Age-adjusted Charlson Comorbidity Index as an effective tool for the choice between simultaneous or staged bilateral total knee arthroplasty.

INTRODUCTION: The choice between simultaneous and staged bilateral total knee arthroplasty (BTKA) remains controversial. Age-adjusted Charlson Comorbidity Index(CCI) is a promising tool for risk-stratification. We aimed to compare the outcomes between patients who underwent simultaneous and staged BTKA, stratified by age-adjusted CCI scores. MATERIALS AND METHODS: We conducted this retrospective, single-surgeon case series from 2010 to 2020. This study consisted of 1558 simultaneous BTKA and 786 staged BTKA procedures. The outcome domains included 30-day and 90-day readmission and 1-year reoperation events. We performed multivariate regression analysis to compare the risk of readmission and reoperation following simultaneous and staged BTKA. Other factors included age, sex, body mass index, diabetes mellitus, rheumatoid arthritis, smoking, receiving thromboprophylaxis and blood transfusion. RESULTS: The rates of 30-day, 90-day readmission and 1-year reoperation following simultaneous BTKA was 1.99%, 2.70% and 0.71%, respectively. The rates of 30-day, 90-day readmission and 1-year reoperation following staged BTKA was 0.89%, 1.78% and 0.89%, respectively. For patients with age-adjusted CCI ≥ 4 points, simultaneous BTKA was associated with a higher risk of 30-day (aOR:3.369, 95% CI:0.990-11.466) and 90-day readmission (aOR:2.310, 95% CI:0.942-5.668). In patients with age-adjusted CCI ≤ 3 points, the risk of readmission and reoperation was not different between simultaneous or staged BTKA. CONCLUSION: Simultaneous BTKA was associated with an increased risk of short-term readmissions in patients with age-adjusted CCI ≥ 4 points but not in those with age-adjusted CCI ≤ 3 points. Age-adjusted CCI can be an effective index for the choice between simultaneous and staged BTKA procedures.

A new tau dephosphorylation-targeting chimera for the treatment of tauopathies.

Abnormal accumulation of hyperphosphorylated tau protein plays a pivotal role in a collection of neurodegenerative diseases named tauopathies, including Alzheimer's disease (AD). We have recently conceptualized the design of hetero-bifunctional chimeras for selectively promoting the proximity between tau and phosphatase, thus specifically facilitating tau dephosphorylation and removal. Here, we sought to optimize the construction of tau dephosphorylating-targeting chimera (DEPTAC) and obtained a new chimera D14, which had high efficiency in reducing tau phosphorylation both in cell and tauopathy mouse models, while showing limited cytotoxicity. Moreover, D14 ameliorated neurodegeneration in primary cultured hippocampal neurons treated with toxic tau-K18 fragments, and improved cognitive functions of tauopathy mice. These results suggested D14 as a cost-effective drug candidate for the treatment of tauopathies.

Assembly-Induced Membrane Selectivity of Artificial Model Peptides through Entropy-Enthalpy Competition.

Peptide design and drug development offer a promising solution for combating serious diseases or infections. In this study, using an AI-human negotiation approach, we have designed a class of minimal model peptides against tuberculosis (TB), among which K7W6 exhibits potent efficacy attributed to its assembly-induced function. Comprising lysine and tryptophan with an amphiphilic α-helical structure, the K7W6 sequence exhibits robust activity against various infectious bacteria causing TB (including clinically isolated and drug-resistant strains) both in vitro and in vivo. Moreover, it synergistically enhances the effectiveness of the first-line antibiotic rifampicin while displaying low potential for inducing drug resistance and minimal toxicity toward mammalian cells. Biophysical experiments and simulations elucidate that K7W6's exceptional performance can be ascribed to its highly selective and efficient membrane permeabilization activity induced by its distinctive self-assembly behavior. Additionally, these assemblies regulate the interplay between enthalpy and entropy during K7W6-membrane interaction, leading to the peptide's two-step mechanism of membrane interaction. These findings provide valuable insights into rational design principles for developing advanced peptide-based drugs while uncovering the functional role played by assembly.

