The Genetics and Functional Genomics of Osteoarthritis.

Osteoarthritis is the most prevalent whole-joint degenerative disorder, and is characterized by the degradation of articular cartilage and the underlying bone structures. Almost 600 million people are affected by osteoarthritis worldwide. No curative treatments are available, and management strategies focus mostly on pain relief. Here, we provide a comprehensive overview of the available human genetic and functional genomics studies for osteoarthritis to date and delineate how these studies have helped shed light on disease etiopathology. We highlight genetic discoveries from genome-wide association studies and provide a detailed overview of molecular-level investigations in osteoarthritis tissues, including methylation-, transcriptomics-, and proteomics-level analyses. We review how functional genomics data from different molecular levels have helped to prioritize effector genes that can be used as drug targets or drug-repurposing opportunities. Finally, we discuss future directions with the potential to drive a step change in osteoarthritis research.

Terminal Group Effect on Two-Dimensional Self-Assembly of Fluorenone-Based Liquid Crystals at the Solid/Liquid Interface.

Self-assemblies of two fluorenone-based derivatives (FE and FEC) consisting of a central 2,7-diphenyl-9-fluorenone polar moiety but differing in the flexible terminal groups were investigated by scanning tunneling microscopy (STM) at the 1-octanoic acid/HOPG interface under different concentrations and density functional theory calculation (DFT). STM results reveal a concentration-dependent polymorphic self-assembly behavior for FE, but without the presence of co-adsorbed solvents. As the concentration decreases, the dimer, bracket-like, and ribbon-like self-assembled structures were observed. On the contrary, FEC molecules assemble into only a type of oval-shaped morphology by the intermolecular N···H-O hydrogen bonds with the solvent molecules. Combined with DFT calculations, it can be deduced that the intermolecular van der Waals forces, dipole-dipole interactions, and hydrogen bonding are the main driving forces to stabilize the molecular packing of fluorenone-based polycatenars with strong polarity. Our work is of significance at the molecular level to further clarify the intermolecular interactions and conformational effects on the formation of molecular packing structures with liquid crystal property.

Effects of sand substrate removal on the intestinal antioxidant and metabolism in Marsupenaeus japonicus.

M. japonicus is an important specie for factory farming, and factory farming requires an environment with sand at the bottom of the pond. However, the physiological responses as well as survival in the process of factory farming without laying sand are currently unknown. In the present study, we explored the effect of sand substrate removal on the intestinal histomorphology, antioxidant enzyme activity, and metabolic profile of M. japonicus. Our results indicate a gradual increase in the mortality rate of kuruma shrimp in ponds lacking sand substrate. The intestinal mucosa exhibited necrosis and the presence of vacuoles, with their number gradually increasing over time. The intestinal villi showed significant erosion, accompanied by a decrease in intestinal superoxide dismutase (SOD) activity and catalase (CAT) activity, and consistent with an upregulation in the expression of apoptosis-related genes such as caspase-3, indicating an adaptive response to the adverse environmental conditions. Additionally, the metabolomic analysis revealed that most significantly differential metabolites were linked to amino acid and lipid metabolism. These findings enhance our understanding of the sand substrate removal on the intestinal health of kuruma shrimp, which provides a basis for the factory farming.

Comprehensive analysis on subchondral bone marrow lesions of human osteoarthritis by integrating bulk and single-cell transcriptomes.

OBJECTIVE: This study aims to demonstrate the cellular composition and underlying mechanisms in subchondral bone marrow lesions (BMLs) of knee osteoarthritis (OA). METHODS: BMLs were assessed by MRI Osteoarthritis Knee Score (MOAKS)≥2. Bulk RNA-sequencing (bulk-seq) and BML-specific differentially expressed genes (DEGs) analysis were performed among subchondral bone samples (including OA-BML=3, paired OA-NBML=3; non-OA=3). The hub genes of BMLs were identified by verifying in independent datasets and multiple bioinformatic analyses. To further estimate cell-type composition of subchondral bone, we utilized two newly developed deconvolution algorithms (MuSiC, MCP-counter) in transcriptomic datasets, based on signatures from open-accessed single-cell RNA sequencing (scRNA-seq). Finally, competing endogenous RNA (ceRNA) and transcription factor (TF) networks were constructed through multiple predictive databases, and validated by public non-coding RNA profiles. RESULTS: A total of 86 BML-specific DEGs (up 79, down 7) were identified. IL11 and VCAN were identified as core hub genes. The "has-miR-424-5p/lncRNA PVT1" was determined as crucial network, targeting IL11 and VCAN, respectively. More importantly, two deconvolution algorithms produced approximate estimations of cell-type composition, and the cluster of heterotopic-chondrocyte was discovered abundant in BMLs, and positively correlated with the expression of hub genes. CONCLUSION: IL11 and VCAN were identified as the core hub genes of BMLs, and their molecular networks were determined as well. We profiled the characteristics of subchondral bone at single-cell level and determined that the heterotopic-chondrocyte was abundant in BMLs and was closely linked to IL11 and VCAN. Our study may provide new insights into the microenvironment and pathological molecular mechanism of BMLs, and could lead to novel therapeutic strategies.

