VX-509 (Decernotinib)-modified tolerogenic dendritic cells alleviate experimental autoimmune neuritis by promoting Th17/Treg rebalance.

BACKGROUND: Guillain-Barré syndrome (GBS) is an auto-inflammatory peripheral nerve disease. Dendritic cell-mediated T cell polarization is of pivotal importance in demyelinating lesions of peripheral nerves and nerve roots. However, the regulatory function of VX-509 (Decernotinib)-modified tolerogenic dendritic cells (VX-509-tolDCs) during immune remodeling following GBS remains unclear. Here, we used experimental autoimmune neuritis (EAN) as a model to investigate these aspects of GBS. METHODS: DCs were treated with varying concentrations of VX-509 (0.25, 1, and 4 µM) or served as a control using 10-8 M 1,25-(OH)2D3. Flow cytometry was employed to assess the apoptosis, phenotype, and capacity to induce T cell responses of the treated DCs. In the in vivo experiments, EAN mice received administration of VX-509-tolDCs or 1,25-(OH)2D3-tolDCs via the tail vein at a dose of 1x106 cells/mouse on days 5, 9, 13, and 17. RESULTS: VX-509 inhibited the maturation of DCs and promoted the development of tolDCs. The function of antigen-specific CD4 + T cells ex vivo was influenced by VX-509-tolDCs. Furthermore, the adoptive transfer of VX-509-tolDCs effectively alleviated inflammatory demyelinating lesions in EAN by promoting Th17/Treg (T helper 17 and regulatory T cells) rebalance. CONCLUSION: The adoptive transfer of VX-509-tolDCs alleviated inflammatory demyelinating lesions in a mouse model of GBS, known as the EAN mouse, by partially restoring the balance between Treg and Th17 cells.

Progestogen-driven B7-H4 contributes to onco-fetal immune tolerance.

Immune tolerance mechanisms are shared in cancer and pregnancy. Through cross-analyzing single-cell RNA-sequencing data from multiple human cancer types and the maternal-fetal interface, we found B7-H4 (VTCN1) is an onco-fetal immune tolerance checkpoint. We showed that genetic deficiency of B7-H4 resulted in immune activation and fetal resorption in allogeneic pregnancy models. Analogously, B7-H4 contributed to MPA/DMBA-induced breast cancer progression, accompanied by CD8+ T cell exhaustion. Female hormone screening revealed that progesterone stimulated B7-H4 expression in placental and breast cancer cells. Mechanistically, progesterone receptor (PR) bound to a newly identified -58 kb enhancer, thereby mediating B7-H4 transcription via the PR-P300-BRD4 axis. PR antagonist or BRD4 degrader potentiated immunotherapy in a murine B7-H4+ breast cancer model. Thus, our work unravels a mechanistic and biological connection of a female sex hormone (progesterone) to onco-fetal immune tolerance via B7-H4 and suggests that the PR-P300-BRD4 axis is targetable for treating B7-H4+ cancer.

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

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

Creating Asymmetric Fe-N3C-N Sites in Single-Atom Catalysts Boosts Catalytic Performance for Oxygen Reduction Reaction.

Fine tuning of the metal site coordination environment of a single-atom catalyst (SAC) to boost its catalytic activity for oxygen reduction reaction (ORR) is of significance but challenging. Herein, we report a new SAC bearing Fe-N3C-N sites with asymmetric in-plane coordinated Fe-N3C and axial coordinated N atom for ORR, which was obtained by pyrolysis of an iron isoporphyrin on polyvinylimidazole (PVI) coated carbon black. The C@PVI-(NCTPP)Fe-800 catalyst exhibited significantly improved ORR activity (E1/2 = 0.89 V vs RHE) than the counterpart SAC with Fe-N4-N sites in 0.1 M KOH. Significantly, the Zn-air batteries equipped with the C@PVI-(NCTPP)Fe-800 catalyst demonstrated an open-circuit voltage (OCV) of 1.45 V and a peak power density (Pmax) of 130 mW/cm2, outperforming the commercial Pt/C catalyst (OCV = 1.42 V; Pmax = 119 mW/cm2). The density functional theory (DFT) calculations revealed that the d-band center of the asymmetric Fe-N3C-N structure shifted upward, which enhances its electron-donating ability, favors O2 adsorption, and supports O-O bond activation, thus leading to significantly promoted catalytic activity. This research presents an intriguing strategy for the designing of the active site architecture in metal SACs with a structure-function controlled approach, significantly enhancing their catalytic efficiency for the ORR and offering promising prospects in energy-conversion technologies.

