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Although hand synovitis is prevalent in the older population, the etiology remains unclear. Hyperuricemia, a modifiable metabolic disorder, may serve as an underlying mechanism of hand synovitis, but little is known about their relationship. We assessed the association between hyperuricemia and hand synovitis in a large population‐based sample. We performed a cross‐sectional study in Longshan County, Hunan Province, China. Hyperuricemia was defined as a serum urate level >420 μmol/L in men and >360 μmol/L in women. Ultrasound examinations were performed on both hands of 4,080 participants, and both gray‐scale synovitis and the Power Doppler signal (PDS) were assessed using semiquantitative scores (grades 0–3). We evaluated the association of hyperuricemia with hand gray‐scale synovitis (grade ≥2) and PDS (grade ≥1), respectively, adjusting for age, sex, and body mass index. All required assessments for analysis were available for 3,286 participants. The prevalence of hand gray‐scale synovitis was higher among participants with hyperuricemia (30.0%) than those with normouricemia (23.3%), with an adjusted odds ratio (aOR) of 1.28 (95% confidence interval [CI] 1.00–1.62). Participants with hyperuricemia also had a higher prevalence of PDS (aOR 2.36; 95% CI 1.15–4.81). Furthermore, hyperuricemia positively associated, both at the hand and joint levels, with the presence of gray‐scale synovitis (aOR 1.27; 95% CI 1.00–1.60 and adjusted prevalence ratio [aPR] 1.26; 95% CI 1.10–1.44, respectively) and PDS (aOR 2.35; 95% CI 1.15–4.79 and aPR 2.34; 95% CI 1.28–4.30, respectively). This population‐based study provides more evidence for a positive association between hyperuricemia and prevalent hand synovitis.

Synovial abnormalities, which are modifiable treatment targets for knee pain, affect ~25% of adults. Ultrasound is a safe, inexpensive, and easily accessible imaging modality for assessing synovial abnormalities, but its diagnostic accuracy is still controversial. We conducted a meta‐analysis by comparing ultrasound with the “reference standard” method, ie, magnetic resonance imaging (MRI), in assessing synovial abnormalities among patients with knee pain. PubMed, Embase, and Web of Science were searched from inception to January 7, 2022, to retrieve studies including patients with knee pain for evaluating 1) the diagnostic accuracy of ultrasound versus MRI for synovial abnormalities (synovitis and synovial effusion) and 2) the correlations of synovial abnormalities assessed by ultrasound and MRI. The summary of diagnostic accuracy was analyzed using the bivariate model, and the correlation coefficients were pooled using the random effects model. Fourteen studies were included, representing a total of 755 patients. The pooled sensitivity, specificity, and area under the curve were 0.88 (95% confidence interval [95% CI] 0.65–0.96), 0.70 (95% CI 0.51–0.84), and 0.81 (95% CI 0.77–0.84) for synovitis and 0.90 (95% CI 0.81–0.95), 0.86 (95% CI 0.77–0.92), and 0.94 (95% CI 0.91–0.96) for synovial effusion, respectively. Strong correlations between ultrasound‐ and MRI‐diagnosed synovitis (r = 0.64, 95% CI 0.56–0.71) and synovial effusion (r = 0.63, 95% CI 0.52–0.73) were observed. Ultrasound demonstrated a promising accuracy in detecting synovial abnormalities among patients with knee pain. The use of ultrasound provides equivalent synovial information to MRI but is less expensive and more accessible. Therefore, it is recommended as an adjuvant for managing patients with knee pain during diagnostic strategy and individualized treatment decision‐making.

Complicated relationships exist in both occurrence and progression of surgical complications, which are difficult to account for using a separate quantitative method such as prediction or grading. Data of 51,030 surgical inpatients were collected from four academic/teaching hospitals in a prospective cohort study in China. The relationship between preoperative factors, 22 common complications, and death was analyzed. With input from 54 senior clinicians and following a Bayesian network approach, a complication grading, cluster-visualization, and prediction (GCP) system was designed to model pathways between grades of complication and preoperative risk factor clusters. In the GCP system, there were 11 nodes representing six grades of complication and five preoperative risk factor clusters, and 32 arcs representing a direct association. Several critical targets were pinpointed on the pathway. Malnourished status was a fundamental cause widely associated (7/32 arcs) with other risk factor clusters and complications. American Society of Anesthesiologists (ASA) score ⩾3 was directly dependent on all other risk factor clusters and influenced all severe complications. Grade III complications (mainly pneumonia) were directly dependent on 4/5 risk factor clusters and affected all other grades of complication. Irrespective of grade, complication occurrence was more likely to increase the risk of other grades of complication than risk factor clusters.

To determine whether patients with rheumatoid arthritis (RA) are at higher risks for SARS–CoV‐2 infection and its severe outcomes before and after COVID‐19 vaccination. Using a UK primary care database, we conducted 2 cohort studies to compare the risks of SARS–CoV‐2 infection, hospitalization, and death from COVID‐19 between patients with RA and the general population according to their COVID‐19 vaccination status. We used exposure score overlap weighting to balance baseline characteristics between 2 comparison cohorts. Among unvaccinated individuals, the weighted incidence rates of SARS–CoV‐2 infection (9.21 versus 8.16 of 1,000 person‐months), hospitalization (3.46 versus 2.14 of 1,000 person‐months), and death (1.19 versus 0.62 of 1,000 person‐months) were higher among patients with RA than the general population over 3 months of follow‐up; the corresponding adjusted hazard ratios (HRs) were 1.10 (95% confidence interval [95% CI] 1.00–1.24), 1.62 (95% CI 1.34–1.96), and 1.88 (95% CI 1.37–2.60), respectively. Among vaccinated individuals, the weighted rates of breakthrough infection (4.17 versus 3.96 of 1,000 person‐months; HR 1.10 [95% CI 1.00–1.20]) and hospitalization (0.42 versus 0.32 of 1,000 person‐months; HR 1.29 [95% CI 0.96–1.75]) were higher among patients with RA than the general population over 9 months of follow‐up; however, no apparent difference in the risk of these outcomes was observed over 3 and 6 months of follow‐up between 2 comparison cohorts. Patients with RA are still at higher risks of SARS–CoV‐2 infection and COVID‐19 hospitalization than the general population after receiving COVID‐19 vaccines. These findings support booster COVID‐19 vaccinations and adherence of other preventive strategies among patients with RA.

