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Objective: 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. Methods: 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. Results: 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). Conclusion: This population‐based study provides more evidence for a positive association between hyperuricemia and prevalent hand synovitis. [ABSTRACT FROM AUTHOR]

Objective: The current guidelines recommend weight loss for patients with overweight or obesity and knee or hip osteoarthritis (OA); however, there is a paucity of data on the relation of weight loss to death among patients with OA. We aimed to examine the relation of the rate of weight loss induced by antiobesity medications over one year to all‐cause mortality among patients with overweight or obesity and knee or hip OA. Methods: Using the IQVIA Medical Research Database, we identified people with overweight or obesity and knee or hip OA. We emulated analyses of a hypothetical target trial to assess the effect of slow‐to‐moderate (2%–10%) or fast (≥10%) weight loss induced by the initiation of antiobesity medications within one year on all‐cause mortality and secondary outcomes over five years' follow‐up. Results: Among 6,524 participants, the five‐year all‐cause mortality rates were 5.3%, 4.0%, and 5.4% for weight gain or stable, slow‐to‐moderate weight loss, and fast weight loss arms, respectively. Compared with the weight gain or stable arm, hazard ratios of all‐cause mortality were 0.72 (95% confidence interval [CI] 0.56–0.92) for the slow‐to‐moderate weight loss arm and 0.99 (95% CI 0.67–1.44) for the fast weight loss arm. We found dose–response protective effects of weight loss on incident hypertension, type 2 diabetes, and venous thromboembolism but a slightly higher risk of cardiovascular disease, albeit not statistically significant, in the fast rate of weight loss arm than in the weight gain or stable arm and no significant relations of weight loss to the risk of cancer. Conclusion: In this population‐based study, a slow‐to‐moderate, but not fast, rate of weight loss induced by antiobesity medications is associated with a lower risk of all‐cause mortality in people with overweight or obesity and knee or hip OA. [ABSTRACT FROM AUTHOR]

Melatonin exhibits potential for pain relief and long‐term safety profile. We examined the analgesic effects of oral melatonin on osteoarthritis (OA) and investigated the underlying mechanism. Using data from a UK primary care database, we conducted a cohort study in individuals with OA to compare the number of oral analgesic prescriptions and the risk of knee/hip replacement between melatonin initiators and hypnotic benzodiazepines (i.e., active comparator) initiators using quantile regression models and Cox‐proportional hazard models, respectively. To elucidate causation, we examined the effects of melatonin on pain behaviors and explored several metabolites that may serve as potential regulatory agents of melatonin in the monoiodoacetate rat model of OA. Using data from another community‐based cohort study, that is, the Xiangya OA Study, we verified the association between the key serum metabolite and incident symptomatic knee OA. Compared with the hypnotic benzodiazepines cohort (n = 8135), the melatonin cohort (n = 813) had significantly fewer subsequent prescriptions of oral analgesics (50th percentile: 5 vs. 7, 75th percentile: 19 vs. 29, and 99th percentile: 140 vs. 162) and experienced a lower risk of knee/hip replacement (hazard ratio = 0.47, 95% Cl: 0.30–0.73) during the follow‐up period. In rats, oral melatonin alleviated pain behaviors and increased serum levels of glycine. There was an inverse association between baseline serum glycine levels and the risk of incident symptomatic knee OA in humans (n = 760). In conclusion, our findings indicate that oral melatonin shows significant potential to be a novel treatment for OA pain. The potential role of glycine in its analgesic mechanism warrants further investigation. [ABSTRACT FROM AUTHOR]

Background: Identification of knee osteoarthritis (OA) pain phenotypes, their transition patterns, and risk factors for worse phenotypes, may guide prognosis and targeted treatment; however, few studies have described them. We aimed to investigate different pain phenotypes, their transition patterns, and potential risk factors for worse pain phenotypes. Methods: Utilizing data from the Osteoarthritis Initiative (OAI), pain severity was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale. We identified the activity-related pain phenotypes and estimated the transition probabilities of pain phenotypes from baseline to the 24-month using latent transition analysis. We examined the risk factors at baseline with the 24-month pain phenotypes and the transition of pain phenotypes. Results: In 4796 participants, we identified four distinct knee pain phenotypes at both baseline and 24-month follow-up: no pain, mild pain during activity (Mild P-A), mild pain during both rest and activity (Mild P-R-A), and moderate pain during both rest and activity (Mod P-R-A). 82.9% knees with no pain at baseline stayed the same at 24-month follow-up, 17.1% progressed to worse pain phenotypes. Among "Mild P-A" at baseline, 32.0% converted to no-pain, 12.8% progressed to "Mild P-R-A", and 53.2% remained. Approximately 46.1% of "Mild P-R-A" and 54.5% of "Mod P-R-A" at baseline experienced remission by 24-month. Female, non-whites, participants with higher depression score, higher body mass index (BMI), higher Kellgren and Lawrence (KL) grade, and knee injury history were more likely to be in the worse pain phenotypes, while participants aged 65 years or older and with higher education were less likely to be in worse pain phenotypes at 24-month follow-up visit. Risk factors for greater transition probability to worse pain phenotypes at 24-month included being female, non-whites, participants with higher depression score, higher BMI, and higher KL grade. Conclusions: We identified four distinct knee pain phenotypes. While the pain phenotypes remained stable in the majority of knees over 24 months period, substantial proportion of knees switched to different pain phenotypes. Several socio-demographics as well as radiographic lesions at baseline are associated with worse pain phenotypes at 24-month follow-up visit and transition of pain phenotypes. [ABSTRACT FROM AUTHOR]

