Metformin use correlated with lower risk of cardiometabolic diseases and related mortality among US cancer survivors: evidence from a nationally representative cohort study.

BACKGROUND: In the USA, the prolonged effective survival of cancer population has brought significant attention to the rising risk of cardiometabolic morbidity and mortality in this population. This heightened risk underscores the urgent need for research into effective pharmacological interventions for cancer survivors. Notably, metformin, a well-known metabolic regulator with pleiotropic effects, has shown protective effects against cardiometabolic disorders in diabetic individuals. Despite these promising indications, evidence supporting its efficacy in improving cardiometabolic outcomes in cancer survivors remains scarce. METHODS: A prospective cohort was established using a nationally representative sample of cancer survivors enrolled in the US National Health and Nutrition Examination Survey (NHANES), spanning 2003 to 2018. Outcomes were derived from patient interviews, physical examinations, and public-access linked mortality archives up to 2019. The Oxidative Balance Score was utilized to assess participants' levels of oxidative stress. To evaluate the correlations between metformin use and the risk of cardiometabolic diseases and related mortality, survival analysis of cardiometabolic mortality was performed by Cox proportional hazards model, and cross-sectional analysis of cardiometabolic diseases outcomes was performed using logistic regression models. Interaction analyses were conducted to explore the specific pharmacological mechanism of metformin. RESULTS: Among 3995 cancer survivors (weighted population, 21,671,061, weighted mean [SE] age, 62.62 [0.33] years; 2119 [53.04%] females; 2727 [68.26%] Non-Hispanic White individuals), 448 reported metformin usage. During the follow-up period of up to 17 years (median, 6.42 years), there were 1233 recorded deaths, including 481 deaths from cardiometabolic causes. Multivariable models indicated that metformin use was associated with a lower risk of all-cause (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.47-0.81) and cardiometabolic (HR, 0.65; 95% CI, 0.44-0.97) mortality compared with metformin nonusers. Metformin use was also correlated with a lower risk of total cardiovascular disease (odds ratio [OR], 0.41; 95% CI, 0.28-0.59), stroke (OR, 0.44; 95% CI, 0.26-0.74), hypertension (OR, 0.27; 95% CI, 0.14-0.52), and coronary heart disease (OR, 0.41; 95% CI, 0.21-0.78). The observed inverse associations were consistent across subgroup analyses in four specific cancer populations identified as cardiometabolic high-risk groups. Interaction analyses suggested that metformin use as compared to non-use may counter-balance oxidative stress. CONCLUSIONS: In this cohort study involving a nationally representative population of US cancer survivors, metformin use was significantly correlated with a lower risk of cardiometabolic diseases, all-cause mortality, and cardiometabolic mortality.

Intense emission at 605†nm from Pr3+-doped fluorotellurite glass fibers.

Pr3+-doped fluorotellurite glass fibers (PDFTFs) were fabricated by using a rod-in-tube method. By using a 976/1400 nm dual-wavelength upconversion pump technique, an intense emission at 605 nm was obtained from a 6 cm long PDFTF, which was attributed to the transition 1D2 → 3H4 of Pr3+ ions. With an increase in power of the 1400 nm laser from ∼34 to ∼136 mW, the spectral bandwidth of the 605 nm emission decreased and the intensity of the 605 nm emission increased monotonically, indicating the generation of 605 nm amplified spontaneous emission (ASE). To the best of our knowledge, this is the first report of 605 nm ASE in PDFTFs. Our results showed that PDFTFs had the potential for constructing red fiber lasers and amplifiers.

Widely tunable S-band ring-cavity Tm3+-doped fluorotellurite fiber laser.

Tm3+-doped fluorotellurite fibers (TDFTFs) are fabricated by using a rod-in-tube method. A 2.1 m long TDFTF is used as the gain medium, in which both ends of the TDFTF are connected to a short piece of a silica fiber by direct fusion splicing. By inserting the above TDFTF and a tunable optical bandpass filter into a ring cavity and employing a 1400/1570 nm dual-wavelength pumping technique, tunable lasing from 1460 to 1526 nm is obtained, which almost covers the whole S-band. To the best of our knowledge, this is the first report of tunable Tm3+-doped fiber laser with a tunable range almost covering the whole S-band. Furthermore, by removing the tunable optical bandpass filter from the ring cavity, free-running multi-wavelength lasers at 1500 and 1901 nm are achieved. Our results show that TDFTFs are promising gain media for constructing S-band fiber lasers.