Objective Although most frequently used in experimental osteoarthritis (OA) pain induction, intra-articular mono-iodoacetate (MIA) injection lacks concluded references for dose selection and timing of intervention. Herein, we aimed to compare the pain intensity of rats induced by different doses of MIA and explored the trajectory of pain.Design PubMed, Embase, and Web of Science were searched up to June 2021 for literatures involving MIA experiments investigating OA pain. Pain intensity was measured based on weightbearing distribution (WBD) and paw withdrawal thresholds (PWT), and the pain trajectory was constructed by evaluating pain intensity at a series of time points after MIA injection. A conventional meta-analysis was conducted.Results A total of 140 studies were included. Compared with saline, MIA injections caused significantly higher pain intensity for WBD and PWT. Dose-response relationships between different doses of MIA and pain intensity were observed (P-for-trend<0.05). A pronounced increase in pain occurred from day 0 to day 7, but the uptrend ceased between day 7 and day 14, after which the pain intensity continued to rise and reached the maximum by day 28.Conclusions Pain intensity after intra-articular MIA injection increased in a dose-dependent manner and the pain trajectory manifested a specific pattern consistent with the pathological mechanisms of MIA-induced pain, providing possible clues for proper dose selection and timing of specific OA pain interventions.

ObjectiveClinical guidelines recommend exercise as a core treatment for knee or hip osteoarthritis (OA). However, how its analgesic effect compares to analgesics, for example, oral non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol—the most commonly used analgesics for OA, remains unknown.DesignNetwork meta-analysis.Data sourcesPubMed, Embase, Scopus, Cochrane Library and Web of Science from database inception to January 2022.Eligibility criteria for selecting studiesRandomised controlled trials (RCTs) comparing exercise therapy with oral NSAIDs and paracetamol directly or indirectly in knee or hip OA.ResultsA total of n=152 RCTs (17 431 participants) were included. For pain relief, there was no difference between exercise and oral NSAIDs and paracetamol at or nearest to 4 (standardised mean difference (SMD)=−0.12, 95% credibility interval (CrI) −1.74 to 1.50; n=47 RCTs), 8 (SMD=0.22, 95% CrI −0.05 to 0.49; n=2 RCTs) and 24 weeks (SMD=0.17, 95% CrI −0.77 to 1.12; n=9 RCTs). Similarly, there was no difference between exercise and oral NSAIDs and paracetamol in functional improvement at or nearest to 4 (SMD=0.09, 95% CrI −1.69 to 1.85; n=40 RCTs), 8 (SMD=0.06, 95% CrI −0.20 to 0.33; n=2 RCTs) and 24 weeks (SMD=0.05, 95% CrI −1.15 to 1.24; n=9 RCTs).ConclusionsExercise has similar effects on pain and function to that of oral NSAIDs and paracetamol. Given its excellent safety profile, exercise should be given more prominence in clinical care, especially in older people with comorbidity or at higher risk of adverse events related to NSAIDs and paracetamol.CRD42019135166

To examine efficacy and safety of tramadol for knee or hip osteoarthritis (OA). PubMed, Embase, Cochrane Library, and Web of Science were searched up to May 2020 for randomized controlled trials (RCTs) comparing any of the following interventions: tramadol 100 mg/day, 200 mg/day, and 300 mg/day, and placebo for knee or hip OA. Pain and function were measured at or near 12 weeks for efficacy. Gastrointestinal, cardiovascular, and central nervous system (CNS) adverse events (AEs), and withdrawals were measured for safety. Bayesian network meta‐analysis was conducted. Six RCTs (3,611 participants) were included. Tramadol 100 mg/day (standardized mean difference [SMD] –0.16 [95% confidence interval (95% CI) –0.34, 0.00]), 200 mg/day (SMD –0.21 [95% CI –0.37, –0.06]), and 300 mg/day (SMD –0.30 [95% CI –0.48, –0.14]) were statistically more effective than placebo in pain relief, but only tramadol 300 mg/day was better than placebo in functional improvement (SMD –0.24 [95% CI –0.47, –0.03]). Tramadol 100 mg/day (relative risk [RR] 2.29 [95% credible interval (CrI) 1.22, 4.25]), 200 mg/day (RR 4.35 [95% CrI 2.31, 8.01]), and 300 mg/day (RR 6.02 [95% CrI 3.22, 11.1]) involved a higher risk of gastrointestinal AEs. Similarly, tramadol 100–300 mg/day showed a higher risk of CNS AEs and withdrawals. However, the risk of cardiovascular AEs remained unclear. Only tramadol 300 mg/day showed minimal improvement in pain and function but with increasing AEs compared with placebo. Tramadol may not be sufficiently recommended for knee or hip OA based on the presented evidence, especially in patients with the risk of gastrointestinal and CNS AEs.