Metformin use and associated risk of total joint replacement in patients with type 2 diabetes: a population-based matched cohort study.

BACKGROUND: It is uncertain whether metformin use is associated with reduced risk of joint replacement in patients with type 2 diabetes mellitus. We aimed to establish whether metformin use was associated with a reduced risk of total knee replacement (TKR) or total hip replacement (THR) among these patients. METHODS: We selected patients with type 2 diabetes mellitus that was diagnosed between 2000 and 2012 from the Taiwan National Health Insurance Research Database. We used prescription time-distribution matching and propensity-score matching to balance potential confounders between metformin users and nonusers. We assessed the risks of TKR or THR using Cox proportional hazards regression. RESULTS: We included 20 347 participants who were not treated with metformin and 20 347 who were treated with metformin, for a total of 40 694 participants (mean age 63 yr, standard deviation 11 yr; 49.8% were women) after prescription time-distribution matching. Compared with participants who did not use metformin, those who used metformin had lower risks of TKR or THR (adjusted hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.60-0.81 for TKR or THR; adjusted HR 0.71, 95% CI 0.61-0.84 for TKR; adjusted HR 0.61, 95% CI 0.41-0.92 for THR) after adjustment for covariates. Propensity-score matching analyses (10 163 participants not treated with metformin v. 10 163 treated with metformin) and sensitivity analyses using inverse probability of treatment weighting and competing risk regression showed similar results. INTERPRETATION: Metformin use in patients with type 2 diabetes mellitus was associated with a significantly reduced risk of total joint replacement. Randomized controlled clinical trials in patients with osteoarthritis are warranted to determine whether metformin is effective in decreasing the need for joint replacement.

Effects of water recirculation rate on the microbial community and water quality in relation to the growth and survival of white shrimp (Litopenaeus vannamei).

BACKGROUND: Microbial community and its management are crucial to the stabilization of culture environment for recirculating aquaculture system (RAS). Although several studies have been carried out for the microbial community of RAS, few studies were on the RAS for shrimp. Water recirculation ratio is an important factor for the microbial community and the management of RAS. Therefore, low (LC), medium (MC) and high (HC) recirculation ratio systems were set to explore the microbial community constitution of RAS for Litopenaeus vannamei and study the effect of water recirculation rate on it. RESULTS: The bacterial community of bioreactor was mainly dominated by Proteobacteria (41.6-70.7%), followed with Planctomycetes (12.5-31.0%), Bacteroidetes (10.5-26.0%), Actinobacteria (1.1-4.8%) and Verrucomicrobia (1.4-6.8%) phylum. The most dominant family of bioreactor was Rhodobacteraceae or Planctomycetaceae. The bacterial community of culture water was simpler than bioreactor and dominated by Proteobacteria (61.8-96.4%). The dominant bacterial groups of bioreactor and culture water are also different among the three water recirculation rates, and the proportions of dominant groups showed a trend with the variety of water recirculation rate. Water quality indexes including ammonia and nitrite decreased with the increasing of water recirculation rate. According to the growth performance of L. vannamei, shrimp had better performance of growth rate and final weight in MC and HC, however, shrimp had higher survival and yield in LC. Shrimp survival and yield had an inverse correlation with water recirculation rate. CONCLUSIONS: The results demonstrate the microbial community of RAS for shrimp, highlight the importance of further studies on the function of bacterial taxa, and promote the understanding of the effects of water recirculation rate on the microbiota. The findings suggest that water recirculation rate has important impacts on the microbial community, water quality and shrimp growth. Increasing the water recirculation rate could improve the water quality and promote the growth of shrimp. However, the survival rate and yield of L. vannamei are higher under low water recirculation rate. Recirculation rate is an effective method to manage RAS, and its impact on RAS needs further study, especially in the application of low level of water recirculation.

