Cost-effectiveness of nivolumab plus gemcitabine-cisplatin as first-line treatment for advanced urothelial carcinoma in China and the United States.

Objective: Nivolumab, recently proven in a phase 3 clinical trial (CheckMate 901) to enhance survival when combined with gemcitabine-cisplatin for advanced urothelial carcinoma. This study aimed to assess its cost-effectiveness against gemcitabine-cisplatin alone, from US and Chinese payers' perspectives. Methods: A partitioned survival model was established to assess the life-years, quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs) of nivolumab plus gemcitabine-cisplatin versus gemcitabine-cisplatin alone as first-line treatment for advanced urothelial carcinoma. Univariate, two-way, and probabilistic sensitivity analyses were conducted to assess the model's robustness. Additionally, subgroup analyses were performed. Results: Nivolumab plus gemcitabine-cisplatin and gemcitabine-cisplatin achieved survival benefits of 4.238 life-years and 2.979 life-years for patients with advanced urothelial carcinoma, respectively. Compared with gemcitabine-cisplatin, nivolumab plus gemcitabine-cisplatin resulted in ICERs of $116,856/QALY in the US and $51,997/QALY in China. The probabilities of achieving cost-effectiveness at the current willingness-to-pay thresholds were 77.5% in the US and 16.5% in China. Cost-effectiveness could be reached if the price of nivolumab were reduced to $920.87/100mg in China. Subgroup analyses indicated that the combination had the highest probability of cost-effectiveness in patients under 65 or with an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 in the US and China. Conclusion: Nivolumab plus gemcitabine-cisplatin first-line treatment for advanced urothelial carcinoma results in longer life expectancy than gemcitabine-cisplatin, but is not cost-effective in China at current price. However, cost-effectiveness is likely to be achieved in most patient subgroups in the US.

Acorus tatarinowii oils exert protective effects on microglia-mediated inflammatory injury via restoring gut microbiota composition in experimental stroke rats.

Growing evidence has demonstrated that gut microbiota could be developed as a therapeutic target due to its contribution to microglia activation in the pathological process of ischemic stroke. Acorus tatarinowii oils (AT oils), which is considered as the active fraction of a traditional Chinese herbal medicine Acorus tatarinowii, exerts various bioactivities and prebiotic effects. However, it remains unclear that the effect of AT oils on inflammatory response after ischemic stroke and whether its underlying mechanism is associated to gut microbiota and the intestinal barrier. In the current study, we aim to investigate the anti-microglial neuroinflammation mechanism of AT oils in a middle cerebral artery occlusion model of ischemic stroke. The compositions of AT oils were identified by GC-MS. Our results demonstrated that AT oils could effectively relieve cerebral infarction, inhibit neuronal apoptosis, degrade the release of pro-inflammatory factors (TNF-α, IL-17, IL-6 and IFN-γ), and mediate the polarization of microglia. Moreover, AT oils restored the composition and the balance of gut microbiota in stroke rats, and reduced abundance of opportunistic genera including Verrucomicrobia, Akkermansia and Tenericutes, as well as increased beneficial bacteria abundance such as Tenericutes and Prevotella_copri. To investigate the role of gut microbiota on AT oils against ischemic stroke, we conducted the fecal microbiota transplantation (FMT) experiments with gut microbiota consumption, which suggested that the depletion of gut microbiota took away the protective effect of AT oils, confirming the importance of gut microbiota in the protective effect of AT oils on ischemic stroke. FMT experiments have demonstrated that AT oils preserved the gut permeability and blood-brain barrier, as well as mediated the microglial phenotype under the intervention of gut microbiota. In summary, AT oils could efficaciously moderate neuronal damage and intervene microglial phenotype by reversing gut microbiota disorder in ischemic stroke rats.

Eriocitrin prevents Sepsis-induced acute kidney injury through anti-inflammation and anti-oxidation via modulating Nrf2/DRP1/OPA1 signaling pathway.