Several studies have examined gut microbiota and sarcopenia using 16S ribosomal RNA amplicon sequencing; however, this technique may not be able to identify altered specific species and functional capacities of the microbes. We performed shotgun metagenomic sequencing to compare the gut microbiome composition and function between individuals with and without sarcopenia. Participants were from a community‐based observational study conducted among the residents of rural areas in China. Appendicular skeletal muscle mass was assessed using direct segmental multi‐frequency bioelectrical impedance and grip strength using a Jamar Hydraulic Hand dynamometer. Physical performance was evaluated using the Short Physical Performance Battery, 5‐time chair stand test and gait speed with the 6 m walk test. Sarcopenia and its severity were diagnosed according to the Asian Working Group for Sarcopenia 2019 algorithm. The gut microbiome was profiled by shotgun metagenomic sequencing to determine the microbial composition and function. A gut microbiota‐based model for classification of sarcopenia was constructed using the random forest model, and its performance was assessed using the area under receiver‐operating characteristic curve (AUC). The study sample included 1417 participants (women: 58.9%; mean age: 63.3 years; sarcopenia prevalence: 10.0%). β‐diversity indicated by Bray–Curtis distance (genetic level: P= 0.004; taxonomic level of species: P= 0.020), but not α‐diversity indicated by Shannon index (genetic level: P= 0.962; taxonomic level of species: P= 0.922), was significantly associated with prevalent sarcopenia. After adjusting for potential confounders, participants with sarcopenia had higher relative abundance of Desulfovibrio piger(P= 0.003, Q = 0.090), Clostridium symbiosum(P< 0.001, Q = 0.035), Hungatella effluvii(P= 0.003, Q = 0.090), Bacteroides fluxus(P= 0.002, Q = 0.089), Absiella innocuum(P= 0.002, Q = 0.072), Coprobacter secundus(P= 0.002, Q = 0.085) and Clostridium citroniae(P= 0.001, Q = 0.060) than those without sarcopenia. The relative abundance of six species (Desulfovibrio piger, Clostridium symbiosum, Hungatella effluvii, Bacteroides fluxus, Absiella innocuum, and Clostridium citroniae) was also positively associated with sarcopenia severity. A differential species‐based model was constructed to separate participants with sarcopenia from controls. The value of the AUC was 0.852, suggesting that model has a decent discriminative performance. Desulfovibrio pigerranked the highest in this model. Functional annotation analysis revealed that the phenylalanine, tyrosine, and tryptophan biosynthesis were depleted (P= 0.006, Q = 0.071), while alpha‐Linolenic acid metabolism (P= 0.008, Q = 0.094), furfural degradation (P= 0.001, Q = 0.029) and staurosporine biosynthesis (P= 0.006, Q = 0.072) were enriched in participants with sarcopenia. Desulfovibrio pigerwas significantly associated with staurosporine biosynthesis (P< 0.001). This large population‐based observational study provided empirical evidence that alterations in the gut microbiome composition and function were observed among individuals with sarcopenia.

Synovitis has long been considered a common and modifiable inflammatory feature of osteoarthritis (OA), but current disease-modifying anti-inflammatory treatments appear ineffective in OA clinical trials. Elucidating the temporal relationship between synovitis and OA could provide insight into the role of synovitis in OA.

We aimed to: (1) perform a nationwide trend analysis of staggered and simultaneous bilateral knee arthroplasty (KA); (2) investigate patient demographics and hospital characteristics in two groups; and (3) compare the outcomes of two groups with a focus on complications, length of stay (LOS) and hospitalization costs.

Patients with rheumatoid arthritis (RA) are at an increased risk of acquiring infections owing to immunologic dysfunction and use of potent immunomodulatory medications; however, few data are available on their risk of COVID‐19. We estimated the rate of COVID‐19 among RA participants and compared it with that of the general population. Using the Health Improvement Network, we identified RA patients before February 2020 and followed them to September 2020. We calculated the rate of COVID‐19 among participants with RA and compared it with that of the general population using a Cox proportional hazards model, adjusting for potential confounders using overlap weighting of exposure score. We repeated the same analysis among participants with osteoarthritis, a nonautoimmune rheumatic disease, as a negative control exposure. We identified 225 cases of suspected and confirmed COVID‐19 among 17,268 RA patients, and 14,234 cases among 1,616,600 participants in the general population (1.4 versus 0.9/1,000 person‐months), with the adjusted hazard ratio (HRadj) being 1.19 (95% confidence interval [95% CI] 1.04–1.36). Confirmed COVID‐19 cases developed in 46 RA participants and in 2,249 in the general population (0.3 versus 0.1/1,000 person‐months), with the HRadjbeing 1.42 (95% CI 1.01–1.95). No statistically significant difference was observed for suspected and confirmed (HR 1.00 [95% CI 0.93–1.07]) or confirmed (HR 1.08 [95% CI 0.92–1.27]) COVID‐19 rates between participants with osteoarthritis and the general population. RA, but not osteoarthritis, was associated with an increased risk of COVID‐19. Our findings provide timely evidence to support recommendations that booster vaccines and priority access to anti–SARS–CoV‐2 monoclonal antibody treatments should be encouraged for RA patients.

Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis (OA). In this study, we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modifying OA drugs (DMOADs). Specifically, human bone marrow-derived mesenchymal stromal cells (MSCs) were expanded in vitroup to passage 10 (P10-MSCs). Following their senescent phenotype formation, P10-MSCs were subjected to pellet culture in chondrogenic medium. Results from qRT-PCR, histology, and immunostaining indicated that cartilage generated from P10-MSCs displayed both senescent and OA-like phenotypes without using other OA-inducing agents, when compared to that from normal passage 4 (P4)-MSCs. Interestingly, the same gene expression differences observed between P4-MSCs and P10-MSC-derived cartilage tissues were also observed between the preserved and damaged OA cartilage regions taken from human samples, as demonstrated by RNA Sequencing data and other analysis methods. Lastly, the utility of this senescence-initiated OA-like cartilage model in drug development was assessed by testing several potential DMOADs and senolytics. The results suggest that pre-existing cellular senescence can induce the generation of OA-like changes in cartilage. The P4- and P10-MSCs derived cartilage models also represent a novel platform for predicting the efficacy and toxicity of potential DMOADs on both preserved and damaged cartilage in humans.

Modulating the activation state and degree of macrophages still remains as a challenge for the topographical design of Ti-based implants. In this work, micro/nano-structured coatings were prepared on Ti substrates by micro-arc oxidation (MAO) and subsequent hydrothermal (HT) treatment. By varying the HT conditions, plate-like nano-structures with an average length of 80, 440 or 780 nm were obtained on MAO-prepared micro-topographical surfaces. Depending on the dimensional features of nano-plates, the specimens were noted as Micro, Micro/Nano-180, Micro/Nano-440 and Micro/Nano-780, respectively. The in vitro results showed that the activation state and degree of macrophages could be effectively modulated by the micro/nano-structured surfaces with various dimensional features. Compared to the Micro surface, the Micro/Nano-180 surface activated both M1 and M2 phenotype in macrophages, while the Micro/Nano-440 and Micro/Nano-780 surfaces polarized macrophages to their M1 phenotype. The activation degree of M1 macrophages followed the trend: Micro < Micro/Nano-180 < Micro/Nano-440 < Micro/Nano-780. However, the osteogenic potential of the activated macrophages in response to various surfaces were in the order: Micro ≈ Micro/Nano-780 < Micro/Nano-180 < Micro/Nano-440. Together, the findings presented in this work indicate that engineering nano-structures with controllable dimensional features is a promising strategy to modulate macrophage activation state and degree. In addition, it is essential to determine the appropriate activation degree of M1 macrophages for enhanced osteogenesis. [ABSTRACT FROM AUTHOR]

Rhein, an anthraquinone derivative, has been employed widely, especially for the treatment of intractable diseases like diabetic nephropathy, arthritis, and cancer in a unique action mechanism. In the last decades, considerable efforts have been made in structural modification of rhein. This paper reviewed patents on pharmacological activity and therapeutic application of rhein and its derivatives from 1978 to 2018. Particularly, an analysis of patents was made, with the top 10 most valuable patents presented, and the interpretation of the legal status of patents was given. Given the properties of superior pharmacological activity, rich resources, cheap price, low toxicity, and mature extraction process, it is believed that an in-depth investigation on rhein and its derivatives is worth trying.