Experimental study on the effect of different cement content on the improvement of dynamic characteristics of seismic-prone poor soil.

The improvement of sandy soils with poor seismic properties to modify their dynamic characteristics is of great importance in seismic design for engineering sites. In this study, a series of dynamic tests on sandy soils sandy soils with poor seismic conditions were conducted using the GCTS resonant column system to investigate the improvements effects of different cement contents on dynamic characteristic parameters. The research findings are as follows: The cement content has certain influences on the dynamic shear modulus, dynamic shear modulus ratio, the maximum dynamic shear modulus, and the damping ratio of sandy soils with poor seismic properties. Among them, the influence on dynamic shear modulus is limited, while the damping ratio is significantly affected. The addition of cement to seismic-poor sandy soils significantly enhances their dynamic characteristics. The most noticeable improvement is observed when the cement content is 8%. Through curve fitting analysis, a relationship equation is established between the maximum dynamic shear modulus and the cement content, and the relevant parameters are provided. A comparative test between the improved soils and the remolded soils reveals that the addition of cement significantly improves the seismic performance of the poor soils. The recommended values for the range of variation of the dynamic shear modulus ratio and damping ratio are provided, considering the effect of improvement. These research findings provide reference guidelines for seismic design and engineering sites.

Nanoparticle-assisted Targeting Delivery Technologies for Preventing Organ Rejection.

Although organ transplantation is a life-saving medical procedure, the challenge of posttransplant rejection necessitates safe and effective immune modulation strategies. Nanodelivery approaches may have the potential to overcome the limitations of small-molecule immunosuppressive drugs, achieving efficacious treatment options for transplant tolerance without compromising overall host immunity. This review highlights recent advances in biomaterial-assisted formulations and technologies for targeted nanodrug delivery with transplant organ- or immune cell-level precision for treating graft rejection after transplantation. We provide an overview of the mechanism of transplantation rejection, current clinically approved immunosuppressive drugs, and their relevant limitations. Finally, we discuss the targeting principles and advantages of organ- and immune cell-specific delivery technologies. The development of biomaterial-assisted novel therapeutic strategies holds considerable promise for treating organ rejection and clinical translation.

Association of hypertension and depression with mortality: an exploratory study with interaction and mediation models.

BACKGROUND: The association of hypertension and depression with mortality has not been fully understood. We aimed to explore the possible independent or joint association of hypertension and depression with mortality. Their interaction effects on mortality and possible mediating role were also investigated. METHODS: Associations of hypertension, depression, and their interaction with all-cause and cardiovascular disease (CVD) mortality were evaluated using multivariate Cox proportional hazards regression models. The mediation analysis was conducted with a Sobel test. RESULTS: A total of 35152 participants were included in the final analysis. Hypertension and depression were independently associated with increased risk of all-cause and CVD mortality. The co-existence of hypertension and depression resulted in a 1.7-fold [95% confidence interval (CI): 1.3-2.1] increase in all-cause mortality and a 2.3-fold (95% CI: 1.4-3.7) increase in CVD mortality compared to those with neither of them. Hypertension and depression showed no significant multiplicative (P for interaction, 0.587) and additive interaction (P for relative excess risk of interaction, 0.243; P for Interaction on additive scale, 0.654) on all-cause mortality, as well as on CVD mortality. Depression did not mediate the relationship between hypertension and all-cause (Z=1.704, P=0.088) and CVD mortality (Z=1.547, P=0.122). Hypertension did not mediate the relationship between all-cause and CVD mortality as well. CONCLUSION: Hypertension and depression were related to all-cause and CVD mortality independently and the co-existence of them increased the risk of mortality. However, there is no interaction effect of them on mortality, and hypertension or depression did not mediate the association of each other with mortality.

The effects of health risk behaviors to excess mortality in the population with depression: A cohort study based on NHANES data.