Is returning farmland to forest an effective measure to reduce phosphorus delivery across distinct spatial scales?

As one typical land use change, the mechanism of returning farmland to forests (RFF) on nonpoint source pollution (NPS) is not clear, especially at multiple spatial scales. In this study, by using the Soil and Water Assessment Tool (SWAT), the changes in several flow-related and NPS-related indicators across several nested catchments were quantified and compared in the Three Gorges Reservoir Region, China. The results indicated that RFF could reduce the total flow and total phosphorus (TP), which are higher in the dry season (41% and 79%, respectively) than in the wet season (21% and 47%, respectively) at the watershed with a total area of 2423.74 km2. In comparison, RFF has a larger impact on the baseflow index during the wet season (367.02%) than during the dry season (166.54%). The results also indicated that a spatial scaling effect did exist, while the reduction in TP increased from 24.57% to 48.46% as the drainage area increased from 65.92 km2 to 2104.35 km2. Specific thresholds of RFF efficiency were also observed (approximately 2000 km2 for the study area). It is suggested that other source control measures could supplement RFF by stabilizing the efficiency of RFF across different spatial scales. The results of this study could provide valuable suggestions for land use development and water quality protection, especially for large, complex watersheds.

Association between cognitive vulnerability to depression - dysfunctional attitudes and glycaemic control among in-patients with type 2 diabetes in a hospital in Beijing: a multivariate regression analysis.

This cross-sectional study aimed to investigate the relationship between glycosylated haemoglobin (HbA1c) and cognitive vulnerability to depression (dysfunctional attitudes) in patients with type 2 diabetes mellitus. A total of 245 valid records from June 2016 to December 2016 were collected from a hospital in Beijing. Participants were asked to complete four questionnaires (Dysfunctional Attitudes Scale, Automatic Thoughts Questionnaire, Zung Self-rating Depression Scale, and World Health Organization Quality of Life Instrument-Short Form) to assess mental health and quality of life. Multivariate regression analysis was conducted to determine the correlations between HbA1c, mental health, quality of life and other clinical variables. The results showed that dysfunctional attitudes were associated with HbA1c, with a standardized regression coefficient (ß) of .13 (p = .01), although 1 h C-peptide (ß = -.75, p < .0001) was the most significant predictor of HbA1c in the regression model. The results indicated that dysfunctional attitudes, as a cognitive vulnerability to depression, were a relevant factor in HbA1c, although further studies are needed to establish the nature of the connection between dysfunctional attitudes and glycaemic control in diabetes patients.

The therapeutic effect and possible harm of puerarin for treatment of stage III diabetic nephropathy: a meta-analysis.

CONTEXT: Diabetic nephropathy (DN) is the main cause of end-stage kidney disease in developed countries. Current therapy can slow the rate of progression of DN, but eventually end-stage renal failure will occur in a proportion of patients. Identification of new strategies and additional complementary and alternative therapies for treating DN are important. OBJECTIVE: The research team wanted to assess the beneficial and harmful effects of using puerarin plus angiotensin converting enzyme inhibitor (ACEI) compared with using only ACEI for treatment of individuals with stage III DN. DESIGN: The research team performed a meta-analysis of randomized, controlled trials (RCTs) by searching the following electronic databases: (1) the Cochrane Database of Systematic Reviews, (2) the Cochrane Central Register of Controlled Trials (CENTRAL), (3) PubMed, (4) EMBASE (Elsevier), (5) the Allied and Complementary Medicine Database (AMED), (6) the Chinese Biomedicine Database (CBM), (7) the China National Knowledge Infrastructure (CNKI), and (8) the Chinese Biomedical Journals (VIP), with no language restrictions, as well as databases of clinical trials. OUTCOME MEASURES: Measured outcomes included (1) urinary protein measured as urinary albumin excretion rate (UAER) (µg/min) and 24-h urine protein (24-h UP) (mg/24 h); (2) renal function measured as blood urea nitrogen (BUN) (mmol/L) and serum creatinine (SCr) (µmol/L); (3) α1-microglobulin (α1-MG) (mg/24 h) and endothelin-1 (ET-1) (ng/24 h); (4) end points (EPs); and (5) adverse events (AEs). RESULTS: Ten RCTs involving 669 participants were included. All trials were conducted and published in China. Treatment of DN with puerarin plus ACEI significantly decreased the UAER-P < .0001, MD = -23.43 (95% CI, -33.95 to -12.91), and had no effect on 24-h UP-P = .09, MD = -56.76 (95% CI, -122.65 to 9.12); BUN-P = .17, MD = -0.51 (95% CI, -1.24 to 0.21); and SCr-P = .26, MD = -4.43 (95% CI, -12.05 to 3.20). One trial reported abdominal discomfort and nausea (2 cases) in the treatment group. CONCLUSIONS: Puerarin may be a beneficial therapy for treating DN; however, this hypothesis needs to be proven by additional high-quality studies using large samples and multicenter evidence.