To assess the relation of symptomatic knee osteoarthritis (OA), knee pain, and radiographic knee OA to All‐cause mortality and to identify mediators in the causal pathway. Participants from the Osteoarthritis Initiative were divided into 4 groups: 1) symptomatic knee OA (i.e., both radiographic knee OA [Kellgren/Lawrence grade ≥2] and knee pain); 2) knee pain only; 3) radiographic knee OA only; and 4) neither radiographic knee OA nor knee pain. We examined the relation of knee OA status to All‐cause mortality using a multivariable Cox proportional hazards model and assessed the extent to which the association was mediated by disability, physical component summary (PCS) and mental component summary (MCS) scores for quality of life (QoL), and use of oral pain‐relief medications (i.e., nonsteroidal antiinflammatory drugs and opioids). Among 4,796 participants, 282 died over the 96‐month follow‐up period. Compared with those with neither radiographic knee OA nor knee pain, multivariable‐adjusted hazard ratios (HRs) of mortality were 2.2 (95% confidence interval [95% CI] 1.6–3.1) for symptomatic knee OA, 0.9 (95% CI 0.6–1.4) for knee pain only, and 2.0 (95% CI 1.4–2.9) for radiographic knee OA only, respectively. Indirect effects (HRs) of symptomatic knee OA on mortality via disability and PCS of QoL were 1.1 (95% CI 1.0–1.4) and 1.2 (95% CI 1.0–1.4), respectively. No apparent mediation effect was observed through either MCS of QoL or oral pain‐relief medications use. Participants with either symptomatic or radiographic knee OA were at an increased risk of All‐cause mortality. Increased risk of mortality from symptomatic knee OA was partially mediated through its effect on disability and PCS of QoL.

•What is the primary question addressed by this study?Does regular opioid use associated with increased dementia risk and poor brain health in chronic pain patients?•What is the main finding of this study?Regular opioid use was associated with higher risk of dementia and poorer neuroimaging outcomes in chronic pain patients than non-opioid analgesics. Number of opioid prescriptions was associated with dose-dependent risk of dementia.•What is the meaning of the finding?These findings imply a need for re-evaluation of opioid prescription practices for chronic pain patients and, if further evidence supports causality, provide insights into strategies to mitigate the burden of dementia.

Memantine, which is an FDA-proven drug for the treatment of dementia, exerts its function by blocking the function of NMDA (N-methyl-D-aspartate) receptor, a calcium-permeable ion channel that reduces cytotoxic calcium overload. Chondrocyte senescence is a crucial cellular event that contributes to articular cartilage degeneration during osteoarthritis (OA) development. To date, the effects of memantine and its downstream NMDA receptor on chondrocyte senescence and OA have been rarely reported.

Aseptic prosthetic loosening (APL) often leads to the failure of prostheses. It is inseparable from wear-particle-induced macrophage-mediated inflammatory responses and osteolysis. Mg2+is a metal ion with excellent anti-inflammatory properties. Herein, Mg2+was introduced into a nanomedicine (MgO nanoparticles (MNPs)) to protect against APL. MNPs could be phagocytized by macrophages and gradually degraded intracellularly. Following MNPs treatment, lipopolysaccharide (LPS)-activated macrophages polarized into deeper M1 phenotype at 6 h but then switched to the M2 phenotype at 48 h. Furthermore, the MNPs suppressed the titanium (Ti) particle-induced osteoclastogenesis and osteolysis in vivo. However, the MNPs exhibited no impact on the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis and even inhibited osteogenesis in vitro. The contrary results between the in vitro and in vivo experiments imply that macrophages are the key factor in the inhibited osteoclastogenesis in vivo because the pathogenic process of APL is mainly attributed to macrophages, osteoblasts, and osteoclasts. Accordingly, an indirect coculture system was designed that considers the immunomodulatory effect of macrophages. RANKL-induced osteoclastogenesis was significantly inhibited under the influence of MNPs in the indirect coculture system. Taken together, the MNPs inhibited the inflammatory responses of macrophages provoked by the Ti particles and thus regulated the expressions of RANKL and OPG in osteoblasts to suppress osteoclastogenesis. The target cell of MNPs was macrophages but not osteoclasts, indicating the importance of the immunomodulatory effect of macrophages. These results collectively demonstrated that MNPs can prevent APL and other osteolysis-related diseases.

AbstractObjective:The aim was to examine the association between dietary selenium intake and nonalcoholic fatty liver disease (NAFLD) in a large group of middle-aged and elderly Chinese persons.Method:The data included in this analysis were from a population-based study, the Xiangya Hospital Health Management Center Study. NAFLD was diagnosed by (1) imaging or histological evidence of hepatic steatosis; (2) absence of specific etiologies of NAFLD; and (3) no heavy consumption of alcohol. Dietary selenium intake was assessed using a validated semi-quantitative food frequency questionnaire. The association between dietary selenium intake and the prevalence of NAFLD was evaluated using logistic and spline regression in a cross-sectional study of 5436 subjects.Results:The prevalence of NAFLD was 36.8%. Compared with the lowest quintile, the energy-adjusted odds ratios for NAFLD were 1.27 (95% confidence interval [CI], 1.07–1.52), 1.30 (95% CI, 1.09–1.55), and 1.58 (95% CI, 1.33–1.89) for the third, fourth, and fifth quintiles of selenium intake, respectively, and there was a positive dose–response relationship (r = 0.88, pfor trend = 0.008). Similar results were observed for men and women separately. The findings were not materially altered by adjustment for potential confounders (i.e., age, gender, body mass index, smoking status, diabetes, hypertension, activity level, nutritional supplements, energy intake, fat intake, fiber intake, cholesterol and saturated fatty acid intake).Conclusions:In this middle-aged and elderly population, subjects with higher dietary selenium intake, even below the recommended nutrient intake in China, had higher prevalence of NAFLD in a dose–response relationship manner.