BACKGROUND: Severe inflammation and oxidative stress are characteristics of sepsis-associated kidney injury with high morbidity and mortality. Eriocitrin (ERI) has shown promise in suppressing sepsis-associated kidney injury and LPS-induced periodontal disease, however, its efficacy in alleviating SAKI remains unexplored. This study aimed to investigate the therapeutic potential of ERI on SAKI through in vivo and in vitro experiments, elucidating its underlying mechanism. METHODS: The therapeutic effects of ERI against SAKI were evaluated by survival rate, changes of serum creatinine (Scr) and blood urea nitrogen (BUN) and statistic of renal histological score in a Cecal ligation and puncture (CLP)-induced septic mice. Impactions about anti-coagulation, anti-inflammation, anti-oxidative stress and improvement of mitochondrial damage and mitochondrial morphology were further assayed. In vitro, HUVECs upon stimulation of LPS with or without different dosage of ERI, followed by evaluating changes in inflammation, mitochondrial dynamic equilibrium and signaling pathways. RESULTS: ERI demonstrated ameliorative effects on SAKI by attenuating inflammation, oxidative stress and coagulation evidenced by the improved survival rate, alleviated kidney histological injury, declined BUN and Scr in serum and diminished levels of inflammation cytokines, and coagulation factors. Mechanistically, ERI suppressed DRP1-regulated mitochondrial fission and promoted OPA1-modulated mitochondrial fusion by activating Nrf2 in septic mice and LPS-stimulated HUVECs, which maintained mitochondrial dynamic equilibrium, improved mitochondrial morphology, assured integrity of mitochondrial function, decreased oxidative stress, impeded overwhelming inflammation, and thus, played a pivotal role in ERI's protection against SAKI. CONCLUSION: Our data confirmed the therapeutic potential of ERI in mitigating SAKI，suggesting its viability as a pharmacological agent in clinic settings.

Construction of porous flower-like Ru-doped CoNiFe layered double hydroxide for supercapacitors and oxygen evolution reaction catalysts.

In recent years, ternary layered double hydroxide (LDH) has become a research hotspot for electrode materials and oxygen evolution reaction (OER) catalyst due to the enhanced synergistic effect between individual elements. However, the application of LDH is greatly limited by its low electrical conductivity and the disadvantage that nanosheets tend to accumulate and mask the active sites. Herein, a novel Ru-doped CoNiFe - LDH was prepared via a facile hydrothermal method. According to the density functional theory (DFT) calculations, the doping of Ru element could improve electron state density and band gaps of LDH and consequently boosted the electrochemical reaction kinetics as well as electrical conductivity. Furthermore, introduction of Ru atom induced the formation of porous flower-like structures in nanosheets. Compared to CoNiFe - LDH (28.9 m2/g), Ru-doped CoNiFe - LDH performed larger specific surface area of 53.1 m2/g, resulting in more electrochemically active sites. In these case, Ru-doped CoNiFe - LDH demonstrated better energy storage performance of 176.0 mAh/g at 1 A/g compared to original CoNiFe - LDH (78.9 mAh/g at 1 A/g). Besides, the assembled Ru-doped CoNiFe - LDH//activated carbon (AC) device delivered a maximum energy density of 36.4 W h kg-1 at the power density of 740.3 W kg-1 and an outstanding cycle life (78.7 % after 10,000 cycles). Meanwhile, Ru-doped CoNiFe - LDH exhibited lower overpotential (339 mV at 50 mA cm-2) and Tafel slope (93.2 mV dec-1). Therefore, this work provided novel and valuable insights into the rational doping of Ru elements for the controlled synthesis of supercapacitor electrode materials and OER catalysts.

[Fire resistance of 15 main economic tree species in Liangshan Prefecture, Sichuan, China.] / 凉山州15ç§ä¸»è¦ç»æµŽæ ‘ç§çš„é˜²ç«æ€§èƒ½.

Liangshan Prefecture is one of the three major forest areas in Sichuan Province and one of the three major disaster areas of forest fire. We measured the physicochemical properties and combustion performances of different organs (leaves and branches) of 15 main economic tree species in Liangshan, and analyzed the bioecology characteristics, silviculture characteristics and value characteristics of different tree species. We investigated the fire resistance of different tree species to screen out fire-resistant species suitable for economic forest development in Liangshan Prefecture, and improve the biological fire prevention ability. The seven physicochemical properties and combustion performances indices of 15 tree species showed significant differences. Except for crude ash and lignin, the weights of moisture content, caloric value, ignition point, crude fat, and crude fibre of leaves were higher than those of branches. Crude fibre index of leaves (9.6%) and the crude ash index of branches (9.9%) were the highest weight indices of the two organs, respectively. Based on the fire resistance, we divided all the species into three classes, i.e., class Ⅰ (excellent fire-resistance trees) Juglans regia and Morus alba; class Ⅱ (better fire-resistant trees) Sapium sebiferum, Mangifera indica, Phyllanthus emblica, Eriobotrya japonica, Ligustrum lucidum, Castanea mollissima, and Punica granatum; class Ⅲ (poor fire-resistant trees) Pinus armandii, Illicium simonsii, Morella rubra, Sapindus mukorossi, Olea europaea and Camellia oleifera. J. regia and M. alba had fireproof solid performance and could be used as the preferred species for fireproof economic forest in Liangshan region. It was suggested that to use class Ⅰ to Ⅱ fire-resistant tree species built the main fireproof isolated forest belt, and pay attention to fire prevention after planting class Ⅲ tree species in a large area.