The influence of shift work: A bibliometric analysis of research progress and frontiers on health effects.

Shift work has been found to disrupt the circadian system, leading to negative health effects. The objective of this study was to assess the progress and frontiers in research on the health-related influence of shift work. The study analyzed 3,696 data points from Web of Science, using the bibliometric software CiteSpace to visualize and analyze the field. The results showed a steady increase in annual publications, particularly in the last 5 years, with a rapid increase in publications from China. The United States contributed the most to the number of publications and worldwide collaborations. The most prolific institution and author were the Brigham and Women's Hospital and Professor Bjorn Bjorvatn, respectively. The Journal of Chronobiology International ranked at the top and focused primarily on shift worker research. In the first decade of study, the primary focus was on the associations between shift work and cardiovascular disease and metabolic disorders. Over time, research on the health effects of shift work has expanded to include cancer and mental health, with subsequent studies investigating molecular mechanisms. This study provides a comprehensive and intuitive analysis of the negative health impacts of shift work. It highlights existing research hotspots and provides a roadmap for future studies. Further research is needed to explore the adverse health consequences and related mechanisms of shift work exposure, as well as interventions to mitigate its health effects.

From reduction to rebalancing: Insights into the long-term effects of sediment dredging on nitrogen transformations in river ecosystems.

Although sediment dredging is a widely employed water management and restoration technique for the removal of internal nitrogen (N), the long-term effects of dredging on N transformation in dredged rivers remain largely undetermined. In this study, we investigated the effects of dredging on N transformation processes spanning three years at ten sites in the purple-soil watershed within the middle reaches of the Fu River Basin. We combined isotopic and molecular techniques to provide novel insights into the interactions associated with microbial utilization capacities between sediment and river water before, during, and after dredging. Initially, dredging was found to significantly reduce the total nitrogen content by approximately 75 %, although over time, there was a slight increase in concentrations. Secondly, significant reductions in microbial richness and diversity were detected in both river water and sediment, with 39 classes reduced, 12 new classes emerging, and an increase in archaea, reshaping the microbial community. Lastly, dredging was found to promote a significant shift in functional contributions, with increases in the abundance of key enzyme activities (1.7.5.1 and 1.7.2.5) and denitrification genes (nirK, norB, and nosZ). This enhancement notably promoted denitrification and dissimilatory nitrate reduction to ammonium (DNRA), accompanied by significant environmental changes in sediment and river water. These changes facilitated the removal of nitrates in the Xiangshuitan watershed. Our study overcomes the limitations associated with watershed and microenvironment scales, providing insights into the mechanisms where by dredging activities influence the interplay between external and internal N transformations.

The cumulative effects of cascade reservoirs control nitrogen and phosphorus flux: Base on biogeochemical processes.

The reservoir serves as a water source, a flood control structure, a navigational aid, and also impacts the downstream ecosystem as well as the reservoir zone. However, debate exists about effectiveness of cascade reservoirs in controlling the transportation of nutrients, particularly in the Yangtze River basin, which has been significantly affected by reservoir development. This research develops a new model X-NPSEM (X with Nitrogen and Phosphorus Steady-state Reservoir Model) based on biogeochemical processes of nitrogen and phosphorus reaction for investigating the dynamic storage capacity of cascade reservoirs at both reservoir- and watershed scales. Then the cumulative effects of cascade reservoirs and the related mechanism were investigated in Fujiang watershed, China. Based on the results, cascade reservoirs retained 16.3 % of nitrogen fluxes and 37.6 % of phosphorus fluxes annually. Downstream reservoirs have higher retention rates of phosphorus (0.48/d) compared to upstream reservoirs (0.10/d), mainly due to inflow sediment. Nitrogen retention rates show seasonal variations: wet season (0.21/d) and dry season (0.17/d). These fluctuations in nitrogen retention are primarily influenced by changes in temperature rather than other factors such as operation period, nitrogen and phosphorus concentration, or the nitrogen/phosphorus ratio. In upstream, the concentration of sediment entering the reservoir plays a decisive role in the transformation of P retention from sink to source. The X-NPSRM coupler model could be used for global reservoir operation and watershed management.