Left atrial strain parameters to predicting elevated left atrial pressure in patients with atrial fibrillation.

OBJECTIVES: To assess the ability of left atrial (LA) strain parameters to discriminate patients with elevated left atrial pressure (LAP) from patients with atrial fibrillation (AF). METHODS AND RESULTS: A total of 142 patients with non-valvular AF who underwent first catheter ablation (CA) between November 2022 and November 2023 were enrolled in the study. Conventional and speckle-tracking echocardiography (STE) were performed in all patients within 24 h before CA, and LAP was invasively measured during the ablation procedure. According to mean LAP, the study population was classified into two groups of normal LAP (LAP < 15 mmHg, n = 101) and elevated LAP (LAP ≥ 15 mmHg, n = 41). Compared with the normal LAP group, elevated LAP group showed significantly reduced LA reservoir strain (LASr) [9.14 (7.97-11.80) vs. 20 (13.59-26.96), p < .001], and increased LA filling index [9.60 (7.15-12.20) vs. 3.72 (2.17-5.82), p < .001], LA stiffness index [1.13 (.82-1.46) vs. .47 (.30-.70), p < .001]. LASr, LA filling index and LA stiffness index were independent predictors of elevated LAP after adjusted by the type of AF, EDT, E/e', mitral E, and peak acceleration rate of mitral E velocity. The receiver-operating characteristic curve (ROC) analysis showed LA strain parameters (area under curve [AUC] .794-.819) could provide similar or greater diagnostic accuracy for elevated LAP, as compared to conventional echocardiographic parameters. Furthermore, the novel algorithms built by LASr, LA stiffness index, LA filling index, and left atrial emptying fraction (LAEF), was used to discriminate elevated LAP in AF with good accuracy (AUC .880, accuracy of 81.69%, sensitivity of 80.49%, and specificity of 82.18%), and much better than 2016 ASE/EACVI algorithms in AF. CONCLUSION: In patients with AF, LA strain parameters could be useful to predict elevated LAP and non-inferior to conventional echocardiographic parameters. Besides, the novel algorithm built by LA strain parameters combined with conventional parameters would improve the diagnostic efficiency.

Fast and facile synthesis of amidine-incorporated degradable lipids for versatile mRNA delivery in vivo.

Lipid nanoparticles (LNPs) are widely used for mRNA delivery, with cationic lipids greatly affecting biodistribution, cellular uptake, endosomal escape and transfection efficiency. However, the laborious synthesis of cationic lipids limits the discovery of efficacious candidates and slows down scale-up manufacturing. Here we develop a one-pot, tandem multi-component reaction based on the rationally designed amine-thiol-acrylate conjugation, which enables fast (1 h) and facile room-temperature synthesis of amidine-incorporated degradable (AID) lipids. Structure-activity relationship analysis of a combinatorial library of 100 chemically diverse AID-lipids leads to the identification of a tail-like amine-ring-alkyl aniline that generally affords efficacious lipids. Experimental and theoretical studies show that the embedded bulky benzene ring can enhance endosomal escape and mRNA delivery by enabling the lipid to adopt a more conical shape. The lead AID-lipid can not only mediate local delivery of mRNA vaccines and systemic delivery of mRNA therapeutics, but can also alter the tropism of liver-tropic LNPs to selectively deliver gene editors to the lung and mRNA vaccines to the spleen.