DEVELOPMENT AND INTERNAL-EXTERNAL VALIDATION OF THE ACCI-SOFA MODEL FOR PREDICTING IN-HOSPITAL MORTALITY OF PATIENTS WITH SEPSIS-3 IN THE ICU: A MULTICENTER RETROSPECTIVE COHORT STUDY.

ABSTRACT: Objective: To achieve a better prediction of in-hospital mortality, the Sequential Organ Failure Assessment (SOFA) score needs to be adjusted and combined with comorbidities. This study aims to enhance the prediction of SOFA score for in-hospital mortality in patients with Sepsis-3. Methods: This study adjusted the maximum SOFA score within the first 3 days (Max Day3 SOFA) in relation to in-hospital mortality using logistic regression and incorporated the age-adjusted Charlson Comorbidity Index (aCCI) as a continuous variable to build the age-adjusted Charlson Comorbidity Index-Sequential Organ Failure Assessment (aCCI-SOFA) model. The outcome was in-hospital mortality. We developed, internally validated, and externally validated the aCCI-SOFA model using cohorts of Sepsis-3 patients from the MIMIC-IV, MIMIC-III (CareVue), and the FAHWMU cohort. The predictive performance of the model was assessed through discrimination and calibration, which was assessed using the area under the receiver operating characteristic and calibration curves, respectively. The overall predictive effect was evaluated using the Brier score. Measurements and main results: Compared with the Max Day3 SOFA, the aCCI-SOFA model showed significant improvement in area under the receiver operating characteristic with all cohorts: development cohort (0.81 vs 0.75, P < 0.001), internal validation cohort (0.81 vs 0.76, P < 0.001), MIMIC-III (CareVue) cohort (0.75 vs 0.68, P < 0.001), and FAHWMU cohort (0.72 vs 0.67, P = 0.001). In sensitivity analysis, it was suggested that the application of aCCI-SOFA in early nonseptic shock patients had greater clinical value, with significant differences compared with the original SOFA scores in all cohorts ( P < 0.05). Conclusion: For septic patients in intensive care unit, the aCCI-SOFA model exhibited superior predictive performance. The application of aCCI-SOFA in early nonseptic shock patients had greater clinical value.

Constructing Hierarchical CoGa2O4-S@NiCo-LDH Core-Shell Heterostructures with Crystalline/Amorphous/Crystalline Heterointerfaces for Flexible Asymmetric Supercapacitors.

The rational design and construction of composite electrodes are crucial for overcoming the issues of poor working stability and slow ionic electron mobility of a single component. Nevertheless, it is a big challenge to construct core-shell heterostructures with crystalline/amorphous/crystalline heterointerfaces in straightforward and efficient methods. Here, we have successfully converted a portion of crystalline CoGa2O4 into the amorphous phase by employing a facile sulfidation process (denoted as CoGa2O4-S), followed by anchoring crystalline NiCo-layered double hydroxide (denoted as NiCo-LDH) nanoarrays onto hexagonal plates and nucleation points of CoGa2O4-S, synthesizing dual-type hexagonal and flower-like 3D CoGa2O4-S@NiCo-LDH core-shell heterostructures with crystalline/amorphous/crystalline heterointerfaces on carbon cloth. Furthermore, we further adjust the Ni/Co ratio in LDH, achieving precise and controllable core-shell heterostructures. Benefiting from the abundant crystalline/amorphous/crystalline heterointerfaces and synergistic effect among various components, the CoGa2O4-S@Ni2Co1-LDH electrode exhibits a specific capacity of 247.8 mAh·g-1 at 1 A·g-1 and good rate performance. A CoGa2O4-S@Ni2Co1-LDH//AC flexible asymmetric supercapacitor provides an energy density of 58.2 Wh·kg-1 at a power density of 850 W·kg-1 and exhibits an impressive capacitance retention of 105.7% after 10,000 cycles at 10 A·g-1. Our research provides profound insights into the design of other similar core-shell heterostructures.

