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Abstract Background To investigate the associations between folate intake and changes in knee pain, inflammation mediators and comorbid conditions over 2 years in patients with symptomatic knee osteoarthritis (OA). Methods A post-hoc analysis was performed based on data from the VIDEO study, a multicenter, randomized, double-blind, placebo-controlled clinical trial aimed at assessing the impact of vitamin D supplementation on patients with knee OA who were also vitamin D deficient. The original trial’s design and inclusion and exclusion criteria were integrated into this subsequent post-hoc analysis. The average daily folate intake was evaluated using the Dietary Questionnaire for Epidemiological Studies version 2 over two years. The progression of knee symptoms was monitored at the baseline and then at months 3, 6, 12, and 24, utilizing the Western Ontario and McMaster Universities Index alongside a 100-mm visual analog scale. Levels of serum inflammatory mediators were quantified using ELISA techniques. Assessments of knee joint structures, leg muscle strength, depressive symptoms, feet pain, and low back pain were treated at both baseline and follow-up intervals. Results Folate intake was correlated with reductions in overall knee pain, dysfunction, and stiffness, as well as decreased levels of Leptin and Apelin. Additionally, it was associated with enhanced leg muscle strength and diminished feet and low back pain. However, there is no association between folate intake and alterations in serum cytokine levels or knee joint structural changes. Within the subsets of overall knee pain, a significant relationship was identified between folate intake and the reduction of pain experienced when ascending or descending stairs and standing for two years. Conclusions Folate intake was linked with reduced knee pain, lower levels of adipokines, and a decreased prevalence of comorbid conditions in individuals with knee OA, implying that folate consumption may be associated with an improvement in knee OA symptoms, but further research is needed to verify this association.

Abstract Background Repetitive transcranial magnetic stimulation (rTMS) has been used to treat various neurological disorders. However, the molecular mechanism underlying the therapeutic effect of rTMS on Parkinson’s disease (PD) has not been fully elucidated. Neuroinflammation like regulatory T-cells (Tregs) appears to be a key modulator of disease progression in PD. If rTMS affects the peripheral Tregs in PD remains unknown. Methods Here, we conducted a prospective clinical study (Chinese ClinicalTrials. gov: ChiCTR 2100051140) involving 54 PD patients who received 10-day rTMS (10 Hz) stimulation on the primary motor cortex (M1) region or sham treatment. Clinical and function assessment as well as flow cytology study were undertaken in 54 PD patients who were consecutively recruited from the department of neurology at Zhujiang hospital between September 2021 and January 2022. Subsequently, we implemented flow cytometry analysis to examine the Tregs population in spleen of MPTP-induced PD mice that received rTMS or sham treatment, along with quantitative proteomic approach reveal novel molecular targets for Parkinson's disease, and finally, the RNA interference method verifies the role of these new molecular targets in the treatment of PD. Results We demonstrated that a 10-day rTMS treatment on the M1 motor cortex significantly improved motor dysfunction in PD patients. The beneficial effects persisted for up to 40 days, and were associated with an increase in peripheral Tregs. There was a positive correlation between Tregs and motor improvements in PD cases. Similarly, a 10-day rTMS treatment on the brains of MPTP-induced PD mice significantly ameliorated motor symptoms. rTMS reversed the downregulation of circulating Tregs and tyrosine hydroxylase neurons in these mice. It also increased anti-inflammatory mediators, deactivated microglia, and decreased inflammatory cytokines. These effects were blocked by administration of a Treg inhibitor anti-CD25 antibody in MPTP-induced PD mice. Quantitative proteomic analysis identified TLR4, TH, Slc6a3 and especially Syt6 as the hub node proteins related to Tregs and rTMS therapy. Lastly, we validated the role of Treg and rTMS-related protein syt6 in MPTP mice using the virus interference method. Conclusions Our clinical and experimental studies suggest that rTMS improves motor function by modulating the function of Tregs and suppressing toxic neuroinflammation. Hub node proteins (especially Syt6) may be potential therapeutic targets. Trial registration Chinese ClinicalTrials, ChiCTR2100051140. Registered 15 December 2021, https://www.chictr.org.cn/bin/project/edit?pid=133691 Graphical Abstract rTMS is a safe and non-invasive method for Parkinson's disease. In this study, we showed the proportion of CD4+CD25+CD127- regulatory T-cells (Tregs) in the peripheral blood was significantly increased after rTMS treatment. Similar effects of rTMS treatment were verified in MPTP-induced PD mice. Proteomic analysis and RNA interference analyses identified TLR4, TH, Slc6a3 and especially Syt6 as hub node proteins that can be modulated by rTMS therapy in PD.