Objective: 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. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Introduction: Decrease in allogenic red blood cell (RBC) transfusion rates following total hip arthroplasty (THA) has been reported in the United States, but whether other countries share the same trend remains unclear. Additionally, the relation of allogenic RBC transfusion to the risk of complications in THA remains controversial. Using the Chinese national inpatient database, the current study aimed to examine trends, complications, charges, and readmission patterns of allogeneic RBC transfusion in THA. Materials and methods: Patients undergoing primary THA between 2013 and 2019 were included, and then stratified into the transfusion and the non-transfusion group based on the database transfusion records. A generalized estimating equation model was used to investigate trends in transfusion rates. After propensity-score matching, a logistic regression model was used to compare the complications, rates and causes of 30-day readmission between two groups. Results: A total of 10,270 patients with transfusion and 123,476 patients without transfusion were included. Transfusion rates decreased from 19.11% in 2013 to 9.94% in 2019 (P for trend < 0.001). After matching, no significant differences in the risk of of in-hospital death (odds ratio [OR], 4.00; 95% confidence interval [CI] 0.85–18.83), wound infection (OR 0.72; 95%CI 0.45–1.17), myocardial infarction (OR 1.17; 95%CI 0.62–2.19), deep vein thrombosis (OR 1.25; 95%CI 0.88–1.78), pulmonary embolism (OR 2.25; 95%CI 0.98–5.17), readmission rates (OR 1.07; 95%CI 0.88–1.30) and readmission causes were observed between two groups. However, the transfusion group had higher hospitalization charges than the non-transfusion group (72,239.89 vs 65,649.57 Chinese yuan [CNY], P < 0.001). Conclusions: This study found that allogeneic RBC transfusion in THA was not associated with the increased risk of complications and any-cause readmission. However, the currently restrictive transfusion policy should be continued because excessive blood transfusion may increase the socioeconomic burden. [ABSTRACT FROM AUTHOR]

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 FTH1 mRNA 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. [ABSTRACT FROM AUTHOR]

Metabolites' connection to sarcopenia through inflammation and mitochondrial dysfunction is presumed, but their impact remains unclear due to limitations in conventional observational studies caused by confounding bias and reverse causation. We conducted a Mendelian randomization (MR) analysis to elucidate the association of serum metabolites with sarcopenia and its related traits, i.e., appendicular lean mass and grip strength. Genetic instruments to proxy the serum metabolites were extracted from the most comprehensive genome-wide association study on the topic published so far. The corresponding summary statistics for the associations of genetic instruments with outcomes were calculated from the UK Biobank (n = 324,976 participants). The primary analyses were assessed by an inverse-variance weighted (IVW) method. The weighted median and MR-PRESSO methods were used as sensitive analyses. Fourteen genetically predicted serum metabolites were associated with the risk of sarcopenia (PIVW < 0.05). Two metabolites showed the overlapped association with sarcopenia and its related traits, which were isovalerylcarnitine (sarcopenia: odds ratio [OR] = 4.00, 95% confidence interval [CI] = 1.11~14.52, PIVW = 0.034; appendicular lean mass: β = −0.45 kg, 95% CI = −0.81~−0.09, PIVW = 0.015; grip strength: β = −1.51 kg, 95% CI = −2.31~−0.71, PIVW = 2.19 × 10−4) and docosapentaenoate (sarcopenia: OR = 0.16, 95% CI = 0.03~0.83, PIVW = 0.029; appendicular lean mass: β = −0.45 kg, 95% CI = 0.08~0.81, PIVW = 0.016). Twenty-seven metabolites were suggestive associated with appendicular lean mass or grip strength. This MR study provided evidence for the potential effects of metabolites on sarcopenia. [ABSTRACT FROM AUTHOR]

Nonsteroidal antiinf lammatory drugs (NSAIDs) remain the mainstay of the pharmacologic management for relieving osteoarthritis pain, and low-dose aspirin is often prescribed to osteoarthritis patients who are at high risk of cardiovascular disease (CVD). We conducted cohort studies using data from The Health Improvement Network (THIN) database (2000–2019) to assess whether the relationship of initiation of naproxen or ibuprofen vs. initiation of other NSAIDs (excluding both naproxen and ibuprofen), respectively, to the risk of CVD was modified by coprescription of low-dose aspirin among the participants with osteoarthritis. Among participants without coprescription of aspirin, the risk of CVD was lower in naproxen initiators (10.3/1000 person-years) than in other NSAIDs initiators (13.2/1000 person-years; hazard ratio = 0.71, 95% confidence interval: 0.60, 0.85). Among participants with coprescription of aspirin, however, the risk of CVD was higher among naproxen initiators (36.9/1000 person-years) than that among other NSAIDs initiators (34.8/1000 person-years; hazard ratio = 1.48, 95% confidence interval: 1.12, 1.84). The association was significantly modified by coprescription of aspirin (P  < 0.001). Similar findings were observed in the association of initiation of ibuprofen vs. other NSAIDs with the risk of CVD, which was significantly modified by coprescription of aspirin (P  < 0.001). These findings suggest that osteoarthritis patients and clinicians should be aware of the potential CVD risk of concurrently taking naproxen or ibuprofen and low-dose aspirin. [ABSTRACT FROM AUTHOR]

Objectives Hand synovitis, a potentially modifiable pathological lesion, is common and associated with pain and hand OA; nevertheless, its pathogenesis remains uncertain. This study investigated the relationship between gut microbiota dysbiosis and hand synovitis prevalence and evaluated whether bile acids mediate the association. Methods Participants were derived from a community-based observational study. Synovitis in each hand joint was assessed using US. Gut microbiota was evaluated using 16S ribosomal RNA amplicon sequencing on faeces, and plasma bile acids were measured by HPLC mass spectrometry. We examined the relationship between gut microbiota dysbiosis and hand synovitis prevalence, as well as the extent to which bile acids were involved in the association. Results Among 1336 participants (mean age: 63.2 years; women: 58.8%), 18.3% had prevalent hand synovitis (unilateral in 13.6% and bilateral in 4.7%). β-diversity, but not α-diversity, of gut microbiota was significantly associated with prevalent hand synovitis. Higher relative abundance of the genus Prevotella and lower relative abundance of the genus Blautia were significantly associated with the prevalence of hand synovitis. Similar associations were also observed for laterality and the number of joints affected by hand synovitis. The association between Prevotella and hand synovitis was partially mediated through its effect on tauroursodeoxycholic acid and glycoursodeoxycholic acid, the mediation proportions being 25.7% and 21.6%, respectively. Conclusion Our findings suggest that gut microbiota dysbiosis is associated with the prevalence of hand synovitis. Such an association appears to be partially mediated by plasma bile acids. [ABSTRACT FROM AUTHOR]

