokines CXCL-1 and interleukin-8 (IL-8), we may discriminate overactive bladder (OAB) symptoms in women between DO and urinary tract infection. (2) Urinary levels of oxidative stress biomarkers such as 8-hydroxydeoxyguanosine (8-OHdG) and 8-isoprostane have a potential being used as a tool to identify women with mixed DO and stress urinary incontinence. (3) Urine levels of total antioxidant capacity (TAC), and prostaglandin E2 (PGE2) are positively correlated with voiding detrusor pressure in patients with DU. (4) Urine levels of brain-derived neurotrophic factor (BDNF) and PGE2 were significantly higher in the DU patients with detrusor function recovery. (5) Women with DV had higher urinary levels of tumor necrosis factor-alpha (TNF-α) and 8-OHdG, and urinary IL-2 level was significantly lower. (6) Urine level of 8-isoprostane was higher in the patients with idiopathic DO and neurogenic DO. (7) Higher urine cytokine levels of monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T-cell expressed and secreted (RANTES), CXCL-10, IL-7, and eotaxin-1 in patients with IC/BPS than controls. (8) The urine levels of IL-8, CXCL-10, BDNF, IL-6, and RANTES were significantly higher in patients with Hunner's IC than non-Hunner's IC. (9) Male patients with IC/BPS had a significantly higher level of eotaxin, MCP-1, TNF-α, 8-OHdG, and TAC. Combining a higher eotaxin and a higher TNF-α can provide a satisfactory diagnostic value in discriminating IC/BPS from other LUTD in men. These studies provide evidence that measurement of cluster of urine biomarkers could be used as a diagnostic tool to differentiate different LUTD in patients with similar LUTS.

Brain protective effect of dexmedetomidine vs propofol for sedation during prolonged mechanical ventilation in non-brain injured patients.

BACKGROUND: Dexmedetomidine and propofol are two sedatives used for long-term sedation. It remains unclear whether dexmedetomidine provides superior cerebral protection for patients undergoing long-term mechanical ventilation. AIM: To compare the neuroprotective effects of dexmedetomidine and propofol for sedation during prolonged mechanical ventilation in patients without brain injury. METHODS: Patients who underwent mechanical ventilation for > 72 h were randomly assigned to receive sedation with dexmedetomidine or propofol. The Richmond Agitation and Sedation Scale (RASS) was used to evaluate sedation effects, with a target range of -3 to 0. The primary outcomes were serum levels of S100-ß and neuron-specific enolase (NSE) every 24 h. The secondary outcomes were remifentanil dosage, the proportion of patients requiring rescue sedation, and the time and frequency of RASS scores within the target range. RESULTS: A total of 52 and 63 patients were allocated to the dexmedetomidine group and propofol group, respectively. Baseline data were comparable between groups. No significant differences were identified between groups within the median duration of study drug infusion [52.0 (IQR: 36.0-73.5) h vs 53.0 (IQR: 37.0-72.0) h, P = 0.958], the median dose of remifentanil [4.5 (IQR: 4.0-5.0) µg/kg/h vs 4.6 (IQR: 4.0-5.0) µg/kg/h, P = 0.395], the median percentage of time in the target RASS range without rescue sedation [85.6% (IQR: 65.8%-96.6%) vs 86.7% (IQR: 72.3%-95.3), P = 0.592], and the median frequency within the target RASS range without rescue sedation [72.2% (60.8%-91.7%) vs 73.3% (60.0%-100.0%), P = 0.880]. The proportion of patients in the dexmedetomidine group who required rescue sedation was higher than in the propofol group with statistical significance (69.2% vs 50.8%, P = 0.045). Serum S100-ß and NSE levels in the propofol group were higher than in the dexmedetomidine group with statistical significance during the first six and five days of mechanical ventilation, respectively (all P < 0.05). CONCLUSION: Dexmedetomidine demonstrated stronger protective effects on the brain compared to propofol for long-term mechanical ventilation in patients without brain injury.

Comparison of Locking Plate Alone and Locking Plate Combined with 3D Printed Polymethylmethacrylate Augmentation in Treating Proximal Humerus Fractures in the Elderly.