Abstract Background Osteoarthritis is a prevalent musculoskeletal condition, but the role of specific serum biomarkers, such as calcium, vitamin D, and C-reactive protein (CRP), in predicting mortality among individuals with osteoarthritis remains unclear. Methods This observational study analyzed longitudinal data from over 500,000 participants in the UK Biobank, identifying those with osteoarthritis using ICD-9/10 codes or self-reported history. We performed multivariable cox-regression and flexible parametric survival model (FPSM) for survival analysis, with adjustments made through the inverse probability of treatment weight (IPTW) for baseline covariates identified by directed acyclic graphs (DAGs). Results Of the 49,082 osteoarthritis population, the average age was 60.69 years, with 58.7% being female. During the follow-up period exceeding 15 years, a total of 5,522 people with osteoarthritis died. High serum calcium levels, compared to normal serum calcium levels, were significantly associated with all-cause mortality (hazard ratio (HR) 1.33, 95% confidence interval (CI) 1.11, 1.59), cardiovascular diseases (CVD)-related deaths (HR 1.55, 95% CI 1.05, 2.29), and other deaths (HR 1.59, 95% CI 1.20, 2.11). Low serum calcium levels, compared to normal serum calcium levels, was linked with CVD-related deaths (HR 2.06, 95% CI 1.02, 4.14). Vitamin D insufficiency, compared to sufficient vitamin D levels, was correlated with all-cause mortality (HR 1.22, 95% CI 1.13, 1.33), CVD-related deaths (HR 1.43, 95% CI 1.20, 1.72), and other deaths (HR 1.26, 95% CI 1.09, 1.45) but not with cancer-related deaths. High serum CRP levels, compared to normal CRP levels, were associated with all outcomes (all-cause mortality: HR 1.22, 95% CI 1.12, 1.33; CVD-related death: HR 1.24, 95%CI 1.03, 1.49; cancer-related death: HR 1.23, 95% CI 1.09, 1.40; other deaths: HR 1.19, 95%CI 1.03, 1.38). Conclusions Both high and low serum calcium levels, elevated CRP, and vitamin D insufficiency are potential predictors of increased mortality risk in the osteoarthritis population. These findings emphasize the importance of monitoring and possibly addressing these serum biomarkers in osteoarthritis populations to improve long-term outcomes. Further studies are needed to understand the underlying mechanisms and to propose therapeutic interventions.

Background: Though anterior cruciate ligament (ACL) tear has been widely accepted as an important accelerator for knee osteoarthritis (KOA), the role of intrinsic ACL degeneration in developing KOA has not been fully investigated. Purpose: To determine whether ACL degeneration, in the absence of ACL tear, is associated with incident KOA over 4 years. Study design: Cohort study; Level of evidence, 2. Methods: Participants’ knees in this nested case–control study were selected from the Osteoarthritis Initiative (OAI) study, with Kellgren–Lawrence grading (KLG) of 0 or 1 ​at baseline (BL). Case knees which had incident KOA (KLG ≥2) over 4 years, were matched 1:1 with control knees by gender, age and radiographic status. ACL signal intensity alteration (0–3 scale) and volume were assessed as compositional feature and morphology of ACL degeneration, using knee MRI at P0 (time of onset of incident KOA), P-1 (1 year prior to P0) and baseline. Conditional logistic regression was applied to analyze the association between measures of ACL degeneration and incident KOA. Results: 337 case knees with incident KOA were matched to 337 control knees. Participants were mostly female (68.5%), with an average age of 59.9 years old. ACL signal intensity alterations at BL, P-1 and P0 were significantly associated with an increased odds of incident KOA respectively (all P for trend ≤0.001). In contrast, ACL volumes were not significantly associated with incident KOA at any time points. Conclusions: ACL signal intensity alteration is associated with increased incident KOA over 4 years, whereas ACL volume is not.The translational potential of this article: This paper focused on ACL signal intensity alteration which could better reflect ACL degeneration rather than ACL tear during the progression of KOA and explored this topic in a nested case–control study. Utilizing MR images from KOA participants, we extracted the imaging features of ACL. In addition, we established a semi-quantitative score for ACL signal intensity alteration and found a significant correlation between it and KOA incidence. Our findings confirmed that the more severe the ACL signal intensity alteration, the stronger relationship with the occurrence of KOA. This suggests that more emphasis should be placed on ACL degeneration rather than ACL integrity in the future.

Abstract Retinal thickness is related to Parkinson’s disease (PD), but its association with the severity of PD is still unclear. We conducted a Mendelian randomized (MR) study to explore the association between retinal thickness and PD. For the two-sample MR analysis, the summary statistics obtained from genome-wide association studies on the thickness of Retinal nerve fiber layer (RNFL) and ganglion cell inner plexiform layer (GCIPL) were employed as exposure, while the summary statistics associated with PD were used as the outcome. The primary approach utilized was inverse variance weighted. To correct for multiple testing, the false discovery rate (FDR) was employed. For sensitivity analysis, an array of robust MR methods was utilized. We found genetically predicted significant association between reduced RNFL thickness and a reduced risk of constipation in PD (odds ratio [OR] = 0.854, 95% confidence interval [CI] (0.782, 0.933), P

Abstract 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 (β = 0.105, 95% CI: 0.023–0.188) and knee OA (β = 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 (β = 0.048, 95% CI: 0.011–0.085), knee OA (β = 0.101, 95% CI: 0.045–0.156), and hip OA (β = 0.150, 95% CI: 0.077–0.224). Only hip OA was significantly linked with genetically predicted reduced total bone BMD (β = 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.

