Aged bone marrow macrophages drive systemic aging and age-related dysfunction via extracellular vesicle-mediated induction of paracrine senescence.

The accumulation and systemic propagation of senescent cells contributes to physiological aging and age-related pathology. However, which cell types are most susceptible to the aged milieu and could be responsible for the propagation of senescence has remained unclear. Here we found that physiologically aged bone marrow monocytes/macrophages (BMMs) propagate senescence to multiple tissues, through extracellular vesicles (EVs), and drive age-associated dysfunction in mice. We identified peroxisome proliferator-activated receptor α (PPARα) as a target of microRNAs within aged BMM-EVs that regulates downstream effects on senescence and age-related dysfunction. Demonstrating therapeutic potential, we report that treatment with the PPARα agonist fenofibrate effectively restores tissue homeostasis in aged mice. Suggesting conservation to humans, in a cohort study of 7,986 participants, we found that fenofibrate use is associated with a reduced risk of age-related chronic disease and higher life expectancy. Together, our findings establish that BMMs can propagate senescence to distant tissues and cause age-related dysfunction, and they provide supportive evidence for fenofibrate to extend healthy lifespan.

Weight loss after initiating anti-obesity medications and gout among overweight and obesity individuals: a population-based cohort study.

OBJECTIVES: Weight loss is conditionally recommended for gout management; however, its impact on incident gout and recurrent gout flares among overweight and obese individuals remains unknown. We aimed to investigate the relationship between weight loss rate following the initiation of anti-obesity medications and the risk of incident gout and recurrent gout flares among overweight/obese individuals. METHODS: Using data from The Health Improvement Network, we selected individuals aged 18 and older who were overweight or obese and started anti-obesity medication. We emulated a target trial to examine the association of different weight loss rates, slow (2-5%), moderate (5-10%), or fast (≥10%), within the first year of treatment with incident gout and recurrent gout flares during a 5-year follow-up period. RESULTS: Among 131,000 participants without gout starting orlistat, the 5-year risk of incident gout was 1.6% for those with weight gain/stable, compared with 1.5%, 1.3%, and 1.2% for those with slow, moderate, and fast weight loss, respectively. Compared with the weight gain/stable arm, the hazard ratios were 0.91 (95% confidence interval [CI]: 0.81 to 1.01), 0.82 (95%CI: 0.72 to 0.92), and 0.73 (95%CI: 0.62 to 0.86) for slow, moderate and fast rate of weight loss arms, respectively. Similar results were observed for the recurrent gout flares among 3,847 overweight or obese individuals with gout starting orlistat. CONCLUSIONS: A higher rate of weight loss after initiating orlistat within 1-year was associated with lower risks of incident gout and lower rates of recurrent gout flares among overweight or obese people.

Bidirectional association identified between synovitis and knee and hand osteoarthritis: a general population-based study.