Veno-arterial extracorporeal membrane oxygenation for the treatment of obstructive shock caused by venous air embolism: A case report.

BACKGROUND: Venous air embolism (VAE) is a potentially lethal condition, with a reported incidence rate of about 0.13%, and the true incidence may be higher since many VAE are asymptomatic. The current treatments for VAE include Durant's maneuver, aspiration and removal of air through venous catheters, and hyperbaric oxygen therapy. For critically ill patients, use of cardiotonic drugs and chest compressions remain useful strategies. The wider availability of extracorporeal membrane oxygenation (ECMO) has brought a new option for VAE patients. CASE SUMMARY: A 53-year-old female patient with VAE presented to the emergency clinic due to abdominal pain with fever for 1 d and unconsciousness for 2 h. One day ago, the patient suffered from abdominal pain, fever, and diarrhea. She suddenly became unconscious after going to the toilet during the intravenous infusion of ciprofloxacin 2 h ago, accompanied by nausea and vomiting, during which a small amount of gastric contents were discharged. She was immediately sent to a local hospital, where cranial and chest computed tomography showed bilateral pneumonia as well as accumulated air visible in the right ventricle and pulmonary artery. The condition deteriorated despite endotracheal intubation, rehydration, and other treatments, and the patient was then transferred to our hospital. Veno-arterial ECMO was applied in our hospital, and the patient's condition gradually improved. The patient was successfully weaned from ECMO and extubated after two days. CONCLUSION: ECMO may be an important treatment for patients with VAE in critical condition.

Hyponatremia Is Associated with Mortality in Acute Pancreatitis Patients.

BACKGROUND: Disorders of serum sodium are common among general patients and are associated with poor outcomes. The prognostic value of serum sodium disorders in patients with acute pancreatitis (AP) has not been studied. We conducted this retrospective study to explore the association between serum sodium levels and the outcomes of patients with AP. MATERIALS AND METHODS: Patients with AP from the Medical Information Mart for Intensive Care III (MIMIC-III) were screened for this study. The laboratory variables, including serum sodium levels, were obtained by analyzing the first blood sample on the first day after admission. Univariate logistic regression was performed to discover potential factors for mortality of AP. The unadjusted and adjusted association between serum sodium level and mortality of AP was shown by the restricted cubic spline (RCS). The categorical cutoff for the detrimental effect of serum sodium level on the prognosis of AP was also confirmed by stepwise logistic regression after adjusting for con-founding effects of significant factors in the univariate logistic regression. RESULTS: A total of 869 patients with AP in the MIMIC-III were included with a mortality of 13.1%. Unadjusted logistic regression showed that age (p < 0.001), simplified acute physiological score (SAPS) (p < 0.001), systolic blood pressure (p < 0.001), diastolic blood pressure (p < 0.001), hemoglobin (p = 0.040), serum creatinine (p = 0.046), and serum phosphorus (p < 0.001) were significantly associated with the mortality of AP. The RCS showed that the serum sodium level was negatively and linearly associated with mortality of AP after adjusting for confounding effects of significant factors in the univariate logistic regression. Serum sodium < 133 mmol/L, which indicated hyponatremia, was significantly correlated with a higher mortality risk than serum sodium ≥ 133 mmol/L (p = 0.013). CONCLUSIONS: Hyponatremia is widely developed among patients with AP and correlates with a higher mortality risk of AP. Physicians should pay more attention to managing patients with AP with hyponatremia.

Magnetic porous microspheres altering interfacial thermodynamics of sewage sludge to drive metabolic cooperation for efficient methanogenesis.

