Integrating Radiomics and Neural Networks for Knee Osteoarthritis Incidence Prediction.

OBJECTIVE: Accurately predicting knee osteoarthritis (KOA) is essential for early detection and personalized treatment. We aimed to develop and test an MRI-based Joint Space Radiomic Model (JS-RM) to predict radiographic KOA incidence through neural networks by integrating meniscus and femorotibial cartilage radiomic features. METHODS: In the Osteoarthritis Initiative cohort, knees without radiographic KOA at baseline but at high risk for radiographic KOA were included. Case knees developed radiographic KOA whereas control knees did not over 4-year. We randomly split the knees into development and test cohorts (D/T=8/2) and extracted features from baseline 3D-DESS-sequence MRI. Model performance was evaluated using an area under the receiver operating characteristic curve (AUC), sensitivity, and specificity in both cohorts. Nine resident surgeons performed the reader experiment without/with the JS-RM aid. RESULTS: Our study included 549 knees in the development cohort (275 cases vs. 274 controls) and 137 knees in the test cohort (68 cases vs. 69 controls). In the test cohort, JS-RM had a favorable accuracy for predicting the radiographic KOA incidence with an AUC of 0.931 (95%CI: 0.876-0.963), a sensitivity of 84.4% (95%CI: 83.9%-84.9%), and a specificity of 85.6% (95%CI: 85.2%-86.0%). The mean specificity and sensitivity of resident surgeons through MRI reading in predicting radiographic KOA incidence were increased from 0.474 (95%CI: 0.333-0.614) and 0.586 (95%CI: 0.429-0.743) without the assistance of JS-RM to 0.874 (95%CI: 0.847-0.901) and 0.812 (95%CI: 0.742-0.881) with JS-RM assistance, respectively (p<.001). CONCLUSION: JS-RM integrating the features of the meniscus and cartilage showed improved predictive values in radiographic KOA incidence.

Diabetes and osteoporosis: a two-sample mendelian randomization study.

BACKGROUND: The effects on bone mineral density (BMD)/fracture between type 1 (T1D) and type 2 (T2D) diabetes are unknown. Therefore, we aimed to investigate the causal relationship between the two types of diabetes and BMD/fracture using a Mendelian randomization (MR) design. METHODS: A two-sample MR study was conducted to examine the causal relationship between diabetes and BMD/fracture, with three phenotypes (T1D, T2D, and glycosylated hemoglobin [HbA1c]) of diabetes as exposures and five phenotypes (femoral neck BMD [FN-BMD], lumbar spine BMD [LS-BMD], heel-BMD, total body BMD [TB-BMD], and fracture) as outcomes, combining MR-Egger, weighted median, simple mode, and inverse variance weighted (IVW) sensitivity assessments. Additionally, horizontal pleiotropy was evaluated and corrected using the residual sum and outlier approaches. RESULTS: The IVW method showed that genetically predicted T1D was negatively associated with TB-BMD (ß = -0.018, 95% CI: -0.030, -0.006), while T2D was positively associated with FN-BMD (ß = 0.033, 95% CI: 0.003, 0.062), heel-BMD (ß = 0.018, 95% CI: 0.006, 0.031), and TB-BMD (ß = 0.050, 95% CI: 0.022, 0.079). Further, HbA1c was not associated with the five outcomes (ß ranged from - 0.012 to 0.075). CONCLUSIONS: Our results showed that T1D and T2D have different effects on BMD at the genetic level. BMD decreased in patients with T1D and increased in those with T2D. These findings highlight the complex interplay between diabetes and bone health, suggesting potential age-specific effects and genetic influences. To better understand the mechanisms of bone metabolism in patients with diabetes, further longitudinal studies are required to explain BMD changes in different types of diabetes.

A parametric design framework for the mass customization of bicycle helmet.

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.

Evaluation of Osteoarthritis Disease Burden in China During 1990-2019 and Forecasting Its Trend Over the Future 25 Years.