AimsThere is an increasing demand for hip arthroplasty in China. We aimed to describe trends in in-hospital mortality after this procedure in China and to examine the potential risk factors.Patients and MethodsWe included 210 450 patients undergoing primary hip arthroplasty registered in the Hospital Quality Monitoring System in China between 2013 and 2016. In-hospital mortality after hip arthroplasty and its relation to potential risk factors were assessed using multivariable Poisson regression.ResultsDuring the study period, 626 inpatient deaths occurred within 30 days after hip arthroplasty. Mortality decreased from 2.9% in 2013 to 2.6% in 2016 (p for trend = 0.02). Compared with their counterparts, old age, male sex, and divorced or widowed patients had a higher rate of mortality (all p < 0.05). Risk ratio (RR) for mortality after arthroplasty for fracture was two-fold higher (RR 2.0, 95% confidence interval (CI) 1.5 to 2.6) than that for chronic disease. RRs for mortality were 3.3 (95% CI 2.7 to 3.9) and 8.2 (95% CI 6.5 to 10.4) for patients with Charlson Comorbidity Index (CCI) of 1 to 2 and CCI ≥ 3, respectively, compared with patients with CCI of 0. The rate of mortality varied according to geographical region, the lowest being in the East region (1.8%), followed by Beijing (2.1%), the North (2.9%), South-West (3.6%), South-Central (3.8%), North-East (4.1%), and North-West (5.2%) regions.ConclusionWhile in-hospital mortality after hip arthroplasty in China appears low and declined during the study period, discrepancies in mortality after this procedure exist according to sociodemographic factors. Healthcare resources should be allocated more to underdeveloped regions to further reduce mortality.Cite this article: Bone Joint J2019;101-B:1209–1217

In the synovial joint, mechanical force creates an important signal that influences chondrocyte behavior. The conversion of mechanical signals into biochemical cues relies on different elements in mechanotransduction pathways and culminates in changes in chondrocyte phenotype and extracellular matrix composition/structure. Recently, several mechanosensors, the first responders to mechanical force, have been discovered. However, we still have limited knowledge about the downstream molecules that enact alterations in the gene expression profile during mechanotransduction signaling. Recently, estrogen receptor α (ERα) has been shown to modulate the chondrocyte response to mechanical loading through a ligand-independent mechanism, in line with previous research showing that ERα exerts important mechanotransduction effects on other cell types, such as osteoblasts. In consideration of these recent discoveries, the goal of this review is to position ERα into the mechanotransduction pathways known to date. Specifically, we first summarize our most recent understanding of the mechanotransduction pathways in chondrocytes on the basis of three categories of actors, namely mechanosensors, mechanotransducers, and mechanoimpactors. Then, the specific roles played by ERα in mediating the chondrocyte response to mechanical loading are discussed, and the potential interactions of ERα with other molecules in mechanotransduction pathways are explored. Finally, we propose several future research directions that may advance our understanding of the roles played by ERα in mediating biomechanical cues under physiological and pathological conditions.

Hand osteoarthritis is a common heterogeneous joint disorder with unclear molecular mechanisms and no disease-modifying drugs. In this study, we performed single-cell RNA sequencing analysis to compare the cellular composition and subpopulation-specific gene expression between cartilage with macroscopically confirmed osteoarthritis (n= 5) and cartilage without osteoarthritis (n= 5) from the interphalangeal joints of five donors. Of 105 142 cells, we identified 13 subpopulations, including a novel subpopulation with inflammation-modulating potential annotated as inflammatory chondrocytes. Fibrocartilage chondrocytes exhibited extensive alteration of gene expression patterns in osteoarthritic cartilage compared with nonosteoarthritic cartilage. Both inflammatory chondrocytes and fibrocartilage chondrocytes showed a trend toward increased numbers in osteoarthritic cartilage. In these two subpopulations from osteoarthritic cartilage, the ferroptosis pathway was enriched, and expression of iron overload-related genes, e.g., FTH1, was elevated. To verify these findings, we conducted a Mendelian randomization study using UK Biobank and a population-based cross-sectional study using data collected from Xiangya Osteoarthritis Study. Genetic predisposition toward higher expression of FTH1mRNA significantly increased the risk of hand osteoarthritis (odds ratio = 1.07, 95% confidence interval: 1.02–1.11) among participants (n= 332 668) in UK Biobank. High levels of serum ferritin (encoded by FTH1), a biomarker of body iron overload, were significantly associated with a high prevalence of hand osteoarthritis among participants (n= 1 241) of Xiangya Osteoarthritis Study (P-for-trend = 0.037). In conclusion, our findings indicate that inflammatory and fibrocartilage chondrocytes are key subpopulations and that ferroptosis may be a key pathway in hand osteoarthritis, providing new insights into the pathophysiology and potential therapeutic targets of hand osteoarthritis.

ObjectivesTo compare the efficacy and safety of topical non-steroidal anti-inflammatory drugs (NSAIDs), including salicylate, for the treatment of osteoarthritis (OA).MethodsPubMed, Embase, Cochrane Library and Web of Science were searched from 1966 to January 2017. Randomised controlled trials (RCTs) comparing topical NSAIDs with placebo or each other in patients with OA and observational studies comparing topical NSAIDs with no treatment or each other irrespective of disease were included. Two investigators identified studies and independently extracted data. Bayesian network and conventional meta-analyses were conducted. The primary outcomes were pain relief for RCTs and risk of adverse effects (AEs) for observational studies.Results43 studies, comprising 36 RCTs (7 900 patients with OA) and seven observational studies (218 074 participants), were included. Overall, topical NSAIDs were superior to placebo for relieving pain (standardised mean difference (SMD)=−0.30, 95% CI −0.40 to –0.20) and improving function (SMD=−0.35, 95% CI −0.45 to –0.24) in OA. Of all topical NSAIDs, diclofenac patches were most effective for OA pain (SMD=−0.81, 95% CI −1.12 to –0.52) and piroxicam was most effective for functional improvement (SMD=−1.04, 95% CI −1.60 to –0.48) compared with placebo. Although salicylate gel was associated with higher withdrawal rates due to AEs, the remaining topical NSAIDs were not associated with any increased local or systemic AEs.ConclusionsTopical NSAIDs were effective and safe for OA. Diclofenac patches may be the most effective topical NSAID for pain relief. No serious gastrointestinal and renal AEs were observed in trials or the general population. However, confirmation of the cardiovascular safety of topical NSAIDs still warrants further observational study.