BACKGROUND: The population with depression had a considerable excess mortality risk. This increased mortality may be attributed to the biological consequences of depression or the substantial prevalence of health risk behaviors (HRBs). This study aimed to quantify the combined effects of four major HRBs - smoking, excessive alcohol use, physical inactivity, and an unhealthy diet - on excess mortality among depressed individuals. METHODS: This study included 35,738 adults from the National Health and Nutrition Examination Survey 2005-06 to 2017-18, with mortality follow-up data censored through 2019. The standardized prevalence of HRBs was calculated for populations with and without depression. Poisson regression models were used to calculate the mortality rate ratio (MRR). Based on model adjusting for socio-demographic factors, the attenuation of MRR was determined after further adjustment for HRBs. RESULTS: A total of 3147 participants were identified as having depression. All HRBs showed a significantly higher prevalence among the population with depression. After adjusting for socio-demographic factors, depression was associated with 1.7 and 1.8 times higher all-cause and cardiovascular disease mortality rate, respectively. Further adjustment for all current HRBs resulted in a 21.9 % reduction in all-cause mortality rate and a 15.4 % decrease in cardiovascular disease mortality rate. LIMITATION: HRBs were reported at a single time point, and we are unable to demonstrate a causal effect. CONCLUSION: At least 1/5 of excess mortality for population with depression was attributable to HRBs. Efforts should be made to address HRBs among population with depression.

Virtual draw of microstructured optical fiber based on physics-informed neural networks.

The implementation of microstructured optical fibers (MOFs) with novel micro-structures and perfect performance is challenging due to the complex fabrication processes. Physics-informed neural networks (PINNs) offer what we believe to be a new approach to solving complex partial differential equations within the virtual fabrication model of MOFs. This study, for what appears to be the first time, integrates the complex partial differential equations and boundary conditions describing the fiber drawing process into the loss function of a neural network. To more accurately solve the free boundary of the fiber's inner and outer diameters, we additionally construct a neural network to describe the free boundary conditions. This model not only captures the evolution of the fiber's inner and outer diameters but also provides the velocity distribution and pressure distribution within the molten glass, thus laying the foundation for a quantitative analysis of capillary collapse. Furthermore, results indicate that the trends in the effects of temperature, feed speed, and draw speed on the fiber drawing process align with actual fabrication conditions, validating the feasibility of the model. The methodology proposed in this study offers what we believe to be a novel approach to simulating the fiber drawing process and holds promise for advancing the practical applications of MOFs.

AMPK activation attenuates central sensitization in a recurrent nitroglycerin-induced chronic migraine mouse model by promoting microglial M2-type polarization.

BACKGROUND: Energy metabolism disorders and neurogenic inflammation play important roles in the central sensitization to chronic migraine (CM). AMP-activated protein kinase (AMPK) is an intracellular energy sensor, and its activation regulates inflammation and reduces neuropathic pain. However, studies on the involvement of AMPK in the regulation of CM are currently lacking. Therefore, this study aimed to explore the mechanism underlying the involvement of AMPK in the central sensitization to CM. METHODS: Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC). Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured. The expression of calcitonin gene-related peptide (CGRP) and cytokines, M1/M2 microglia, and NF-κB pathway activation were detected after the intervention. RESULTS: Repeated NTG injections resulted in a gradual decrease in AMPK protein expression, and the negative regulation of AMPK by increased ubiquitin-like plant homeodomain and RING finger domain 1 (UHRF1) expression may counteract AMPK activation by increasing ADP/ATP. AICAR can reduce the hyperalgesia and pain-like behaviors of CM mice, improve the activity of mice, reduce the expression of CGRP, IL-1ß, IL-6, and TNF-α in the TNC region, and increase the expression of IL-4 and IL-10. Moreover, AMPK in TNC was mainly located in microglia. AICAR could reduce the expression of inducible NO synthase (iNOS) in M1 microglia and increase the expression of Arginase 1 (Arg1) in M2 microglia by inhibiting the activation of NF-κB pathway. CONCLUSIONS: AMPK was involved in the central sensitization of CM, and the activation of AMPK reduced neuroinflammation in NTG-induced CM mice. AMPK may provide new insights into interventions for energy metabolism disorders and neurogenic inflammation in migraine.

Abnormal theta and alpha oscillations in children and adolescents with first-episode psychosis and clinical high-risk psychosis.