Associations of childhood-to-adulthood body size trajectories and genetic susceptibility with the risks of osteoarthritis: a population-based cohort study of UK Biobank data.

BACKGROUND: Large adulthood body size was associated with increased risk of osteoarthritis. We aimed to examine the association between body size trajectories from childhood to adulthood and potential interactions with genetic susceptibility on osteoarthritis risk. METHODS: We included participants from the UK Biobank aged 38-73 years in 2006-10. Childhood body size information was collected by questionnaire. Adulthood BMI was assessed and transformed into three categories (<25 kg/m2 for normal, 25-29·9 kg/m2 for overweight, and >30 kg/m2 for obesity). A Cox proportional hazards regression model was applied to assess the association between body size trajectories and osteoarthritis incidence. Osteoarthritis-related polygenic risk score (PRS) was constructed to evaluate its interactions with body size trajectories on osteoarthritis risk. FINDINGS: For the 466 292 participants included, we identified nine body size trajectories [thinner to normal (11·6%), overweight (17·2%), or obesity (26·9%); average to normal (11·8%), overweight (16·2%), or obesity (23·7%); and plumper to normal (12·3%), overweight (16·2%), or obesity (23·6%)]. Compared with individuals in the average-to-normal group, all other trajectory groups had higher risks of osteoarthritis, after adjustment for demographic, social-economic and lifestyle covariates (hazard ratios [HRs] 1·05-2·41; all p<0·01). Among them, thinner-to-obesity (HR 2·41; 95% CI 2·23-2·49) had the most prominent association with increased osteoarthritis risk. A high PRS was significantly associated with an increased risk of osteoarthritis (1·14; 1·11-1·16), whereas no interaction between childhood-to-adulthood body size trajectories and PRS on osteoarthritis risks was observed. The population attributable fraction suggested that body size towards normal in adulthood could eliminate osteoarthritis cases by 18·67% for thinner-to-overweight to 38·74% for plumper-to-obesity. INTERPRETATION: Average-to-normal body size seems to be the healthiest childhood-to-adulthood trajectory for osteoarthritis risk, whereas a trajectory of increased body size from thinner to obesity has the highest risk for osteoarthritis. These associations are independent of osteoarthritis genetic susceptibility. FUNDING: The National Natural Science Foundation of China (32000925) and Guangzhou Science and Technology Program (202002030481).

Osteoporosis and osteoarthritis: a bi-directional Mendelian randomization study.

OBJECTIVE: To investigate the causal relationship between low bone mineral density (BMD) and osteoarthritis (OA) using Mendelian randomization (MR) design. METHODS: Two-sample bi-directional MR analyses were performed using summary-level information on OA traits from UK Biobank and arcOGEN. Sensitivity analyses including MR-Egger, simple median, weighted median, MR pleiotropy residual sum, and outlier approaches were utilized in conjunction with inverse variance weighting (IVW). Gene ontology (GO) enrichment analyses and expression quantitative trait locus (eQTL) colocalization analyses were used to investigate the potential mechanism and shared genes between osteoporosis (OP) and OA. RESULTS: The IVW method revealed that genetically predicted low femoral neck BMD was significantly linked with hip (ß = 0.105, 95% CI: 0.023-0.188) and knee OA (ß = 0.117, 95% CI: 0.049-0.184), but not with other site-specific OA. Genetically predicted low lumber spine BMD was significantly associated with OA at any sites (ß = 0.048, 95% CI: 0.011-0.085), knee OA (ß = 0.101, 95% CI: 0.045-0.156), and hip OA (ß = 0.150, 95% CI: 0.077-0.224). Only hip OA was significantly linked with genetically predicted reduced total bone BMD (ß = 0.092, 95% CI: 0.010-0.174). In the reverse MR analyses, no evidence for a causal effect of OA on BMD was found. GO enrichment analysis and eQTL analysis illustrated that DDN and SMAD-3 were the most prominent co-located genes. CONCLUSIONS: These findings suggested that OP may be causally linked to an increased risk of OA, indicating that measures to raise BMD may be effective in preventing OA. More research is required to determine the underlying processes via which OP causes OA.

