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Background: Diclofenac diethylamine (DDEA) gel has demonstrated efficacy for treatment of ankle sprains in both the 1.16% four-times-daily (QID) and 2.32% twice-daily (BID) formulations. The objective of this study was to compare, for the first time, the efficacy of DDEA 2.32% gel BID and DDEA 1.16% gel QID. Methods: This was a phase 3, randomized, double-blind, multicenter, active-controlled, parallel-group study conducted in China from October 2019 to November 2020, designed to determine the noninferiority of DDEA 2.32% gel BID relative to DDEA 1.16% gel QID for treatment of grade I–II ankle sprain. At study entry, patients must have had pain on movement (POM) ≥50 mm on a 100-mm visual analogue scale (VAS), and not received any pain medication. The primary efficacy endpoint was the noninferiority of DDEA 2.32% gel BID vs DDEA 1.16% gel QID for POM as assessed by the patient using the 100-mm VAS, conducted on day 5. Secondary endpoints included measures of ankle tenderness, joint function, swelling, and patient-reported pain intensity and pain relief. Results: A total of 302 patients were randomized and 95.4% completed the study. The mean (SD) change in POM from baseline to day 5 using the 100-mm VAS was − 42.8 mm (19.7 mm) with DDEA 2.32% gel BID and − 43.1 mm (18.1 mm) with DDEA 1.16% gel QID for the per-protocol population. The least squares mean difference (DDEA gel 2.32% – DDEA gel 1.16%) at this timepoint was 1.11 mm (95% CI − 3.00, 5.22; P = 0.595), and the upper limit (5.22 mm) of the 95% CI was less than the noninferiority margin of 13 mm, demonstrating that DDEA 2.32% gel BID was noninferior to DDEA 1.16% gel QID. Similar trends were seen for the secondary efficacy endpoints. There was no significant difference in the incidence of treatment-emergent adverse events or adverse events adjudicated as being treatment related. All treatment-related adverse events were dermatological; one patient discontinued from the DDEA 2.32% gel BID arm due to application-site inflammation. Conclusions: DDEA 2.32% gel BID offers a convenient alternative to DDEA 1.16% gel QID, with similar pain reduction and relief, anti-inflammatory effects, and tolerability. Trial registration: NCT04052620. [ABSTRACT FROM AUTHOR]

Noise-induced tipping from a low-amplitude oscillation state to a high-amplitude one is widespread in airfoil systems. Its occurrence may cause fatigue damage to the wing structure of an aircraft, which directly threatens its flight safety. Therefore, it is of utmost importance to predict the occurrence of noise-induced high-amplitude oscillations as the system parameters vary in airfoil systems. Taking a two-degrees-of-freedom airfoil model with random loadings as a prototype class of real systems, the prediction of noise-induced tipping from low-amplitude to high-amplitude oscillations is carried out in the present study. First, we analyze the effects of random fluctuations on the system response. The results show that noise-induced catastrophic high-amplitude oscillations take place before the bifurcation point of the corresponding deterministic airfoil model. Subsequently, the possibility that the low-amplitude oscillation state of the given noisy model jumps to the high-amplitude one is analyzed based on the escape probability. Then, the new concept of the high-risk region is defined. This is an efficient early warning indicator to approximately quantify the ranges of the system parameters where noise-induced high-amplitude oscillations may occur. Compared with the existing early warning indicators, this method is a non-local universal concept of stability. More importantly, it may provide theoretical guidance for aircraft designers to take some measures to avoid such catastrophic critical jump phenomena in practical engineering applications. [ABSTRACT FROM AUTHOR]

In stochastic complex systems, some sudden critical transitions (CTs) from one desirable state to another contrasting one can take place because of noise, which may even lead to catastrophic consequences. To keep a certain system in one desirable state of performance, methods that suppress these catastrophic CTs in the presence of noise need to be developed. In this paper, the ability of an external linear augmentation method to suppress Gaussian white noise-induced CTs away from a desirable state is investigated from a new perspective. This control is designed in such a way that, as a noise-induced CT is impending, the desirable state of performance in a stochastic complex system can be stabilized using a specific type of coupling with a linear dynamical system. Then, the contrasting state is annihilated with increasing coupling strength. Taking a bi-stable system with one CT (from the desirable state to the undesirable one) and a tri-stable system with two CTs (from the desirable state to the sub-desirable one and from the sub-desirable state to the undesirable one) as the prototype class of real complex systems, the potential of our technique is demonstrated. [ABSTRACT FROM AUTHOR]