Background: 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. Methods: We conducted a prospective cohort study based on the baseline and three-year follow-up data from the Xiangya Osteoarthritis (XO) Study. We assessed bidirectional associations between ultrasound-detected synovitis and radiographic and symptomatic OA at knee and hand sites using generalized estimating equations. Additionally, we performed bidirectional Mendelian randomization (MR) analyses to test these hypotheses utilising whole-genome sequencing data in the XO population. Age, sex, body mass index, smoking, alcohol consumption, educational level, physical activity, and joint injury history were adjusted for these analyses. Findings: A total of 2211, 2420, 2280, and 2600 participants were enrolled for analyses of radiographic knee OA (RKOA), symptomatic knee OA (SKOA), radiographic hand OA (RHOA) and symptomatic hand OA (SHOA), respectively. The baseline synovitis (i.e., with synovitis vs. without synovitis) was associated with the incident RKOA (76/277 vs. 557/3674 knees), SKOA (49/387 vs. 287/4213 knees), RHOA (171/358 vs. 686/3664 hands) and SHOA (35/689 vs. 76/4327 hands), with adjusted odds ratio (aORs) of 2.2 (95% CI 1.7-3.1), 2.0 (1.3-2.9), 3.4 (2.7-4.4), and 2.4 (1.5-3.8), respectively. The baseline RKOA (with OA vs. without OA: 409/1246 vs. 481/3758 knees), SKOA (200/576 vs. 675/4356 knees), RHOA (192/778 vs. 410/3723 hands), and SHOA (41/162 vs. 548/4285 hands) were also associated with the incident synovitis, with aORs of 3.4 (95% CI 2.9-4.1), 2.7 (2.1-3.4), 2.3 (1.8-2.9) and 1.9 (1.2-2.8), respectively. These bidirectional associations were stronger when more active synovitis was compared with the reference group (all P < 0.05). MR analyses further supported bidirectional associations that synovitis significantly increased the odds of incident OA at both sites and vice versa (all ORs ranged from 1.2-1.7). Interpretation: Our population-based cohort study found novel evidence of a bidirectional association between synovitis and OA, which was further validated through MR analysis and suggested that the bidirectional association is likely causal. Our findings indicated that synovitis is both a risk factor and a consequence of the OA rather than solely a risk factor. Funding: The National Key Research and Development Plan, the National Natural Science Foundation of China, the Key Research and Development Program of Hunan Province, the Natural Science Foundation of Hunan Province, the Central South University Innovation-Driven Research Programme, and the Fundamental Research Funds for the Central Universities of Central South University.

Memantine attenuates the development of osteoarthritis by blocking NMDA receptor mediated calcium overload and chondrocyte senescence.

Background: 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. Methods: The protein levels of NMDA receptor and its agonistic ligand, glutamate, were compared between normal and OA chondrocytes. The quantity of intracellular calcium ions and the level of mitochondrial damage were evaluated using specific fluorescent probes and transmission electron microscopy (TEM), respectively. Chondrocyte senescence was evaluated by senescence-associated ß-galactosidase (SA-ß-Gal) staining and p16INK4a analysis. The function of NMDA receptor in chondrocyte senescence and OA was tested via agonists activation and gene knockdown experiments. The therapeutic effects of memantine on OA were examined both in vitro and in vivo. Additionally, to verify the findings from animal samples, a propensity score-matched cohort study was conducted using data from a United Kingdom primary care database (i.e., IQVIA Medical Research Database [IMRD]) to compare the risk of OA-related joint replacement involved in memantine initiators versus active comparators (i.e., acetylcholinesterase [AchE] initiators) in patients with dementia. Results: The protein expression of NMDA receptor and the secretion of glutamate were both significantly increased in OA chondrocytes. NMDA receptor activation was found to stimulate chondrocyte calcium overload, which further led to mitochondrial fragmentation and chondrocyte senescence. Blocking the NMDA receptor with memantine and N-methyl-D-aspartate receptor subunit 1(NR1, the gene encoding NMDA receptor) knockdown resulted in reduced calcium influx, mitochondrial fragmentation, as well as cellular senescence in OA chondrocytes. Intra-articular injection of memantine in OA mice also exhibited protective effects against cartilage degeneration. Moreover, in the 1:5 propensity score-matched cohort study consisting of 6218 patients (n = 1435 in the memantine cohort; n = 4783 in the AchE cohort), the memantine initiator was associated with a lower risk of OA-related joint replacement than AchE initiators (Hazard ratio = 0.56, 95 % confidence interval: 0.34 to 0.99). Conclusion: NMDA receptor plays an important role in inflammatory-induced cytotoxic calcium overload in chondrocytes, while memantine can effectively block the NMDA receptor to reduce chondrocyte senescence and retard the development of OA. The translational potential of this article: As a clinically licensed drug used for the treatment of dementia, memantine has shown promising therapeutic effects on OA. Mechanistically, it functions by blocking NMDA receptor from mediating chondrocyte senescence. The protective effects of memantine against OA were verified not only by in vivo and in vitro experiments but also via a propensity score-matched human cohort study. These findings presented robust evidence for repurposing memantine for the treatment of OA.