Objective: Gout is associated with a higher risk of fracture; however, findings on the associations of hyperuricemia and urate‐lowering therapy (ULT) with the risk of fracture have been inconsistent. We examined whether lowering serum urate (SU) levels with ULT to a target level (i.e., <360 μmoles/liter) reduces the risk of fracture among individuals with gout. Methods: We emulated analyses of a hypothetical target trial using a "cloning, censoring, and weighting" approach to examine the association between lowering SU with ULT to the target levels and the risk of fracture using data from The Health Improvement Network, a UK primary care database. Individuals with gout who were age 40 years or older and for whom ULT was initiated were included in the study. Results: Among 28,554 people with gout, the 5‐year risk of hip fracture was 0.5% for the "achieving the target SU level" arm and 0.8% for the "not achieving the target SU level" arm. The risk difference and hazard ratio for the "achieving the target SU level" arm was –0.3% (95% confidence interval [95% CI] –0.5%, –0.1%) and 0.66 (95% CI 0.46, 0.93), respectively, compared with the "not achieving the target SU level" arm. Similar results were observed when the associations between lowering SU level with ULT to the target levels and the risk of composite fracture, major osteoporotic fracture, vertebral fracture, and nonvertebral fracture were assessed. Conclusion: In this population‐based study, lowering the SU level with ULT to the guideline‐based target level was associated with a lower risk of incident fracture in people with gout. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives Angiotensin II is implicated in GCA pathology. We examined whether the use of angiotensin receptor blockers (ARBs) is associated with GCA risk compared with angiotensin-converting enzyme inhibitors (ACEis) or other antihypertensives. Methods We performed a matched cohort study including adults who were initiators of antihypertensives in UK primary care data between 1995 and 2019. Treatment-naïve individuals without prior GCA or PMR were categorized into three groups—ARB initiators, ACEi initiators, or other antihypertensive initiators (beta-blockers, calcium channel blockers, diuretics or alpha-adrenoceptor blockers)—and followed for up to 5 years. Incident GCA was defined using validated Read codes, with age of onset ≥50 years and two or more glucocorticoid prescriptions. Inverse probability–weighted Cox models were used to model outcome risk, adjusting for lifestyle parameters, comorbidities and comedications. Results Among >1 million new starters of antihypertensives (81 780 ARBs, 422 940 ACEis and 873 066 other antihypertensives), the incidence rate of GCA per 10 000 patient-years was 2.73 (95% CI 2.12, 3.50) in the ARB group, 1.76 (95% CI 1.25, 2.39) in the ACEi group and 1.90 (95% CI 1.37, 2.56) in the other antihypertensives group. The hazard of GCA was higher in ARB initiators [hazard ratio (HR) 1.55; 95% CI 1.16, 2.06] than initiators of ACEis, but similar between initiators of other antihypertensives and ACEis (HR 1.08; 95% CI 0.87, 1.35). Conclusions Initiation of ARBs is associated with a higher risk of GCA compared with ACEis or other antihypertensives. Mechanistic studies of angiotensin receptor biology will provide further clarity for our findings. [ABSTRACT FROM AUTHOR]

Purpose: Previous studies highlighted an increased risk of venous thromboembolism (VTE) among patients with anterior cruciate ligament reconstruction (ACLR); however, the risk for those with ACL tear but without undergoing ACLR has not been reported yet. The aim of this study was to evaluate the risk of VTE among ACL tear individuals with or without ACLR derived from the general population. Methods: A cohort study was conducted using data from the IQVIA Medical Research Database of the United Kingdom. Up to five non-ACL tear individuals (n = 22,235) were matched to each case of ACL tear (n = 4474) by age, sex, body mass index and entry-time. The relation of ACL tear to VTE [pulmonary embolism (PE) and deep vein thrombosis (DVT)] was examined using a multivariable Cox proportional hazard model. A sub-cohort analysis, in which the ACL tear individuals were stratified into those with ACLR and those without ACLR, was also conducted. Results: VTE developed in 13 individuals with ACL tear and nine individuals without ACL tear (incidence rates: 3.1 vs. 0.4/1000 person-years), with multivariable-adjusted hazard ratio (HR) being 6.59 (95% CI 2.28–19.08) in 1-year follow-up. For ACL tear individuals with ACLR, the HR was 11.44 (95% CI 2.71–48.28), and for those without ACLR, the HR was 6.02 (95% CI 1.44–24.25), compared with individuals without ACL tear. Conclusion: This large-sample population-based cohort study provides the first evidence on an increased risk of VTE in ACL tear individuals regardless of subsequent ACLR, which supports the necessity for monitoring venous-thromboembolic complications in the target population, including those without ACLR. Level of evidence: III. [ABSTRACT FROM AUTHOR]

Objective: 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. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Introduction: Attentions have been paid to the optimal anesthesia for knee arthroplasty (KA). We sought to investigate whether neuraxial anesthesia (NA) is superior to general anesthesia (GA) in terms of perioperative outcomes and resource utilization following KA. Methods: Patients undergoing primary KA registered in the Hospital Quality Monitoring System (HQMS) in China during 2013–2019 were identified. By utilizing a time-stratified propensity score matching, every patient receiving NA was matched by propensity score to a patient receiving GA. Then, we conducted Poisson, logistic, and linear regression to compare NA with GA in terms of perioperative outcomes and resource utilization. Results: Of 109,132 included participants, 75,945 (69.59%) underwent KA with GA and 33,187 (30.41%) with NA. After propensity score matching (26,425 participants per group), NA was associated with lower incidence of blood transfusion (OR: 0.82, 95% CI 0.77–0.87; p < 0.0001), 30-day readmission (OR: 0.76, 95% CI 0.68–0.84; p < 0.0001), and 90-day readmission (OR: 0.83, 95% CI 0.77–0.90; p < 0.0001). No statistically significant difference in in-hospital mortality, incidence of pulmonary embolism, deep vein thrombosis, and surgical site infection was found. In addition, NA was associated with a 1% decrease in length of stay (95% CI 0–2%; p = 0.0070) and a 3% lower total hospital charge (95% CI 2–4%; p < 0.0001) when compared with GA. Conclusion: Compared with GA, NA was associated with decreased incidence of blood transfusion, readmission, reduced length of stay, and total hospital charge following KA, suggesting the favorable role of NA for perioperative outcomes and resource utilization in KA. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Both BNT162b2 (Pfizer–BioNTech) and ChAdOx1 nCoV-19 (Oxford–AstraZeneca) vaccines have shown high efficacy against COVID-19 in randomized controlled trials. However, their comparative effectiveness against COVID-19 is unclear in the real world. We evaluated the comparative effectiveness of the BNT162b2 and ChAdOx1 nCoV-19 vaccines against COVID-19 in the UK general population. Methods: We emulated a target trial using IQVIA Medical Research Database (IMRD), an electronic primary care database from the UK (2021). We included 1,311,075 participants, consisting of 637,549 men and 673,526 women age≥18 years, who received vaccination with BNT162b2 or ChAdOx1 nCoV-19 between January 1 and August 31, 2021. The outcomes consisted of confirmed diagnosis of SARS-CoV-2 infection, hospitalisation for COVID-19 and death from COVID-19 in the IMRD. We performed a cox-proportional hazard model to compare the risk of each outcome variable between the two vaccines adjusting for potential confounders with time-stratified overlap weighting of propensity score (PS). Results: During a mean of 6.7 months of follow-up, 20,070 confirmed SARS-CoV-2 infection occurred in individuals who received BNT162b2 vaccine (PS weighted incidence rate: 3.65 per 1000 person-months), and 31,611 SARS-CoV-2 infection occurred in those who received ChAdOx1 nCoV-19 vaccine (PS weighted incidence rate: 5.25 per 1000 person-months). The time-stratified PS weighted rate difference of SARS-CoV-2 infection for BNT162b2 group vs. ChAdOx1 nCoV-19 group was -1.60 per 1000 person-months (95% confidence interval [CI]: -1.76 to -1.43 per 1000 person-months), and the hazard ratio was 0.69 (95% CI: 0.68 to 0.71). The results were similar across the stratum of sex, age (<65 and ≥65 years), and study periods (i.e., alpha-variant predominance period and delta-variant predominance period). The PS weighted incidence of hospitalisation for COVID-19 was also lower in the BNT162b2 vaccine group than that in the ChAdOx1 vaccine group (RD: -0.09, 95%CI: -0.13 to -0.05 per 1000 person-months; HR: 0.65, 95%CI: 0.57 to 0.74). No significant difference in the risk of death from COVID-19 was observed between the two comparison groups. Conclusions: In this population-based study, the BNT162b2 vaccine appears to be more efficacious than the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2 infection and hospitalisation for COVID-19 but not death from COVID-19. [ABSTRACT FROM AUTHOR]