Background: The coronavirus disease 2019 (COVID-19) rapidly spreads worldwide and causes more suffering. The relation about the aggravation of inguinal pain and COVID-19 was unclear in patients with total hip arthroplasty (THA). This study aimed to evaluate the risk of groin pain aggravation in short-term THA patients after COVID-19. Methods: Between 2020 and 2022, 129 patients with THA who were affected COVID-19 were enrolled. A short-standardized questionnaire was administered during follow-up to inquire about the aggravation of groin ache before and after SARS-COV-2 affection. Furthermore, we evaluated the potential association between the presence of increased pain and various factors, including age, gender, body mass index, diagnosis, and length of hospital stay. Results: The case-crossover study revealed an increased risk of inguinal soreness aggravation when comparing 8 weeks after COVID-19 with 12 weeks before COVID-19 (Relative risk [RR], 9.5; 95% Confidence intervals [CI], 2.259–39.954). For COVID-19 positive patients, multivariate analysis showed length of stay was an independent factor significantly associated with increased risk of aggravation of groin pain (Odds ratio [OR], 1.26; 95%CI, 1.03–1.55, p = 0.027). Conclusion: This study confirms the association between COVID-19 and the exacerbation of soreness in the groin region in THA patients and extended length of stay is a possible contributing factor. This study expands the current literature by investigating the risk of aggravation of inguinal pain in patients with THA after COVID-19, providing valuable insights into postoperative outcomes in this specific population. Trial registration This retrospective study was approved by the Institutional Review Board of Shanghai general hospital (No.2023-264). [ABSTRACT FROM AUTHOR]

Considering that random fluctuations can affect the rolling process of cold rolling mills, leading to abnormal cold mill performance and defects in the rolled product. Therefore, it is crucial to study the influence of random fluctuations on the system of cold rolling mills. In this paper, taking a model of the vertical vibration of a four-roller cold rolling mill under harmonic excitation as a prototype class for a real system, the effects of random fluctuations on the system response are analyzed. Firstly, based on the deterministic vertical vibration model of a four-roller cold rolling mill under harmonic excitation, a stochastic vertical vibration model of a four-roller cold rolling mill with random fluctuation as Gaussian white noise is introduced. Subsequently, the vertical vibration model of a four-roller rolling mill is theoretically analyzed by the averaging method and the stochastic averaging method, respectively. The effectiveness of the proposed theoretical method is verified by numerical simulation results, and the influences of harmonic excitation and random excitation on the system response are also investigated in detail. Finally, the results show that the noise induces the occurrence of stochastic transitions and bifurcations, and the steady-state probability density function and time history diagrams are given to further explain the existence of these dynamic phenomena. The related research can provide theoretical guidance for the realization of vibration control and reliability design in the four-roller cold rolling mill system. • Approximate analytical solutions are deduced by the stochastic averaging method. • Numerical simulations are conducted to verify results of theoretical analysis, and influences for amplitude of harmonic excitation and noisy parameters are explored. • Stochastic transitions and bifurcations are observed. [ABSTRACT FROM AUTHOR]

Periprosthetic osteolysis (PPO) along with aseptic loosening (AL) caused by wear particles after artificial joint replacement is the key factor in surgical failure and subsequent revision surgery, however, the precise molecular mechanism underlying PPO remains unclear. Aseptic inflammation triggered by metal particles, resulting in the imbalance between bone formation by osteoblasts and bone resorption by osteoclasts may be the decisive factor. Pyroptosis is a new pro-inflammatory pattern of regulated cell death (RCD), mainly mediated by gasdermins (GSDMs) family, among which GSDMD is the best characterized. Recent evidence indicates that activation of NLRP3 inflammasomes and pyroptosis play a pivotal role in the pathological process of PPO. Here, we review the pathological process of PPO, the molecular mechanism of pyroptosis and the interventions to inhibit the inflammation and pyroptosis of different cells during the PPO. Conclusively, this review provides theoretical support for the search for new strategies and new targets for the treatment of PPO by inhibiting pyroptosis and inflammation. [ABSTRACT FROM AUTHOR]