Macrophage-derived extracellular vesicles regulate skeletal stem/progenitor Cell lineage fate and bone deterioration in obesity.

Obesity-induced chronic inflammation exacerbates multiple types of tissue/organ deterioration and stem cell dysfunction; however, the effects on skeletal tissue and the underlying mechanisms are still unclear. Here, we show that obesity triggers changes in the microRNA profile of macrophage-secreted extracellular vesicles, leading to a switch in skeletal stem/progenitor cell (SSPC) differentiation between osteoblasts and adipocytes and bone deterioration. Bone marrow macrophage (BMM)-secreted extracellular vesicles (BMM-EVs) from obese mice induced bone deterioration (decreased bone volume, bone microstructural deterioration, and increased adipocyte numbers) when administered to lean mice. Conversely, BMM-EVs from lean mice rejuvenated bone deterioration in obese recipients. We further screened the differentially expressed microRNAs in obese BMM-EVs and found that among the candidates, miR-140 (with the function of promoting adipogenesis) and miR-378a (with the function of enhancing osteogenesis) coordinately determine SSPC fate of osteogenic and adipogenic differentiation by targeting the Pparα-Abca1 axis. BMM miR-140 conditional knockout mice showed resistance to obesity-induced bone deterioration, while miR-140 overexpression in SSPCs led to low bone mass and marrow adiposity in lean mice. BMM miR-378a conditional depletion in mice led to obesity-like bone deterioration. More importantly, we used an SSPC-specific targeting aptamer to precisely deliver miR-378a-3p-overloaded BMM-EVs to SSPCs via an aptamer-engineered extracellular vesicle delivery system, and this approach rescued bone deterioration in obese mice. Thus, our study reveals the critical role of BMMs in mediating obesity-induced bone deterioration by transporting selective extracellular-vesicle microRNAs into SSPCs and controlling SSPC fate.

The mediation effects of malalignment on the relation of sex to the risk of incidence tibiofemoral osteoarthritis.

OBJECTIVE: To investigate to what extent the higher risk of tibiofemoral radiographic osteoarthritis (TFROA) in females vs. males can be explained by knee malalignment. DESIGN: Using data from Multicenter Osteoarthritis Study (MOST) and Osteoarthritis Initiative (OAI), we examined the relation of sex to the incident medial and lateral TFROA and performed mediation analyses to assess to what extent varus and valgus malalignments account for sex differences in the incident medial or lateral TFROA. RESULTS: Of the 3462 knees without medial and lateral TFROA in MOST, the 7-year risks of medial and lateral TFROA were 16.9% and 10.0% in females, and 15.8% and 4.2% in males, respectively. Females had 2.31-fold (95% confidence interval [95% CI]: 1.73 to 3.08) higher incident lateral TFROA than males, and the relative risk (RR) of the indirect effect of sex on lateral TFROA through valgus malalignment was 1.15 (95% CI: 1.09 to 1.20), accounting for 23% of its total effect on lateral TFROA. In OAI (n = 3095 knees), females had 1.54-fold (95% CI: 1.15 to 2.04) higher incident lateral TFROA than males, and RR of the indirect effect of sex on lateral TFROA through valgus malalignment was 1.10 (95% CI: 1.04 to 1.21), accounting for 26% of its total effect on lateral TFROA. No apparent sex difference in the incident medial TFROA was found in MOST (RR = 1.05, 95% CI: 0.89 to 1.25) or OAI (RR = 1.02, 95% CI: 0.84 to 1.19). CONCLUSION: Females had a higher risk of developing lateral TFROA than males; however, valgus malalignment only modestly explained such a difference.

Mechanical protein polycystin-1 directly regulates osteoclastogenesis and bone resorption.