BACKGROUND: Locking plates are widely used in open reduction internal fixation (ORIF) for proximal humeral fracture (PHF). However, the optimal surgical treatment of unstable, displaced PHF in elderly patients remains controversial. This study aimed to compare the radiological and clinical outcomes of surgical treatment of PHF in the elderly with locking plate (LP) alone and locking plate combined with 3D printed polymethylmethacrylate (PMMA) prosthesis augmentation (LP-PA). METHODS: From May 2015 to April 2021, a total of 97 patients aged ≥ 60 years with acute unstable PHF who underwent osteosynthesis with either LP (46 patients) or LP-PA (51 patients) were retrospectively analyzed. For the LP-PA group, a customized proximal humeral prosthesis made of PMMA cement was intra-operatively fabricated by a three-dimensional (3D) printed prototype mold for the humeral medial support. Radiological outcomes were analyzed by measuring the value of neck-shaft angle (NSA) and humeral head height (HHH). The clinical outcomes were evaluated using Constant-Murley Score (CMS), Disabilities of the Arm Shoulder and Hand (DASH) score, American Shoulder and Elbow Surgeons (ASES) score, and the shoulder range of motion (ROM). Pain was measured using a visual analogue scale (VAS). RESULTS: At the one-year follow-up, all fractures healed radiologically and clinically. The mean changes of NSA and HHH over the follow-up period were markedly smaller in the LP-PA group (3.8 ± 0.9° and 1.7 ± 0.3 mm) than those in the LP group (9.7 ± 2.1° and 3.2 ± 0.6 mm, both P < 0.0001). The LP-PA group also presented lower DASH score (17.1 ± 3.6), higher ASES score (89.5 ± 11.2) and better ROM in forward elevation (142 ± 26°) and external rotation (59 ± 11°) compared to the LP group (28.9 ± 4.8 for DASH score, P < 0.0001; 82.3 ± 9.0 for ASES score, P < 0.001; 129 ± 21° for forward elevation, P = 0.008; and 52 ± 9° for external rotation, P = 0.001). There was no significant difference in overall complication rate between the two groups, although the complication rate of screw perforation was higher in the LP-PA group (P = 0.172). CONCLUSIONS: For PHF in elderly patients, the combination of LP fixation and PMMA prosthesis augmentation effectively improved humeral head support and reduction maintenance, providing satisfactory outcomes both radiologically and clinically. This technique also reduced the incidence of screw perforation associated with plate fixation alone, making it a reasonable option to ensure satisfactory clinical outcomes.

Real-Life Treatment Outcome of Botulinum Toxin A Injection on Overactive Bladder and Voiding Dysfunction in Patients with Central Nervous System Lesions.

PURPOSE: Neurogenic lower urinary tract dysfunction (NLUTD) is common in patients with neurological lesions in the central nervous system (CNS). Medical treatment usually cannot adequately relieve NLUTD. This study reported the real-life treatment outcome of botulinum toxin A (BoNT-A) for overactive bladders (OAB) and voiding dysfunction in patients with CNS lesions. METHODS: We retrospectively analyzed the first-time treatment outcome of 74 patients who received detrusor 100 U BoNT-A for OAB and 45 patients who received a urethral sphincter 100 U BoNT-A injection for voiding dysfunction. The treatment outcome, therapeutic duration, and adverse events (AE) after BoNT-A were compared among different CNS lesions and among patients with different urodynamic characteristics. RESULTS: The study included 74 patients receiving detrusor injections for OAB (36 with cerebrovascular accidents, 13 with Parkinson's disease, and 25 with dementia) and 45 patients receiving a urethral sphincter injection for voiding dysfunction (26 with cerebrovascular accidents, 7 with Parkinson's disease, and 12 with dementia). After detrusor BoNT-A treatment, urinary continence was achieved in 28.4% of patients with neurogenic OAB, postoperative difficult urination in 59.5%, acute urinary retention (AUR) in 9.5%, and urinary tract infection (UTI) in 14.9%, with a therapeutic duration of 6.43 months. There were no differences among subgroups or between patients with detrusor overactivity (DO) and DO with detrusor underactivity (DU) in terms of treatment outcomes and AEs. The improvement rate of urethral sphincter BoNT-A injections was 75.6% without any difference among subgroups. After treatment, 24.4% of the patients had exacerbated urinary incontinence, 33.3% had persistent difficult urination, and 15.6% had UTI. Patients with dementia had higher rates of difficult urination and UTI, higher postvoid residual volume, and a shorter therapeutic duration. Patients with DU and those without urethral sphincter dyssynergia had less favorable outcomes after their urethral sphincter BoNT-A injection. CONCLUSIONS: The therapeutic efficacy of detrusor BoNT-A injection for OAB due to CNS lesions is limited, with high rates of difficult urination, AUR, and UTI. Although urethral sphincter BoNT-A injection is effective in treating voiding dysfunction; however, exacerbated urinary incontinence and persistent difficult urination remain a problem, particularly in patients with dementia.