Controllable and recyclable magnetic porous microspheres (MPMs) have been proposed as a means for enhancing the anaerobic digestion (AD) of sludge, as they do not require continuous replenishment and can serve as carriers for anaerobes. However, the effects of MPMs on the interfacial thermodynamics of sludge and the biological responses triggered by abiotic effects in AD systems remain to be clarified. Herein, the underlying mechanisms by which MPMs alter the solid-liquid interface of sludge to drive methanogenesis were investigated. A significant increase in the contents of 13C and 2H (D) in methane molecules was observed in the presence of MPMs, suggesting that MPMs might enhance the CO2-reduction methanogenesis and participation of water in methane generation. Experimental results demonstrated that the addition of MPMs did not promote the anaerobic bioconversion of soluble organics for methanogenesis, suggesting that the enhanced methanogenesis and water participation were not achieved through promotion of the bioconversion of original liquid-state organics in sludge. Analyses of the capillary force, surface adhesion force, and interfacial proton-coupled electron transfer (PCET) of MPMs revealed that MPMs can enhance mass transfer, effective contact, and electron-proton transfer with sludge. These outcomes were confirmed by the statistical analyses of variations in the interfacial thermodynamics and PCET of sludge with and without MPMs during AD. It was thus proposed that the MPMs enhanced the PCET of sludge and PCET-driven release of protons from water by promoting the interfacial Lewis acid-base interactions of sludge, thereby resulting in the enrichment of free and attached methanogenic consortia and the high energy-conserving metabolic cooperation. This proposition was further confirmed by identifying the predominant syntrophic partners, suggesting that PCET-based efficient methanogenesis was attributable to the enrichment of genomes harbouring CO2-reducing pathway and genes encoding water-mediated proton transfer. These findings offer new insights into how substrate properties can be altered by exogenous materials to enable highly efficient methanogenesis.

S5Utis: Structured State-Space Sequence SegNeXt UNet-like Tongue Image Segmentation in Traditional Chinese Medicine.

Intelligent Traditional Chinese Medicine can provide people with a convenient way to participate in daily health care. The ease of acceptance of Traditional Chinese Medicine is also a major advantage in promoting health management. In Traditional Chinese Medicine, tongue imaging is an important step in the examination process. The segmentation and processing of the tongue image directly affects the results of intelligent Traditional Chinese Medicine diagnosis. As intelligent Traditional Chinese Medicine continues to develop, remote diagnosis and patient participation will play important roles. Smartphone sensor cameras can provide irreplaceable data collection capabilities in enhancing interaction in smart Traditional Chinese Medicine. However, these factors lead to differences in the size and quality of the captured images due to factors such as differences in shooting equipment, professionalism of the photographer, and the subject's cooperation. Most current tongue image segmentation algorithms are based on data collected by professional tongue diagnosis instruments in standard environments, and are not able to demonstrate the tongue image segmentation effect in complex environments. Therefore, we propose a segmentation algorithm for tongue images collected in complex multi-device and multi-user environments. We use convolutional attention and extend state space models to the 2D environment in the encoder. Then, cross-layer connection fusion is used in the decoder part to fuse shallow texture and deep semantic features. Through segmentation experiments on tongue image datasets collected by patients and doctors in real-world settings, our algorithm significantly improves segmentation performance and accuracy.

Ligand exchange induced crystal structure and morphology evolution of copper-tin-sulfur binary and ternary compounds.