The effect of systemic iron status on osteoarthritis: A mendelian randomization study.

Objective: To assess the causal effect of systemic iron status by using four biomarkers (serum iron; transferrin saturation; ferritin; total iron-binding capacity) on knee osteoarthritis (OA), hip OA, total knee replacement, and total hip replacement using 2-sample Mendelian randomization (MR) design. Methods: Three instrument sets were used to construct the genetic instruments for the iron status: Liberal instruments (variants associated with one of the iron biomarkers), sensitivity instruments (liberal instruments exclude variants associated with potential confounders), and conservative instruments (variants associated with all four iron biomarkers). Summary-level data for four OA phenotypes, including knee OA, hip OA, total knee replacement, and total hip replacement were obtained from the largest genome-wide meta-analysis with 826,690 individuals. Inverse-variance weighted based on the random-effect model as the main approach was conducted. Weighted median, MR-Egger, and Mendelian randomization pleiotropy residual sum and outlier methods were used as sensitivity MR approaches. Results: Based on liberal instruments, genetically predicted serum iron and transferrin saturation were significantly associated with hip OA and total hip replacement, but not with knee OA and total knee replacement. Statistical evidence of heterogeneity across the MR estimates indicated that mutation rs1800562 was the SNP significantly associated with hip OA in serum iron (odds ratio, OR = 1.48), transferrin saturation (OR = 1.57), ferritin (OR = 2.24), and total-iron binding capacity (OR = 0.79), and hip replacement in serum iron (OR = 1.45), transferrin saturation (OR = 1.25), ferritin (OR = 1.37), and total-iron binding capacity (OR = 0.80). Conclusion: Our study suggests that high iron status might be a causal factor of hip OA and total hip replacement where rs1800562 is the main contributor.

Data processing and analysis in real-world traditional Chinese medicine clinical data: challenges and approaches.

Traditional Chinese medicine (TCM) is a clinical-based discipline in which real-world clinical practice plays a significant role for both the development of clinical therapy and theoretical research. The large-scale clinical data generated during the daily clinical operations of TCM provide a highly valuable knowledge source for clinical decision making. Secondary analysis of these data would be a vital task for TCM clinical studies before the randomised controlled trials are conducted. In this article, we discuss the challenges and issues, such as structured data curation, data preprocessing and quality, large-scale data management and complex data analysis requirements, in the data processing and analysis of real-world TCM clinical data. Furthermore, we also discuss related state-of-the-art research and solutions in China. We have shown that the clinical data warehouse based on the collection of structured electronic medical record data and clinical terminology would be a promising approach for generating clinical hypotheses and helping the discovery of clinical knowledge from large-scale real-world TCM clinical data.

New framework for managing the water environmental capacity integrating the watershed model and stochastic algorithm.

Integrated calculations of pollution load and water environmental capacity (WEC) are essential for effective water quality management. However, few studies have focused on the dynamic WEC and pollution load in a nonpoint source pollution (NPS)-dominant temperate monsoon watershed under changing rainfall conditions. In this study, a new framework based on the watershed model and WEC calculation with stochastic rainfall input (SR-WEC), was proposed to reveal the dynamic WEC and pollution load under changing rainfall conditions. Stochastic rainfall series was generated by a first-order Markov chain and gamma distribution, and further input into the Soil and Water Assessment Tool (SWAT) to explore the dynamic response of water quality to rainfall. The framework was applied to the Daning River watershed, Three Georges Reservoir Region, China. The results suggested that compared with the new SR-WEC, the traditional return period method with limited observed rainfall input would result in an underestimation of ideal WEC and NPS pollution load by 23% and 48% for TN and 48% and 51% for TP, respectively. Approximately 46% of the annual TN reduction and 51% of the annual TP reduction were concentrated from April to June in a relatively small area. The regression relationships between rainfall and the ideal WEC, pollution load and remnant WEC obtained by the SR-WEC were superior to those of the traditional method, with R2 values increasing from 0.005-0.797 to 0.718-0.989. Specific threshold (120 mm/month for the study area) was observed for the effect of rainfall on water quality, beyond which the remnant WEC of organic N would change from decreasing to increasing. The new framework proposed identifies the key periods and areas with consideration of uncertainty of rainfall on water quality, and provides basis for NPS pollution management.