OBJECTIVE: This study aimed to estimate the temporal trend of osteoarthritis (OA) burden in China by age, sex, and joint sites from 1990 to 2019 and predict the long-term trend over the next 25 years. METHODS: Using data from the Global Burden of Disease Study 2019, we estimated incident cases, prevalent cases, disability-adjusted life years (DALYs) of OA, and DALYs of OA attributed to high body mass index (BMI), as well as corresponding age-standardized rates (ASRs) for aforementioned indicies. Estimated annual percentage change (EAPC) and Nordpred age-period-cohort model were used to describe temporal trend changes and predict future disease burden. RESULTS: From 1990 to 2019, the ASR of OA incidence increased from 472.53 per 100,000 to 509.84 per 100,000 people (EAPC: 0.36, 95% confidence interval [CI] 0.29-0.44); the ASR of OA prevalence increased from 5,880.58 per 100,000 to 6,330.06 per 100,000 people (EAPC 0.35, 95% CI 0.28-0.42); the ASR of OA DALYs increased from 206.38 per 100,000 to 224.78 per 100,000 people (EAPC 0.40, 95% CI 0.32-0.48). The ASR of OA DALYs attributed to high BMI increased rapidly, especially in men and patients with hip OA. Projections suggest an increasing trend in the incidence, prevalence, and DALYs of OA from 2019 to 2044, with the prevalent cases and DALYs of OA in China expected to increase by approximately 1.5 times over the next 25 years. CONCLUSION: The disease burden of OA has increased in China over the past 30 years and is expected to continue rising over the next 25 years.

The association between anterior cruciate ligament degeneration and incident knee osteoarthritis: Data from the osteoarthritis initiative.

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 (Kellgren-Lawrence grading) of 0 or 1 â€‹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.

Single-cell atlas of human infrapatellar fat pad and synovium implicates APOE signaling in osteoarthritis pathology.

The infrapatellar fat pad (IPFP) and synovium play essential roles in maintaining knee joint homeostasis and in the progression of osteoarthritis (OA). The cellular and transcriptional mechanisms regulating the function of these specialized tissues under healthy and diseased conditions are largely unknown. Here, single-cell and single-nuclei RNA sequencing of human IPFP and synovial tissues were performed to elucidate the cellular composition and transcriptional profile. Computational trajectory analysis revealed that dipeptidyl peptidase 4+ mesenchymal cells function as a common progenitor for IPFP adipocytes and synovial lining layer fibroblasts, suggesting that IPFP and synovium represent an integrated tissue unit. OA induced a profibrotic and inflammatory phenotype in mesenchymal lineage cells with biglycan+ intermediate fibroblasts as a major contributor to OA fibrosis. Apolipoprotein E (APOE) signaling from intermediate fibroblasts and macrophages was identified as a critical regulatory factor. Ex vivo incubation of human cartilage with soluble APOE accelerated proteoglycan degeneration. Inhibition of APOE signaling by intra-articular injection of an anti-APOE neutralizing antibody attenuated the progression of collagenase-induced OA in mice, demonstrating a detrimental effect of APOE on cartilage. Our studies provide a framework for designing further therapeutic strategies for OA by describing the cellular and transcriptional landscape of human IPFP and synovium in healthy versus OA joints.

On the Ion Coordination and Crystallization of Metal Halide Perovskites by In Situ Dynamic Optical Probing.

Controlling the crystallization to achieve high-quality homogeneous perovskite film is the key strategy in developing perovskite electronic devices. Here, an in situ dynamic optical probing technique is demonstrated that can monitor the fast crystallization of perovskites and effectively minimize the influence of laser excitation during the measurement. This study finds that the typical static probing technique would damage and induce phase segregation in the perovskite films during the excitation. These issues can be effectively resolved with the dynamic probing approach. It also found that the crystallization between MAPbI3 and MAPbI2 Br is strikingly different. In particular, MAPbI2 Br suffers from inefficient nucleation during the spin-coating that strongly affects the uniform crystal growth in the annealing process. The commonly used pre-heating process is found at a lower temperature not only can further promote the nucleation but also to complete the crystallization of MAPbI2 Br. The role of further annealing at a higher temperature is to facilitate ion-dissociation on the crystal surface to form a passivation layer to stabilize the MAPbI2 Br lattices. The device performance is strongly correlated with the film formation mechanism derived from the in situ results. This work demonstrates that the in situ technique can provide deep insight into the crystallization mechanism, and help to understand the growth mechanism of perovskites with different compositions and dimensionalities.

Extracellular Vesicles in Infrapatellar Fat Pad from Osteoarthritis Patients Impair Cartilage Metabolism and Induce Senescence.

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.

Mendelian randomization reveals association between retinal thickness and non-motor symptoms of Parkinson's disease.