Objective: Gout patients often have multiple comorbidities, making them susceptible to SARS–CoV‐2 infection and poor outcomes. This study was undertaken to examine the association between gout and the risk of SARS–CoV‐2 infection and severe outcomes, especially in patients who have received a SARS–CoV‐2 vaccine. Methods: We conducted 2 cohort studies using The Health Improvement Network in the UK. Individuals with gout and those without gout from the general population were followed up from December 8, 2020 to October 31, 2021. We estimated the rate difference (RD) and hazard ratio (HR) of SARS–CoV‐2 infection and severe outcomes (i.e., hospitalization and death within 30 days after SARS–CoV‐2 infection) for individuals with gout versus those without gout using a Cox proportional hazards model according to SARS–CoV‐2 vaccination status. We adjusted for potential confounders by using overlap weighting of exposure scores. Results: Among the vaccinated cohort, 1,955 cases of breakthrough COVID‐19 infection occurred in 54,576 individuals with gout (4.68 cases per 1,000 person‐months), and 52,468 cases occurred in 1,336,377 individuals without gout (3.76 cases per 1,000 person‐months). The partially adjusted RD of breakthrough infection was 0.91 cases per 1,000 person‐months (95% confidence interval [95% CI] 0.62–1.20 cases per 1,000 person‐months), and the partially adjusted HR was 1.24 (95% CI 1.19–1.30). Gout was also associated with an increased risk of hospitalization (adjusted HR 1.30 [95% CI 1.10–1.53]) and death (adjusted HR 1.36 [95% CI 0.87–2.13]). Women with gout had an increased risk of hospitalization (adjusted HR 1.55 [95% CI 1.15–2.10]) and death (adjusted HR 2.46 [95% CI 1.12–5.41]). Similar associations with gout were observed in the unvaccinated cohort. Conclusion: These general population data suggest that individuals with gout, especially women, have higher risks of SARS–CoV‐2 infection and severe outcomes, even when vaccinated. [ABSTRACT FROM AUTHOR]

Objective: To examine efficacy and safety of tramadol for knee or hip osteoarthritis (OA). Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Background: Baker’s cyst is the most common cystic disease of the knee, and a fast and accurate diagnosis of Baker’s cyst is essential for a better management. Ultrasound is a rapid, portable, widely available, inexpensive and noninvasive imaging modality. However, the diagnostic accuracy of ultrasound on Baker’s cyst still remains undetermined. We conducted the first meta-analysis to comprehensively assess the accuracy of ultrasound for the detection of Baker’s cyst. Methods: PubMed, Embase and Web of Science were searched from inception to July 14, 2022, without language restrictions. Studies providing cross-tabulations of ultrasound versus pathology (gold standard) or MRI (standard imaging technique) for diagnosis of Baker’s cyst were included. Indicators for the diagnostic accuracy of ultrasound, including sensitivity, specificity and area under the curve, were calculated using a bivariate model. Sensitivity analysis was conducted to evaluate the heterogeneity and robustness of the results. Results: A total of 13 studies with 1,011 subjects (mean age 32.2 years; men 53.5%) met the inclusion criteria. The pooled sensitivity, specificity and area under the curve of ultrasound for diagnosis of Baker’s cyst, compared with pathology, were 0.97 (95% confidence intervals: 0.73–1.00), 1.00 (0.98–1.00) and 1.00 (0.99–1.00), respectively. The pooled estimates of ultrasound versus MRI were 0.94 (0.87–0.98) for sensitivity, 1.00 (0.83–1.00) for specificity and 0.97 (0.95–0.98) for area under the curve. Sensitivity analysis did not change the results materially. Conclusion: Ultrasound shows excellent diagnostic accuracy for the assessment of Baker’s cyst and provides similar diagnostic information (absent or present) compared to MRI. Because of its advantages of low cost, portability and accessibility, ultrasound is likely to be a choice of imaging technique for screening Baker’s cyst in clinical and population settings as well as in follow-ups. [ABSTRACT FROM AUTHOR]