Abstract Objectives This study aimed to investigate the long-term effect of vitamin D supplementation compared to placebo over 5 years in participants with knee osteoarthritis (OA). We also aimed to describe the effect of maintaining sufficient serum vitamin D levels over five years in knee OA. Methods Participants (n = 173) from the Hobart centre of the Vitamin D Effects on Osteoarthritis (VIDEO) trial were extensively followed up 3 years after the cessation of 2-year investigational treatment. Participants were classified as maintaining sufficient vitamin D (n = 79) and not maintaining sufficient vitamin D (n = 61) groups. Results There was no significant difference in change in the knee symptoms, depression, and serum levels of IL6 and hs-CRP between both comparisons after 3 years of cessation of the clinical trial. However, among participants who reported no knee surgery (KS), there was a significant improvement in WOMAC function (β: − 83.7, 95% CI: − 167.3, 0) and depression scores (β: − 1.3, 95% CI: − 2.3, − 0.2) in vitamin D group compared to the placebo group. Similarly, those who maintained adequate vitamin D levels over 5 years had significantly less WOMAC knee pain (β: − 33.9, 95% CI: − 65.7, − 2) and physical dysfunction (β: − 105.5, 95% CI: − 198.2, − 12.8) than participants with vitamin D deficiency over 5 years. Conclusion Vitamin D supplementation over 2 years or maintaining vitamin D sufficiency for 5 years was not associated with statistically significant differences in change in knee symptom scores over 5 years. However, among participants who did not report KS, 2-year vitamin D supplementation and maintaining sufficient vitamin D was linked to modest improvements in knee symptoms and depression scores in knee OA.

Abstract 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.

Cluster analysis of 3D head shapes plays a crucial role in the mass customization design of products related to the head. Head shapes exhibit variations across different races, and designing helmets exclusively for Chinese individuals cannot solely rely on or reference foreign head models. Currently, research on cluster analysis of Chinese head shapes is limited, especially concerning shape variances. To address this, we developed an improved k-medoids algorithm and integrated Cluster Validity Index as an assessment metric. This enabled us to cluster 339 Chinese young males aged 18 to 30 into 7 groups based on their head shapes. By comparing our improved algorithm to the traditional k-medoids method, we affirmed its superiority in achieving higher sample participation rates and reducing inter-cluster sample disparities. To simplify the helmet design and editing process, and to improve the efficiency of mass customization, we have developed a parametric modeling program for bicycle helmets based on the head shape clustering results. Results from the Helmet Fit Index and stress simulation analysis demonstrate that our approach significantly enhances helmet fit and wearer comfort.

Abstract Infrapatellar fat pad (IPFP) is closely associated with the development and progression of knee osteoarthritis (OA), but the underlying mechanism remains unclear. Here, it is find that IPFP from OA patients can secret small extracellular vesicles (sEVs) and deliver them into articular chondrocytes. Inhibition the release of endogenous osteoarthritic IPFP‐sEVs by GW4869 significantly alleviated IPFP‐sEVs‐induced cartilage destruction. Functional assays in vitro demonstrated that IPFP‐sEVs significantly promoted chondrocyte extracellular matrix (ECM) catabolism and induced cellular senescence. It is further demonstrated that IPFP‐sEVs induced ECM degradation in human and mice cartilage explants and aggravated the progression of experimental OA in mice. Mechanistically, highly enriched let‐7b‐5p and let‐7c‐5p in IPFP‐sEVs are essential to mediate detrimental effects by directly decreasing senescence negative regulator, lamin B receptor (LBR). Notably, intra‐articular injection of antagomirs inhibiting let‐7b‐5p and let‐7c‐5p in mice increased LBR expression, suppressed chondrocyte senescence and ameliorated the progression of experimental OA model. This study uncovers the function and mechanism of the IPFP‐sEVs in the progression of OA. Targeting IPFP‐sEVs cargoes of let‐7b‐5p and let‐7c‐5p can provide a potential strategy for OA therapy.

Abstract Vitamin D deficiency is a globally common situation and closely related with many chronic diseases. It is a hot topic to examine if vitamin D supplementation is effective for the treatment of diseases, and there have been dozens of clinical trials published in recent years. However, most studies have not proved the extra‐skeletal benefits of vitamin D supplementation on these diseases. Some inherent shortcomings of these trials, such as inclusion with vitamin D‐sufficient and obese participants, low response rate from participants and the insensitive changes in chosen outcomes over a shorter period, may be main reasons why most studies have yet to demonstrate effects of vitamin D supplementation. In this editorial, we aim to discuss the perspectives on how can we design a proper trial for vitamin D treatment of diseases based on the evidence‐based practice framework PICOS (participants, intervention, control, outcomes and study design) in the future. First, right participants should be chosen, which is crucial for the success of vitamin D clinical trials. Participants with vitamin D sufficiency (e.g., baseline 25(OH)D of >50 nmol/L), obesity (e.g., body mass index > 30 kg/m2) and/or high vitamin D response index could be excluded from the trials. Second, intervention with vitamin D in right forms or dosages should be used. Vitamin D3 supplementation with appropriate dosages that keep 25(OH)D levels between 75 and 100 nmol/L is recommended. Third, ‘contamination’ in the control groups needs to pay attention. To diminish this, it is ideal to include participants less interfered by sun exposure (such as living in places at a high latitude) or with greater compliance (less interference by supplemental vitamin D‐containing nutrients). Fourth, the outcome measures should be sensitive to change to avoid type II error. For outcomes such as bone density, radiographic osteoarthritis and cardiovascular diseases, follow‐up period of 3–5 years may be required to observe the changes. Last, precision clinical trials may be the only way to prove the benefits of vitamin D supplementation.

