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Abstract Vascular calcification (VC) arises from the accumulation of calcium salts in the intimal or tunica media layer of the aorta, contributing to higher risk of cardiovascular events and mortality. Despite this, the mechanisms driving VC remain incompletely understood. We previously described that nesfatin-1 functioned as a switch for vascular smooth muscle cells (VSMCs) plasticity in hypertension and neointimal hyperplasia. In this study, we sought to investigate the role and mechanism of nesfatin-1 in VC. The expression of nesfatin-1 was measured in calcified VSMCs and aortas, as well as in patients. Loss- and gain-of-function experiments were evaluated the roles of nesfatin-1 in VC pathogenesis. The transcription activation of nesfatin-1 was detected using a mass spectrometry. We found higher levels of nesfatin-1 in both calcified VSMCs and aortas, as well as in patients with coronary calcification. Loss-of-function and gain-of-function experiments revealed that nesfatin-1 was a key regulator of VC by facilitating the osteogenic transformation of VSMCs. Mechanistically, nesfatin-1 promoted the de-ubiquitination and stability of BMP-2 via inhibiting the E3 ligase SYTL4, and the interaction of nesfatin-1 with BMP-2 potentiated BMP-2 signaling and induced phosphorylation of Smad, followed by HDAC4 phosphorylation and nuclear exclusion. The dissociation of HDAC4 from RUNX2 elicited RUNX2 acetylation and subsequent nuclear translocation, leading to the transcription upregulation of OPN, a critical player in VC. From a small library of natural compounds, we identified that Curculigoside and Chebulagic acid reduced VC development via binding to and inhibiting nesfatin-1. Eventually, we designed a mass spectrometry-based DNA-protein interaction screening to identify that STAT3 mediated the transcription activation of nesfatin-1 in the context of VC. Overall, our study demonstrates that nesfatin-1 enhances BMP-2 signaling by inhibiting the E3 ligase SYTL4, thereby stabilizing BMP-2 and facilitating the downstream phosphorylation of SMAD1/5/9 and HDAC4. This signaling cascade leads to RUNX2 activation and the transcriptional upregulation of MSX2, driving VC. These insights position nesfatin-1 as a potential therapeutic target for preventing or treating VC, advancing our understanding of the molecular mechanisms underlying this critical cardiovascular condition.

In the era of antiretroviral therapy (ART), mortality among people living with the human immunodeficiency virus (HIV) has significantly decreased, yet the population of people living with HIV remains substantial. Among people living with HIV (PLWH), HIV-associated lymphoma (HAL) has surpassed Kaposi’s sarcoma to become the most common tumor in this population in developed countries. However, there remains a dearth of comprehensive and systematic understanding regarding HIV-associated lymphomas. This review aims to shed light on the changes in the immune system among PLWH and the characteristics of the immune microenvironment in HIV-associated lymphoma, with a specific focus on the immune system’s role in these individuals. Additionally, it seeks to explore recent advancements in immunotherapy for the treatment of HIV-associated lymphoma, intending to enhance strategies for immunotherapy in this specific population.

SignificancePlaques are clogging deposits formed by the accumulation of fat and calcium on the inner walls of arteries. Their formation can lead to narrowing the inner diameter of the blood vessel and hardening the blood vessel wall, thereby limiting blood flow and inducing various cardiovascular diseases such as coronary heart disease and peripheral arterial disease. Numerous factors, such as lifestyle changes and population aging, have lead to an increase in the number of patients with cardiovascular disease in China in recent years. The annual growth rate of vascular interventional therapy has remained at around 17% for a decade due to the continuous development of interventional medical means. China's large population of vascular disease and the special situation of calcified plaque lesions have created a huge demand for rotational interventional therapy. By analyzing the current research on rotary grinding, this paper summarizes the existing deficiencies and suggests a follow-up research direction to accelerate the exploration of rotary grinding's mechanism and master the core technology theory. Progress: Firstly, the research on rotary grinding instruments is summed up in three parts: (1) The rotary grinding therapeutic apparatus mentioned here contains a description of its basic features, including the RA from Boston Science and the OA from CSI. The differences between the two were compared in terms of technical indications, clinical indications, mechanism of action, and product upgrades. (2) The preparation method for the grinding wheel and the differential cutting of the grinding wheel are presented in summary. Currently, grinding wheels are mostly created by electroplating, and some experts have suggested using the "engraving" technique. Differential grinding wheel cutting involves two primary principles. Boston Science proposed differential cutting that utilizes the theory of workpiece deformation during the cutting process of flexible materials. The second mechanism is based upon the theory of the dynamic pressure film in water. (3) A summary was provided regarding the structure and techniques of two different types of special rotary grinding guide wires, as well as the potential negative consequences during operation. Secondly, the differences between treatments are compared, such as rotational atherectomy, conventional balloon stenting, rotational resection, ELCA and shock wave balloon. The advantages of plaque rotary grinding are explained in detail. The likelihood of occurrence, explanations, methods of treatment, and other research on complications following rotational grinding are evaluated and summarized. Slow/non-reflow, vascular dissection, vascular perforation, grinding head incarceration, guide wire bias, etc., are all included. Engineering proposes controlling grinding parameters and improving the performance of related equipment to reduce the probability of complications. Finally, the research related to the mechanism of rotary grinding is examined. The main factors are rotary grinding force, rotary grinding heat, and rotary grinding debris. The grinding force is analyzed in a specific way by the current research, which focuses on the impact of grinding wheel speed and quality, blood vessel diameter, fluid dynamic pressure, and other factors on the grinding force. Research on rotary grinding heat focuses on reducing temperature through liquid scrubbing, but there is limited attention paid to thermal damage from an engineering perspective. The analysis of the wear debris mostly discusses the relationship between the size and the speed of the grinding wheel.Conclusions and Prospects(1) At present, the rotary grinding device and related consumables are all imported from the United States. In the future, Chinese substitution will be an important development direction. The development of Chinese rotary grinding products is under process now. (2) The study of the differential cutting mechanism and the design of the surface characteristics of the rotary grinding head to achieve non-invasive vascular tissue removal and efficient plaque tissue removal plays an important role in reducing other injuries caused by surgery. (3) The safety of the grinding process could be improved by optimizing the grinding parameters. There are few discussions on whether other factors in the grinding process will affect parameters such as grinding force, grinding debris and grinding heat. This is the direction of continuous research. (4) There are few theoretical studies on the grinding guide wire, and the performance of the guide wire is the main factor in determining whether it is biased or broken during the operation. Explore the possibility of processing different materials into high-performance grinding guide wires and new processing methods. On the premise of ensuring product performance, minimizing device costs and surgical costs is also a key research direction in the future. (5) According to the characteristics of plaque removal, the development of new products with better performance, such as laser plaque ablation products, shock wave balloons, etc., is also very marketable.

Abstract Human immunodeficiency virus (HIV) infection is strongly associated with a heightened incidence of lymphomas. To mirror the natural course of human HIV infection, animal models have been developed. These models serve as valuable tools to investigate disease pathobiology, assess antiretroviral and immunomodulatory drugs, explore viral reservoirs, and develop eradication strategies. However, there are currently no validated in vivo models of HIV‐associated lymphoma (HAL), hampering progress in this crucial domain, and scant attention has been given to developing animal models dedicated to studying HAL, despite their pivotal role in advancing knowledge. This review provides a comprehensive overview of the existing animal models of HAL, which may enhance our understanding of the underlying pathogenesis and approaches for malignancies linked to HIV infection.

Abstract Background The respiratory chain plays a key role in the growth of Mycobacterium tuberculosis complex (MTBC). However, the exact regulatory mechanisms of this system still need to be elucidated, and only a few studies have investigated the impact of genetic mutations within the respiratory chain on MTBC transmission. This study aims to explore the impact of respiratory chain gene mutations on the global spread of MTBC. Results A total of 13,402 isolates of MTBC were included in this study. The majority of the isolates (n = 6,382, 47.62%) belonged to lineage 4, followed by lineage 2 (n = 5,123, 38.23%). Our findings revealed significant associations between Single Nucleotide Polymorphisms (SNPs) of specific genes and transmission clusters. These SNPs include Rv0087 (hycE, G178T), Rv1307 (atpH, C650T), Rv2195 (qcrA, G181C), Rv2196 (qcrB, G1250T), Rv3145 (nuoA, C35T), Rv3149 (nuoE, G121C), Rv3150 (nuoF, G700A), Rv3151 (nuoG, A1810G), Rv3152 (nuoH, G493A), and Rv3157 (nuoM, A1243G). Furthermore, our results showed that the SNPs of atpH C73G, atpA G271C, qcrA G181C, nuoJ G115A, nuoM G772A, and nuoN G1084T were positively correlated with cross-country transmission clades and cross-regional transmission clades. Conclusions Our study uncovered an association between mutations in respiratory chain genes and the transmission of MTBC. This important finding provides new insights for future research and will help to further explore new mechanisms of MTBC pathogenicity. By uncovering this association, we gain a more complete understanding of the processes by which MTBC increases virulence and spread, providing potential targets and strategies for preventing and treating tuberculosis.