Background: Numerous observational studies have revealed an increased risk of death and complications with transfusion, but this observation has not been confirmed in randomized controlled trials (RCTs). The "transfusion kills patients" paradox persists in real-world observational studies despite application of analytic methods such as propensity-score matching. We propose a new design to address this long-term existing issue, which if left unresolved, will be deleterious to the healthy generation of evidence that supports optimized transfusion practice. Methods: In the new design, we stress three aspects for reconciling observational studies and RCTs on transfusion safety: (1) re-definition of the study population according to a stable hemoglobin range (gray zone of transfusion decision; 7.5–9.5 g/dL in this study); (2) selection of comparison groups according to a trigger value (last hemoglobin measurement before transfusion; nadir during hospital stay for control); (3) dealing with patient heterogeneity according to standardized mean difference (SMD) values. We applied the new design to hospitalized older patients (aged ≥60 years) undergoing general surgery at four academic/teaching hospitals. Four datasets were analyzed: a base population before (Base Match−) and after (Base Match+) propensity-score matching to simulate previous observational studies; a study population before (Study Match−) and after (Study Match+) propensity-score matching to demonstrate effects of our design. Results: Of 6141 older patients, 662 (10.78%) were transfused and showed high heterogeneity compared with those not receiving transfusion, particularly regarding preoperative hemoglobin (mean: 11.0 vs. 13.5 g/dL) and intraoperative bleeding (≥500 mL: 37.9% vs. 2.1%). Patient heterogeneity was reduced with the new design; SMD of the two variables was reduced from approximately 100% (Base Match−) to 0% (Study Match+). Transfusion was related to a higher risk of death and complications in Base Match− (odds ratio [OR], 95% confidence interval [CI]: 2.68, 1.86–3.86) and Base Match+ (2.24, 1.43–3.49), but not in Study Match− (0.77, 0.32–1.86) or Study Match+ (0.66, 0.23–1.89). Conclusions: We show how choice of study population and analysis could affect real-world study findings. Our results following the new design are in accordance with relevant RCTs, highlighting its value in accelerating the pace of transfusion evidence generation and generalization. [ABSTRACT FROM AUTHOR]

Chrysanthemi Flos 'Hangbaiju' (HBJ) is a common Chinese medicinal material with the same origin as the medicinal and edible cognate plant in China, whose quality is seriously affected by the place of origin. In this study, four stable isotope ratios (δ15N, δ2H, δ13C, and δ18O) and 44 elements were detected and analyzed in 191 HBJ flower samples from six locations in China to trace the origin of HBJ. An ANOVA analysis of δ15N, δ2H, δ13C, and δ18O values, as well as milti-elements, showed that there were significant differences among the six places of origin. Partial least squares discriminant analysis (PLSDA) and one-class partial least squares discriminant analysis (OPLS-DA) models were established to trace the origin of HBJ from these six locations. The results showed that the classification effect of the PLSDA model is poor; however, the established OPLS-DA model can distinguish between products of national geographic origin (Tongxiang City, Zhejiang Province, China) and samples from other origins, among which Ni, Mo, δ13C, Cu, and Ce elements (VIP > 1) contribute the most to this classification. Therefore, this study provides a new method for tracing the origins of HBJ, which is of great significance for the protection of origin labeling of products. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is the most prevalent joint disorder characterized by joint structural pathological changes with the loss of articular cartilage as its hallmark. Tools that can predict cartilage loss would help identify people at high risk, thus preventing OA development. The recent advance of the metabolomics provides a new avenue to systematically investigate metabolic alterations in disease and identify biomarkers for early diagnosis. Using a metabolomics approach, the current study aimed to identify serum metabolomic signatures for predicting knee cartilage volume loss over 10 years in the Tasmania Older Adult Cohort (TASOAC). Cartilage volume was measured in the medial, lateral, and patellar compartments of the knee by MRI at baseline and follow-up. Changes in cartilage volume over 10 years were calculated as percentage change per year. Fasting serum samples collected at 2.6-year follow-up were metabolomically profiled using the TMIC Prime Metabolomics Profiling Assay and pairwise metabolite ratios as the proxies of enzymatic reaction were calculated. Linear regression was used to identify metabolite ratio(s) associated with change in cartilage volume in each of the knee compartments with adjustment for age, sex, and BMI. The significance level was defined at α = 3.0 × 10−6 to control multiple testing. A total of 344 participants (51% females) were included in the study. The mean age was 62.83 ± 6.13 years and the mean BMI was 27.48 ± 4.41 kg/m2 at baseline. The average follow-up time was 10.84 ± 0.66 years. Cartilage volume was reduced by 1.34 ± 0.72%, 1.06 ± 0.58%, and 0.98 ± 0.46% per year in the medial, lateral, and patellar compartments, respectively. Our data showed that the increased ratios of hexadecenoylcarnitine (C16:1) to tetradecanoylcarnitine (C14) and C16:1 to dodecanoylcarnitine (C12) were associated with 0.12 ± 0.02% reduction per year in patellar cartilage volume (both p < 3.03 × 10−6). In conclusion, our data suggested that alteration of long chain fatty acid β-oxidation was involved in patellar cartilage loss. While confirmation is needed, the ratios of C16:1 to C14 and C12 might be used to predict long-term cartilage loss. [ABSTRACT FROM AUTHOR]

Aims Previous studies have found high sodium intake to be associated with increased risks of cardiovascular disease (CVD) and all-cause mortality among individuals with hypertension; findings on the effect of intake among individuals without hypertension have been equivocal. We aimed to compare the risks of incident CVD and all-cause mortality among initiators of sodium-containing acetaminophen with the risk of initiators of non-sodium-containing formulations of the same drug according to the history of hypertension. Methods and results Using The Health Improvement Network, we conducted two cohort studies among individuals with and without hypertension. We examined the relation of sodium-containing acetaminophen to the risk of each outcome during 1-year follow-up using marginal structural models with an inverse probability weighting to adjust for time-varying confounders. The outcomes were incident CVD (myocardial infarction, stroke, and heart failure) and all-cause mortality. Among individuals with hypertension (mean age: 73.4 years), 122 CVDs occurred among 4532 initiators of sodium-containing acetaminophen (1-year risk: 5.6%) and 3051 among 146 866 non-sodium-containing acetaminophen initiators (1-year risk: 4.6%). The average weighted hazard ratio (HR) was 1.59 [95% confidence interval (CI) 1.32–1.92]. Among individuals without hypertension (mean age: 71.0 years), 105 CVDs occurred among 5351 initiators of sodium-containing acetaminophen (1-year risk: 4.4%) and 2079 among 141 948 non-sodium-containing acetaminophen initiators (1-year risk: 3.7%), with an average weighted HR of 1.45 (95% CI 1.18–1.79). Results of specific CVD outcomes and all-cause mortality were similar. Conclusion The initiation of sodium-containing acetaminophen was associated with increased risks of CVD and all-cause mortality among individuals with or without hypertension. Our findings suggest that individuals should avoid unnecessary excessive sodium intake through sodium-containing acetaminophen use. [ABSTRACT FROM AUTHOR]