Abstract Background Repetitive transcranial magnetic stimulation (rTMS), as a non-invasive brain stimulation technique, has shown potentials for consciousness recovery of patients with disorders of consciousness (DoC), as, to a certain extent, it is effective in regulating the excitability of central nervous system. However, it is difficult to achieve satisfactory effect with “one size fits all” rTMS treatment due to different clinical conditions of patients. There is an urgent need to develop individualized strategy to improve the effectiveness of rTMS on patients with DoC. Methods Our protocol is a randomized double-blind sham-controlled crossover trial that includes 30 DoC patients. Each patient will received 20 sessions, in which 10 sessions will be rTMS-active stimulus, and the other 10 sessions will be sham stimulus, separated by no less than 10 days’ washout period. The rTMS-active will include 10 Hz rTMS over the individualized-targeted selection area for each patient according to the different insult regions of the brain. Coma Recovery Scale-Revised (CRS-R) will be used as primary outcome at baseline, after the first stage of stimulation, at the end of the washout period, and after the second stage of stimulation. Secondary outcomes will be measured at the same time, including efficiency, relative spectral power, and functional connectivity of high-density electroencephalograph (EEG). Adverse events will be recorded during the study. Discussion rTMS has obtained grade A evidence in treating patients with several central nervous system diseases, and there has been some evidence showing partial improvement on level of consciousness in DoC patients. However, the effectiveness of rTMS in DoC is only 30~36%, mostly due to the non-specific target selection. In this protocol, we present a double-blind crossover randomized sham-controlled trial based on the individualized-targeted selection strategy that aims to study the effectiveness of rTMS therapy for DoC, and the result may provide new insights to non-invasive brain stimulation. Trial registration ClinicalTrials.gov : NCT05187000. Registered on January 10, 2022.

ABSTRACTThe musculoskeletal system is important for balancing metabolic activity and maintaining health. Recent studies have shown that distortions in homeostasis of the intestinal microbiota are correlated with or may even contribute to abnormalities in musculoskeletal system function. Research has also shown that the intestinal flora and its secondary metabolites can impact the musculoskeletal system by regulating various phenomena, such as inflammation and immune and metabolic activities. Most of the existing literature supports that reasonable nutritional intervention helps to improve and maintain the homeostasis of intestinal microbiota, and may have a positive impact on musculoskeletal health. The purpose of organizing, summarizing and discussing the existing literature is to explore whether the intervention methods, including nutritional supplement and moderate exercise, can affect the muscle and bone health by regulating the microecology of the intestinal flora. More in-depth efficacy verification experiments will be helpful for clinical applications.

AbstractBackground Although there is an assertion that weather conditions affect osteoarthritis (OA) pain, the results from clinical studies remain inconsistent. This meta-analysis was performed to evaluate the association between weather conditions and OA pain.Methods Cochrane Library, Embase, PubMed, and Web of Science were searched from inception to September 30, 2022. Observational studies that explored all weather conditions associated with pain intensity were included. In the systematic review, the methodological quality of the selected studies was assessed and a best-evidence synthesis was used to make qualitative conclusions. Based on homogeneous results, Fisher’s Z scores derived from the effect size of temperature (T), barometric pressure (BP) or relative humidity (RH) related to OA pain were synthesized and further transformed to the correlation coefficients (summary r) in meta-analysis.Results A total of 14 studies were included in the best-evidence synthesis of a qualitative systematic review. There was strong evidence with 13 of 14 studies reporting consistent findings that weather factors in general, including any kind of meteorological condition, were associated with OA pain. Subsequently, 3 studies regarding BP or T, and 5 studies regarding RH with the pain of OA were included in quantitative meta-analyses. Both BP (pooled Fisher’s Z = 0.37, 95% CI 0.15 to 0.59; summary r = 0.35, 95% CI 0.15 to 0.53) and RH (pooled Fisher’s Z = 0.10, 95% CI 0.01 to 0.18; summary r = 0.086, 95% CI −0.05 to 0.22) were positively related to OA pain, while T was negatively related to OA pain (pooled Fisher’s Z = −0.38, 95% CI −0.60 to −0.16; summary r = −0.36, 95% CI −0.54 to −0.16).Conclusions In this study, weather factors in general were significantly associated with OA pain. It may provide useful references for the daily health management of OA. More studies designed with the consistent meteorological condition are warranted to validate the findings.KEY MESSAGEMany people with osteoarthritis think their joint pain is affected by the weather, while the association between OA pain and weather conditions is still unclear.This is a systematic review and meta-analysis of 14 observational studies for the association between weather conditions and OA pain.Weather conditions appear to be associated with OA pain. Barometric pressure and relative humidity were positively correlated to OA pain intensity, while temperature was negatively correlated to OA pain.