BACKGROUND: Cognitive control deficits are one of the main symptoms of psychosis. The basic neural oscillation patterns associated with cognitive control are already present in early adolescence. However, as previous studies have focused on adults with psychosis, it is unclear whether neurobiological impairments in cognitive control are present in children and adolescents with first-episode psychosis (FEP) or clinical high-risk (CHR) state for psychosis. AIMS: To explore the deficits of electroencephalogram related to cognitive control tasks in children and adolescents with FEP and CHR. METHOD: Electroencephalogram was recorded in untreated 48 patients with FEP, 24 patients with CHR and 42 healthy controls aged 10-17 years, while performing the visual oddball task. The N2 amplitude, theta and alpha oscillations were then analysed and compared between groups. RESULTS: There was no significant group difference in N2 amplitude (P = 0.099). All groups showed increased theta and alpha oscillations relative to baseline before the stimulus in the frontal, central, left fronto-central and right fronto-central areas. These changes differed significantly between groups, with the FEP group showing significantly smaller theta (P < 0.001) and alpha (P < 0.01) oscillation than healthy controls. Theta and alpha oscillations in the CHR group did not differ significantly from the FEP group and healthy controls. CONCLUSIONS: These results suggest that neural damage has already occurred in the early stage of psychosis, and that abnormal rhythmic activity of neurons may constitute the pathophysiological mechanism of cognitive dysfunction related to early-onset psychosis.

[Modeling and comfort analysis of arrayed air cushion mattress for pressure ulcer prevention and assisted repositioning].

Assisting immobile individuals with regular repositioning to adjust pressure distribution on key prominences such as the back and buttocks is the most effective measure for preventing pressure ulcers. However, compared to active self-repositioning, passive assisted repositioning results in distinct variations in force distribution on different body parts. This incongruity can affect the comfort of repositioning and potentially lead to a risk of secondary injury, for certain trauma or critically ill patients. Therefore, it is of considerable practical importance to study the passive turning comfort and the optimal turning strategy. Initially, in this study, the load-bearing characteristics of various joints during passive repositioning were examined, and a wedge-shaped airbag configuration was proposed. The airbags coupled layout on the mattress was equivalently represented as a spring-damping system, with essential model parameters determined using experimental techniques. Subsequently, different assisted repositioning strategies were devised by adjusting force application positions and sequences. A human-mattress force-coupled simulation model was developed based on rigid human body structure and equivalent flexible springs. This model provided the force distribution across the primary pressure points on the human body. Finally, assisted repositioning experiments were conducted with 15 participants. The passive repositioning effectiveness and pressure redistribution was validated based on the simulation results, experimental data, and questionnaire responses. Furthermore, the mechanical factors influencing comfort during passive assisted repositioning were elucidated, providing a theoretical foundation for subsequent mattress design and optimization of repositioning strategies.

Bidirectional mode-locked erbium-doped fiber laser based on an all-fiber gold nanofilm saturable absorber.

We demonstrate a bidirectional mode-locked erbium-doped fiber laser by incorporating gold nanofilm as a saturable absorber (SA). The gold nanofilm SA has the advantages of high stability and high optical damage threshold. Besides, the SA exhibits a large modulation depth of 26% and a low saturation intensity of 1.22 MW/cm2 at 1.56 µm wavelength band, facilitating the mode-locking of bidirectional propagating solitons within a single laser cavity. Bidirectional mode-locked solitons are achieved, with the clockwise pulse centered at 1568.35 nm and the counter-clockwise one at 1568.6 nm, resulting in a slight repetition rate difference of 19 Hz. Moreover, numerical simulations are performed to reveal the counter-propagating dynamics of the two solitons, showing good agreement with the experimental results. The asymmetric cavity configuration gives rise to distinct buildup and evolution dynamics of the two counter-propagating pulses. These findings highlight the advantage of the gold nanofilm SA in constructing bidirectional mode-locked fiber lasers and provide insights for understanding the bidirectional pulse propagation dynamics.

The combined association of adherence to recommended physical activity and glycemic control with depression: an exploratory study with mediation and moderation models.