Metformin is hypothesized to protect against the risk of venous thromboembolism (VTE); however, there is a paucity of data supporting this hypothesis. Among individuals aged 40–90 years with a diagnosis of type 2 diabetes in the Health Improvement Network database (2000–2019), we compared the risks of incident VTE, pulmonary embolism, and deep vein thrombosis among metformin initiators with those among sulfonylurea initiators. Individuals were followed from their first prescription refill to an incident VTE, drug discontinuation, switching or augmenting, plan disenrollment, or the end of the study, whichever occurred first. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox model, adjusting for confounders using inverse probability of treatment weighting. Among 117,472 initiators of metformin and 13,835 initiators of sulfonylureas, 555 (1.3/1,000 person-years) and 75 (2.1/1,000 person-years) VTE cases occurred in each group, respectively. The multivariable-adjusted HR was 0.65 (95% CI: 0.51, 0.84). The corresponding risks for pulmonary embolism (adjusted HR = 0.71, 95% CI: 0.50, 1.01) and deep vein thrombosis (adjusted HR = 0.64, 95% CI: 0.48, 0.87) were also lower in metformin initiators than in sulfonylurea initiators. Our study provided empirical evidence to support a lower risk of VTE after initiation of metformin as compared with sulfonylureas among patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: 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. Methods: 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. Results: 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 HRadj being 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Objective: Hyperuricemia is a precursor to gout and is often present in other metabolic diseases that are promoted by microbiome dysbiosis. We undertook this study to examine the association of gut microbiota with hyperuricemia and serum urate levels in humans. Methods: Study participants were derived from a community‐based observational study, the Xiangya Osteoarthritis Study (discovery cohort). Hyperuricemia was defined as the presence of a serum urate level >357 μmoles/liter in women and >416 μmoles/liter in men. Gut microbiota were analyzed using 16S ribosomal RNA sequencing of stool samples. We examined the relationship of microbiota dysbiosis (i.e., richness, diversity, composition, and relative abundance of microbiota taxa) and predicted functional pathways to prevalent hyperuricemia and serum urate levels. We verified the associations in an independent observational study, the Step Study (validation cohort). Results: The discovery cohort consisted of 1,392 subjects from rural areas (mean age 61.3 years, 57.4% women, 17.2% with hyperuricemia). Participants with hyperuricemia had decreased richness and diversity, altered composition of microbiota, and lower relative abundances of genus Coprococcus compared to those with normouricemia. Predicted KEGG metabolism pathways including amino acid and nucleotide metabolisms were significantly altered in subjects with hyperuricemia compared to those with normouricemia. Gut microbiota richness, diversity, and low relative abundances of genus Coprococcus were also associated with high levels of serum urate. These findings were replicated in the validation cohort with 480 participants. Conclusion: Gut microbiota dysbiosis is associated with elevated serum urate levels. Our study examines the possibility that microbiota dysbiosis may modulate these levels. [ABSTRACT FROM AUTHOR]

Background: Two recent randomized clinical trials of escalating doses of allopurinol for the progression of chronic kidney disease (CKD) reported no benefits but potentially increased risk for death. Whether the risk could occur in patients with gout and concurrent CKD remains unknown.Objective: To examine the relation of allopurinol initiation, allopurinol dose escalation, and achieving target serum urate (SU) level after allopurinol initiation to all-cause mortality in patients with both gout and CKD.Design: Cohort study.Setting: The Health Improvement Network U.K. primary care database (2000 to 2019).Participants: Patients aged 40 years or older who had gout and concurrent moderate-to-severe CKD.Measurements: The association between allopurinol initiation and all-cause mortality over 5-year follow-up in propensity score (PS)-matched cohorts was examined. Analysis of hypothetical trials were emulated: achieving target SU level (<0.36 mmol/L) versus not achieving target SU level and dose escalation versus no dose escalation for mortality over 5-year follow-up in allopurinol initiators.Results: Mortality was 4.9 and 5.8 per 100 person-years in 5277 allopurinol initiators and 5277 PS-matched noninitiators, respectively (hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.93]). In the target trial emulation analysis, the HR of mortality for the achieving target SU level group compared with the not achieving target SU level group was 0.87 (CI, 0.75 to 1.01); the HR of mortality for allopurinol in the dose escalation group versus the no dose escalation group was 0.88 (CI, 0.73 to 1.07).Limitation: Residual confounding cannot be ruled out.Conclusion: In this population-based data, neither allopurinol initiation, nor achieving target SU level with allopurinol, nor allopurinol dose escalation was associated with increased mortality in patients with gout and concurrent CKD.Primary Funding Source: Project Program of National Clinical Research Center for Geriatric Disorders. [ABSTRACT FROM AUTHOR]

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 vitro up 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. [ABSTRACT FROM AUTHOR]

Objective: Systemic inflammatory factors have been implicated in symptomatic hand osteoarthritis (OA). Gut microbiome dysbiosis promotes systemic inflammation. The aim of this study was to examine the association between the gut microbiome and the presence of symptomatic hand OA in a population‐based study. Methods: Study participants were subjects of the Xiangya Osteoarthritis Study, a community‐based observational study conducted in the Hunan Province of China. Symptomatic hand OA was defined as the presence of both symptoms and radiographic OA in the same hand. The gut microbiome was analyzed using 16S ribosomal RNA gene sequencing in stool samples. We examined the relation of α‐diversity, β‐diversity, relative abundance of taxa, and potential bacterial functional pathways to symptomatic hand OA. Results: A total of 1,388 participants (mean age 61.3 years, 57.4% women) were included in the study, of whom 72 had symptomatic hand OA (prevalence of symptomatic hand OA 5.2%). Beta‐diversity of the gut microbiome, but not α‐diversity, was significantly associated with the presence of symptomatic hand OA (P = 0.003). Higher relative abundance of the genera Bilophila and Desulfovibrio as well as lower relative abundance of the genus Roseburia was associated with symptomatic hand OA. Most functional pathways (i.e., those annotated in the KEGG Ortholog hierarchy) that were observed to be altered in participants with symptomatic hand OA belonged to the amino acid, carbohydrate, and lipid metabolic pathways. Conclusion: This large, population‐based study provides the first evidence that alterations in the composition of the gut microbiome were observed among study participants who had symptomatic hand OA, and a low relative abundance of Roseburia but high relative abundance of Bilophila and Desulfovibrio at the genus level were associated with prevalent symptomatic hand OA. These findings may help investigators understand the role of the microbiome in the development of symptomatic hand OA and could contribute to potential translational opportunities. [ABSTRACT FROM AUTHOR]