No current pharmacological approach is capable of simultaneously inhibiting the symptomatology and structural progression of osteoarthritis. M1 macrophages and activated synovial fibroblasts (SFs) mutually contribute to the propagation of joint pain and cartilage destruction in osteoarthritis. Here, we report the engineering of an apoptotic neutrophil membrane-camouflaged liposome (termed “NM@Lip”) for precise delivery of triamcinolone acetonide (TA) by dually targeting M1 macrophages and activated SFs in osteoarthritic joints. NM@Lip has a high cellular uptake in M1 macrophages and activated SFs. Furthermore, TA-loaded NM@Lip (TA-NM@Lip) effectively repolarizes M1 macrophages to the M2 phenotype and transforms pathological SFs to the deactivated phenotype by inhibiting the PI3K/Akt pathway. NM@Lip retains in the joint for up to 28 days and selectively distributes into M1 macrophages and activated SFs in synovium with low distribution in cartilage. TA-NM@Lip decreases the levels of pro-inflammatory cytokines, chemokines, and cartilage-degrading enzymes in osteoarthritic joints. In a rodent model of osteoarthritis-related pain, a single intra-articular TA-NM@Lip injection attenuates synovitis effectively and achieves complete pain relief with long-lasting effects. In a rodent model of osteoarthritis-related joint degeneration, repeated intra-articular TA-NM@Lip injections induce no obvious cartilage damage and effectively attenuate cartilage degeneration. Taken together, TA-NM@Lip represents a promising nanotherapeutic approach for osteoarthritis therapy.

ObjectiveTo estimate the effect of denosumab compared with oral bisphosphonates on reducing the risk of type 2 diabetes in adults with osteoporosis.DesignPopulation based study involving emulation of a randomized target trial using electronic health records.SettingIQVIA Medical Research Data primary care database in the United Kingdom, 1995-2021.ParticipantsAdults aged 45 years or older who used denosumab or an oral bisphosphonate for osteoporosis.Main outcome measuresThe primary outcome was incident type 2 diabetes, as defined by diagnostic codes. Cox proportional hazards models were used to estimate adjusted hazard ratios and 95% confidence intervals, comparing denosumab with oral bisphosphonates using an as treated approach.Results4301 new users of denosumab were matched on propensity score to 21 038 users of an oral bisphosphonate and followed for a mean of 2.2 years. The incidence rate of type 2 diabetes in denosumab users was 5.7 (95% confidence interval 4.3 to 7.3) per 1000 person years and in oral bisphosphonate users was 8.3 (7.4 to 9.2) per 1000 person years. Initiation of denosumab was associated with a reduced risk of type 2 diabetes (hazard ratio 0.68, 95% confidence interval 0.52 to 0.89). Participants with prediabetes appeared to benefit more from denosumab compared with an oral bisphosphonate (hazard ratio 0.54, 0.35 to 0.82), as did those with a body mass index ≥30 (0.65, 0.40 to 1.06).ConclusionsIn this population based study, denosumab use was associated with a lower risk of incident type 2 diabetes compared with oral bisphosphonate use in adults with osteoporosis. This study provides evidence at a population level that denosumab may have added benefits for glucose metabolism compared with oral bisphosphonates.

Background: Dietary magnesium deficiency, which is common in modern diet, has been associated with osteoarthritis (OA) susceptibility. Despite this clinical association, no study has addressed if dietary magnesium deficiency accelerates OA development, especially at molecular level. This study aimed to explore aggravating effects of dietary magnesium deficiency on cartilage damage in an injury-induced murine OA model and to determine the underlying mechanism. Methods: Twelve-week-old C57BL/6J mice subject to injury-induced OA modeling were randomized into different diet groups in which the mice were fed a diet with daily recommended magnesium content (500 mg/kg) or diets with low magnesium content (100 or 300 mg/kg). Articular cartilage damage was evaluated using the OARSI score. To determine molecular mechanisms in vitro, mouse chondrocytes were treated with media of low magnesium conditions at 0.1 and 0.4 mM, compared with normal magnesium condition at 0.7 mM as control. Anabolic and catabolic factors, autophagy markers, β-catenin, Wnt ligands, and a magnesium channel transient receptor potential cation channel subfamily member 7 (TRPM7) were analyzed by quantitative real-time PCR and immunoblotting. Autolysosomes were detected by DALGreen staining via fluorescence microscopy and autophagosomes were evaluated by transmission electron microscopy. Autophagy markers, β-catenin, and TRPM7 were assessed in vivo in the mouse cartilage, comparing between dietary magnesium deficiency and normal diet, by immunohistochemistry. Results: Dietary magnesium deficiency aggravated injury-induced cartilage damage, indicated by significant higher OARSI scores. Autophagy markers LC3-II and Beclin-1 were decreased both in low magnesium diet-fed mice and low magnesium-treated chondrocytes. The number of autolysosomes and autophagosomes was also reduced under low magnesium conditions. Moreover, magnesium deficiency induced decreased anabolic and increased catabolic effect of chondrocytes which could be restored by autophagy activator rapamycin. In addition, reduced autophagy under low magnesium conditions is mediated by activated Wnt/β-catenin signaling. The expression of TRPM7 also decreased in low magnesium diet-fed mice, indicating that downstream changes could be regulated through this channel. Conclusions: Dietary magnesium deficiency contributes to OA development, which is mediated by reduced autophagy through Wnt/β-catenin signaling activation. These findings indicated potential benefits of adequate dietary magnesium for OA patients or those individuals at high risk of OA.