Abstract The assembly of polymers at liquid-liquid interfaces offers a promising strategy for fabricating two-dimensional polymer films. However, a significant challenge arises when the polymers lack inherent interfacial traction. In response, we introduce an approach termed chaperone solvent-assisted assembly. This approach utilizes a target polymer, X, along with three solvents: α, β, and γ. α and β are poor solvents for X and immiscible with each other, while γ is a good solvent for X and miscible with both α and β, thus serving as the chaperone solvent. The cross-interface diffusion of γ induces the assembly of interfacially nonactive X at the α-β interface, and this mechanism is verified through systematic in situ and ex situ studies. We show that chaperone solvent-assisted assembly is versatile and reliable for the interfacial assembly of polymers, including those that are interfacially nonactive. Several practical applications based on chaperone solvent-assisted assembly are also demonstrated.

Abstract The optimal timing and type of hematopoietic stem cell transplantation (HSCT) for treating peripheral T-cell lymphoma (PTCL) remain controversial. This retrospective real-world study investigated the application pattern and outcomes of HSCT in China. The analysis encompassed 408 PTCL patients with a median age of 45.5 years, all of whom received initial adequate therapy at five hospitals. Among patients with nodal PTCL who responded effectively to first-line therapy (the “responders”, n = 127) and subsequently underwent HSCT consolidation (n = 47, 37.0%), 93.6% received auto-HSCT, while 6.4% underwent allo-HSCT. Front-line auto-HSCT showed potential for long-term disease control in nodal PTCL responders. Among non-nodal PTCL responders (n = 80) with HSCT (n = 26, 32.5%), 46.2% underwent allo-HSCT and 53.8% received auto-HSCT. Upfront allo-HSCT provides longer progression-free survival (PFS) for non-nodal PTCL responders, with lower 3-year cumulative incidence of relapse (CIR) (16.7% vs. 56.0%) and comparable non-relapse mortality (NRM) (10.4% vs. 11.0%) compared to auto-HSCT. For patients who achieved remission with second-line salvage regimens, allo-HSCT was the primary choice (82.4%) for non-nodal PTCL, while auto-HSCT was more common (82.4%) in nodal PTCL. Nodal PTCL patients underwent auto-HSCT after ≥ 3 lines of treatment had a higher 3-year CIR (81.0%) compared to those treated in the first (26.0%) or second line (26.0%). Non-nodal PTCL patients underwent allo-HSCT after ≥ 3 lines had a higher 3-year NRM (37.5%) compared to after first (10.4%) or second line treatment (8.5%). These findings highlight distinct HSCT application patterns for PTCL in China, emphasizing the impact of early disease control and upfront consolidative HSCT.

Abstract Star anise (Illicium verum), a valuable spice tree, faces significant threats from fungal diseases, particularly Alternaria leaf spot. This study investigates the potential of a soil-derived actinomycete strain, YG-5, as a biocontrol agent against Alternaria tenuissima, the causative pathogen on Alternaria leaf spot in star anise. Through comprehensive morphology, physiology, biochemistry, and genetic analyses, we identified the isolate as Streptomyces sp. YG-5. The strain exhibited broad-spectrum antimicrobial activity against several plant pathogens, with inhibition rates ranging between 36.47 to 80.34%. We systematically optimized the fermentation conditions for YG-5, including medium composition and cultivation parameters. The optimized process resulted in an 89.56% inhibition rate against A. tenuissima, a 14.72% improvement over non-optimized conditions. Notably, the antimicrobial compounds produced by YG-5 demonstrated stability across various temperatures, pH levels, and UV irradiation. In vivo efficacy trials showed promising results, with YG-5 fermentation broth reducing Alternaria leaf spot incidence on star anise leaves by 56.95%. These findings suggest that Streptomyces sp. YG-5 holds significant potential as a biocontrol agent against Alternaria leaf spot in star anise cultivation, offering a sustainable approach to disease management in this valuable crop.

Abstract Background Appropriate iron supplementation is essential for neonatal growth and development. However, there are few reports on the effects of iron overload on neonatal growth and immune homeostasis. Thus, the aim of this study was to investigate the effects of iron nutrition on neonatal growth and intestinal immunity by administering different levels of iron to neonatal pigs. Results We found that iron deficiency and iron overload resulted in slow growth in neonatal pigs. Iron deficiency and iron overload led to down-regulation of jejunum intestinal barrier and antioxidant marker genes, and promoted CD8+ T cell differentiation in jejunum and mesenteric lymph nodes (MLN) of pigs, disrupting intestinal health. Moreover, iron levels altered serum iron and tissue iron status leading to disturbances in redox state, affecting host innate and adaptive immunity. Conclusions These findings emphasized the effect of iron nutrition on host health and elucidated the importance of iron in regulating redox state and immunity development. This study provided valuable insights into the regulation of redox state and immune function by iron metabolism in early life, thus contributing to the development of targeted interventions and nutritional strategies to optimize iron nutrition in neonates.

In this study, a single-screw extruder was used to extrude distiller's grains (DGs) and the effect of extrusion material moisture (21%, 24%, 27%, 30%, 33%) on prolamins from DGs (PDGs) was studied by measuring the physicochemical (solubility, hydrophobicity, sulfhydryl and the disulfide bonds contents), functional (water and oil holding capacities) and secondary and tertiary structure properties. The results showed that the modification effect of PDGs was significantly affected by different extrusion material moisture. The damage degree of the natural structure of PDGs was increased gradually with the increase of extrusion material moisture, and the change of molecular conformation promoted the exposure of internal hydrophilic groups and the formation of disulphide bonds. The solubility was increased by 1.56 times to 34.75%, the surface hydrophobicity was reduced by 56.11% at 27% extrusion materials moisture, and the water holding capacity was enhanced accordingly. The thermal denaturation temperature was increased from 96.79 ℃ to 102.53 ℃, indicating the thermal stability was stronger. The order of protein aggregates increased after the denaturation rearrangement of extruded PDGs. Extrusion led to excessive degeneration of PDGs when the material moisture was too high (higher than 27%), and the destruction of the stable aggregation state would weaken the hydrophilicity, thermal property and order degree of PDGs, indicating that the extrusion material moisture played a very important role in regulating the variation of PDGs properties.

Delayed bone-healing of senile osteoporotic fractures remains a clinical challenge due to the alterations caused by aging in bone and immune systems. The novel biomaterials that address the deficiencies in both skeletal cells and immune systems are required to effectively treat the bone injuries of older patients. Zinc (Zn) has shown promise as a biodegradable material for use in orthopedic implants. To address the bone-healing deficiencies in elderly patients with bone injuries, we developed a biodegradable Zn-based alloy (Zn–2Cu-0.5Zr) with enhanced mechanical properties, including a yield strength of 198.7 MPa and ultimate tensile strength of 217.6 MPa, surpassing those of pure Zn and Zn–2Cu alloys. Cytotoxicity tests conducted on bone marrow mesenchymal stem cells (BMSCs) and MC3T3-E1 cells demonstrated that the extracts from Zn–2Cu-0.5Zr alloy exhibited no observable cytotoxic effects. Furthermore, the extracts of Zn–2Cu-0.5Zr alloy exhibited significant anti-inflammatory effects through regulation of inflammation-related cytokine production and modulation of macrophage polarization. The improved immune-osteo microenvironment subsequently contributed to osteogenic differentiation of BMSCs. The potential therapeutic application of Zn–2Cu-0.5Zr in senile osteoporotic fracture was tested using a rat model of age-related osteoporosis. The Zn–2Cu-0.5Zr alloy met the requirements for load-bearing applications and accelerated the healing process in a tibial fracture in aged rats. The imaging and histological analyses showed that it could accelerate the bone-repair process and promote the fracture healing in senile osteoporotic rats. These findings suggest that the novel Zn–2Cu-0.5Zr alloy holds potential for influencing the immunomodulatory function of macrophages and facilitating bone repair in elderly individuals with osteoporosis.