Insufficient apoptosis of inflammatory macrophages and osteoclasts (OCs) in rheumatoid arthritis (RA) joints contributes toward the persistent progression of joint inflammation and destruction. Here, we deliver celastrol (CEL) to selectively induce apoptosis of OCs and macrophages in arthritic joints, with enzyme-responsive nanoparticles (termed PRNPs) composed of RGD modified nanoparticles (termed RNPs) covered with cleavable PEG chains. CEL-loaded PRNPs (CEL-PRNPs) dually target OCs and inflammatory macrophages derived from patients with RA via an RGD-αvβ3 integrin interaction after PEG cleavage by matrix metalloprotease 9, leading to increased apoptosis of these cells. In an adjuvant-induced arthritis rat model, PRNPs have an arthritic joint-specific distribution and CEL-PRNPs efficiently reduce the number of OCs and inflammatory macrophages within these joints. Additionally, rats with advanced arthritis go into inflammatory remission with bone erosion repair and negligible side effects after CEL-PRNPs treatment. These findings indicate potential for targeting chemotherapy-induced apoptosis in the treatment of advanced inflammatory arthritis. Celastrol might be useful in treating rheumatoid arthritis in part by inhibiting apoptosis of macrophages; however, systemic toxicity is a concern. Here the authors design celastrol-loaded nanoparticles that release a payload in response to MMP9 cleavage and show these NPs are effective at inducing apoptosis of human macrophages in vitro and a therapeutic effect with an adjuvant-induced arthritis model in rats. [ABSTRACT FROM AUTHOR]

Objective: 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. Methods: 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). Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) stress has been shown to promote chondrocyte apoptosis and osteoarthritis (OA) progression, but the precise mechanisms via which ER stress is modulated in OA remain unclear. Here we report that DEP domain‐containing mTOR‐interacting protein (DEPTOR) negatively regulated ER stress and OA development independent of mTOR signaling. DEPTOR is ubiquitinated in articular chondrocytes and its expression is markedly reduced along with OA progression. Deletion of DEPTOR in chondrocytes significantly promoted destabilized medial meniscus (DMM) surgery‐induced OA development, whereas intra‐articular injection of lentivirus‐expressing DEPTOR delayed OA progression in mice. Proteomics analysis revealed that DEPTOR interplayed with TRC8, which promoted TRC8 auto‐ubiquitination and degraded by the ubiquitin–proteasome system (UPS) in chondrocytes. Loss of DEPTOR led to TRC8 accumulation and excessive ER stress, with subsequent chondrocyte apoptosis and OA progression. Importantly, an inhibitor of ER stress eliminated chondrocyte DEPTOR deletion‐exacerbated OA in mice. Together, these findings establish a novel mechanism essential for OA pathogenesis, where decreasing DEPTOR in chondrocytes during OA progression relieves the auto‐ubiquitination of TRC8, resulting in TRC8 accumulation, excessive ER stress, and OA progression. Targeting this pathway has promising therapeutic potential for OA treatment. © 2020 American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Objectives To examine trends in the initial prescription of commonly-prescribed analgesics and patient- as well as practice-level factors related to their selection in incident OA. Methods Patients consulting with incident clinical OA between 2000–2016 were identified within The Health Improvement Network in the United Kingdom (UK) general practice. Excluded were patients who had history of cancer or were prescribed the analgesics of interest within 6 months before diagnosis of OA. Initial analgesic prescription included oral non-selective NSAID, oral selective cyclooxygenase-2 inhibitor, topical NSAID, paracetamol, topical salicylate or oral/transdermal opioid within 1 month after OA diagnosis. Results ∼44% of patients with incident OA (n  = 125 696) were prescribed one of these analgesics. Incidence of oral NSAID prescriptions decreased whereas other analgesic prescriptions, including oral opioid prescriptions, increased (all P -for-trend < 0.001). Patients with a history of gastrointestinal disease were more likely to receive topical NSAIDs, paracetamol or oral/transdermal opioids. Only 38% of patients with history of gastrointestinal disease and 21% of patients without it had co-prescription of gastroprotective agent with oral NSAIDs. Oral/transdermal opioid prescription was higher among the elderly (≥65 years), women, obesity, current smoker, and patients with gastrointestinal, cardiovascular or chronic kidney disease. Prescription of oral opioids increased with social deprivation (P -for-trend < 0.05) and was highest in Scotland, whereas transdermal opioid prescription was highest in Northern Ireland (all P -for-homogeneity-test < 0.05). Conclusion The initial prescription pattern of analgesics for OA has changed over time in the UK. Co-prescription of gastroprotective agents with oral NSAIDs remains suboptimal, even among those with prior gastrointestinal disease. [ABSTRACT FROM AUTHOR]

Objectives: Osteoarthritis is a leading cause of immobility and joint replacement, two strong risk factors for venous thromboembolism (VTE). We aimed to examine the relation of knee, hip and hand osteoarthritis to the risk of VTE and investigate joint replacement as a potential mediator.Methods: We conducted three cohort studies using data from The Health Improvement Network. Up to five individuals without osteoarthritis were matched to each case of incident knee (n=20 696), hip (n=10 411) or hand (n=6329) osteoarthritis by age, sex, entry time and body mass index. We examined the relation of osteoarthritis to VTE (pulmonary embolism and deep vein thrombosis) using a multivariable Cox proportional hazard model.Results: VTE developed in 327 individuals with knee osteoarthritis and 951 individuals without osteoarthritis (2.7 vs 2.0 per 1000 person-years), with multivariable-adjusted HR being 1.38 (95% CI 1.23 to 1.56). The indirect effect (HR) of knee osteoarthritis on VTE through knee replacement was 1.07 (95% CI 1.01 to 1.15), explaining 24.8% of its total effect on VTE. Risk of VTE was higher in hip osteoarthritis than non-osteoarthritis (3.3 vs 1.8 per 1000 person-years; multivariable-adjusted HR=1.83, 95% CI 1.56 to 2.13). The indirect effect through hip replacement yielded an HR of 1.14 (95% CI 1.04 to 1.25), explaining 28.1% of the total effect. No statistically significant difference in VTE risk was observed between hand osteoarthritis and non-osteoarthritis (1.5 vs 1.6 per 1000 person-years; multivariable-adjusted HR=0.88, 95% CI 0.67 to 1.16).Conclusion: Our large population-based cohort study provides the first evidence that knee or hip osteoarthritis, but not hand osteoarthritis, was associated with an increased risk of VTE, and such an association was partially mediated through knee or hip replacement. [ABSTRACT FROM AUTHOR]