The cellular-centered view of hypoxia tumor microenvironment: Molecular mechanisms and therapeutic interventions.

Cancer is a profoundly dynamic, heterogeneous and aggressive systemic ailment, with a coordinated evolution of various types of tumor niches. Hypoxia plays an indispensable role in the tumor micro-ecosystem, drastically enhancing the plasticity of cancer cells, fibroblasts and immune cells and orchestrating intercellular communication. Hypoxia-induced signals, particularly hypoxia-inducible factor-1α (HIF-1α), drive the reprogramming of genetic, transcriptional, and proteomic profiles. This leads to a spectrum of interconnected processes, including augmented survival of cancer cells, evasion of immune surveillance, metabolic reprogramming, remodeling of the extracellular matrix, and the development of resistance to conventional therapeutic modalities like radiotherapy and chemotherapy. Here, we summarize the latest research on the multifaceted effects of hypoxia, where a multitude of cellular and non-cellular elements crosstalk with each other and co-evolve in a synergistic manner. Additionally, we investigate therapeutic approaches targeting hypoxic niche, encompassing hypoxia-activated prodrugs, HIF inhibitors, nanomedicines, and combination therapies. Finally, we discuss some of the issues to be addressed and highlight the potential of emerging technologies in the treatment of cancer.

Neointimal hyperplasia after endoluminal injury in mice is dependent on tissue factor- and angiopoietin-2 dependent interferon gamma production by fibrocytes and macrophages.

Background: The intimal hyperplasia (IH) and vascular remodelling that follows endovascular injury, for instance after post-angioplasty re-stenosis, results in downstream ischaemia and progressive end organ damage. Interferon gamma (IFNγ) is known to play a critical role in this process. In mouse models we have previously shown that fibrocytes expressing tissue factor (TF) are recruited early to the site of injury. Through thrombin generation and protease activated receptor-1 (PAR-1) activation, fibrocytes secrete angiopoietin-2, stimulate neointimal cell proliferation, inhibit apoptosis and induce CXCL-12 production, all of which contribute to the progressive IH that then develops. In this study we investigated the relationship between TF, angiopoietin-2 and IFNγ. Methods and results: IH developing in carotid arteries of wild-type mice 4 weeks after endoluminal injury contained a significant proportion of IFNγ+ fibrocytes and macrophages, which we show, using a previously defined adoptive transfer model, were derived from circulating CD34+ cells. IH did not develop after injury in IFNγ-deficient mice, except after transplantation of WT bone marrow or adoptive transfer of WT CD34+ cells. In vitro, CD34+ cells isolated from post-injury mice did not express IFNγ, but this was induced when provided with FVIIa and FX, and enhanced when prothrombin was also provided: In both cases IFNγ secretion was TF-dependent and mediated mainly through protease activated PAR-1. IFNγ was predominantly expressed by fibrocytes. In vivo, all IFNγ+ neointimal cells in WT mice co-expressed angiopoietin-2, as did the small numbers of neointimal cells recruited in IFNγ-/- mice. Adoptively transferred WT CD34+ cells treated with either an anti-TIE-2 antibody, or with siRNA against angiopoetin-2 inhibited the expression of IFNγ and the development of IH. Conclusion: TF-dependent angiopoietin-2 production by newly recruited fibrocytes, and to a lesser extent macrophages, switches on IFNγ expression, and this is necessary for the IH to develop. These novel findings enhance our understanding of the pathophysiology of IH and expose potential targets for therapeutic intervention.

Synthesis and Biological Activities of Scleropentaside D.

We report the first total synthesis of scleropentaside D, a unique C-glycosidic ellagitannin, from the ketal derivative of scleropentaside A employing site-selective O4-protection of C-acyl glycoside and copper-catalyzed oxidative coupling reaction of galloyl groups as the key steps. Our study confirms the proposed structure of this natural product, scleropentaside D, and demonstrates its effectiveness as an inhibitor of α-glycosidase.