In this manuscript, a simple one-pot heat-up method has been used to prepare multi-component copper-tin-sulfur nanomaterials, including binary Cu1.94S, ternary Cu4SnS4, and Cu1.94S/Cu4SnS4 nanocrystals by varying the reaction temperature, reaction time, and the type of copper source. Post-synthetic ligand exchange (LE) has further been introduced to replace the long-chain ligands originating from 1-dodecanethiol. It has been found that the LE process not only changes the surface ligands but also significantly affects the crystal structure and optical properties of nanocrystals. After LE, the crystal structures of Cu1.94S and Cu4SnS4 transformed to Cu7S4 and Cu3SnS4, respectively, with the Cu1.94S/Cu4SnS4 nanocrystals showing the same trend. This phenomenon could be ascribed to the loss of Cu+ originating from the strong complexation of Cu+ and ammonia with the formation of [Cu(NH3)n]2+ ions under aerobic conditions. Proton nuclear magnetic resonance (1H NMR) has been used to characterize the ligands on the surface before and after LE, which further demonstrated that the -SH was replaced during LE. Meanwhile, the band gaps of the obtained nanocrystals after LE show an obvious shift in the near-infrared region due to the evolution of crystal structures. This study will provide useful guidance for the LE of nanocrystals and the application of copper-based sulfide nanomaterials in optoelectronics and other fields.

Hydrometeorological conditions drive long-term changes in the spatial distribution of Potamogeton crispus in a subtropical lake.

Globally, anthropogenic disturbance and climate change caused a rapid decline of submerged macrophytes in lake ecosystems. Potamogeton crispus (P. crispus), a species that germinates in winter, explosively expanded throughout many Chinese lakes, yet the underlying mechanism remained unclear. Here, this study examined the long-term changes in the distribution patterns of P. crispus in Lake Gaoyou by combining remote sensing images and hydrometeorological data from 1984 to 2022 and water quality data from 2009 to 2022. It aims to unravel the relationships between the distribution patterns of P. crispus and hydrometeorological and water quality factors. The results showed that the area of P. crispus in Lake Gaoyou showed a slight increase from 1984 to 2009, a marked increase from 2010 to 2019, followed by a decline after 2020. Spatially, P. crispus was primarily distributed in the western and northern parts of Lake Gaoyou, with less distribution in the central and southeastern parts of the lake. Wind speed (WS), temperature (Temp), water level (WL), ammonia nitrogen (NH3-N), and Secchi depth (SD) were identified as the key factors regulating the variation in the P. crispus area in Lake Gaoyou. We found that the P. crispus area showed an increasing trend with increasing Temp, WL, and SD and decreasing WS and NH3-N. The influence of environmental factors on the area of P. crispus in Lake Gaoyou varied among seasons. The results indicated that hydrometeorology (WS, Temp, and WL) may override water quality (NH3-N and SD) in driving the succession of P. crispus distribution. The findings of this study offer valuable insights into the recent widespread expansion of P. crispus in shallow lakes across Eastern China.

Enhanced photocatalytic removal of bromate in drinking water by Au/TiO2 under ultraviolet light.

The photo-reduction of bromate (BrO3 -) has attracted much attention due to the carcinogenesis and genotoxicity of BrO3 - in drinking water. In this study, a heterojunction photocatalyst was developed by depositing Au nanoparticles (NPs) onto P25 TiO2 NPs through a one-pot, solvent-thermal process. Due to the unique properties of Au, the Au NPs deposited on the TiO2 surface created a Schottky barrier between the metal and the semiconductor, leading to an effective separation of photo-generated charge carriers as the Au nanoparticles served as electron sinks. The Au/TiO2 photocatalyst demonstrated efficient reduction of BrO3 - under UV light illumination without the need for sacrificial agents. The effect of different Au loading of Au/TiO2 was systematically investigated for its influence on the generation of electrons and the reduction ability of BrO3 -. The results indicate that the 1% Au/TiO2 catalyst exhibited a higher concentration of localized electrons, rendering it more effective in BrO3 - removal. The photocatalytic efficiency for BrO3 - reduction decreased upon the addition of K2S2O8 as an electron quencher, suggesting that the primary factor in this photo-reduction process was the availability of electrons. These findings hold promise for the potential application of the Au/TiO2 catalyst in the removal of BrO3 - from drinking water through photo-reduction.

Nitrogen-Mediated Promotion of Cobalt-Based Oxygen Evolution Catalyst for Practical Anion-Exchange Membrane Electrolysis.