Osteoarthritis is a highly prevalent joint disease; however, effective treatments are lacking. Protopine (PTP) is an isoquinoline alkaloid with potent anti-inflammatory and antioxidant properties; however, it has not been studied in osteoarthritis. This study aimed to investigate whether PTP can effectively protect chondrocytes from ferroptosis. Primary mouse chondrocytes were treated with tert -butyl hydroperoxide (TBHP) to simulate oxidative stress in an in vitro model of osteoarthritis. Two concentrations of PTP (10 and 20 μg/mL) were validated for in vitro experiments. Cellular inflammation and metabolism were detected using RT-qPCR and western blotting (WB). Ferroptosis was assessed via WB, qPCR, reactive oxygen species (ROS) levels, lipid ROS, and immunofluorescence staining. In vitro, PTP significantly ameliorated chondrocyte inflammation and cytolytic metabolism and significantly suppressed chondrocyte ferroptosis through the activation of the Nrf2 pathway. The anterior cruciate ligament transection (ACLT) mouse model was used to validate the in vivo effects of PTP. The joint cartilage was assessed using the Osteoarthritis Research Society International (OARSI) score, Safranin O staining, and immunohistochemistry. The intra-articular administration of PTP alleviated cartilage inflammation and ferroptosis, as evidenced by the expression of MMP3, MMP13, COL2A1, GPX4, and Nrf2. Overall, we find that PTP exerted anti-ferroptosis and anti-inflammatory effects on chondrocytes to protect the articular cartilage. • PTP is an isoquinoline alkaloid with anti-inflammatory and antioxidant properties. • PTP significantly ameliorated chondrocyte inflammation and ferroptosis. • Repression of chondrocyte ferroptosis was mediated by activating the Nrf2 pathway. • PTP exerts these effects on chondrocytes to protect the articular cartilage. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a chronic joint disorder that causes cartilage degradation and subchondral bone abnormalities. Nangibotide, also known as LR12, is a dodecapeptide with considerable anti-inflammatory properties, but its significance in OA is uncertain. The aim of the study was to determine whether nangibotide could attenuate the progression of OA, and elucidate the underlying mechanism. In vitro experiments showed that nangibotide strongly inhibited TNF-α-induced osteogenic reduction, significantly enhanced osteoblast proliferation and prevented apoptosis in MC3T3-E1 cells. Male C57BL/6 J mice aged 2 months were randomly allocated to three groups: sham, ACLT, and ACLT with nangibotide therapy. Nangibotide suppressed ACLT-induced cartilage degradation and MMP-13 expression. MicroCT analysis revealed that nangibotide attenuated in vivo subchondral bone loss induced by ACLT. Histomorphometry results showed that nangibotide attenuated ACLT-induced osteoblast inhibition; TUNEL assays and immunohistochemical staining of cleaved-caspase3 further confirmed the in vivo anti-apoptotic effect of nangibotide on osteoblasts. Furthermore, we found that nangibotide exerted protective effects by suppressing TGF-β signaling mediated by Smad2/3 to restore coupled bone remodeling in the subchondral bone. In conclusion, the findings suggest that nangibotide might exert a protective effect on the bone-cartilage unit and maybe an alternative treatment option for OA. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is widely recognized as the most common chronic joint disease accompanied by progressive cartilage and subchondral bone damage. Toddalolactone (TOD), a natural compound extracted from Toddalia asiatica (L.) Lam., has been widely used in the treatment of stroke, rheumatoid arthritis, and oedema. Nevertheless, what TOD acts as in the pathogenesis and progression of OA hasn't been reported. In this investigation, we have aimed to determine how TOD affects OA in vitro and in vivo. Methods: LPS (10 µg/ml) and IL-1β (10 ng/ml) were employed to induce chondrocyte inflammation or RANKL to induce osteoclast differentiation in bone marrow derived macrophages (BMMs). The effects of TOD on chondrocyte inflammation and osteoclast differentiation were evaluated. Anterior cruciate ligament transection (ACLT) was performed to develop an OA animal model and study the effects of TOD. Results: We found that TOD inhibited the expression of inflammatory and catabolic mediators (IL-6, IL-8, TNF-α, MMP2, MMP9, and MMP13) in inflammatory chondrocytes in vitro. Furthermore, TOD was proven to inhibit RANKL-induced-osteoclastogenesis and inhibit the expression of osteoclast marker genes. Our data also confirmed that TOD suppressed the destruction of articular cartilage and osteoclastogenesis via inhibiting the activation of NF-κB and MAPK signalling pathways. In the ACLT mouse model, we found that TOD attenuated cartilage erosion and inhibited bone resorption. Conclusions: These results showed that TOD can be adopted as a potential therapeutic agent for OA. [ABSTRACT FROM AUTHOR]

Objectives: Aseptic loosening (AL) is the most common reason of total hip arthroplasty (THA) failure and revision surgery. Osteolysis, caused by wear particles released from implant surfaces, has a vital role in AL. Although previous studies suggest that wear particles always lead to osteoblast programmed death in the process of AL, the specific mechanism remains incompletely understood and osteoblast ferroptosis maybe a new mechanism of AL. Materials and Methods: CoCrMo nanoparticles (CoNPs) were prepared to investigate the influence of ferroptosis in osteoblasts and calvaria resorption animal models. Periprosthetic osteolytic bone tissue was collected from patients who underwent AL after THA to verify osteoblast ferroptosis. Results: Our study demonstrated that CoNPs induced significant ferroptosis in osteoblasts and particles induced osteolysis (PIO) animal models. Blocking ferroptosis with specific inhibitor Ferrostatin‐1 dramatically reduced particle‐induced ferroptosis in vitro. Moreover, in osteoblasts, CoNPs significantly downregulated the expression of Nrf2 (nuclear factor erythroid 2‐related factor 2), a core element in the antioxidant response. The overexpression of Nrf2 by siKeap1 or Nrf2 activator Oltipraz obviously upregulated antioxidant response elements (AREs) and suppressed ferroptosis in osteoblasts. Furthermore, in PIO animal models, the combined utilization of Ferrostatin‐1 and Oltipraz dramatically ameliorated ferroptosis and the severity of osteolysis. Conclusions: These results indicate that CoNPs promote osteoblast ferroptosis by regulating the Nrf2‐ARE signalling pathway, which suggests a new mechanism underlying PIO and represents a potential therapeutic approach for AL. [ABSTRACT FROM AUTHOR]