Rheumatoid arthritis (RA) is a common chronic inflammatory disease characterized by the proliferation of fibroblast-like synoviocytes (FLS), pannus development, cartilage, and bone degradation, and, eventually, loss of joint function. Fibroblast activating protein (FAP) is a particular product of activated FLS and is highly prevalent in RA-derived fibroblast-like synoviocytes (RA-FLS). In this study, zinc ferrite nanoparticles (ZF-NPs) were engineered to target FAP+ (FAP positive) FLS. ZF-NPswere discovered to better target FAP+ FLS due to the surface alteration of FAP peptide and to enhance RA-FLS apoptosis by activating the endoplasmic reticulum stress (ERS) system via the PERK-ATF4-CHOP, IRE1-XBP1 pathway, and mitochondrial damage of RA-FLS. Treatment with ZF-NPs under the influence of an alternating magnetic field (AMF) can significantly amplify ERS and mitochondrial damage via the magnetocaloric effect. It was also observed in adjuvant-induced arthritis (AIA) mice that FAP-targeted ZF-NPs (FAP-ZF-NPs) could significantly suppress synovitis in vivo, inhibit synovial tissue angiogenesis, protect articular cartilage, and reduce M1 macrophage infiltration in synovium in AIA mice. Furthermore, treatment of AIA mice with FAP-ZF-NPs was found to be more promising in the presence of an AMF. These findings demonstrate the potential utility of FAP-ZF-NPs in the treatment of RA.

Abstract 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.

Abstract Objective The aim of this study was to explore the longitudinal associations between baseline quadriceps strength and knee joint structural abnormalities in knee osteoarthritis (KOA). Methods This study is a longitudinally observational study based on Osteoarthritis Initiative (OAI) cohort, including men and women aged 45–79. Quadriceps strength was measured by isometric knee extension testing at baseline. Knee joint structural abnormalities, including cartilage damage, bone marrow lesions (BMLs), effusion-synovitis and Hoffa-synovitis, were evaluated by Magnetic Resonance Imaging Osteoarthritis Knee Score (MOAKS) at baseline and 1-year follow-up. Generalized estimating equations were employed to examine the associations between quadriceps strength and knee structural abnormalities. All analyses were stratified by sex. Results One thousand three hundred thirty-eight participants (523 men and 815 women) with a mean age of 61.8 years and a mean BMI of 29.4 kg/m2 were included in this study. For men, no significantly longitudinal association of quadriceps strength with structural abnormalities was detected. In contrast, quadriceps strength was significantly and negatively associated with changes in cartilage damage and BMLs in lateral patellofemoral joint (PFJ) (cartilage damage: OR: 0.91, 95% CI 0.84 to 0.99, P = 0.023; BMLs: OR: 0.85, 95% CI 0.74 to 0.96, P = 0.011) and effusion-synovitis (OR = 0.88, 95% CI 0.78 to 0.99, P = 0.045) among females longitudinally. Higher quadriceps strength was significantly associated with less progression of lateral PFJ cartilage damage, BMLs and effusion-synovitis in females. Conclusions Higher quadriceps strength was associated with changes in cartilage damage and BMLs within the lateral PFJ and effusion-synovitis among females, suggesting the potential protective role of quadriceps strength on joint structures in women.

Osteoarthritis (OA) is the most prevalent musculoskeletal disease characterized by multiple joint structure damages, including articular cartilage, subchondral bone and synovium, resulting in disability and economic burden. Bone marrow lesions (BMLs) are common and important magnetic resonance imaging (MRI) features in OA patients. Basic and clinical research on subchondral BMLs in the pathogenesis of OA has been a hotspot. New evidence shows that subchondral bone degeneration, including BML and angiogenesis, occurs not only at or after cartilage degeneration, but even earlier than cartilage degeneration. Although BMLs are recognized as important biomarkers for OA, their exact roles in the pathogenesis of OA are still unclear, and disputes about the clinical impact and treatment of BMLs remain. This review summarizes the current basic and clinical research progress of BMLs. We particularly focus on molecular pathways, cellular abnormalities and microenvironmental changes of subchondral bone that contributed to the formation of BMLs, and emphasize the crosstalk between subchondral bone and cartilage in OA development. Finally, potential therapeutic strategies targeting BMLs in OA are discussed, which provides novel strategies for OA treatment.