Intervention with fructooligosaccharides, Saccharomyces boulardii, and their combination in a colitis mouse model.

Objective: To examine the effects of an intervention with fructooligosaccharides (FOS), Saccharomyces boulardii, and their combination in a mouse model of colitis and to explore the mechanisms underlying these effects. Methods: The effects of FOS, S. boulardii, and their combination were evaluated in a DSS-induced mouse model of colitis. To this end, parameters such as body weight, the disease activity index (DAI), and colon length were examined in model mice. Subsequently, ELISA was employed to detect the serum levels of proinflammatory cytokines. Histopathological analysis was performed to estimate the progression of inflammation in the colon. Gas chromatography was used to determine the content of short-chain fatty acids (SCFAs) in the feces of model mice. Finally, 16S rRNA sequencing technology was used to analyze the gut microbiota composition. Results: FOS was slight effective in treating colitis and colitis-induced intestinal dysbiosis in mice. Meanwhile, S. boulardii could significantly reduced the DAI, inhibited the production of IL-1ß, and prevented colon shortening. Nevertheless, S. boulardii treatment alone failed to effectively regulate the gut microbiota. In contrast, the combined administration of FOS/S. boulardii resulted in better anti-inflammatory effects and enabled microbiota regulation. The FOS/S. boulardii combination (109 CFU/ml and 107 CFU/ml) significantly reduced the DAI, inhibited colitis, lowered IL-1ß and TNF-α production, and significantly improved the levels of butyric acid and isobutyric acid. However, FOS/S. boulardii 109 CFU/ml exerted stronger anti-inflammatory effects, inhibited IL-6 production and attenuated colon shortening. Meanwhile, FOS/S. boulardii 107 CFU/ml improved microbial regulation and alleviated the colitis-induced decrease in microbial diversity. The combination of FOS and S. boulardii significantly increased the abundance of Parabacteroides and decreased the abundance of Escherichia-Shigella. Additionally, it promoted the production of acetic acid and propionic acid. Conclusion: Compared with single administration, the combination can significantly increase the abundance of beneficial bacteria such as lactobacilli and Bifidobacteria and effectively regulate the gut microbiota composition. These results provide a scientific rationale for the prevention and treatment of colitis using a FOS/S. boulardii combination. They also offer a theoretical basis for the development of nutraceutical preparations containing FOS and S. boulardii.

Long-term gastrointestinal symptoms and sleep quality sequelae in adolescents after COVID-19: a retrospective study.

Objective: To evaluate the long-term gastrointestinal (GI) symptoms and sleep quality sequelae in adolescents with COVID-19. Methods: Between June and July 2023, an online survey was done in Xiaoshan District, Hangzhou City, Zhejiang Province, China, using the GI Symptom Rating Scale (GSRS) and the Pittsburgh Sleep Quality Inventory (PSQI). Results: GI symptoms in COVID-19 patients increased by 11.86% compared to before infection, while sleep quality decreased by 10.9%. Over time, there was a significant increase in the cumulative incidence rate of GI symptoms and sleep disorders (p < 0.001). Follow-up of COVID-19 positive patients within 6 months of infection showed that GI symptoms and sleep quality began to ease starting from the first month after infection. Further analysis indicated a significant linear relationship between the severity of GI symptoms and sleep quality (R > 0.5, p < 0.001). Moreover, females, older age, and higher education were identified as risk factors influencing the long-term effects of COVID-19. Conclusion: SARS-CoV-2 affects GI symptoms and sleep quality in adolescents during both the acute phase and post-infection periods. Over time, these symptoms gradually alleviate. A significant correlation exists between GI symptoms and sleep quality.

Regulation of candidalysin underlies Candida albicans persistence in intravascular catheters by modulating NETosis.