Abstract To investigate the positive feed-forward regulatory mechanism of nitrate uptake by rice, its responses to various light and carbohydrates were compared. In order to measure nitrate uptake in real time, the non-invasive method was used. The results showed that net nitrate uptake increased in the light and decreased in the dark, and finally reached a steady state after about 5 h. Based on it, carbohydrates effects could be investigated without considering light effects. After sucrose addition for 2 h, net nitrate uptake increased by about 80% without a lag, while glucose, fructose and raffinose had a slight effect with a lag and other sugars had no effect. It provided an evidence that sucrose was a positive feed-forward signal molecule of nitrate uptake by rice roots. To further analyze the effect of sucrose on the expression of high affinity nitrate transporter genes OsNRT2.1, OsNRT2.2, OsNRT2.3a and OsNRT2.3b, qRT-PCR was used to further verify after treated with 10 mM sucrose. The results revealed that these genes expression was immediately up-regulated, which indicated that these genes were post transcriptionally regulated. Further, 15N exchange dynamics analyzed N transport. It is benefit for increasing nitrate uptake by rice and improving its yield.

Multi-principal component alloy has been proved to form disordered solid solution in most cases. However, multi-principal component alloy with single phase solid solution has a few disadvantages in mechanical properties, such as low strength or poor plasticity. Aiming at CoCrNi-based multi-principal component alloy with low strength, this paper proposed a method to enhance the multi-principal component alloy through composition design. CoCrNiVAlx multi-principal component alloy was melted by non-consumable vacuum arc melting, and the content of σ phase in the multi-principal component alloy was changed by adjusting the content of Al element. With the addition of Al element, the fcc disordered phase in the multi-principal component alloy gradually went to the ordered L12 phase with the same structure. When the amount of Al was 1.5 wt%, the compressive strength reached 2347 MPa and the hardness reached 760.8HV, which were 30% and 20% higher than the compressive strength (1828 MPa) and hardness (619.3HV) of CoCrNiV multi-principal component alloy, respectively. With the further increase of Al element to 2.0 wt%, the σ phase in the multi-principal component alloy increased further, resulting in the simultaneous decrease of strength and plasticity. The strengthening mechanism of multi-principal component alloy was analyzed, and the strengthening action of L12 phase was confirmed. The results showed that the strengthening of multi-principal component alloy was mainly provided by L12 phase strengthening (1229.55 MPa, 52.39%) and grain boundary strengthening (376 MPa, 16.02%). This paper provided a probable strategy to increase the strength of the multi-principal component alloy, which opened up a new idea for the composition design of multi-principal component alloy.

Abstract Objective An increasing number of studies shown that inadequate energy intake causes an increase in adverse incidents in chronic kidney disease (CKD) patients on low-protein diets (LPD). The study aimed to investigate the relationship between energy intake and cardiovascular mortality in CKD patients on a LPD. Methods This was a cross-sectional study, a total of 4264 CKD patients were enrolled from the NHANES database between 2009 and 2018. Restricted cubic spline plots and Cox regression analysis were used to analyze the association between energy intake and cardiovascular mortality in CKD patients on a LPD. Additionally, a nomogram was constructed to estimate cardiovascular survival in CKD patients on a LPD. Results Among CKD patients on a LPD in the United States, 90.05% had an energy intake of less than 25 kcal/kg/day, compared to 36.94% in CKD patients on a non-LPD. Energy intake and cardiovascular mortality showed a linear relationship in CKD patients on a LPD, while a ‘U-shaped’ relationship was observed in CKD patients on a non-LPD. Multifactorial Cox regression models revealed that for Per-standard deviation (Per-SD) decrement in energy intake, the risk of cardiovascular mortality increased by 41% (HR: 1.41, 95% CI: 1.12, 1.77; P = 0.004) in CKD patients on a LPD. The concordance index of the nomogram was 0.79 (95% CI, 0.75, 0.83). Conclusion CKD patients, especially those on a LPD, have significantly inadequate energy intake. Lower energy intake is associated with higher cardiovascular mortality in CKD patients on a LPD.

Abstract Background Although broadband music with inaudible high-frequency components may benefit human well-being, this research area is largely unexplored and lacks sufficient studies on the topic. This study aimed to investigate and compare the effects of broadband and audible band music on relaxation states and cognitive function in young adults. Methods A single-blind randomized controlled trial was conducted in a professional soundproof laboratory from December 22, 2022, to January 18, 2023 with 32 participants randomly assigned to two groups, “Day 1 broadband + Day 2 audible band” (n = 16) and “Day 1 audible band + Day 2 broadband” (n = 16), listening to either broadband or audible band music (the same music piece played on the piano and harp) for two sessions of 15 min each on two consecutive days. Cognitive function was measured using CNS Vital Signs at pre-listening, after the 1st session, and after the 2nd session, while heart rate was monitored throughout the experiment. Visual Analog Scale was also administered for self-reported arousal, stress, thinking ability, and attention following each listening session. Results No significant differences were found in heart rate, cognitive flexibility, and executive function between the broadband listening group and the audible band-listening group (p > 0.05). However, the broadband group exhibited significant differences in mean heart rate at several time points, as well as a significant improvement in VAS stress level during the 2nd listening session compared to the 1st (p

Abstract The intracellular bacterial pathogen Legionella pneumophila modulates host cell functions by secreting multiple effectors with diverse biochemical activities. In particular, effectors of the SidE family interfere with host protein ubiquitination in a process that involves production of phosphoribosyl ubiquitin (PR-Ub). Here, we show that effector LnaB converts PR-Ub into ADP-ribosylated ubiquitin, which is further processed to ADP-ribose and functional ubiquitin by the (ADP-ribosyl)hydrolase MavL, thus maintaining ubiquitin homeostasis in infected cells. Upon being activated by actin, LnaB also undergoes self-AMPylation on tyrosine residues. The activity of LnaB requires a motif consisting of Ser, His and Glu (SHxxxE) present in a large family of toxins from diverse bacterial pathogens. Thus, our study sheds light on the mechanisms by which a pathogen maintains ubiquitin homeostasis and identifies a family of enzymes capable of protein AMPylation.

Abstract Background Migraine is one of the most common diseases worldwide while current treatment options are not ideal. New therapeutic classes of migraine, the calcitonin gene-related peptide (CGRP) antagonists, have been developed and shown considerable effectiveness and safety. The present study aimed to systematically evaluate the efficacy and safety of atogepant, a CGRP antagonist, for migraine prophylaxis from the results of randomized controlled trials (RCTs). Methods The Cochrane Library, Embase, PubMed and https://www.clinicaltrials.gov/ were searched for RCTs that compared atogepant with placebo for migraine prophylaxis from inception of the databases to Feb 1, 2024. Outcome data involving efficacy and safety were combined and analyzed using Review Manager Software version 5.3 (RevMan 5.3). For each outcome, risk ratios (RRs) or standardized mean difference (SMD) were calculated. Results 4 RCTs with a total of 2813 subjects met our inclusion criteria. The overall effect estimate showed that atogepant was significantly superior to placebo in terms of the reduction of monthly migraine (SMD − 0.40, 95% CI -0.46 to -0.34) or headache (SMD − 0.39, 95% CI -0.46 to -0.33) days, the reduction of acute medication use days (SMD − 0.45, 95% CI -0.51 to -0.39) and 50% responder rate (RR 1.66, 95% CI 1.46 to 1.89), while no dose-related improvements were found between different dosage groups. For the safety, significant number of patients experienced treatment-emergent adverse events (TEAEs) with atogepant than with placebo (RR 1.10, 95% CI 1.02–1.21) while there was no obvious difference between the five dosage groups. Most TEAEs involved constipation (RR 2.55, 95% CI 1.91–3.41), nausea (RR 2.19, 95% CI 1.67–2.87) and urinary tract infection (RR 1.49, 95% CI 1.05–2.11). In addition, a high dosage of atogepant may also increase the risk of treatment-related TEAEs (RR 1.64, 95% CI 1.02–2.63) and fatigue (RR 3.07, 95% CI 1.13–8.35). Conclusions This meta-analysis suggests that atogepant is effective and tolerable for migraine prophylaxis including episodic or chronic migraine compared with placebo. It is critical to weigh the benefits of different doses against the risk of adverse events in clinical application of atogepant. Longer and multi-dose trials with larger sample sizes are required to verify the current findings.