Abstract Background To describe the longitudinal associations between the morphological parameters of proximal tibiofibular joint (PTFJ) and joint structural changes in tibiofemoral compartments in patients with knee osteoarthritis (OA). Methods The participants were selected from the Vitamin D Effects on Osteoarthritis (VIDEO) study. PTFJ morphological parameters were measured on coronal and sagittal MRI. The contacting area (S) of PTFJ and its projection areas onto the horizontal (load-bearing area, Sτ), sagittal (lateral stress-bolstering area, Sφ), and coronal plane (posterior stress-bolstering area, Sυ) were assessed. Knee structural abnormalities, including cartilage defects, bone marrow lesions (BMLs), and cartilage volume, were evaluated at baseline and after 2 years. Log binominal regression models and linear regression models were used to assess the associations between PTFJ morphological parameters and osteoarthritic structural changes. Results In the longitudinal analyses, the S (RR: 1.45) and Sτ (RR: 1.55) of PTFJ were significantly and positively associated with an increase in medial tibial (MT) cartilage defects. The Sτ (β: − 0.07), Sυ (β: − 0.07), and S (β: − 0.06) of PTFJ were significantly and negatively associated with changes in MT cartilage volume. The Sτ (RR: 1.55) of PTFJ was positively associated with an increase in MT BMLs, and Sφ (RR: 0.35) was negatively associated with an increase in medial femoral BMLs. Conclusions This longitudinal study suggests that higher load-bearing area of PTFJ could be a risk factor for structural changes in medial tibiofemoral (MTF) compartment in knee OA. Trial registration Clinicaltrials.gov Identifier: NCT01176344 Anzctr.org.au Identifier: ACTRN12610000495022 Date of registration: 7 May 2010

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.

Osteoarthritis (OA) is the commonest musculoskeletal disease worldwide, with an increasing prevalence due to aging. It causes joint pain and disability, decreased quality of life, and a huge burden on healthcare services for society. However, the current main diagnostic methods are not suitable for early diagnosing patients of OA. The use of machine learning (ML) in OA diagnosis has increased dramatically in the past few years. Hence, in this review article, we describe the research progress in the application of ML in the early diagnosis of OA, discuss the current trends and limitations of ML approaches, and propose future research priorities to apply the tools in the field of OA. Accurate ML-based predictive models with imaging techniques that are sensitive to early changes in OA ahead of the emergence of clinical features are expected to address the current dilemma. The diagnostic ability of the fusion model that combines multidimensional information makes patient-specific early diagnosis and prognosis estimation of OA possible in the future.

Background Despite the survival benefits observed with immune checkpoint blockade (ICB) treatment—programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1), many patients with cancer have not benefited from these agents because of impaired antigen presentation and other resistance mechanisms. To overcome resistance to checkpoint therapy, we designed bispecific antibodies (BsAbs) targeting CD89 and tumor antigens. We demonstrated their immunomodulatory efficacy as a separate treatment strategy or combined with immune checkpoint inhibitors.Methods We have previously generated a heterodimeric one-arm IgG1 Fc-based bispecific antibody. For animal efficacy studies, murine tumors in a humanized transgenic mice model were used to determine the effects of CD89-bispecific antibodies on antigen presentation and immune cell recruitment. The efficacy of the CD89 bispecific antibody against tumors resistant to pembrolizumab was evaluated in double-transgenic mice.Results BsAbs targeting CD89 on tumor-associated macrophages (TAMs) increased the ratio of M1:M2 and activated the antigen presentation, leading to increased cytotoxic T cell-mediated tumor regression. CD89-BsAbs also potentiated a combinational antitumor effect with PD-1/PD-L1 inhibitors and overcame the ICB resistance by augmenting cytotoxic T-cell infiltration and reshaping tumor immune microenvironment. In an hCD89/hPD-1 double transgenic mouse model engrafted with pembrolizumab-resistant B16-HER2 tumor cells, the HER2-CD89 bispecific antibody potently inhibited tumor growth.Conclusions CD89 BsAbs targeting tumor antigens and TAMs controlled tumor growth in animal models by improving antigen presentation and T-cell infiltration. Our results suggest a general strategy for overcoming resistance to ICB.

Abstract Background To describe demographic and clinical factors associated with the presence and incidence of depression and explore the temporal relationship between depression and joint symptoms in patients with symptomatic knee osteoarthritis (OA). Methods Three hundred ninety-seven participants were selected from a randomized controlled trial in people with symptomatic knee OA and vitamin D deficiency (age 63.3 ± 7.1 year, 48.6% female). Depression severity and knee joint symptoms were assessed using the patient health questionnaire (PHQ-9) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), respectively, at baseline and 24 months. Results The presence and incidence of depression was 25.4 and 11.2%, respectively. At baseline, having younger age, a higher body mass index (BMI), greater scores of WOMAC pain (PR: 1.05, 95%CI:1.03, 1.07), dysfunction (PR: 1.02, 95%CI:1.01, 1.02) and stiffness (PR: 1.05, 95%CI: 1.02, 1.09), lower education level, having more than one comorbidity and having two or more painful body sites were significantly associated with a higher presence of depression. Over 24 months, being female, having a higher WOMAC pain (RR: 1.05, 95%CI: 1.02, 1.09) and dysfunction score (RR: 1.02, 95%CI: 1.01, 1.03) at baseline and having two or more painful sites were significantly associated with a higher incidence of depression. In contrast, baseline depression was not associated with changes in knee joint symptoms over 24 months. Conclusion Knee OA risk factors and joint symptoms, along with co-existing multi-site pain are associated with the presence and development of depression. This suggests that managing common OA risk factors and joint symptoms may be important for prevention and treatment depression in patients with knee OA. Trial registration ClinicalTrials.gov identifier: NCT01176344 . Anzctr.org.au identifier: ACTRN12610000495022 .