Urinary Viral Spectrum in Patients with Interstitial Cystitis/Bladder Pain Syndrome and the Clinical Efficacy of Valacyclovir Treatment.

Our previous study showed that the Epstein-Barr virus (EBV) may be the etiology for some patients with interstitial cystitis/bladder pain syndrome (IC/BPS); hence, the current study aimed to investigate the urinary viral spectrum in patients with IC/BPS and the clinical efficacy of valacyclovir. Twenty-eight patients were prospectively enrolled for valacyclovir 500 mg twice a day for 4 weeks. Urine samples were collected from IC/BPS patients and 30 controls. The primary outcome was the difference in the visual analog scale (VAS) pain score, and secondary outcomes included changes in the urinary viral spectrum and urinary inflammatory cytokine level (ClinicalTrials.gov Identifier: NCT05094414). Urinary EBV was detected in 14.2% IC/BPS patients but not in the controls. Urinary John Cunningham virus and BK virus were detected in 18 (64.3%) and 2 (7.1%) patients with IC/BPS, respectively, with similar prevalences noted for the controls. No cytomegalovirus, varicella-zoster virus, or herpes simplex virus was detected in the urine samples. The VAS pain score in patients with IC/BPS significantly decreased after 4 weeks (from 7.5 [5.52-9.0] to 5 [1.5-6.0], p = 0.0003). Urinary EBV was undetectable in any sample after valacyclovir treatment, and the decreases in urinary interleukin (IL)-1ß (from 0.66 [0.55-0.82] pg/mL to 0.58 [0.55-0.64] pg/mL, p = 0.0034), IL-8 (from 6.81 [2.38 to 29.1] pg/mL to 4.33 [1.53-11.04] pg/mL, p = 0.0361), IL-10 (from 1.06 [0.94-1.18] pg/mL to 0.92 [0.88-1.02], p = 0.0086), and tumor necrosis factor-α (from 1.61 [1.50-1.72] pg/mL to 1.50 [1.44-1.55] pg/mL, p = 0.0079) were significant. Valacyclovir could relieve bladder pain, eliminate urinary EBV, and reduce bladder inflammation.

Caffeic acid phenethyl ester: an effective antiviral agent against porcine reproductive and Respiratory Syndrome Virus.

Porcine Reproductive and Respiratory Syndrome (PRRS) presents a formidable viral challenge in swine husbandry. Confronting the constraints of existing veterinary pharmaceuticals and vaccines, this investigation centers on Caffeic Acid Phenethyl Ester (CAPE) as a prospective clinical suppressant for the Porcine Reproductive and Respiratory Syndrome Virus (PRRSV). The study adopts an integrated methodology to evaluate CAPE's antiviral attributes. This encompasses a dual-phase analysis of CAPE's interaction with PRRSV, both in vitro and in vivo, and an examination of its influence on viral replication. Varied dosages of CAPE were subjected to empirical testing in animal models to quantify its efficacy in combating PRRSV infections. The findings reveal a pronounced antiviral potency, notably in prophylactic scenarios. As a predominant component of propolis, CAPE stands out as a promising candidate for clinical suppression, showing exceptional effectiveness in pre-exposure prophylaxis regimes. This highlights the potential of CAPE in spearheading cutting-edge strategies for the management of future PRRSV outbreaks.