Osteosarcoma (OS) is the most common pediatric bone cancer in children and young adults. Previous studies have suggested the importance of osteoblast activity in OS tumorigenesis and metastasis, as OS is characterized by abnormal bone formation, while osteoblast is the predominant cell type both in OS and in metastatic tumor tissues. RUNX2 is a known essential transcription factor for osteoblast differentiation. RUNX2 has also been linked to many human cancers, including bone cancers and cancer metastasis in bone. However, the view of RUNX2 during OS tumorigenesis has not been unanimous. In this manuscript, we reviewed the osteoblastic origin in OS etiology. The oncogenic property of RUNX2 in human OS studies was briefly summarized. RUNX2 may be involved in OS pathogenesis by regulating cell cycle controlling of (pre)-osteoblasts, which subsequently convert to OS cells. The roles and mechanisms of RUNX2 during OS metastasis and bone metastasis in target cancers (herein prostate and breast cancers), were as described. The potential involvement of Runx2 in multiple mouse OS models that use human OS cell lines (Xenografts), tumor suppressor genes p53 and Rb1 were also discussed. Finally, we updated some microRNAs studies and their relation with RUNX2 in OS pathogenesis. This review provides a comprehensive understanding of RUNX2’s function during OS pathogenesis and will help with the research designing and strategy in controlling OS.

The type X collagen gene, COL10A1, is specifically expressed by hypertrophic chondrocytes during endochondral ossification. Endochondral ossification is a well-coordinated process that involves a cartilage intermediate and leads to formation of most of the skeleton in vertebrates during skeletogenesis. Chondrocyte hypertrophy is a critical stage of endochondral ossification linking both bone and cartilage development. Given its specific association with chondrocyte hypertrophy, type X collagen plays essential roles in endochondral ossification. It was previously shown that transgenic mice with mutant type X collagen develop variable skeleton-hematopoietic abnormalities indicating defective endochondral ossification, while mutations and abnormal expression of human COL10A1cause abnormal chondrocyte hypertrophy that has been seen in many skeletal disorders, including skeletal chondrodysplasia and osteoarthritis. In this review, we summarized the skeletal chondrodysplasia with COL10A1gene mutation that shows growth plate defect. We also reviewed recent studies that correlate the type X collagen gene expression and chondrocyte hypertrophy with osteoarthritis. Due to its significant clinical relevance, the type X collagen gene regulation has been extensively studied over the past two decades. Here, we focus on recent progress characterizing the cis-enhancer elements and their binding factors that together confer hypertrophic chondrocyte-specific murine type X collagen gene (Col10a1) expression. Based on literature review and our own studies, we surmise that there are multiple factors that contribute to hypertrophic chondrocyte-specific Col10a1expression. These factors include both transactivators (such as Runx2, MEF2C etc.) and repressors (such as AP1, NFATc1, Sox9 etc.), while other co-factors or epigenetic control of Col10a1expression may not be excluded.

Synovial fibroblasts in rheumatoid arthritis (RA) joints mediate synovial hyperplasia, progressive joint destruction, and the potential spread of disease between joints by producing multiple pathogenic proteins. Here, we deliver all-trans retinoic acid (ATRA) to selectively down-regulate these pathogenic factors, with a Golgi-targeting platelet microparticle-mimetic nanoplatform (termed Gol-PMMNP) which comprises a nanoparticle core and a platelet microparticle membrane coating labeled with a Golgi apparatus-targeting peptide. Gol-PMMNPs are shown to target synovial fibroblasts derived from RA patients via integrin α2β1-mediated endocytosis and accumulate in the Golgi apparatus by retrograde transport. ATRA-loaded Gol-PMMNPs (ATRA-Gol-PMMNPs) cause structural disruption of the Golgi apparatus, leading to an efficient reduction of pathogenic protein secretion in RA synovial fibroblasts. In rats with collagen-induced arthritis, Gol-PMMNPs display an arthritic joint-specific distribution, and ATRA-Gol-PMMNPs effectively reduce concentrations of pathogenic factors therein, including inflammatory cytokines, chemokines, and matrix-degrading enzymes within these joints. Additionally, ATRA-Gol-PMMNP treatment results in inflammatory remission and decreased bone erosion in both arthritic and proximal joints. Furthermore, ATRA-Gol-PMMNPs induce negligible toxicity to major organs. Taken together, ATRA-Gol-PMMNPs inhibit the progression of RA through reducing the production of multiple pathogenic mediators by synovial fibroblasts.

The severity of avascular necrosis (AVN) after closed reduction of developmental dysplasia of the hip determines the final clinical outcomes. Our study aimed to correlate the possible predictors with the severity of AVN. After follow-up of the patients on skeletal maturity, 37 patients (39 hips) were included. Age at reduction is important to predict the severity of AVN. Older patients are at a greater risk of suffering from more severe AVN. Other values such as the degree of initial dislocation or the impact of the femoral head ossific nucleus show no precognition to the severity of AVN.

Background: There is paucity of data on the prevalence of ultrasound-detected synovial abnormalities in the general population, and the relationship between synovial changes and knee pain remains unclear. We examined the prevalence of synovial abnormalities on ultrasound and the relationship of these features with knee pain and radiographic osteoarthritis (ROA) in a community sample. Methods: Participants aged 50 years or over were from the Xiangya Osteoarthritis Study, a community-based cohort study. Participants were questioned about chronic knee pain and underwent (1) ultrasonography of both knees to determine presence of synovial hypertrophy (≥ 4 mm), effusion (≥ 4 mm), and Power Doppler signal [PDS; yes/no]; and (2) standard radiographs of both knees (tibiofemoral and patellofemoral views) to determine ROA. Results: There were 3755 participants (mean age 64.4 years; women 57.4%). The prevalence of synovial hypertrophy, effusion, and PDS were 18.1% (men 20.2%; women 16.5%), 46.6% (men 49.9%; women 44.2%), and 4.9% (men 4.9%; women 5.0%), respectively, and increased with age (P for trend &lt; 0.05). Synovial abnormalities were associated with knee pain, with adjusted odds ratios (aORs) of 2.39 (95% confidence interval [CI] 2.00–2.86) for synovial hypertrophy, 1.58 (95%CI 1.39–1.80) for effusion, and 4.36 (95%CI 3.09–6.17) for PDS. Similar associations with ROA were observed, the corresponding aORs being 4.03 (95%CI 3.38–4.82), 2.01 (95%CI 1.76–2.29), and 6.49 (95%CI 4.51–9.35), respectively. The associations between synovial hypertrophy and effusion with knee pain were more pronounced among knees with ROA than those without ROA, and the corresponding Pfor interaction were 0.004 and 0.067, respectively. Conclusions: Knee synovial hypertrophy and effusion are more common and increase with age, affecting men more than women. All three ultrasound-detected synovial abnormalities associate both with knee pain and ROA, and knee synovial hypertrophy or effusion and ROA may interact to increase the risk of knee pain.