Smart Enzyme-Like Polyphenol-Copper Spray for Enhanced Bacteria-Infected Diabetic Wound Healing.

Developing functional medical materials is urgent to treat diabetic wounds with a high risk of bacterial infections, high glucose levels and oxidative stress. Here, a smart copper-based nanocomposite acidic spray has been specifically designed to address this challenge. This copper-based nanocomposite is pH-responsive and has multienzyme-like properties. It enables the spray to effectively eliminate bacteria and alleviate tissue oxidative pressure, thereby accelerating the healing of infected diabetic wounds. The spray works by generating hydroxyl radicals through catalysing H2O2, which has a high sterilization efficiency of 97.1%. As alkaline micro-vessel leakage neutralizes the acidic spray, this copper-based nanocomposite modifies its enzyme-like activity to eliminate radicals. This reduces the level of reactive oxygen species in diabetic wounds by 45.3%, leading to a similar wound-healing effect between M1 diabetic mice and non-diabetic ones by day 8. This smart nanocomposite spray provides a responsive and regulated microenvironment for treating infected diabetic wounds. It also offers a convenient and novel approach to address the challenges associated with diabetic wound healing.

Short-interval second ejaculation improves sperm quality, blastocyst formation in oligoasthenozoospermic males in ICSI cycles: a time-lapse sibling oocytes study.

Background: Does short-interval second ejaculation improve sperm quality, embryo development and clinical outcomes for oligoasthenozoospermia males received intracytoplasmic sperm injection (ICSI) treatment? Methods: All enrolled male patients underwent short-interval secondary ejaculation on the day of oocyte retrieval, and 786 sibling MII oocytes from 67 cycles were equally divided into two groups based on whether the injected spermatozoons originated from the first or second ejaculation. Semen parameters, embryo development efficiency, morphokinetic parameters and clinical outcomes were compared between the two groups to assess the efficiency and clinical value of short-interval second ejaculation in ICSI cycles. Results: Short-interval second ejaculation significantly improved sperm motility, normal morphological rate, and sperm DNA integrity both before and after sperm swim-up. The high-quality blastocyst rate (24.79% versus 14.67%), available blastocyst rate (57.56% versus 48.44%), and oocyte utilization rate (52.93% versus 45.29%) were significantly higher in the second ejaculation group (P<0.05). The clinical pregnancy rate (59.09% versus 47.37%), implantation rate (42.11% versus 32.35%) and live birth rate (40.91% versus 31.58%) were higher in the second ejaculation group, but the differences were not significant (P>0.05). Time-lapse analysis showed that morphokinetic time points after the 7-cell stage were earlier in the second ejaculation group but without a significant difference (P>0.05), and abnormal embryo cleavage patterns between the two groups were not significantly different (P>0.05). Conclusions: Short-interval second ejaculation significantly improves sperm quality in oligoasthenozoospermic males, and is beneficial for blastocyst formation efficiency in ICSI cycles. This study suggested a non-invasive and simple but effective strategy for improving ICSI treatment outcomes.

GOx-Powered Janus Platelet Nanomotors for Targeted Delivery of Thrombolytic Drugs in Treating Thrombotic Diseases.

Low efficiency of targeting and delivery toward the thrombus site poses challenges to using thrombolytic drugs. Inspired by the biomimetic system of platelet membranes (PMs) and glucose oxidase (GOx) modification technologies, we develop a novel GOx-powered Janus nanomotor by asymmetrically attaching the GOx to polymeric nanomotors coated with the PMs. Then the PM-coated nanomotors were conjugated with urokinase plasminogen activators (uPAs) on their surfaces. The PM-camouflaged design conferred excellent biocompatibility to the nanomotors and improved their targeting ability to thrombus. The Janus distribution of GOx also allows the uneven decomposition of glucose in biofluids to produce a chemophoretic motion, increasing the drug delivery efficiency of nanomotors. In addition, these nanomotors are located at the lesion site due to the mutual adhesion and aggregation of platelet membranes. Furthermore, thrombolysis effects of nanomotors are enhanced in static and dynamic thrombus as well as in mouse models. It is believed that the novel PM-coated enzyme-powered nanomotors represent a great value for thrombolysis treatment.