Scarce and expensive iridium oxide is still the cornerstone catalyst of polymer-electrolyte membrane electrolyzers for green hydrogen production because of its exceptional stability under industrially relevant oxygen evolution reaction (OER) conditions. Earth-abundant transition metal oxides used for this task, however, show poor long-term stability. We demonstrate here the use of nitrogen-doped cobalt oxide as an effective iridium substitute. The catalyst exhibits a low overpotential of 240 mV at 10 mA cm-2 and negligible activity decay after 1000 h of operation in an alkaline electrolyte. Incorporation of nitrogen dopants not only triggers the OER mechanism switched from the traditional adsorbate evolution route to the lattice oxygen oxidation route but also achieves oxygen nonbonding (ONB) states as electron donors, thereby preventing structural destabilization. In a practical anion-exchange membrane water electrolyzer, this catalyst at anode delivers a current density of 1000 mA cm-2 at 1.78 V and an electrical efficiency of 47.8 kW-hours per kilogram hydrogen.

[Effect of triptolide on reproductive toxicity in female rats with â ¡ type collagen induced arthritis].

In order to study the toxic effect and mechanism of triptolide(TP) on the reproductive system of female rats with Ⅱ type collagen induced arthritis(CIA), 50 SD rats were randomly divided into normal control group, CIA model group, and three groups receiving TP tablets at clinically equivalent doses of 0. 5, 1, and 2 times, respectively(with TP dosages of 3. 75, 7. 5, and 15 µg·kg~(-1)·d~(-1)), each comprising 10 rats. Intragastric administration was started on the day after the first immunization, once a day, for 42 days.The results were taken on the 21st and 42nd days to calculate the uterine and ovarian organ indexes; pathological and morphological changes in uterus and ovaries were observed under a light microscope; and the levels of estradiol(E_2) and cytochrome P450A1(aromatase,CYP19A1) in ovarian homogenate were detected by ELISA. Furthermore, immunohistochemistry was employed to detect the expression levels of transforming growth factor ß3( TGFß3) pathway-related proteins, mothers against decapentaplegic homolog 3(Smad3) and steroidogenic factor-1(SF-1) in ovarian tissues. In vitro, the mouse Chinese hamster ovary(CHO) cell line was established, and after 24 hours of TP administration(30, 60, 120 nmol·L~(-1)), cell proliferation was detected by the thiazolyl blue tetrazolium bromide(MTT) method, apoptosis by the flow cytometry, and TGFß3, Smad3 and SF-1 protein expression in cells by the Western blot method, and the nuclear entry of SF-1 was detected by immunofluorescence. The results showed that compared with the CIA model group, all TP administration groups showed decreased number of uterine glands, total follicles, mature follicles, and corpus luteum on days 21 and 42 of administration, but there was no statistical difference, and only the administration of 2 times the clinically equivalent dose of TP could significantly increase the number of atretic follicles at 42 days of administration. TP at 3. 75 µg·kg-1·d-1significantly reduced the level of E_2 at 21 days of administration and the expression of TGFß3 and Smad3 factors in ovarian tissues,but had no significant effect on the rate-limiting enzyme in estrogen synthesis CYP19A1. TP at 7. 5 and 15 µg·kg~(-1)·d~(-1) significantly reduced the expression of SF-1 regardless of administration for 21 days or 42 days. TP can significantly promote ovarian cell apoptosis in vitro, with apoptosis mainly concentrated in the late stage of apoptosis after 24 hours of administration. In addition, 60 nmol·L~(-1) TP significantly reduced the protein expression of TGFß3, Smad3 and SF-1 in a dose-dependent manner. In summary, intragastric administration of TP at less than 2 times the clinically equivalent dose for 21 days and 42 days did not cause obvious reproductive damage to the uterus and ovarian tissues of CIA rats, and the number of atretic follicles changed significantly only when the 2 times the clinically equivalent dose was administered for 42 days. TP exerted reproductive toxicity in vivo on reproductive target organs and in vitro on ovarian cells by inhibiting the expression of TGFß3/Smad3/SF-1 pathway.