Background: Osteoarthritis (OA) is the most prevalent form of arthritis and the major cause of disability and overall diminution of quality of life in the elderly population. Currently there is no cure for OA, partly due to the large gaps in our understanding of its underlying molecular and cellular mechanisms. Macrophage migration inhibitory factor (MIF) is a procytokine that mediates pleiotropic inflammatory effects in inflammatory diseases such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, data on the role of MIF in OA is limited with conflicting results. We undertook this study to investigate the role of MIF in OA by examining MIFgenotype, mRNA expression, and protein levels in the Newfoundland Osteoarthritis Study. Methods: One hundred nineteen end-stage knee/hip OA patients, 16 RA patients, and 113 healthy controls were included in the study. Two polymorphisms in the MIFgene, rs755622, and -794 CATT5-8, were genotyped using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) and PCR followed by automated capillary electrophoresis, respectively. MIFmRNA levels in articular cartilage and subchondral bone were measured by quantitative polymerase chain reaction. Plasma concentrations of MIF, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) were measured by enzyme-linked immunosorbent assay. Results: rs755622 and -794 CATT5-8genotypes were not associated with MIFmRNA or protein levels or OA (all p≥ 0.19). MIFmRNA level in cartilage was lower in OA patients than in controls (p= 0.028) and RA patients (p= 0.004), while the levels in bone were comparable between OA patients and controls (p= 0.165). MIF protein level in plasma was lower in OA patients than in controls (p= 3.01 × 10−10), while the levels of TNF-α, IL-6 and IL-1β in plasma were all significantly higher in OA patients than in controls (all p≤ 0.0007). Multivariable logistic regression showed lower MIF and higher IL-1β protein levels in plasma were independently associated with OA (OR per SD increase = 0.10 and 8.08; 95% CI = 0.04–0.19 and 4.42–16.82, respectively), but TNF-α and IL-6 became non-significant. Conclusions: Reduced MIFmRNA and protein expression in OA patients suggested MIF might have a protective role in OA and could serve as a biomarker to differentiate OA from other joint disorders.

Background: Metformin could activate adenosine monophosphate-activated protein kinase (AMPK) which was postulated as a potential therapeutic target for osteoarthritis. This study aimed to examine the effects of metformin on cartilage and pain in osteoarthritis mouse model. Methods: Eighty 10-week-old male C57BL/6 mice were randomized to 6 groups: non-operation, sham-operation, destabilization of the medial meniscus (DMM)-operation with intragastric saline/metformin, and DMM-operation with intraarticular saline/metformin. Articular cartilage degeneration was examined by scanning electron microscopy (SEM) and graded using the scoring system recommended by Osteoarthritis Research Society International (OARSI). Mechanical withdrawal threshold and hind paw weight distribution were measured to assess the pain-related behavior. Cell Counting Kit-8 assay, quantificational real-time polymerase chain reaction, and western blot analysis were conducted to examine the anabolic and anti-catabolic effect of metformin and the role of AMPK in mediating its effects on interleukin-1β stimulated primary mice chondrocytes. Results: Compared with mice receiving intragastric and intraarticular saline, mice in both intragastric and intraarticular metformin displayed attenuated articular cartilage degeneration, indicated by less cartilage damage under SEM and significantly lower OARSI scores. A higher paw withdrawal threshold and a decreased weight-bearing asymmetry were observed in the intragastric and intraarticular metformin mice compared with their corresponding saline groups in DMM model of osteoarthritis. In vitro experiments showed that metformin not only decreased the level of matrix metalloproteinase 13, but also elevated type II collagen production through activating AMPK pathway. Conclusions: Metformin attenuates osteoarthritis structural worsening and modulates pain, suggesting its potential for osteoarthritis prevention or treatment.

Background: To examine the relation between inflammatory potential of diet and incident knee osteoarthritis (OA) and the role of BMI in the association of interest. Methods: In the Osteoarthritis Initiative, the energy-adjusted dietary inflammatory index (E-DII™) scores were calculated based on the Block Brief 2000 Food Frequency Questionnaire and categorized into sex-specific quartiles. Outcomes were incident (1) radiographic knee OA (ROA) (i.e., a KL grade ≥ 2) and (2) symptomatic knee OA (SxOA) (i.e., a combination of frequent knee pain and ROA). We fitted generalized estimating equation models to examine the association between E-DII scores and incident knee OA. We performed mediation analyses to assess the potential mediation by BMI in the DII-OA relation. Results: Over a 48-month follow-up period, 232 and 978 knees developed ROA and SxOA, respectively. Compared with the lowest (most anti-inflammatory) E-DII quartile, the odds ratio (OR) of incident ROA for the highest (most pro-inflammatory) E-DII quartile was 1.73 (95% confidence interval (CI) 1.15 to 2.62, Ptrend= 0.007). The corresponding OR for SxOA was 1.43 (95% CI 1.16 to 1.76, Ptrend= 0.001). The DII-OA association was significantly mediated via BMI with an indirect effect of 1.08 (95% CI 1.04, 1.13) for ROA and 1.13 (95% CI 1.09, 1.16) for SxOA, accounting for 20.4% and 44.5% of the total effect, respectively. Conclusions: A higher inflammatory potential of diet increased the risk of knee OA. The association was significantly mediated via BMI. Targeting the inflammatory potential of diet may be beneficial to reduce the risk of knee OA.

Perioperative safety in China is unclear. This study aims to develop a seamless safety management system to ensure patient safety in each period by improving team communication, consistency of care, and safety culture.