Association between Metformin Use and Risk of Total Knee Arthroplasty and Degree of Knee Pain in Knee Osteoarthritis Patients with Diabetes and/or Obesity: A Retrospective Study.

Objectives: We aimed to examine whether metformin (MET) use is associated with a reduced risk of total knee arthroplasty (TKA) and low severity of knee pain in patients with knee osteoarthritis (OA) and diabetes and/or obesity. Methods: Participants diagnosed with knee OA and diabetes and/or obesity from June 2000 to July 2019 were selected from the information system of a local hospital. Regular MET users were defined as those with recorded prescriptions of MET or self-reported regular MET use for at least 6 months. TKA information was extracted from patients' surgical records. Knee pain was assessed using the numeric rating scale. Log-binomial regression, linear regression, and propensity score weighting (PSW) were performed for statistical analyses. Results: A total of 862 participants were included in the analyses. After excluding missing data, there were 346 MET non-users and 362 MET users. MET use was significantly associated with a reduced risk of TKA (prevalence ratio: 0.26, 95% CI: 0.15 to 0.45, p < 0.001), after adjustment for age, gender, body mass index, various analgesics, and insurance status. MET use was significantly associated with a reduced degree of knee pain after being adjusted for the above covariates (ß: −0.48, 95% CI: −0.91 to −0.05, p = 0.029). There was a significantly accumulative effect of MET use on the reduced risk of TKA. Conclusion: MET can be a potential therapeutic option for OA. Further clinical trials are needed to determine if MET can reduce the risk of TKA and the severity of knee pain in metabolic-associated OA patients.

Osteophytes mediate the associations between cartilage morphology and changes in knee symptoms in patients with knee osteoarthritis.

AIMS: To investigate whether the associations between cartilage defects and cartilage volumes with changes in knee symptoms were mediated by osteophytes. METHODS: Data from the Vitamin D Effects on Osteoarthritis (VIDEO) study were analyzed as a cohort. The Western Ontario and McMaster Universities Osteoarthritis Index was used to assess knee symptoms at baseline and follow-up. Osteophytes, cartilage defects, and cartilage volumes were measured using magnetic resonance imaging at baseline. Associations between cartilage morphology and changes in knee symptoms were assessed using linear regression models, and mediation analysis was used to test whether these associations were mediated by osteophytes. RESULTS: A total of 334 participants (aged 50 to 79 years) with symptomatic knee osteoarthritis were included in the analysis. Cartilage defects were significantly associated with change in total knee pain, change in weight-bearing pain, and change in non-weight-bearing pain after adjustment for age, sex, body mass index, and intervention. Cartilage volume was significantly associated with change in weight-bearing pain and change in physical dysfunction after adjustment. Lateral tibiofemoral and patellar osteophyte mediated the associations of cartilage defects with change in total knee pain (49-55%) and change in weight-bearing pain (61-62%) and the association of cartilage volume with change in weight-bearing pain (27-30%) and dysfunction (24-25%). Both cartilage defects and cartilage volume had no direct effects on change in knee symptoms. CONCLUSIONS: The significant associations between cartilage morphology and changes in knee symptoms were indirect and were partly mediated by osteophytes.

Effect of Tempering Treatment on Microstructural Evolution and Mechanical Behavior of Heavy-Wall Heat Induction Seamless Bend Pipe.

In this paper, the microstructure and mechanical properties of heavy-wall seamless bend pipe after quenching at different tempering temperatures, including 550 °C, 600 °C, 650 °C, and 700 °C, were studied. Microstructure and dislocations observations were characterized by means of an optical microscope, a scanning electron microscope, a transmission electron microscope, and X-ray diffraction. As the tempering temperature increases, the dislocation density in the test steel gradually decreases, and the precipitation behavior of (Nb, V)(C, N) increases. The sample tempered at 650 °C exhibits a granular bainite structure with a dislocation cell structure and a large number of smaller precipitates. The yield platforms of tempered samples at 650 °C and 700 °C are attributed to the pinning effect of the Cottrell atmosphere on dislocations. The sample tempered at 650 °C not only presents the highest strength, but also the highest uniform elongation, which is attributed to the higher strain-hardening rate and instantaneous work-hardening index. This is closely related to the multiplication of dislocations, the interaction between dislocations and dislocations, and the interaction between dislocations and precipitates during plastic deformation of the 650 °C-tempered samples with low dislocation density, which delays the occurrence of necking.