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 < 0.001, FDR-corrected P = 0.018). Genetically predicted reduced RNFL thickness was associated with a reduced Unified Parkinson's Disease Rating Scale total score (ß = -0.042, 95% CI (-0.079, 0.005), P = 0.025), and reduced GCIPL thickness was associated with a lower risk of constipation (OR = 0.901, 95% CI (0.821, 0.988), P = 0.027) but a higher risk of depression (OR = 1.103, 95% CI (1.016, 1.198), P = 0.020), insomnia (OR = 1.090, 95% CI (1.013, 1.172), P = 0.021), and rapid eye movement sleep behaviour disorder (RBD) (OR = 1.198, 95% CI (1.061, 1.352), P = 0.003). In conclusion, we identify an association between retinal thickness and non-motor symptoms (constipation, depression, insomnia and RBD) in PD, highlighting the potential of retinal thickness as a biomarker for PD nonmotor symptoms.

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.

Progress of linking gut microbiota and musculoskeletal health: casualty, mechanisms, and translational values.

The 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.

Long-term effects of vitamin D supplementation and maintaining sufficient vitamin D on knee osteoarthritis over 5 years.

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 (ß: - 83.7, 95% CI: - 167.3, 0) and depression scores (ß: - 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 (ß: - 33.9, 95% CI: - 65.7, - 2) and physical dysfunction (ß: - 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.

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.

Evaluating the causal effect of circulating proteome on the risk of osteoarthritis-related traits.

OBJECTIVES: This study aims to identify circulating proteins that are causally associated with osteoarthritis (OA)-related traits through Mendelian randomisation (MR)-based analytical framework. METHODS: Large-scale two-sample MR was employed to estimate the effects of thousands of plasma proteins on 12 OA-related traits. Additional analyses including Bayesian colocalisation, Steiger filtering analysis, assessment of protein-altering variants and mapping expression quantitative trait loci to protein quantitative trait loci were performed to investigate the reliability of the MR findings; protein-protein interaction, pathway enrichment analysis and evaluation of drug targets were conducted to deepen the understanding and identify potential therapeutic targets of OA. RESULTS: Dozens of circulating proteins were identified to have putatively causal effects on OA-related traits, and a majority of these proteins were either drug targets or considered druggable. CONCLUSIONS: Through MR analysis, we have identified numerous plasma proteins associated with OA-related traits, shedding light on protein-mediated mechanisms and offering promising therapeutic targets for OA.

Treatment with FAP-targeted zinc ferrite nanoparticles for rheumatoid arthritis by inducing endoplasmic reticulum stress and mitochondrial damage.

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.

A Morphometric Study of Head in the Population of Young Chinese Adults / Estudio Morfométrico de la Cabeza en la Población de Adultos Jóvenes Chinos

SUMMARY: Due to the complexity of head shape, limited 1D or 2D head anthropometry fail to fully capture its shape characteristics. Currently, there is limited research on clustering analysis of head shape from a shape difference perspective, especially for the head shape of Chinese people. Head shape is influenced by factors such as race, sex, and age, making it imperative to create a head shape database for Chinese individuals. In this study, three-dimensional head data of 339 Chinese young adult were collected, and the head shapes were clustered into 7 clusters using an improved k-medoids algorithm. The differences between clusters and the average head shape were further analyzed. It can be foreseen that the head shape database for Chinese young adult constructed in this study has important reference value for the ergonomic design of head-related products and head morphology research, among other fields.

Debido a la complejidad de la forma de la cabeza, la antropometría limitada de ésta, en 1D o 2D, no logra capturar completamente sus características de forma. Actualmente, existen estudios limitados sobre el análisis de agrupamiento de la forma de la cabeza, desde una perspectiva de diferencia de forma, especialmente en el caso de la población china. La forma de la cabeza está influenciada por factores como la raza, el sexo y la edad, por lo que resulta imperativo crear una base de datos sobre la forma de la cabeza de los individuos chinos. En este estudio, se recopilaron datos tridimensionales de la cabeza de 339 adultos jóvenes chinos, y las formas de la cabeza se agruparon en 7 grupos utilizando un algoritmo k-medoids mejorado. Las diferencias entre los grupos y la forma promedio de la cabeza se analizaron a profundidad. Se puede prever que la base de datos sobre la forma de la cabeza de adultos jóvenes chinos construida en este estudio, tiene un valor de referencia importante para el diseño ergonómico de productos relacionados con la morfología de la cabeza, entre otros campos.

Effects of 10 Hz individualized repetitive transcranial magnetic stimulation on patients with disorders of consciousness: a study protocol for an exploratory double-blind crossover randomized sham-controlled trial.

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.

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.