Abstract Background Osteoarthritis (OA) is a common chronic disease in older adults. Currently, there are no effective therapies to reduce disease severity and progression of knee OA (KOA), particularly in mid- to late-stages. This study aims to examine the effect of methotrexate (MTX) on knee effusion-synovitis and pain in symptomatic patients with mid- to late-stage KOA. Methods/design This protocol describes a multicentre randomised placebo-controlled clinical trial aiming to recruit 200 participants with mid- to late-stage symptomatic KOA and with effusion-synovitis grade of ≥ 2. Participants will be randomly allocated to the MTX group (start from 5 mg per week for the first 2 weeks and increase to 10 mg per week for the second 2 weeks and 15 mg per week for the remaining period if tolerated) or the placebo group. Primary outcomes are effusion-synovitis size measured by magnetic resonance imaging (MRI) and knee pain assessed by visual analogue scale (VAS). Secondary outcomes are signal intensity alteration within infrapatellar fat pad (IPFP) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score and subscores, and the Outcome Measures in Rheumatology Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) responders. Both intention-to-treat and per-protocol analyses will be performed. Discussion If MTX intervention can relieve symptoms and reduce inflammation in patients with mid- to late-stage KOA, it has the potential for significant clinical and public health impact as this low-cost and commonly used intervention would delay the time to knee replacement, leading to substantial cost savings and improve quality of life. Trial registration ClinicalTrials.gov NCT03815448 . Registered on 21 January 2019.

Background: Osteoarthritis (OA), a disease with whole-joint damage and dysfunction, is the leading cause of disability worldwide. The progressive loss of hyaline cartilage extracellular matrix (ECM) is considered as its hallmark, but its exact pathogenesis needs to be further clarified. MicroRNA(miRNA) contributes to OA pathology and may help to identify novel biomarkers and therapies against OA. Here we identified miR-214–3p as an important regulator of OA. Methods: qRT-PCR and in situ hybridization were used to detect the expression level of miR-214–3p. The function of miR-214–3p in OA, as well as the interaction between miR-214–3p and its downstream mRNA target (IKBKB), was evaluated by western blotting, immunofluorescence, qRT-PCR and luciferase assay. Mice models were introduced to examine the function and mechanism of miR-214–3p in OA in vivo. Findings: In our study, we found that miR-214–3p, while being down-regulated in inflamed chondrocytes and OA cartilage, regulated ECM metabolism and cell apoptosis in the cartilage. Mechanically, the protective effect of miR-214–3p downregulated the IKK-β expression and led to the dysfunction of NF-κB signaling pathway. Furthermore, intra-articular injection of miR-214–3p antagomir in mice joints triggered spontaneous cartilage loss while miRNA-214–3p agomir alleviated OA in the experimental mouse models. Interpretation: Decreased miR-214–3p activates the NF-κB signaling pathway and aggravates OA development through targeting IKKβ, suggesting miR-214–3p may be a novel therapeutic target for OA. Funding: This study was financially supported by grants from the National Natural Science Foundation of China (81,773,532, 81,974,342).

Introduction The infrapatellar fat pad (IPFP) is commonly resected during total knee arthroplasty (TKA) for better exposure. However, our previous studies have suggested that IPFP size was protective against, while IPFP signal intensity alteration was detrimental on knee symptoms and structural abnormalities. We hypothesise that an IPFP with normal qualities, rather than abnormal qualities, should be preserved during TKA. The aim of this study is to compare, over a 1-year period, the postoperative clinical outcomes of IPFP preservation versus resection after TKA in patients with normal or abnormal IPFP signal intensity alteration on MRI.Methods and analysis Three hundred and sixty people with end-stage knee osteoarthritis and on the waiting list for TKA will be recruited and identified as normal IPFP quality (signal intensity alteration score ≤1) or abnormal IPFP quality (signal intensity alteration score ≥2). Patients in each hospital will then be randomly allocated to IPFP resection group or preservation group. The primary outcomes are the summed score of self-reported Knee Injury and Osteoarthritis Outcome Score (KOOS), KOOS subscales assessing function in daily activities and function in sport and recreation. Secondary endpoints will be included: KOOS subscales (pain, symptoms and quality of life), Knee Society Score, 100 mm Visual Analogue Scale (VAS) Pain, timed up-and-go test, patellar tendon shortening, 100 mm VAS self-reported efficacy of reduced pain and increased quality of life, and Insall-Salvati index assessed on plain X-ray. Adverse events will be recorded. Intention-to-treat analyses will be used.Ethics and dissemination The study is approved by the local Medical Ethics Committee (Zhujiang Hospital Ethics Committee, reference number 2017-GJGBK-001) and will be conducted according to the principle of the Declaration of Helsinki (64th, 2013) and the Good Clinical Practice standard, and in compliance with the Medical Research Involving Human Subjects Act . Data will be published in peer-reviewed journals and presented at conferences, both nationally and internationally.Trial registration number This trial was registered at Clinicaltrial.gov website on 19 October 2018 with identify number NCT03763448.