Candida albicans is a leading cause of intravascular catheter-related infections. The capacity for biofilm formation has been proposed to contribute to the persistence of this fungal pathogen on catheter surfaces. While efforts have been devoted to identifying microbial factors that modulate C. albicans biofilm formation in vitro, our understanding of the host factors that may shape C. albicans persistence in intravascular catheters is lacking. Here, we used multiphoton microscopy to characterize biofilms in intravascular catheters removed from candidiasis patients. We demonstrated that, NETosis, a type of neutrophil cell death with antimicrobial activity, was implicated in the interaction of immune cells with C. albicans in the catheters. The catheter isolates exhibited reduced filamentation and candidalysin gene expression, specifically in the total parenteral nutrition culture environment. Furthermore, we showed that the ablation of candidalysin expression in C. albicans reduced NETosis and conferred resistance to neutrophil-mediated fungal biofilm elimination. Our findings illustrate the role of neutrophil NETosis in modulating C. albicans biofilm persistence in an intravascular catheter, highlighting that C. albicans can benefit from reduced virulence expression to promote its persistence in an intravascular catheter.

Discovery of a class of glycosaminoglycan lyases with ultrabroad substrate spectrum and their substrate structure preferences.

Glycosaminoglycan (GAG) lyases are often strictly substrate specific, and it is especially difficult to simultaneously degrade GAGs with different types of glycosidic bonds. Herein, we found a new class of GAG lyases (GAGases) from different bacteria. These GAGases belong to polysaccharide lyase 35 family and share quite low homology with the identified GAG lyases. The most surprising thing is that GAGases can not only degrade three types of GAGs: hyaluronan, chondroitin sulfate, and heparan sulfate but also even one of them can also degrade alginate. Further investigation of structural preferences revealed that GAGases selectively act on GAG domains composed of non/6-O-/N-sulfated hexosamines and d-glucoronic acids as well as on alginate domains composed of d-mannuronic acids. In addition, GAG lyases were once speculated to have evolved from alginate lyases, but no transitional enzymes have been found. The discovery of GAGases not only broadens the category of GAG lyases, provides new enzymatic tools for the structural and functional studies of GAGs with specific structures, but also provides candidates for the evolution of GAG lyases.

Maize ZmSRO1e promotes mesocotyl elongation and deep sowing tolerance by inhibiting the activity of ZmbZIP61.

Deep sowing is a traditional method for drought resistance in maize production, and mesocotyl elongation is strongly associated with the ability of maize to germinate from deep soil. However, little is known about the functional genes and mechanisms regulating maize mesocotyl elongation. In the present study, we identified a plant-specific SIMILAR TO RCD-ONE (SRO) protein family member, ZmSRO1e, involved in maize mesocotyl elongation. The expression of ZmSRO1e is strongly inhibited upon transfer from dark to white light. The loss-of-function zmsro1e mutant exhibited a dramatically shorter mesocotyl than the wild-type in both constant light and darkness, while overexpression of ZmSRO1e significantly promoted mesocotyl elongation, indicating that ZmSRO1e positively regulates mesocotyl elongation. We showed that ZmSRO1e physically interacted with ZmbZIP61, an ortholog of Arabidopsis ELONGATED HYPOCOTYL 5 (HY5) and showed a function similar to that of HY5 in regulating photomorphogenesis. We found that ZmSRO1e repressed the transcriptional activity of ZmbZIP61 toward target genes involved in the regulation of cell expansion, such as ZmEXPB4 and ZmEXPB6, by interfering with the binding of ZmbZIP61 to the promoters of target genes. Our results provide a new understanding of the mechanism by which SRO regulates photomorphogenesis and highlight its potential application in deep sowing-resistant breeding.

Discovery and Development of NLRP3 Inhibitors Targeting the LRR Domain to Disrupt NLRP3-NEK7 Interaction for the Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease. Targeting NLRP3 inflammasome, specifically its interaction with NEK7 via the LRR domain of NLRP3, is a promising therapeutic strategy. Our research aimed to disrupt this interaction by focusing on the LRR domain. Through virtual screening, we identified five compounds with potent anti-inflammatory effects and ideal LRR binding affinity. Lead compound C878-1943 underwent structural optimization, yielding pyridoimidazole derivatives with different anti-inflammatory activities. Compound I-19 from the initial series effectively inhibited caspase-1 and IL-1ß release in an adjuvant-induced arthritis (AIA) rat model, significantly reducing joint swelling and spleen/thymus indices. To further enhance potency and extend in vivo half-life, a second series including II-8 was developed, demonstrating superior efficacy and longer half-life. Both I-19 and II-8 bind to the LRR domain, inhibiting NLRP3 inflammasome activation. These findings introduce novel small molecule inhibitors targeting the LRR domain of NLRP3 protein and disrupt NLRP3-NEK7 interaction, offering a novel approach for RA treatment.