Abstract Background Hypertension is a common comorbidity of osteoarthritis (OA). Joint pain is the main clinical manifestation of OA. Knowledge about the relationship between hypertension and OA pain is limited. This study aimed to investigate whether blood pressure parameters are associated with knee pain severity in individuals with or at risks for OA. Methods Our sample consisted of 2598 subjects (60.7% female, aged 45–79 years) collected from the Osteoarthritis Initiative. Blood pressure parameters included blood pressure stage, systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP). Radiographic evaluation using Kellgren-Lawrence system and pain severity evaluation using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee Injury and Osteoarthritis Outcome Score (KOOS), and Numeric Rating Scale (NRS) were performed for right knee. Linear regression was used to examine the relationship between blood pressure parameters and knee pain severity. Results For the overall sample, blood pressure stage, SBP, and PP were positively correlated with WOMAC and NRS pain scores when adjusting for age, sex, and body mass index (BMI) (p ≤ 0.024) and were inversely correlated with KOOS score (p ≤ 0.004). After further adjusting for all covariates, PP remained a positive correlation with WOMAC score (p = 0.037) while other associations between blood pressure parameters and pain scores did not reach the statistical significance. In female, higher blood pressure stage, SBP, and PP were significantly associated with increased WOMAC and NRS scores and decreased KOOS score after adjustments of age and BMI (p ≤ 0.018). When adjusting for all covariates, the correlations of PP with WOMAC, KOOS and NRS scores remained significant (p = 0.008–0.049). In male sample, SBP was positively correlated with WOMAC score when adjusting for age and BMI (p = 0.050), but other associations between blood pressure parameters and pain scores were not statistically significant. No significant correlation was observed in male when further adjusting for other covariates. Conclusions Increased PP is a risk factor for knee pain and mainly affects females, which suggested that controlling PP may be beneficial in preventing or reducing knee pain in females with or at risks for OA.

Abstract Star field affiliation is an important part of ancient Chinese gazetteers. The gazetteers of Taiwan in the Qing Dynasty presented many ‘different opinions’ about the star field affiliation of Taiwan. These different opinions illustrate the difficulty of self-consistency in traditional Chinese star field affiliation theory and reflect the influence of the concept of grand unification on traditional Chinese geographical knowledge. During the Qianlong period, with the introduction of Western surveying and mapping knowledge, the sundial began to replace star field affiliation and became a new geographical positioning theory. Taiwan, whose geographical positioning also completed the transformation from the star field affiliation to sundial theory at the end of the Qing Dynasty, witnessed the replacement of traditional Chinese place knowledge with cosmopolitan knowledge. Looking back at the writings regarding the star field affiliation in Taiwan gazetteers in the Qing Dynasty, there was both debate and consensus.

For the situation that coal is still capable of oxidative spontaneous combustion under different oxygen conditions, we choose three coals with different metamorphic degrees: lignite, gas coal and fatty coal, selected as experimental samples to carry out programmed temperature gas chromatography(TPGC) experiments and molecular dynamics simulations based on ReaxFF force fields at oxygen concentrations of 3%, 5%, 10%, 14% and 18%, to investigate the characteristics of changes in the oxygen influence of groups under oxygen-poor conditions in coals with different degrees of metamorphosis according to the production patterns and pathways of CO and CO2, etc. The results show that coal is easily affected by temperature and oxygen to produce indicator gases such as CO and CO2, and when the indicator gas tends to increase exponentially, the lower the degree of coal deterioration and the lower the temperature at which the indicator gas is produced at the same oxygen concentration. The simulations show that the reaction of coal with oxygen under oxygen-poor conditions is likely to be an active intermediate fragment reaction between oxygen and coal affected by temperature, rather than a direct attack on the main structure of the coal. The coal structural groups are not directly altered when the coal is subjected to temperature, but undergo structural adjustments for bond twisting, breaking and atomic transformations to produce reactive intermediate fragments suitable for reaction with oxygen. The higher the degree of metamorphosis, the more stable the molecular structure of the coal and the less likely it is to be affected by temperature to produce reactive intermediate fragments, and when oxygen is introduced, the rate of reaction of oxygen with the reactive intermediate is lower than the rate at which the coal is affected by temperature to produce the reactive intermediate, therefore, oxygen under depleted conditions is generally reacted with reactive intermediates to produce indicator gases such as water, CO, rather than with the main structure of the coal among them. A combination of experimental and simulation analysis reveals that the amount of water and oxygen containing gases increases significantly at 3%-5% oxygen concentration for lignite, 10%-14% oxygen concentration for gas coal and 14%-18% oxygen concentration for fat coal compared to the other stages, indicating that these three coals with different degrees of deterioration are more affected by oxygen in this oxygen-poor concentration range and accelerated the process of coal oxidation reaction.

To reveal the grinding removal mechanism of 2D SiCf/SiC composites, according to the weaving structure characteristics of 2D SiCf/SiC composites, scratching experiments were conducted on the woven surface (WS) and stacking surface (SS) of 2D SiCf/SiC along 0°, 45°, and 90° directions. The experiments measured the scratching force and scratching depth and observed the scratching surface morphology. The results show that the removal modes for the SiCf/SiC material on WS0 (0° direction of fiber woven surface) are mainly shear, tensile, and bending fracture of longitudinal fibers (ie. the fiber axis is consistent with the feed rate direction), and shear, bending, and tensile fracture of transverse fibers (ie. the fiber axis is perpendicular to the feed rate direction). On WS45 (45° direction of fiber woven surface), the main removal modes are shear, bending, and tensile fracture. On SS0 (0° direction of fiber stacking surface), the main removal modes are extrusion and bending fractures of normal fibers (ie. the fiber axis is perpendicular to the scratching surface), as well as shear, tensile, and bending fractures of longitudinal fibers. On SS90 (90° direction of fiber stacking surface), the main removal modes are ductile removal, shear and bending fractur of normal fibers, and shear, bending, and tensile fracture of transverse fibers. Due to the anisotropy of SiC fibers, different directions and fracture modes exhibit varying mechanical properties. Shear fracture requires the least force, while tensile fracture requires the most force. At the same scratch depth, due to the different fracture modes in the WS0, WS45, SS0, and SS90 directions and varying proportions of shear, bending, and tensile fractures, the order of scratch forces is FSS0 > FWS45 > FSS90 > FWS0. When abrasive particles penetrate the composite material, the SiC matrix is peeled off and removed along with crack expansion and mutual penetration. Part of the matrix is removed by compression and then re-scratched by abrasive particles to form ductile scratches. When cutting 2D SiCf/SiC composite materials, it is advisable to choose the WS0 direction and avoid the SS0 direction as much as possible.

Abstract Killer cell lectin-like receptor G1 (KLRG1) is an immune checkpoint receptor expressed predominantly in NK and T-cell subsets that downregulates the activation and proliferation of immune cells and participates in cell-mediated immune responses. Accumulating evidence has demonstrated the importance of KLRG1 as a noteworthy disease marker and therapeutic target that can influence disease onset, progression, and prognosis. Blocking KLRG1 has been shown to effectively mitigate the effects of downregulation in various mouse tumor models, including solid tumors and hematologic malignancies. However, KLRG1 inhibitors have not yet been approved for human use, and the understanding of KLRG1 expression and its mechanism of action in various diseases remains incomplete. In this review, we explore alterations in the distribution, structure, and signaling pathways of KLRG1 in immune cells and summarize its expression patterns and roles in the development and progression of autoimmune diseases, infectious diseases, and cancers. Additionally, we discuss the potential applications of KLRG1 as a tool for tumor immunotherapy.

Abstract Despite the importance of spliceosome core components in cellular processes, their roles in cancer development, including hepatocellular carcinoma (HCC), remain poorly understood. In this study, we uncover a critical role for SmD2, a core component of the spliceosome machinery, in modulating DNA damage in HCC through its impact on BRCA1/FANC cassette exons and expression. Our findings reveal that SmD2 depletion sensitizes HCC cells to PARP inhibitors, expanding the potential therapeutic targets. We also demonstrate that SmD2 acetylation by p300 leads to its degradation, while HDAC2-mediated deacetylation stabilizes SmD2. Importantly, we show that the combination of Romidepsin and Olaparib exhibits significant therapeutic potential in multiple HCC models, highlighting the promise of targeting SmD2 acetylation and HDAC2 inhibition alongside PARP inhibitors for HCC treatment.