Mechanical loading is required for bone homeostasis, but the underlying mechanism is still unclear. Our previous studies revealed that the mechanical protein polycystin-1 (PC1, encoded by Pkd1) is critical for bone formation. However, the role of PC1 in bone resorption is unknown. Here, we found that PC1 directly regulates osteoclastogenesis and bone resorption. The conditional deletion of Pkd1 in the osteoclast lineage resulted in a reduced number of osteoclasts, decreased bone resorption, and increased bone mass. A cohort study of 32,500 patients further revealed that autosomal dominant polycystic kidney disease, which is mainly caused by loss-of-function mutation of the PKD1 gene, is associated with a lower risk of hip fracture than those with other chronic kidney diseases. Moreover, mice with osteoclast-specific knockout of Pkd1 showed complete resistance to unloading-induced bone loss. A mechanistic study revealed that PC1 facilitated TAZ nuclear translocation via the C-terminal tail-TAZ complex and that conditional deletion of Taz in the osteoclast lineage resulted in reduced osteoclastogenesis and increased bone mass. Pharmacological regulation of the PC1-TAZ axis alleviated unloading- and estrogen deficiency- induced bone loss. Thus, the PC1-TAZ axis may be a potential therapeutic target for osteoclast-related osteoporosis.

Association of Regular Opioid Use With Incident Dementia and Neuroimaging Markers of Brain Health in Chronic Pain Patients: Analysis of UK Biobank.

OBJECTIVES: We aimed to investigate the association of regular opioid use, compared with non-opioid analgesics, with incident dementia and neuroimaging outcomes among chronic pain patients. DESIGN: The primary design is a prospective cohort study. To triangulate evidence, we also conducted a nested case-control study analyzing opioid prescriptions and a cross-sectional study analyzing neuroimaging outcomes. SETTING AND PARTICIPANTS: Dementia-free UK Biobank participants with chronic pain and regular analgesic use. MEASUREMENTS: Chronic pain status and regular analgesic use were captured using self-reported questionnaires and verbal interviews. Opioid prescription data were obtained from primary care records. Dementia cases were ascertained using primary care, hospital, and death registry records. Propensity score-matched Cox proportional hazards analysis, conditional logistic regression, and linear regression were applied to the data in the prospective cohort, nested case-control, and cross-sectional studies, respectively. RESULTS: Prospective analyses revealed that regular opioid use, compared with non-opioid analgesics, was associated with an increased dementia risk over the 15-year follow-up (Hazard ratio [HR], 1.18 [95% confidence interval (CI): 1.08-1.30]; Absolute rate difference [ARD], 0.44 [95% CI: 0.19-0.71] per 1000 person-years; Wald χ2 = 3.65; df = 1; p <0.001). The nested case-control study suggested that a higher number of opioid prescriptions was associated with an increased risk of dementia (1 to 5 prescriptions: OR = 1.21, 95% CI: 1.07-1.37, Wald χ2 = 3.02, df = 1, p = 0.003; 6 to 20: OR = 1.27, 95% CI: 1.08-1.50, Wald χ2 = 2.93, df = 1, p = 0.003; more than 20: OR = 1.43, 95% CI: 1.23-1.67, Wald χ2 = 4.57, df = 1, p < 0.001). Finally, neuroimaging analyses revealed that regular opioid use was associated with lower total grey matter and hippocampal volumes, and higher white matter hyperintensities volumes. CONCLUSION: Regular opioid use in chronic pain patients was associated with an increased risk of dementia and poorer brain health when compared to non-opioid analgesic use. 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.

A colorimetric sensor based on 4-MPBA Au@AgNPs for accurately identification of EnshiYulu tea grade.