BACKGROUND: Both physical activity and dysglycemia are associated with depression. However, the combined association of adherence to recommended physical activity (RPA) and glycemic control with depression is unknown. Moreover, the extent to which glycemic control mediates the association between physical activity and depression is not established. METHODS: The sample included 31,302 adults from the National Health and Nutrition Examination Survey 2007-08 to 2017-18. Adherence to RPA for aerobic activity was defined according to the WHO 2020 guidelines. HbA1c was classified as < 5.7%, 5.7-6.4%, 6.5-6.9%, and ≥ 7.0%. Depression was evaluated according to the 9-item Patient Health Questionnaire. The odds ratio for depression stratified by adherence to RPA and HbA1c level were estimated by logistic regressions. Mediation analysis was performed to estimate the direct associations (not through glycemic control) and indirect associations (through glycemic control). RESULTS: A total of 2871 participants were diagnosed with depression. Compared to participants with HbA1c level < 5.7% who adhere to RPA, those with HbA1c level < 5.7%, 5.7-6.4%, 6.5-6.9%, and ≥ 7.0% who did not adhere to RPA had increased odds ratio for depression, especially in women and older adults. Individuals with HbA1c ≥ 7.0% still had an increased odds ratio for depression even though they were physically active. The results of the mediation analysis were insignificant. CONCLUSION: There was a combined association of adherence to RPA and glycemic control with depression in women and older adults. We did not find out evidence of glycemic control mediation on the pathway from physical activity to depression.

Value of P300 amplitude in the diagnosis of untreated first-episode schizophrenia and psychosis risk syndrome in children and adolescents.

BACKGROUND: Identifying the characteristic neurobiological changes of early psychosis is helpful for early clinical diagnosis. However, previous studies on the brain electrophysiology of children and adolescents with psychosis are rare. METHODS: This study compared P300 amplitude at multiple electrodes between children and adolescents with first-episode schizophrenia (FES, n = 48), children and adolescents with psychosis risk syndrome (PRS, n = 24), and healthy controls (HC, n = 30). Receiver operating characteristic (ROC) analysis was used to test the ability of P300 amplitude to distinguish FES, PRS and HC individuals. RESULTS: The P300 amplitude in the FES group were significantly lower than those in the HC at the Cz, Pz, and Oz electrodes. The P300 amplitude was also significantly lower in the prodromal group than in the HC at the Pz and Oz electrodes. ROC curve analysis showed that at the Pz electrode, the P300 amplitude evoked by the target and standard stimulus showed high sensitivity, specificity, accuracy, and area under the curve value for distinguishing FES from HC individuals. CONCLUSIONS: This study found early visual P300 deficits in children and adolescents with FES and PRS, with the exclusion of possible influence of medication and chronic medical conditions, suggesting the value of P300 amplitude for the identification of early psychosis.

Machine learning-based early diagnosis of autism according to eye movements of real and artificial faces scanning.

Background: Studies on eye movements found that children with autism spectrum disorder (ASD) had abnormal gaze behavior to social stimuli. The current study aimed to investigate whether their eye movement patterns in relation to cartoon characters or real people could be useful in identifying ASD children. Methods: Eye-tracking tests based on videos of cartoon characters and real people were performed for ASD and typically developing (TD) children aged between 12 and 60 months. A three-level hierarchical structure including participants, events, and areas of interest was used to arrange the data obtained from eye-tracking tests. Random forest was adopted as the feature selection tool and classifier, and the flattened vectors and diagnostic information were used as features and labels. A logistic regression was used to evaluate the impact of the most important features. Results: A total of 161 children (117 ASD and 44 TD) with a mean age of 39.70 ± 12.27 months were recruited. The overall accuracy, precision, and recall of the model were 0.73, 0.73, and 0.75, respectively. Attention to human-related elements was positively related to the diagnosis of ASD, while fixation time for cartoons was negatively related to the diagnosis. Conclusion: Using eye-tracking techniques with machine learning algorithms might be promising for identifying ASD. The value of artificial faces, such as cartoon characters, in the field of ASD diagnosis and intervention is worth further exploring.

Over 50 W all-fiber mid-infrared supercontinuum laser.