Abstract Background While the number of emergency patients worldwide continues to increase, emergency doctors often face moral distress. It hampers the overall efficiency of the emergency department, even leading to a reduction in human resources. Aim This study explored the experience of moral distress among emergency department doctors and analyzed the causes of its occurrence and the strategies for addressing it. Method Purposive and snowball sampling strategies were used in this study. Data were collected through in-depth, semi-structured interviews with 10 doctors working in the emergency department of a tertiary general hospital in southwest China. The interview data underwent processing using the Nvivo 14 software. The data analysis was guided by Colaizzi’s phenomenological analysis method. Study findings This study yielded five themes: (1) imbalance between Limited Medical Resources and High-Quality Treatment Needs; (2) Ineffective Communication with Patients; (3) Rescuing Patients With no prospect of treatment; (4) Challenges in Sustaining Optimal Treatment Measures; and (5) Strategies for Addressing Moral Distress. Conclusion The moral distress faced by emergency doctors stems from various aspects. Clinical management and policymakers can alleviate this distress by enhancing the dissemination of emergency medical knowledge to the general public, improving the social and economic support systems, and strengthening multidisciplinary collaboration and doctors’ communication skills.

Abstract Background The diagnostic complexities that arise in radiographic distinction between ectopic pleural thymoma and other thoracic neoplasms are substantial, with instances of co-occurring T-cell lymphocytosis and osseous metastasis being exceedingly rare. Case presentation A 51-year-old woman was admitted to our hospital with dyspnea and chest pain. Upon imaging examination, she was found to have diffuse and nodular pleural thickening on the left side, collapse of the left lung and a compression in the second thoracic vertebrae. All lesions showed significant 18F-FDG uptake on 18F-FDG PET/CT examination. Furthermore, she exhibited T-cell lymphocytosis in her peripheral blood, lymph nodes, and bone marrow. After ruling out malignant pleural mesothelioma (MPM), lung cancer with pleural metastasis, and T-cell lymphoma, the definitive diagnosis asserted was ectopic pleural thymoma with T-cell lymphocytosis and bone metastasis. Conclusion Physicians need to expand their knowledge of the imaging features of ectopic pleural thymoma. Cases with T-cell lymphocytosis may exhibit increased aggressiveness and prone to bone metastasis.

Abstract Objective This study aims to examine the impact of PE/PPE gene mutations on the transmission of Mycobacterium tuberculosis (M. tuberculosis) in China. Methods We collected the whole genome sequencing (WGS) data of 3202 M. tuberculosis isolates in China from 2007 to 2018 and investigated the clustering of strains from different lineages. To evaluate the potential role of PE/PPE gene mutations in the dissemination of the pathogen, we employed homoplastic analysis to detect homoplastic single nucleotide polymorphisms (SNPs) within these gene regions. Subsequently, logistic regression analysis was conducted to analyze the statistical association. Results Based on nationwide M. tuberculosis WGS data, it has been observed that the majority of the M. tuberculosis burden in China is caused by lineage 2 strains, followed by lineage 4. Lineage 2 exhibited a higher number of transmission clusters, totaling 446 clusters, of which 77 were cross-regional clusters. Conversely, there were only 52 transmission clusters in lineage 4, of which 9 were cross-regional clusters. In the analysis of lineage 2 isolates, regression results showed that 4 specific gene mutations, PE4 (position 190,394; c.46G > A), PE_PGRS10 (839,194; c.744 A > G), PE16 (1,607,005; c.620T > G) and PE_PGRS44 (2,921,883; c.333 C > A), were significantly associated with the transmission of M. tuberculosis. Mutations of PE_PGRS10 (839,334; c.884 A > G), PE_PGRS11 (847,613; c.1455G > C), PE_PGRS47 (3,054,724; c.811 A > G) and PPE66 (4,189,930; c.303G > C) exhibited significant associations with the cross-regional clusters. A total of 13 mutation positions showed a positive correlation with clustering size, indicating a positive association. For lineage 4 strains, no mutations were found to enhance transmission, but 2 mutation sites were identified as risk factors for cross-regional clusters. These included PE_PGRS4 (338,100; c.974 A > G) and PPE13 (976,897; c.1307 A > C). Conclusion Our results indicate that some PE/PPE gene mutations can increase the risk of M. tuberculosis transmission, which might provide a basis for controlling the spread of tuberculosis.

Abstract Background Tooth avulsion represents the most severe form of dental trauma, necessitating tooth replantation as the primary treatment. However, the risk of replacement root resorption (RRR) poses a significant threat to tooth retention following replantation. This study preliminarily aimed to investigate the effect of physiological occlusal force on RRR after the replantation of avulsed teeth and to explore the potential underlying mechanisms. Methods Thirty-six 4-week-old male Sprague-Dawley rats underwent extraction and immediate replantation of their left maxillary molars. The rats were randomly divided into two major groups: the occluded (n = 18) group, where the opposite mandibular teeth were preserved; non-occluded (n = 18) group, where the opposite mandibular teeth were extracted. Within each major group, there were three subgroups corresponding to 7 days, 14 days, and 2 months, resulting in a total of six subgroups, (n = 6 per subgroup). The right maxillary first molars served as the normal control. Various periodontal characteristics were assessed using haematoxylin-eosin (H&E), tartrate-resistant acid phosphatase (TRAP) staining, and micro-computed tomography (micro-CT). Results Histological staining revealed that under occlusal force, the early stage (day 7) after tooth replantation mainly manifested as root surface resorption, especially in the non-occluded group, which gradually diminished over time. Cementum and periodontal ligament (PDL) repair was observed on day 14. Micro-CT analysis indicated a significant decrease in PDL width in the non-occluded group two months after replantation, consistent with the histological findings, signifying severe RRR in the non-occluded group. Conclusions This study provides preliminary evidence that physiological occlusal force may attenuate osteoclastogenesis during the early stage of tooth replantation, thereby reducing the occurrence of RRR and promoting periodontal healing.

The role of gut microbiome in acute kidney injury (AKI) is increasing recognized. Caloric restriction (CR) has been shown to enhance the resistance to ischemia/reperfusion injury to the kidneys in rodents. Nonetheless, it is unknown whether intestinal microbiota mediated CR protection against ischemic/reperfusion-induced injury (IRI) in the kidneys. Herein, we showed that CR ameliorated IRI-elicited renal dysfunction, oxidative stress, apoptosis, and inflammation, along with enhanced intestinal barrier function. In addition, gut microbiota depletion blocked the favorable effects of CR in AKI mice. 16S rRNA and metabolomics analysis showed that CR enriched the gut commensal Parabacteroides goldsteinii (P. goldsteinii) and upregulated the level of serum metabolite dodecafluorpentan. Intestinal colonization of P. goldsteinii and oral administration of dodecafluorpentan showed the similar beneficial effects as CR in AKI mice. RNA sequencing and experimental data revealed that dodecafluorpentan protected against AKI-induced renal injury by antagonizing oxidative burst and NFκB-induced NLRP3 inflammasome activation. In addition, we screened and found that Hamaudol improved renal insufficiency by boosting the growth of P. goldsteinii. Our results shed light on the role of intestinal microbiota P. goldsteinii and serum metabolites dodecafluorpentan in CR benefits to AKI.

Congenital portosystemic shunts (CPSS) are rare pediatric vascular malformations characterized by abnormal development of the portal vein, which is attributed to incomplete embryonic remodeling of the hepatic and surrounding vasculature. CPSS manifests in two main forms: intrahepatic and extrahepatic. This study details the management of a pediatric patient diagnosed with Congenital Intrahepatic Portosystemic Shunt (CIPS) who was referred to our institution. By using a computer-assisted surgical system, the right hepatectomy was successfully performed, guided by precise intraoperative navigation based on three-dimensional reconstructions of enhanced CT imagery. The patient exhibited a favorable postoperative recovery trajectory, with the absence of complications or recurrence throughout the monitoring period.