[Temporal and Spatial Evolution and Prediction of Ecosystem Carbon Storage in Jiangxi Province Based on PLUS-InVEST Model].

Land-use changes are an important factor affecting the change in carbon storage in terrestrial ecosystems. Exploring the relationship between land-use changes and carbon storage provides reliable data support for optimizing regional land-use structure and maintaining regional carbon balance. Taking Jiangxi Province as an example, we first analyzed the land-use changes; then simulated the land-use pattern under three scenarios (i.e., natural development, ecological priority, and economic development scenarios) in 2030 based on the PLUS model; and finally estimated the carbon storage change in the past (i.e., 1990-2020) and future periods (i.e., three scenarios in 2030) using the InVEST model, analyzed the spatial-temporal characteristics, and proposed the corresponding suggestions. The results showed:① The carbon storage in Jiangxi Province showed a downward trend from 1990 to 2020, with a total reduction of 4.58×107 t. The increase in the water bodies and construction land and the decrease in cultivated land, woodland, grassland, and unused land was the major cause. ② The carbon storage under natural development, ecological priority, and economic development scenarios in Jiangxi Province in 2030 were 2.20×109, 2.24×109 and 2.19×109 t, respectively. ③ The carbon storage under the three scenarios showed similar spatial characteristics, wherein the high carbon storage was distributed in northern, northwest, and western regions, and the low carbon storage was distributed near the central region. These results can provide data support for future land spatial planning and improving the carbon storage of terrestrial ecosystems in Jiangxi Province.

Pediatric high-altitude pulmonary edema and acute mountain sickness: Clinical features and risk determinants.

OBJECTIVE: This investigation aimed to delineate the clinical manifestations associated with high-altitude pulmonary edema (HAPE) and acute mountain sickness (AMS) in pediatric populations and find the risk factors of HAPE. METHODS: We conducted a retrospective analysis of clinical data from children under 18 years diagnosed with HAPE and AMS at an average altitude of 3000 m. The clinical data between these two groups were compared. RESULTS: The study encompassed 74 pediatric patients, 27 with AMS and 47 with HAPE. HAPE presentations included classic HAPE (55.3%), reentry HAPE (27.7%), and high-altitude resident pulmonary edema (HARPE, 17.0%). Notably, 87.2% of HAPE cases were male, and 68.1% had a high body mass index (BMI). HARPE instances followed viral infections, prominently SARS-CoV-2. HAPE cases exhibited higher BMI, respiratory tract infections within 1 week preceding symptom onset, an increase in white blood cell counts (WBCs), lower peripheral arterial oxygen saturation (SpO2), and higher heart rate compared to the AMS group. Multivariate logistic regression pinpointed high BMI as an independent HAPE risk factor (odds ratio = 19.389, 95% confidence interval: 1.069-351.759, p = .045). CONCLUSION: HAPE occurs predominantly in males, with high BMI identified as a critical independent risk factor. The study underscores the need for heightened awareness and preventive strategies against HAPE in children at high altitudes.

Overlooked shelf sediment reductive sinks of dissolved rhenium and uranium in the modern ocean.