Fabrication of TiN Coatings Deposited on Laser Shock Micro-Textured Substrates for Improving the Interface Adhesion Properties of Coatings.

This paper aims to investigate the strengthening mechanism of laser shock peening on the interfacial bonding properties between TiN coatings and TC4 titanium alloy substrates. The different surface textures were induced by LSP on a TC4 titanium alloy substrate. Subsequently, titanium nitride (TiN) coatings were deposited on the surface texture. A scratch test and reciprocating sliding wear assessment were conducted to evaluate the impact of LSP on the interfacial bonding properties and wear performance of the coatings. The experimental results demonstrated that the adhesion of TiN coatings deposited on the surface texture formed by laser shock peening was significantly enhanced. The efficacy of laser shock treatment in reducing wear rates was found to be significantly enhanced in cases of both increased spot overlapping rate and increased laser power density. The surface texture created using laser parameters of 6.43 GW/cm2 and a 50% overlapping rate was found to have the most significant effect on improving the adhesion and anti-wear properties of the coating. The laser shock texture was identified as the main contributor to this improvement, providing a large interfacial contact area and a mechanical bond between the coating and the substrate. This bond inhibited the initiation and propagation of micro-cracks caused by the concentration of internal stress and interfacial stress of the coating.

Application prospects of the 2BS cell-adapted China fixed rabies virus vaccine strain 2aG4-B40.

BACKGROUND: Rabies is a fatal zoonotic disease whose pathogenesis has not been fully elucidated, and vaccination is the only effective method for protecting against rabies virus infection. Most inactivated vaccines are produced using Vero cells, which are African green monkey kidney cells, to achieve large-scale production. However, there is a potential carcinogenic risk due to nonhuman DNA contamination. Thus, replacing Vero cells with human diploid cells may be a safer strategy. In this study, we developed a novel 2BS cell-adapted rabies virus strain and analysed its sequence, virulence and immunogenicity to determine its application potential as a human diploid cell inactivated vaccine. METHODS AND RESULTS: The 2BS cell-adapted rabies virus strain 2aG4-B40 was established by passage for 40 generations and selection of plaques in 2BS cells. RNA sequence analysis revealed that mutations in 2BS cell-adapted strains were not located at key sites that regulate the production of neutralizing antibodies or virulence in the aG strain (GQ412744.1). The gradual increase in virulence (remaining above 7.0 logLD50/ml from the 40th to 55th generation) and antigen further indicated that these mutations may increase the affinity of the adapted strains for human diploid cells. Identification tests revealed that the 2BS cell-adapted virus strain was neutralized by anti-rabies serum, with a neutralization index of 19,952. PrEP and PEP vaccination and the NIH test further indicated that the vaccine prepared with the 2aG4-B40 strain had high neutralizing antibody levels (2.24 to 46.67 IU/ml), immunogenicity (protection index 270) and potency (average 11.6 IU/ml). CONCLUSIONS: In this study, a 2BS cell-adapted strain of the 2aG4 rabies virus was obtained by passage for 40 generations. The results of sequencing analysis and titre determination of the adapted strain showed that the mutations in the adaptive process are not located at key sequence regions of the virus, and these mutations may enhance the affinity of the adapted strain for human diploid cells. Moreover, vaccines made from the adapted strain 2aG4-B40 had high potency and immunogenicity and could be an ideal candidate rabies virus strain for inactivated vaccine preparation.

Meaningful nomograms based on systemic immune inflammation index predicted survival in metastatic pancreatic cancer patients receiving chemotherapy.