Enshi Yulu green tea (ESYL) is the most representative traditional steamed green tea in Enshi, Hubei. Different ESYL grades exhibit distinct flavors, tastes, and prices. In this study, a visual sensor based on 4-MPBA Au@AgNPs was developed for the rapid and accurate identification of ESYL grades. The recognition mechanism involved the binding of 4-MPBA Au@AgNPs with polyphenolic compounds in ESYL to form borate esters and the conversion of Ag+ to Ag0, with the generated Ag0 depositing on the surface of 4-MPBA Au@AgNPs. The results showed that the sensor can amplify the color differences of different grades of ESYL. The visual results were also validated by the partial least squares discriminant analysis model, demonstrating an enhancement in recognition accuracy from 68.2 % to 95.5 % compared to the original extraction solution. The colorimetric sensor developed in this study is expected to provide a new approach for traceability research of other foods.

Association Between Hyperuricemia and Ultrasound-Detected Hand Synovitis.

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.

Global burden of early-onset osteoarthritis, 1990-2019: results from the Global Burden of Disease Study 2019.

OBJECTIVES: Early-onset osteoarthritis (OA) is an emerging health issue amidst the escalating prevalence of overweight and obesity. However, there are scant data on its disease, economic burden and attributable burden due to high body mass index (BMI). METHODS: Using data from the Global Burden of Diseases Study 2019, we examined the numbers of incident cases, prevalent cases, years lived with disability (YLDs) and corresponding age-standardised rates for early-onset OA (diagnosis before age 55) from 1990 to 2019. The case definition was symptomatic and radiographically confirmed OA in any joint. The average annual percentage changes (AAPCs) of the age-standardised rates were calculated to quantify changes. We estimated the economic burden of early-onset OA and attributable burden to high BMI. RESULTS: From 1990 to 2019, the global incident cases, prevalent cases and YLDs of early-onset OA were doubled. 52.31% of incident OA cases in 2019 were under 55 years. The age-standardised rates of incidence, prevalence and YLDs increased globally and for countries in all Sociodemographic Index (SDI) quintiles (all AAPCs>0, p<0.05), with the fastest increases in low-middle SDI countries. 98.04% of countries exhibited increasing trends in all age-standardised rates. Early-onset OA accounts for US$46.17 billion in healthcare expenditure and US$60.70 billion in productivity loss cost in 2019. The attributable proportion of high BMI for early-onset OA increased globally from 9.41% (1990) to 15.29% (2019). CONCLUSIONS: Early-onset OA is a developing global health problem, causing substantial economic costs in most countries. Targeted implementation of cost-effective policies and preventive intervention is required to address the growing health challenge.

Trends and benefits of early hip arthroplasty for femoral neck fracture in China: a national cohort study.

BACKGROUND: Limited studies have examined the benefits of early arthroplasty within 48 h from admission to surgery for femoral neck fractures (FNFs). Using the national inpatient database, the authors aimed to investigate the trends in early arthroplasty within 48 h for FNFs in China and to assess its effect on in-hospital complications and 30-day readmission patterns. MATERIALS AND METHODS: This was a retrospective cohort study. Patients receiving primary total hip arthroplasty (THA) or hemiarthroplasty (HA) for FNFs in the Hospital Quality Monitoring System between 2013 and 2019 were included. After adjusting for potential confounders with propensity score matching, a logistic regression model was performed to compare the differences in in-hospital complications [i.e. in-hospital death, pulmonary embolism, deep vein thrombosis (DVT), wound infection, and blood transfusion], rates and causes of 30-day readmission between early and delayed arthroplasty. RESULTS: During the study period, the rate of early THA increased from 18.0 to 19.9%, and the rate of early HA increased from 14.7 to 18.4% ( P <0.001). After matching, 11 731 pairs receiving THA and 13 568 pairs receiving HA were included. Compared with delayed THA, early THA was associated with a lower risk of pulmonary embolism [odds ratio (OR) 0.51, 95% CI: 0.30-0.88], DVT (OR 0.59, 95% CI: 0.50-0.70), blood transfusion (OR 0.62, 95% CI: 0.55-0.70), 30-day readmission (OR 0.82, 95% CI: 0.70-0.95), and venous thromboembolism-related readmission (OR 0.50, 95% CI: 0.34-0.74). Similarly, early HA was associated with a lower risk of DVT (OR 0.70, 95% CI: 0.61-0.80) and blood transfusion (OR 0.74, 95% CI: 0.68-0.81) than delayed HA. CONCLUSION: Despite a slight increase, the rate of early arthroplasty remained at a low level in China. Given that early arthroplasty can significantly improve prognosis, more efforts are needed to optimize the procedure and shorten the time to surgery.