Rhenium (Re) and uranium (U) are essential proxies in reconstructing past oceanic oxygenation evolution. However, their removal in continental shelf sediments, hotspots of early diagenesis, were previously treated as quantitatively unimportant sinks in the ocean. Here we examine the sedimentary reductive removal of Re and U and their coupling with organic carbon decomposition, utilizing the 224Ra/228Th disequilibria within the East China Sea shelf. We identified positive correlations between their removal fluxes and the rates of sediment oxygen consumption or organic carbon decomposition. These correlations enable an evaluation of global shelf reductive sinks that are comparable to (for Re) or higher than (~4-fold for U) previously established suboxic/anoxic sinks. These findings suggest potential imbalances in the modern budgets of Re and U, or perhaps a substantial underestimation of their sources. Our study thus highlights shelf sedimentary reductive removal as critical yet overlooked sinks for Re and U in the modern ocean.

IFN-α affects Th17/Treg cell balance through c-Maf and associated with the progression of EBV- SLE.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease, of which the pathogens is remains obscure. Viral infection, particularly Epstein Barr viru (EBV) infection, has been considered a common pathogenic factor. This study suggests that c-Maf may be an important target in T cell differentiation during SLE progression, providing a potentially new perspective on the role of viral infection in the pathogenesis of autoimmune diseases. METHODS: Cytokines of EBV-infected SLE patients were measured by ELISA and assessed in conjunction with their clinical data. IFN-α, c-Maf, and the differentiation of Th17/Treg cells in SLE patients and MRL/LPR mice were analyzed using FCM, WB, RT-PCR, etc. Following the infection of cells and mice with EBV or viral mimic poly (dA:dT), the changes of the aforementioned indicators were investigated. The relationship among IFN-α, STAT3, c-Maf and Th17 cells was determined by si-RNA technique. RESULTS: Many SLE patients are found to be complicated by viral infections; Further, studies have demonstrated that viral infection, especially EBV, is involved in SLE development. This study showed that viral infections might promote IFN-α secretion, inhibit c-Maf expression by activating STAT3, increase Th17 cell differentiation, and lead to the immune imbalance of Th17/Treg cells, thus playing a role in the onset and progression of SLE. CONCLUSION: This study demonstrates that EBV infections may contribute to SLE development by activating STAT3 through IFN-α, inhibiting c-Maf, and causing Th17/Treg immune imbalance. Our work provided a new insight into the pathogenesis and treatment of SLE.

The thermal degradation of glucomoringin and changes of phenolic compounds in moringa seed kernels during different degrees of roasting.

The effect of heat treatment on the abundant bioactive compounds in moringa seed kernels (MSKs) during different degrees of roasting remains sparingly explored despite the flour of roasted MSKs has been incorporated into the human diet (e.g., cakes, cookies, and burgers) as a substitute to enrich the nutritional content. Therefore, we investigated the impacts of different roasting conditions (e.g., temperature and duration) on bioactive compounds (e.g., glucosinolates (GSLs), phenolic acids and alkaloids) and antioxidant capacity of MSKs. Our results showed that light and medium roasting increased the glucomoringin (GMG, the main GSL in MSKs) content from 43.7 (unroasted MSKs) to 69.7-127.3 µmol/g MSKs (dry weight), while excessive/dark roasting caused thermally-induced degradation of GMG (trace/undetectable level) in MSKs, resulting in the formation of various breakdown products (e.g., thiourea, nitrile, and amide). In addition, although roasting caused a significant reduction of some phenolic compounds (e.g., gallic, chlorogenic, p-coumaric acids, and trigonelline), other phenolic acids (e.g., caffeic and ferulic acids) and alkaloids (e.g., caffeine, theobromine, and theophylline) remarkably increased after roasting, which may contribute to the enhanced total phenolic content (up to 2.9-fold) and antioxidant capacity (up to 5.8-fold) of the roasted MSKs.

Short-Term Outcomes of Transcatheter Aortic Valve Replacement in Low-Risk Patients With Pure Severe Aortic Regurgitation.