OBJECTIVE: The purpose of the study is to construct meaningful nomogram models according to the independent prognostic factor for metastatic pancreatic cancer receiving chemotherapy. METHODS: This study is retrospective and consecutively included 143 patients from January 2013 to June 2021. The receiver operating characteristic (ROC) curve with the area under the curve (AUC) is utilized to determine the optimal cut-off value. The Kaplan-Meier survival analysis, univariate and multivariable Cox regression analysis are exploited to identify the correlation of inflammatory biomarkers and clinicopathological features with survival. R software are run to construct nomograms based on independent risk factors to visualize survival. Nomogram model is examined using calibration curve and decision curve analysis (DCA). RESULTS: The best cut-off values of 966.71, 0.257, and 2.54 for the systemic immunological inflammation index (SII), monocyte-to-lymphocyte ratio (MLR), and neutrophil-to-lymphocyte ratio (NLR) were obtained by ROC analysis. Cox proportional-hazards model revealed that baseline SII, history of drinking and metastasis sites were independent prognostic indices for survival. We established prognostic nomograms for primary endpoints of this study. The nomograms' predictive potential and clinical efficacy have been evaluated by calibration curves and DCA. CONCLUSION: We constructed nomograms based on independent prognostic factors, these models have promising applications in clinical practice to assist clinicians in personalizing the management of patients.

Injectable long-acting formulations (ILAFs) and manufacturing techniques.

INTRODUCTION: Most therapeutics delivered using short-acting formulations need repeated administration, which can harm patient compliance and raise failure risks related to inconsistent treatment. Injectable long-acting formulations (ILAFs) are controlled/sustained-release formulations fabricated to deliver active pharmaceutical ingredients (APIs) and extend their half-life over days to months. Longer half-lives of ILAFs minimize the necessity for frequent doses, increase patient compliance, and reduce the risk of side effects from intravenous (IV) infusions. Using ILAF technologies, the immediate drug release can also be controlled, thereby minimizing potential adverse effects due to high initial drug blood concentrations. AREA COVERED: In this review, we have discussed various ILAFs, their physiochemical properties, fabrication technologies, advantages, and practical issues, as well as address some major challenges in their application. Especially, the approved ILAFs are highlighted. EXPERT OPINION: ILAFs are sustained-release formulations with extended activity, which can improve patient compliance. ILAFs are designed to deliver APIs like proteins and peptides and extend their half-life over days to months. The specific properties of each ILAF preparation, such as extended-release and improved drug targeting capabilities, make them an effective approach for precise and focused therapy. Furthermore, this is especially helpful for biopharmaceuticals with short biological half-lives and low stability since most environmental conditions can protect them from sustained-release delivery methods.

Hypertension in frail older adults: current perspectives.

Hypertension is one of the most common chronic diseases in older people, and the prevalence is on the rise as the global population ages. Hypertension is closely associated with many adverse health outcomes, including cardiovascular disease, chronic kidney disease and mortality, which poses a substantial threat to global public health. Reasonable blood pressure (BP) management is very important for reducing the occurrence of adverse events. Frailty is an age-related geriatric syndrome, characterized by decreased physiological reserves of multiple organs and systems and increased sensitivity to stressors, which increases the risk of falls, hospitalization, fractures, and mortality in older people. With the aging of the global population and the important impact of frailty on clinical practice, frailty has attracted increasing attention in recent years. In older people, frailty and hypertension often coexist. Frailty has a negative impact on BP management and the prognosis of older hypertensive patients, while hypertension may increase the risk of frailty in older people. However, the causal relationship between frailty and hypertension remains unclear, and there is a paucity of research regarding the efficacious management of hypertension in frail elderly patients. The management of hypertension in frail elderly patients still faces significant challenges. The benefits of treatment, the optimal BP target, and the choice of antihypertensive drugs for older hypertensive patients with frailty remain subjects of ongoing debate. This review provides a brief overview of hypertension in frail older adults, especially for the management of BP in this population, which may help in offering valuable ideas for future research in this field.