Traditionally, extracting single, flat- or curved-rooted teeth through twisting is unfeasible. However, our clinical practice suggests that such teeth can be extracted efficiently through moderate twisting in a minimally invasive manner. Given the lack of studies on biomechanics of the tooth–periodontal ligament (PDL) complex during torsion, which has further constrained its application, we assessed the feasibility of the torsion method for extracting single-rooted teeth and evaluated its minimally invasive potential. Using three-dimensional finite element analysis, we examined the stress distribution of the tooth and PDL during torsion. Then, we examined changes in the optimal torsion angle (OTA) and stress distribution across various anatomical scenarios. During torsion loading, stress concentration was primarily observed on the sing-rooted tooth surface near the alveolar crest, whereas molars at the root furcation. The OTA was found to increase under conditions such as narrowing of root width, decrease in the root apical curvature, change from type I to IV bone, alveolar bone loss, and shortening of root length. Moreover, the clinically validated model demonstrated that 74% of outcomes fell within the standard OTA range. In conclusion, the decrease in PDL area necessitated a larger angle for complete PDL tearing. Single-rooted teeth with root width-to-thickness ratios of ≥0.42 and apical curvatures of ≤30°are suitable for extraction using the torsion method. This study confirms the feasibility of the torsion method for minimally invasive tooth extraction and expands its indications, laying the theoretical foundation and essential insights for its clinical application.

Background: Transmembrane and tetratricopeptide repeat containing 1 (TMTC1) is a recently discovered enzyme involved in the O-mannosylation of cadherins and protocadherins. It has been implicated in various types of cancer, but the overall prognostic significance of TMTC1 in pan-cancer and its potential as an immunotherapeutic target remain unclear. Methods: We applied various bioinformatics methods to investigate the potential oncogenic roles of TMTC1 using public databases. This analysis involved examining the expression, prognosis, genetic alterations, immune infiltration, immunotherapy response, drug sensitivity, and regulatory mechanisms of the TMTC1 gene in diverse cancer types. Results: In this study, we observed that TMTC1 expression is reduced in 19 types of cancer (ACC, BLCA, BRCA, CESC, COAD, ESCA, GBM, KICH, KIRC, KIRP, LAML, LUAD, LUSC, PRAD, READ, STAD, THCA, UCEC, and UCS) compared to normal tissues. Conversely, TMTC1 expression is elevated in OV and PAAD relative to normal tissues. Moreover, our analysis revealed that high expression of TMTC1 was associated with worse overall survival (OS) outcomes in patients with ACC, BLCA, COAD, GBM, KIRP, OV, STAD, and UCEC, but better OS outcomes in patients with CESC, KIRC, LUSC, and PAAD. Notably, patients with TMTC1 mutations or deep deletions demonstrated longer OS, while those with TMTC1 amplification showed shorter OS. There was a significant correlation between the expression level of TMTC1 and the infiltration of cancer-associated fibroblasts (CAFs) and endothelial cells. Using data from six real-world immunotherapy cohorts of BLCA, SKCM and RCC, we discovered that high TMTC1 expression was associated with better OS or progression-free survival (PFS). Lastly, through TMTC1-related gene enrichment analysis, some biological processes and pathways were found to be significantly enriched, such as vascular endothelial growth factor receptor signaling pathway and ECM-receptor interaction. Conclusions: Our study demonstrates the prognostic significance of TMTC1 in pan-cancer and highlights its potential as an immunotherapeutic target.

BackgroundChronic kidney disease (CKD) stages 3-4 present a significant clinical challenge due to the absence of a systematic approach to managing associated medication-related problems (MRPs). This lack of a structured framework hinders the timely identification and effective intervention for these complications, potentially compromising patient safety and prognosis.ObjectiveThis study aims to leverage the Delphi method to establish an evaluation index for a rational drug use evaluation system dedicated to CKD patients in stages 3-4. This system will function as a platform for the continuous identification and management of MRPs, ultimately contributing to improved medication safety and patient outcomes.MethodsThis research uses the modified Delphi technique to develop an evaluation system for rational drug use in patients with chronic kidney disease. The initial questionnaire was developed by literature review for patients with chronic kidney disease. Twenty-six senior experts formed a panel in order to evaluate items across two Delphi rounds. Consensus was defined as at least 95% agreement (first round) and 85% agreement (second round), agreeing with an average score of at least 4.5 (first round) and 4.0 (second round). Items that fulfill the stipulated criteria are eligible for inclusion in the consensus list.ResultsAll experts participated in both rounds (100% response rate). Consensus was achieved on three patient-related items in the first round of 34 items. Based on expert feedback, 18 revised items were included in the second round after refining, restructuring, and removing some elements. Following two rounds of consultation, 20 items achieved consensus, encompassing aspects such as drug selection, dosage assessment, treatment duration, prescription and dispensing practices, patient-related factors, and other relevant considerations.ConclusionThis study has successfully identified 20 key evaluation indicators for a rational drug use evaluation system specifically designed for CKD patients in stages 3 and 4. This system will serve as a tool for continuous MRP identification and timely intervention, ultimately enhancing medication safety and patient prognosis.

Abstract Although hypoxia is known to be associated with immune resistance, the adaptability to hypoxia by different cell populations in the tumor microenvironment and the underlying mechanisms remain elusive. This knowledge gap has hindered the development of therapeutic strategies to overcome tumor immune resistance induced by hypoxia. Here, bulk, single‐cell, and spatial transcriptomics are integrated to characterize hypoxia associated with immune escape during carcinogenesis and reveal a hypoxia‐based intercellular communication hub consisting of malignant cells, ALCAMhigh macrophages, and exhausted CD8+ T cells around the tumor boundary. A hypoxic microenvironment promotes binding of HIF‐1α complex is demonstrated to the ALCAM promoter therefore increasing its expression in macrophages, and the ALCAMhigh macrophages co‐localize with exhausted CD8+ T cells in the tumor spatial microenvironment and promote T cell exhaustion. Preclinically, HIF‐1ɑ inhibition reduces ALCAM expression in macrophages and exhausted CD8+ T cells and potentiates T cell antitumor function to enhance immunotherapy efficacy. This study reveals the systematic landscape of hypoxia at single‐cell resolution and spatial architecture and highlights the effect of hypoxia on immunotherapy resistance through the ALCAMhigh macrophage‐exhausted T cell axis, providing a novel immunotherapeutic strategy to overcome hypoxia‐induced resistance in cancers.

The red blood cell (RBC) lifespan is a crucial indicator used in clinical diagnostics, treatment, and disease monitoring. This biomarker quantifies the duration that red blood cells (RBCs) circulate within the bloodstream after being released from the bone marrow, serving as a sensitive and direct indicator of red blood cell turnover. Conventional techniques for RBC lifespan measurement, including differential agglutination, 51Cr labeling, and 15N glycine labeling, each present their own set of challenges, such as complexity, radioactive exposure, and potential allergic reaction. The carbon monoxide (CO) breath test has emerged as an advanced and non-invasive alternative, indirectly assessing RBC lifespan through hemoglobin (Hb) renewal rates. This method is convenient, rapid, and lacks the drawbacks of traditional approaches. The CO breath test for RBC lifespan is widely utilized in benign anemia, malignant hematological disorders, neonatal hyperbilirubinemia, and diabetes mellitus, offering valuable insights into disease mechanisms, progression, and treatment outcomes.

ObjectiveThe aim of this report is to provide a comprehensive overview of clinical trials and protocols related to traumatic brain injury over the past two decades.MethodsWe collected information on clinical trials related to traumatic brain injury (TBI) from the ClinicalTrials.gov database, identified key categorical variables, and assessed their characteristics.ResultsA total of 367 TBI-related trials were identified for analysis. All identified trials were interventional clinical trials. Most trials were small-scale, with 75.2% enrolling 1–100 participants, and only about 20% were funded by industry or the National Institutes of Health (NIH). In most trials, participants were gender-neutral (96.5%), and the primary age group was adults and older adults (56.9%). Of all identified TBI trials, 78.2% were randomized, and 69.4% were blinded. Additionally, the primary purpose of 297 trials (80.9%) was treatment, with drug therapy as the most common intervention. A total of 153 trials (41.7%) were completed; however, only 58 trials submitted results to the registry. Furthermore, 81 trials (22.1%) were discontinued early, primarily due to recruitment problems. Clinical trials started between 2004 and 2013 reported a higher proportion of results compared with those started between 2014 and 2023 (35.1% vs. 11.1%, p

ObjectiveNivolumab, 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.MethodsA 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.ResultsNivolumab 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.ConclusionNivolumab 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.