Environment-friendly protic amine carboxylic acid ionic liquids (ILs) as solvents is a significant breakthrough with respect to traditional highly coordinating and toxic solvents in achieving efficient and stable perovskite solar cells (PSCs) with a simple one-step air processing and without an antisolvent treatment approach. However, it remains mysterious for the improved efficiency and stability of PSCs without any passivation strategy. Here, we unambiguously demonstrate that the three functions of solvents, additive, and passivation are present for protic amine carboxylic acid ILs. We found that the ILs have the capability to dissolve a series of perovskite precursors, induce oriented crystallization, and chemically passivate the grain boundaries. This is attributed to the unique molecular structure of ILs with carbonyl and amine groups, allowing for strong interaction with perovskite precursors by forming C=O…Pb chelate bonds and N-H…I hydrogen bonds in both solution and film. This finding is generic in nature with extension to a wide range of IL-based perovskite optoelectronics.

Abstract Backgroud The natural history of semi-quantitative magnetic resonance imaging (MRI)-detected osteophytes (MRI-detected OPs) has not been described and it is unknown whether knee structural abnormalities can predict MRI-detected OP change over time. Thus, the aim of current study is to describe the natural history of knee MRI-detected OP, and to determine if knee structural abnormalities are associated with change of MRI-detected OP in a longitudinal study of older adults. Methods Randomly selected older adults (n = 837, mean age 63 years) had MRI at baseline and 413 of them had MRI 2.6 years later to measure MRI-detected OP, cartilage defects, cartilage volume, bone marrow lesions (BMLs), meniscal extrusion, infrapatellar fat pad (IPFP) quality score/maximum area and effusion-synovitis. Results Over 2.6 years, average MRI-detected OP score increased significantly in all compartments. The total MRI-detected OP score remained stable in 53% of participants, worsened (≥ 1-point increase) in 46% and decreased in 1%. Baseline cartilage defects (RR, 1.25–1.35), BMLs (RR, 1.16–1.17), meniscal extrusion (RR, 1.22–1.33) and IPFP quality score (RR, 1.08–1.20) site-specifically and independently predicted an increase in MRI-detected OP (p values all ≤ 0.05), after adjustment for covariates. Presence of IPFP abnormality was significantly associated with increased MRI-detected OPs but became non-significant after adjustment for other structural abnormalities. Total (RR, 1.27) and suprapatellar pouch effusion-synovitis (RR, 1.22) were both associated with increased MRI-detected OPs in the lateral compartment only (both p

Controlling the composition and crystal phase of layered heterostructures is important. Here, the authors report the liquid-phase epitaxial growth of Sn0.5W0.5S2 nanosheets with 83% metallic phase on SnS2 nanoplates, which are used as 100 ppb level chemiresistive gas sensors at room temperature.

Abstract Background Osteoarthritis (OA) is the most prevalent chronic joint disease, characterized by joint structural deterioration, pain and loss of function among the elders. It is also associated with several extra-articular symptoms (fatigue, sleep disorders, anxiety and depression) and a reduction of life quality. Studies have revealed that patients with OA benefitted from enhanced management via telemedicine. Guangdong Online Hospital (GOH) is the first officially recognized web-based hospital that provides telemedicine service in China. However, the effective implementation of GOH telemedicine (GOHT) to enhance management for patients with OA remains unknown. Methods/design An assessor-blinded, parallel randomized controlled trial will be performed to study the feasibility and effectiveness of GOHT in the enhanced management of OA. Forty participants with knee OA will be recruited for a 6-month study. Patients meeting the inclusion criteria will be randomly allocated to receive conventional therapy (CT) or conventional therapy plus a brief GOH-based intervention (CT-GOHT). The primary outcome is the feasibility of a full-scale randomized controlled trial. The secondary outcomes include the self-reported total score of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Multidimensional Fatigue Inventory (MFI), the Pittsburgh Sleep Quality Index (PSQI) and the Hospital Anxiety and Depression Scale (HADS). Assessments will be performed at baseline, 2 weeks, 3 months and 6 months later after the initiation of the study. Discussion This trial is intended to test the application of GOHT in the chronic management in knee OA. The hypothesis is that OA patients may receive disease management via this network platform conveniently and effectively, especially those in the remote areas of our country. GOHT telemedicine would be an attractive alternative to traditional methods for disease management in knee OA. The results could provide preliminary experiences and guidance for an upcoming full-scale randomized controlled trial (RCT) in disease management via telemedicine. Trial registration ChiCTR: ChiCTR1800014465. Registered on 16 January 2018.