Transcatheter aortic valve replacement (TAVR) has emerged as an alternative treatment for patients with pure severe aortic regurgitation (PSAR) who are contraindicated for surgery or have a high surgical risk. However, the therapeutic efficacy and safety of TAVR in low Society of Thoracic Surgeons (STS) score risk patients remain to be clarified. This study aimed to explore the feasibility of TAVR treatment in different STS-risk patients and to compare the adverse events between the groups. In this study, patients with PSAR who underwent TAVR at Zhongshan Hospital, Fudan University, China, during the inclusion period were included and categorized into 3 groups based on STS scores. The baseline data, imaging results, and follow-up data of the patients were documented. Therefore, of 75 TAVR patients, 38 (50.7%) were categorized as low risk (STS <4), and 37 (49.3%) patients were categorized as intermediate and high risk (STS ≥4). Compared with patients at intermediate and high risk, those in the low-risk group were younger, had a lower body mass index, had a lower prevalence of hypertension, chronic obstructive pulmonary disease, and previous percutaneous coronary intervention, and had better cardiac function (p all <0.05). In the hospital and at the 1-month follow-up, the degree of aortic regurgitation and cardiac function were significantly improved. No significant difference was found between the 2 groups in the hospital or during the 30-day follow-up. In conclusion, TAVR for PSAR in low-STS-risk patients is safe and efficient during 30 days of follow-up compared with intermediate- and high-STS-risk groups. TAVR for PSAR should not be limited to inoperable or STS-defined high-risk patients. Long-term follow-up is needed for further investigation.

Practice Algorithm of Rotational Thromboelastometry-Guided (ROTEM-Guided) Bleeding Management in Liver Transplantation.

Liver transplantation (LT) is frequently complicated by coagulopathy associated with end-stage liver disease, which is often multifactorial and associated with hemostatic disturbances affecting both the procoagulant and anticoagulant systems. This rebalanced coagulation system may lead to bleeding diathesis or increased clot formation. Conventional coagulation tests cannot reflect these complex changes because they can only illustrate deficiencies in the procoagulant system. Viscoelastic tests such as rotational thromboelastometry (ROTEM) have been used in LT and have shown useful for detecting coagulopathy and guiding transfusions. Implementation of ROTEM-guided bleeding management algorithms has proven effectiveness in reducing bleeding, transfusion needs, complication rates, and healthcare costs in LT. This document is intended to provide a practice algorithm for the management of major bleeding and coagulopathy during LT and to encourage adaptation of the guidelines to individual institutional circumstances and resources.

Mild hyperthermia enhanced synergistic uric acid degradation and multiple ROS elimination for an effective acute gout therapy.

BACKGROUND: Acute gouty is caused by the excessive accumulation of Monosodium Urate (MSU) crystals within various parts of the body, which leads to a deterioration of the local microenvironment. This degradation is marked by elevated levels of uric acid (UA), increased reactive oxygen species (ROS) production, hypoxic conditions, an upsurge in pro-inflammatory mediators, and mitochondrial dysfunction. RESULTS: In this study, we developed a multifunctional nanoparticle of polydopamine-platinum (PDA@Pt) to combat acute gout by leveraging mild hyperthermia to synergistically enhance UA degradation and anti-inflammatory effect. Herein, PDA acts as a foundational template that facilitates the growth of a Pt shell on the surface of its nanospheres, leading to the formation of the PDA@Pt nanomedicine. Within this therapeutic agent, the Pt nanoparticle catalyzes the decomposition of UA and actively breaks down endogenous hydrogen peroxide (H2O2) to produce O2, which helps to alleviate hypoxic conditions. Concurrently, the PDA component possesses exceptional capacity for ROS scavenging. Most significantly, Both PDA and Pt shell exhibit absorption in the Near-Infrared-II (NIR-II) region, which not only endow PDA@Pt with superior photothermal conversion efficiency for effective photothermal therapy (PTT) but also substantially enhances the nanomedicine's capacity for UA degradation, O2 production and ROS scavenging enzymatic activities. This photothermally-enhanced approach effectively facilitates the repair of mitochondrial damage and downregulates the NF-κB signaling pathway to inhibit the expression of pro-inflammatory cytokines. CONCLUSIONS: The multifunctional nanomedicine PDA@Pt exhibits exceptional efficacy in UA reduction and anti-inflammatory effects, presenting a promising potential therapeutic strategy for the management of acute gout.