[Display omitted] • CoP-challenged macrophages can accelerate osteoclastogenesis. • CoPs result in macrophages pyroptosis and release of inflammatory cytokines. • CoPs stimulation promotes ROS accumulation and subsequently activates NLRP3. • High-concentration CoPs suppress mitophagy, further enhancing macrophages pyroptosis. • By promoting mitophagy and inhibiting NLRP3, CoP-induced osteolysis can be delayed. Wear particles derived from implant surfaces are the important factors causing periprosthetic osteolysis (PPO), which is the main reason for total joint revision. To date, the specific pathogenesis of PPO remains largely unknown, and developing new therapeutic strategies is urgently necessary. Our study indicated the most clinically common cobalt- chromium-molybdenum (CoCrMo) wear particles (CoPs) activated macrophages and further accelerated osteoclastogenesis. Subsequently, we put emphasis on the pathologic change in macrophages after CoPs stimulation. Meaningfully, high-concentration CoPs induced reactive oxygen species (ROS) accumulation in macrophages and activated NOD-like receptor pyrin domain-containing 3 (NLRP3)-dependent pyroptosis, promoting the release of cytokines such as IL-18, IL-1β and HMGB1, and subsequent formation of extracellular inflammatory microenvironment, which is crucial for osteoclastogenesis. More interestingly, transmission electron microscopy and flow cytometry results revealed that there were accumulation of endamaged mitochondria in high-concentration CoP-challenged macrophages, which accelerated intracellular ROS accumulation and mediated NLRP3-dependent pyroptosis. Mechanismly, high-concentration CoPs induced macrophage mitophagy impairment and the loss of mitochondrial membrane potential via inhibiting PINK1/Parkin signalling pathway. Furthermore, by subcutaneous injection of salidroside and/or CY-09 in situ significantly delayed CoP-induced mice calvaria osteolysis. Collectively, this study demonstrates a novel mechanism underlying the pathogenesis of PPO and provides a potential therapy avenue. [ABSTRACT FROM AUTHOR]

We aimed to identify RNA N6-methyladenosine methylation associated genes in osteoarthritis (OA), and to explore possible regulatory mechanisms of these RNA methylation associated genes. Bioinformatics analyses, including differential expression analysis, functional enrichment analysis, verification analysis, and box plot analysis, were conducted based on different datasets from OA and non-OA patients. Gene expression at mRNA and protein levels was determined by quantitative reverse transcription PCR, western blot and immunofluorescence. Interleukin 1β (IL-1β)-treated SW1353 cells was used as cell model. Lentiviral vector was used for over-expression METTL3 in vitro. CCK-8 assay kit was used to determine cell viability and inflammatory cytokines (IL-1α, IL-6, IL-8, IL-10 and TNF-α) was detected using ELISA kits. Bioinformatics analysis showed that METTL3 expression was decreased in OA group, which was confirmed in clinical samples. Expression of METTL3 was also reduced in IL-1β-treated cells. Levels of inflammatory cytokines were obviously reduced in the METTL3 overexpression group, while IL-1β treatment reversed such decrease caused by METTL3 overexpression (p < 0.05). Both METTL3 overexpression and IL-1β treatment promoted expression of p65 protein and p-ERK (p < 0.01). Additionally, increased expression of MMP1 and MMP3 , and decreased expression of MMP13 , TIMP-1 , and TIMP-2 at both mRNA and protein levels were observed in the METTL3 overexpression group when compared with the control group (p < 0.01). Expression of m6A methylation gene METTL3 was reduced in OA. METTL3 is involved in OA probably by regulating the inflammatory response. METTL 3 overexpression may affect extracellular matrix degradation in OA by adjusting the balance between TIMPs and MMPs. • METTL3 and YTHDC2 were identified as m6A methylation-related genes in OA. • METTL3 may be involved in OA by regulating the inflammatory response. • METTL3 overexpression may affect ECM degradation in OA. [ABSTRACT FROM AUTHOR]