Background: Denosumab is effective for osteoporosis, but discontinuation leads to rapid reversal of its therapeutic effect.Objective: To estimate the risk for fracture among users of denosumab who delayed subsequent doses compared with users who received doses on time.Design: Population-based cohort study.Setting: The Health Improvement Network U.K. primary care database, 2010 to 2019.Patients: Persons aged 45 years or older who initiated denosumab therapy for osteoporosis.Measurements: Observational data were used to emulate an analysis of a hypothetical trial with 3 dosing intervals: subsequent denosumab injection given within 4 weeks after the recommended date ("on time"), delay by 4 to 16 weeks ("short delay"), and delay by more than 16 weeks ("long delay"). The primary outcome was a composite of all fracture types at 6 months after the recommended date. Secondary outcomes were major osteoporotic fracture, vertebral fracture, hip fracture, and nonvertebral fracture.Results: Investigators identified 2594 patients initiating denosumab therapy. The risk for composite fracture over 6 months was 27.3 in 1000 for on-time dosing, 32.2 in 1000 for short delay, and 42.4 in 1000 for long delay. Compared with on-time injections, short delay had a hazard ratio (HR) for composite fracture of 1.03 (95% CI, 0.63 to 1.69) and long delay an HR of 1.44 (CI, 0.96 to 2.17) (P for trend = 0.093). For vertebral fractures, short delay had an HR of 1.48 (CI, 0.58 to 3.79) and long delay an HR of 3.91 (CI, 1.62 to 9.45).Limitation: Dosing schedules were not randomly assigned.Conclusion: Although delayed administration of subsequent denosumab doses by more than 16 weeks is associated with increased risk for vertebral fracture compared with on-time dosing, evidence is insufficient to conclude that fracture risk is increased at other anatomical sites with long delay.Primary Funding Source: National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation. [ABSTRACT FROM AUTHOR]

Objective Statins are reported to have a potential benefit on progression of OA and on disease activity in RA, but existing evidence is conflicting. Our objective was to examine whether statins associate with reduction in the risk for joint replacement due to OA and RA. Methods This was a propensity score-matched cohort study. Electronic health records from the UK Clinical Practice Research Datalink were used. We selected people prescribed statins and people never prescribed statins. Each statin user was matched to a non-user by age, gender, practice and propensity score for statin prescription. The main outcome measures were knee or hip joint replacement overall, and specifically because of OA or RA. The association between statins and risk of joint replacement was assessed using Cox proportional hazard regression. Statin exposure was categorized according to the potency of reducing low-density lipoprotein as low (21–28%), medium (32–38%) or high (42–55%) intensity. Results A total of 178 467 statin users were matched with 178 467 non-users by age, gender, practice and propensity score. Overall, statin was not associated with reduced risk of knee or hip replacement (hazard ratio 0.99, 95% CI: 0.97, 1.03), unless prescribed at high strength (0.86, 0.75–0.98). The reduced risk was only observed for joint replacement due to RA (0.77, 0.63–0.94) but not OA (0.97, 0.94–1.01). Conclusion Statins at high intensity may reduce the risk of hip or knee replacement. This effect may be RA specific. Further studies to investigate mechanisms of risk reduction and the impact in people with RA are warranted. [ABSTRACT FROM AUTHOR]

Several professional organizations have recommended tramadol as one of the first‐line or second‐line therapies for patients with chronic noncancer pain and its prescription has been increasing rapidly worldwide; however, the safety profile of tramadol, such as risk of fracture, remains unclear. This study aimed to examine the association of tramadol with risk of hip fracture. Among individuals age 50 years or older without a history of hip fracture, cancer, or opioid use disorder in The Health Improvement Network (THIN) database in the United Kingdom general practice (2000–2017), five sequential propensity score–matched cohort studies were assembled, ie, participants who initiated tramadol or those who initiated one of the following medications: codeine (n = 146,956) (another commonly used weak opioid), naproxen (n = 115,109) or ibuprofen (n = 107,438) (commonly used nonselective nonsteroidal anti‐inflammatory drugs [NSAIDs]), celecoxib (n = 43,130), or etoricoxib (n = 27,689) (cyclooxygenase‐2 inhibitors). The outcome was incident hip fracture over 1 year. After propensity‐score matching, the included participants had a mean age of 65.7 years and 56.9% were women. During the 1‐year follow‐up, 518 hip fracture (3.7/1000 person‐years) occurred in the tramadol cohort and 401 (2.9/1000 person‐years) occurred in the codeine cohort. Compared with codeine, hazard ratio (HR) of hip fracture for tramadol was 1.28 (95% confidence interval [CI] 1.13 to 1.46). Risk of hip fracture was also higher in the tramadol cohort than in the naproxen (2.9/1000 person‐years for tramadol, 1.7/1000 person‐years for naproxen; HR = 1.69, 95% CI 1.41 to 2.03), ibuprofen (3.4/1000 person‐years for tramadol, 2.0/1000 person‐years for ibuprofen; HR = 1.65, 95% CI 1.39 to 1.96), celecoxib (3.4/1000 person‐years for tramadol, 1.8/1000 person‐years for celecoxib; HR = 1.85, 95% CI 1.40 to 2.44), or etoricoxib (2.9/1000 person‐years for tramadol, 1.5/1000 person‐years for etoricoxib; HR = 1.96, 95% CI 1.34 to 2.87) cohort. In this population‐based cohort study, the initiation of tramadol was associated with a higher risk of hip fracture than initiation of codeine and commonly used NSAIDs, suggesting a need to revisit several guidelines on tramadol use in clinical practice. © 2020 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]