Severe pneumonia (SP) is a prevalent respiratory ailment characterized by high mortality and poor prognosis. Current scoring systems for pneumonia are not only time-consuming but also exhibit limitations in early SP prediction. To address this gap, this study aimed to develop a machine-learning model using inflammatory markers from peripheral blood for early prediction of SP. A total of 204 pneumonia patients from seven medical centers were studied, with 143 (68 SP cases) in the training cohort and 61 (32 SP cases) in the test cohort. Clinical characteristics and laboratory test results were collected at diagnosis. Various models including Logistic Regression, Random Forest, Naïve Bayes, XGBoost, Support Vector Machine, and Decision Tree were built and evaluated. Seven predictors—age, sex, WBC count, T-lymphocyte count, NLR, CRP, TNF-α, IL-4/IFN-γ ratio, IL-6/IL-10 ratio—were selected through LASSO regression and clinical insight. The XGBoost model, exhibiting best performance, achieved an AUC of 0.901 (95 % CI: 0.827 to 0.985) in the test cohort, with an accuracy of 0.803, sensitivity of 0.844, specificity of 0.759, and F1_score of 0.818. Indeed, SHAP analysis emphasized the significance of elevated WBC counts, older age, and elevated CRP as the top predictors. The use of inflammatory biomarkers in this concise predictive model shows significant potential for the rapid assessment of SP risk, thereby facilitating timely preventive interventions.

Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Loncastuximab tesirine (Lonca), an antibody conjugate targeting CD19, has demonstrated significant clinical benefit in R/R DLBCL in a global phase 2 LOTIS-2 study. In the China bridging pivotal phase 2 OL-ADCT-402-001 study, eligible patients aged ≥18 years with R/R DLBCL who had failed ≥ 2 lines of systemic therapies were enrolled and treated with Lonca every 3 week with 150 μg/kg for 2 cycles; then 75 μg/kg for subsequent cycles (up to 1 year). The primary endpoint was overall response rate (ORR) assessed by independent review committee. Primary analyses for efficacy and safety were performed on the patients who received at least one treatment and had at least 6 months of follow-up following an initial documented response. As of data-cutoff, 64 patients received Lonca (median: 4.0 cycles [range: 1 to 17]). The median number of prior lines of therapies was 3.0 (range: 2 to 12). The ORR was 51.6% (95% CI: 38.7% to 64.2%), and the complete response rate was 23.4%. Hematological events accounted for the majority of the most common (≥15%) Grade ≥3 treatment-emergent adverse events (TEAEs), in which increased gamma glutamyltransferase (25.0%), and hypokalaemia (18.8%) also were reported. Serious TEAEs were reported in 35 of 64 patients with 4 fatal TEAEs. In conclusion, Lonca monotherapy demonstrated clinically meaningful efficacy and was well-tolerated in heavily pretreated Chinese patients with R/R DLBCL, which was consistent with the results of the LOTIS-2 study in Caucasian patients.

IntroductionWearable exoskeletons assist individuals with mobility impairments, enhancing their gait and quality of life. This study presents the iP3T model, designed to optimize gait phase prediction through the fusion of multimodal time-series data.MethodsThe iP3T model integrates data from stretch sensors, inertial measurement units (IMUs), and surface electromyography (sEMG) to capture comprehensive biomechanical and neuromuscular signals. The model's architecture leverages transformer-based attention mechanisms to prioritize crucial data points. A series of experiments were conducted on a treadmill with five participants to validate the model's performance.ResultsThe iP3T model consistently outperformed traditional single-modality approaches. In the post-stance phase, the model achieved an RMSE of 1.073 and an R2 of 0.985. The integration of multimodal data enhanced prediction accuracy and reduced metabolic cost during assisted treadmill walking.DiscussionThe study highlights the critical role of each sensor type in providing a holistic understanding of the gait cycle. The attention mechanisms within the iP3T model contribute to its interpretability, allowing for effective optimization of sensor configurations and ultimately improving mobility and quality of life for individuals with gait impairments.

Antibiotics are frequently employed to control bacterial diseases in honeybees, but their broad-spectrum action can disrupt the delicate balance of the gut microbiome, leading to dysbiosis. This imbalance in the gut microbiota of honeybees adversely affects their physiological health and weakens their resistance to pathogens, including viruses that significantly threaten honeybee health. In this study, we investigated whether tetracycline-induced gut microbiome dysbiosis promotes the replication of Israeli acute paralysis virus (IAPV), a key virus associated with colony losses and whether IAPV infection exacerbates gut microbiome dysbiosis. Our results demonstrated that tetracycline-induced gut microbiome dysbiosis increases the susceptibility of honeybees to IAPV infection. The viral titer in worker bees with antibiotic-induced gut microbiome dysbiosis prior to IAPV inoculation was significantly higher than in those merely inoculated with IAPV. Furthermore, we observed a synergistic effect between tetracycline and IAPV on the disruption of the honeybee gut microbiome balance. The progression of IAPV replication could, in turn, exacerbate antibiotic-induced gut microbiome dysbiosis in honeybees. Our research provides novel insights into the role of the gut microbiota in host-virus interactions, emphasizing the complex interplay between antibiotic use, gut microbiome health, and viral susceptibility in honeybees. We highlight the crucial role of a balanced gut microbiota in honey bees for their immune response against pathogens and emphasize the importance of careful, safe antibiotic use in beekeeping to protect these beneficial microbes.

N6-methyladenosine (m6A) methylation is one of the most predominant internal RNA modifications in eukaryotes and has become a hot spot in the field of epigenetics in recent years. Cardiovascular diseases (CVDs) are a leading cause of death globally. Emerging evidence demonstrates that RNA modifications, such as the m6A modification, are associated with the development and progression of many diseases, including CVDs. An increasing body of studies has indicated that programmed cell death (PCD) plays a vital role in CVDs. However, the molecular mechanisms underlying m6A modification and PCD in CVDs remain poorly understood. Herein, elaborating on the highly complex connections between the m6A mechanisms and different PCD signaling pathways and clarifying the exact molecular mechanism of m6A modification mediating PCD have significant meaning in developing new strategies for the prevention and therapy of CVDs. There is great potential for clinical application.

Abstract The incidence, clinical characteristics, and prognostic factors of HIV-associated lymphoma remain poorly defined compared to HIV-negative lymphoma. Currently, there are no standard guidelines for treatment of these patients. We summarized several latest reports of HIV associated lymphoma from the 2023 ASH Annual Meeting (ASH2023).

The development of dielectric materials with low permittivity and low loss is a great challenge in wireless communication. In this study, LiLn(PO3)4 (Ln = La, Sm, Eu) ceramic systems were successfully prepared using the traditional solid-state method. X-ray diffraction analysis indicated that the LiLn(PO3)4 ceramics crystallized in a monoclinic structure when sintered at 850–940 ℃. The characteristic peak shifted to higher angles with variations in the Ln element, which was ascribed to a reduction in the cell volume. Further analysis by structure refinement revealed that the reduction in the cell volume resulted from the decrease in chemical bond lengths and the compression of [LiO4] and [PO4] tetrahedra. Remarkably, the LiLn(PO3)4 ceramic system displayed exceptional performance at low sintering temperatures (910–925 ℃), including a high quality factor (Q·f) of 41,607–75,968 GHz, low temperature coefficient of resonant frequency (τf) ranging from −19.64 to −47.49 ppm/℃, low permittivity (εr) between 5.04 and 5.26, and low density (3.04–3.26 g/cm3). The application of Phillips–van Vechten–Levine (P–V–L) theory revealed that the increased Q·f value of the LiLn(PO3)4 systems can be attributed to the enhanced packing fraction, bond covalency, and lattice energy, and the stability of τf was associated with the increase in the bond energy. Furthermore, a prototype microstrip patch antenna using LiEu(PO3)4 ceramics was fabricated. The measurement results demonstrated excellent antenna performance with a bandwidth of 360 MHz and a peak gain of 5.11 dB at a central frequency of 5.08 GHz. Therefore, low-εr LiLn(PO3)4 ceramic systems are promising candidates for microwave/millimeter-wave communication.