Melatonin is a potential novel analgesic agent for osteoarthritis: Evidence from cohort studies in humans and preclinical research in rats.

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.

Phenotypes of osteoarthritis-related knee pain and their transition over time: data from the osteoarthritis initiative.

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.

Age-related secretion of grancalcin by macrophages induces skeletal stem/progenitor cell senescence during fracture healing.

Skeletal stem/progenitor cell (SSPC) senescence is a major cause of decreased bone regenerative potential with aging, but the causes of SSPC senescence remain unclear. In this study, we revealed that macrophages in calluses secrete prosenescent factors, including grancalcin (GCA), during aging, which triggers SSPC senescence and impairs fracture healing. Local injection of human rGCA in young mice induced SSPC senescence and delayed fracture repair. Genetic deletion of Gca in monocytes/macrophages was sufficient to rejuvenate fracture repair in aged mice and alleviate SSPC senescence. Mechanistically, GCA binds to the plexin-B2 receptor and activates Arg2-mediated mitochondrial dysfunction, resulting in cellular senescence. Depletion of Plxnb2 in SSPCs impaired fracture healing. Administration of GCA-neutralizing antibody enhanced fracture healing in aged mice. Thus, our study revealed that senescent macrophages within calluses secrete GCA to trigger SSPC secondary senescence, and GCA neutralization represents a promising therapy for nonunion or delayed union in elderly individuals.

Secular trend of gout incidence in the UK: an age-period-cohort analysis.

OBJECTIVES: The incidence of gout in the UK appears to have declined since 2013; however, whether such a trend occurred across participants born in different years (ie, birth cohort) is unknown. We aimed to examine the effects of the birth cohort on gout incidence using an age-period-cohort (APC) model. DESIGN: Cross-sectional study. SETTING: Nationwide data from the UK primary care database. PARTICIPANTS: Individuals between 30 and 89 years of age were included. We excluded individuals who had gout history when entering the database and individuals with less than 1 year of continuous follow-up between 1 January 1999 and 31 December 2019. PRIMARY AND SECONDARY OUTCOME MEASURES: Gout was identified using READ codes assigned by general practitioners. The incidence of gout between 1999-2013 and 2011-2019 was analysed with APC model. RESULTS: The incidence of gout between 1999 and 2013 increased with birth cohorts. Compared with those born in 1949-1953 (reference), the age-adjusted and period-adjusted rate ratios (RRs) of incident gout increased from 0.39 (95% CI 0.34 to 0.46) in participants born in 1910-1914 to 2.36 (95% CI 2.09 to 2.66) in participants born in 1979-1983 (p for trend <0.001). In contrast, the incidence of gout between 2011 and 2019 decreased with birth cohorts. Compared with those born in 1949-1953 (reference), the age-adjusted and period-adjusted RRs of incident gout declined from 2.75 (95% CI 2.30 to 3.28) in participants born in 1922-1926 to 0.75 (95% CI 0.65 to 0.87) in participants born in 1976-1980 but then increased slightly to 0.95 (95% CI 0.77 to 1.17) in participants born in 1985-1989. CONCLUSIONS: The gout incidence between 1999 and 2013 in the UK increased with the birth cohorts and then decreased between 2011 and 2019 except for those born after 1980. Future monitoring is needed to help identify aetiological factors and guide preventive and treatment strategies for gout.

Trends, complications, and readmission of allogeneic red blood cell transfusion in primary total hip arthroplasty in china: a national retrospective cohort study.

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.

Diagnostic Accuracy of Ultrasound for Assessment of Synovial Abnormalities Among Patients With Knee Pain: A Meta-Analysis.

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.