Broadband supercontinuum laser sources in the mid-infrared region have attracted enormous interest and found significant applications in spectroscopy, imaging, sensing, defense, and security. Despite recent advances in mid-infrared supercontinuum laser sources using infrared fibers, the average power of those laser sources is limited to 10-watt-level, and further power scaling to over 50 W (or hundred-watt-level) remains a significant technological challenge. Here, we report an over 50 W all-fiber mid-infrared supercontinuum laser source with a spectral range from 1220 to 3740 nm, by using low loss (<0.1 dB/m) fluorotellurite fibers we developed as the nonlinear medium and a tilted fusion splicing method for reducing the reflection from the fluorotellurite-silica fiber joint. Furthermore, the scalability of all-fiber mid-infrared supercontinuum laser sources using fluorotellurite fibers is analyzed by considering thermal effects and optical damage, which verifies its potential of power scaling to hundred-watt-level. Our results pave the way for realizing all-fiber hundred-watt-level mid-infrared lasers for real applications.

Investigation on low-loss hollow-core anti-resonant terahertz fiber.

In this work, a hollow-core anti-resonant terahertz (THz) fiber with elliptical cladding and nested tubes is proposed and fabricated. It is an effective way to reduce the loss of THz waves by transmitting them in an air core and breaking the material absorption. After parameter optimization of the initial structure, multiple transmission windows exist in the 0.2-0.8 THz band, where confinement loss is as low as 3.47×10-3cm-1 at 0.8 THz. At 0.2-0.7 THz, confinement losses lie between 10-3 and 10-2cm-1. The 3D printed samples are characterized by a THz time-domain spectroscopy system. Experimental results showed that the designed fiber structure transmits loss coefficients up to 10-2cm-1 in the 0.2-0.8 THz band (the minimum value is located at 0.46 THz, corresponding to a loss coefficient of 0.0284cm-1). The experiments show that the designed THz fiber achieves a good transmission effect.

Numerical simulation modeling and kinematic analysis onto double wedge-shaped airbag of nursing appliance.

In previous studies, the numerical modeling and analyzing methods onto industrial or vehicle airbags dynamics were revealed to have high accuracy regarding their actual dynamic properties, but there are scarcely airbag stiffness modeling and comfortableness investigations of nursing cushion or mattress airbags. This study constructs a numerical model illustrating the association between the stiffness property and the internal gas mass of the wedge-shaped airbag of nursing appliance, and then the airbag stiffness variation discipline is described based on various inflation volumes. To start with, based on an averaged pressure prerequisite, a dynamic simulation model of the wedge-shaped airbag is established by the fluid cavity approach. For this modeling, the elastic mechanical behaviors of airbag material are determined according to a material constitutive model built by the quasi-static uniaxial tensile test. Besides, verification experiments clarify that the presented modeling method is accurate for airbag stiffness behavior prediction, and then can be effectively applied into design and optimization phases of wedge-shaped airbags. Ultimately, based on the simulation and experimental results, it is found that the wedge-shaped airbag stiffness exhibits a three stages characteristic evolution with the gas mass increase. Then the mathematical relationship between the airbag stiffness and gas mass is obtained by numerical fitting, which provides a vital basis for structural optimization and differentiated control of nursing equipment airbags.

Tuina Manipulation to Reduce Inflammation and Cartilage Loss in Knee Osteoarthritis Rats.

Clinical trials suggest that Tuina manipulation is effective in treating knee osteoarthritis (KOA), while further studies are required to discover its mechanism. Therefore, the manipulation of animal models of knee osteoarthritis is critical. This protocol provides a standard process for Tuina manipulation on KOA rats and a preliminary exploration of the mechanism of Tuina for KOA. The press and kneading manipulation method (a kind of Tuina manipulation that refers to pressing and kneading the specific area of the body surface) is applied on 5 acupoints around the knee joint of rats. The force and frequency of the manipulation were standardized by finger pressure recordings, and the position of the rat during manipulation is described in detail in the protocol. The effect of manipulation can be measured by pain behavior tests and microscopic findings in synovial and cartilage. KOA rats showed significant improvement in pain behavior. The synovial tissue inflammatory infiltration was reduced in the Tuina group, and the expression of tumor necrosis factor (TNF)-α was significantly lower. Compared to the control group, chondrocyte apoptosis was less in the Tuina group. This study provides a standardized protocol for Tuina manipulation on KOA rats and preliminary proof that the therapeutic effects of Tuina may be related to reducing synovial inflammation and delayed chondrocyte apoptosis.