Abstract Background Randomized controlled trials (RCTs) are usually the basis of evidence-based medicine, but whether the results of RCTs can be correctly translated into clinical practice depends on the quality of the literature reported. In this study, we evaluated the general characteristics and quality of paediatric RCTs published in China to provide evidence for the reporting of paediatric RCTs and their application in clinical practice. Methods We conducted a cross-sectional observational study of paediatric RCTs published in paediatric journals in China between January 1, 1999, and December 30, 2022. All RCTs that included children (younger than 18 years old) were retrieved, and the general characteristics of the RCTs were extracted and analysed. The quality of the RCTs was assessed by the Cochrane quality assessment protocol. Results After screening 20 available paediatric journals, 3545 RCTs were included for analysis. The average annual growth rate of the number of published paediatric RCTs from 1999 to 2022 was 7.8% (P = 0.005, R2 = 0.311). Most of the studies were carried out in East China [1148 (32.4%]; the centres of the RCTs were mainly single-centre [3453 (97.4%], and the interventions were mainly medication [2442 (68.9%)]. Comparing RCTs published in 2017–2022 with RCTs published in 1999–2004, the quality of RCTs significantly improved in terms of random sequence generation, allocation concealment, blinding participants and personnel, incomplete outcome data and selective outcome reporting. RCTs published in multiple centres from the Chinese Science Citation Database were identified, and the approval of the ethics committee was of better quality for all the analysed risk of bias items. Conclusion The number and quality of paediatric RCTs reported in China have improved in recent years, but the overall quality was relatively low. Special attention should be given to allocation concealment and blinding outcome assessment, and dropouts, adverse effects and sample size calculations should be reported. Promoting government policies, strengthening the standardization of journal publishing and advancing the registration of clinical trials are feasible measures.

The polymer composites with significantly higher permittivity and low loss tangent are vital for the advancement of advanced energy storage capacitors. However, the pursuit of elevated permittivity often comes at the cost of increased loss, imposing limitations on practical applications. In this work, we propose a novel approach of multi-layer composites, comprising positive and negative-ε′ layers. We systematically examine the influence of the relative positioning of single layers within 2-, 3-, and 5-layers structure, as well as the thickness ratio between the positive and negative permittivity layers, to unlock the potential for simultaneously achieving high permittivity, low loss, and moderate energy density. In a remarkable observation, the spatial stacking arrangement of a 5-layer composite (97679) exhibits a substantial increase in permittivity, achieving an impressive 847 as the thickness ratio reached to 1:1:20:1:1. This enhancement represents a remarkable 176-fold increase in permittivity and a one-order-of-magnitude reduction in dielectric loss compared to pristine PI matrix (ε' ≈ 4.8, tanδ ≈ 0.012 at 10 kHz). The 5-layer composite with the content of 97679 demonstrates an enhanced energy density (Ud) of up to 2.49 J/cm³ while concurrently exhibiting an exceptional efficiency (η) of 93.8%. The underlying mechanism responsible for these excellent properties presents that the BDS is influenced by the positioning of the positive-ε′ layer, and the dielectric constant is primarily governed by the arrangement of negative-ε′ layer. The strategic modulation of a multi-layer structure with positive and negative permittivity layers opens a novel design for enhancing energy storage density and tailoring dielectric performances.

Abstract Background Colorectal cancer (CRC) incidence is increasing in recent years due to intestinal flora imbalance, making oral probiotics a hotspot for research. However, numerous studies related to intestinal flora regulation ignore its internal mechanisms without in-depth research. Results Here, we developed a probiotic microgel delivery system (L.r@(SA-CS)2) through the layer-by-layer encapsulation technology of alginate (SA) and chitosan (CS) to improve gut microbiota dysbiosis and enhance anti-tumor therapeutic effect. Short chain fatty acids (SCFAs) produced by L.r have direct anti-tumor effects. Additionally, it reduces harmful bacteria such as Proteobacteria and Fusobacteriota, and through bacteria mutualophy increases beneficial bacteria such as Bacteroidota and Firmicutes which produce butyric acid. By binding to the G protein-coupled receptor 109A (GPR109A) on the surface of colonic epithelial cells, butyric acid can induce apoptosis in abnormal cells. Due to the low expression of GPR109A in colon cancer cells, MK-6892 (MK) can be used to stimulate GPR109A. With increased production of butyrate, activated GPR109A is able to bind more butyrate, which further promotes apoptosis of cancer cells and triggers an antitumor response. Conclusion It appears that the oral administration of L.r@(SA-CS)2 microgels may provide a treatment option for CRC by modifying the gut microbiota.

Abstract Diabetic individuals with diabetic cardiomyopathy (DbCM) present with abnormal myocardial structure and function. DbCM cannot be accurately diagnosed due to the lack of suitable diagnostic biomarkers. In this study, 171 eligible participants were divided into a healthy control (HC), type 2 diabetes mellitus (T2DM) patients without DbCM (T2DM), or DbCM group. Serum fibrinogen-like protein 1 (FGL-1) and other biochemical parameters were determined for all participants. Serum FGL-1 levels were significantly higher in patients with DbCM compared with those in the T2DM group and HCs. Serum FGL-1 levels were negatively correlated with left ventricular fractional shortening and left ventricular ejection fraction (LVEF) and positively correlated with left ventricular mass index in patients with DbCM after adjusting for age, sex and body mass index. Interaction of serum FGL-1 and triglyceride levels on LVEF was noted in patients with DbCM. A composite marker including serum FGL-1 and triglycerides could differentiate patients with DbCM from those with T2DM and HCs with an area under the curve of 0.773 and 0.789, respectively. Composite marker levels were negatively correlated with N-terminal B-type natriuretic peptide levels in patients with DbCM. Circulating FGL-1 may therefore be a valuable index reflecting cardiac functions in DbCM and to diagnose DbCM.

Abstract Although bortezomib (BTZ) is the cornerstone of anti-multiple myeloma (MM) therapy, the inevitable primary and secondary drug resistance still seriously affects the prognosis of patients. New treatment strategies are in need. Sodium-calcium exchanger 1 (NCX1) is a calcium-permeable ion transporter on the membrane, and our previous studies showed that low NCX1 confers inferior viability in MM cells and suppressed osteoclast differentiation. However, the effect of NCX1 on BTZ sensitivity of MM and its possible mechanism remain unclear. In this study, we investigated the effect of NCX1 on BTZ sensitivity in MM, focusing on cellular processes of autophagy and cell viability. Our results provide evidence that NCX1 expression correlates with MM disease progression and low NCX1 expression increases BTZ sensitivity. NCX1/Ca2+ triggered autophagic flux through non-canonical NFκB pathway in MM cells, leading to attenuated the sensitivity of BTZ. Knockdown or inhibition of NCX1 could potentiate the anti-MM activity of BTZ in vitro and vivo, and inhibition of autophagy sensitized NCX1-overexpressing MM cells to BTZ. In general, this work implicates NCX1 as a potential therapeutic target in MM with BTZ resistance and provides novel mechanistic insights into its vital role in combating BTZ resistance.

Abstract Background Neutral cholesterol ester hydrolase 1 (NCEH1) plays a critical role in the regulation of cholesterol ester metabolism. Deficiency of NCHE1 accelerated atherosclerotic lesion formation in mice. Nonetheless, the role of NCEH1 in endothelial dysfunction associated with diabetes has not been explored. The present study sought to investigate whether NCEH1 improved endothelial function in diabetes, and the underlying mechanisms were explored. Methods The expression and activity of NCEH1 were determined in obese mice with high-fat diet (HFD) feeding, high glucose (HG)-induced mouse aortae or primary endothelial cells (ECs). Endothelium-dependent relaxation (EDR) in aortae response to acetylcholine (Ach) was measured. Results Results showed that the expression and activity of NCEH1 were lower in HFD-induced mouse aortae, HG-exposed mouse aortae ex vivo, and HG-incubated primary ECs. HG exposure reduced EDR in mouse aortae, which was exaggerated by endothelial-specific deficiency of NCEH1, whereas NCEH1 overexpression restored the impaired EDR. Similar results were observed in HFD mice. Mechanically, NCEH1 ameliorated the disrupted EDR by dissociating endothelial nitric oxide synthase (eNOS) from caveolin-1 (Cav-1), leading to eNOS activation and nitric oxide (NO) release. Moreover, interaction of NCEH1 with the E3 ubiquitin-protein ligase ZNRF1 led to the degradation of Cav-1 through the ubiquitination pathway. Silencing Cav-1 and upregulating ZNRF1 were sufficient to improve EDR of diabetic aortas, while overexpression of Cav-1 and downregulation of ZNRF1 abolished the effects of NCEH1 on endothelial function in diabetes. Thus, NCEH1 preserves endothelial function through increasing NO bioavailability secondary to the disruption of the Cav-1/eNOS complex in the endothelium of diabetic mice, depending on ZNRF1-induced ubiquitination of Cav-1. Conclusions NCEH1 may be a promising candidate for the prevention and treatment of vascular complications of diabetes.