Unraveling the genetic basis of the causal association between inflammatory cytokines and osteonecrosis.

Background: Previous studies have reported that the occurrence and development of osteonecrosis is closely associated with immune-inflammatory responses. Mendelian randomization was performed to further assess the causal correlation between 41 inflammatory cytokines and osteonecrosis. Methods: Two-sample Mendelian randomization utilized genetic variants for osteonecrosis from a large genome-wide association study (GWAS) with 606 cases and 209,575 controls of European ancestry. Another analysis included drug-induced osteonecrosis with 101 cases and 218,691 controls of European ancestry. Inflammatory cytokines were sourced from a GWAS abstract involving 8,293 healthy participants. The causal relationship between exposure and outcome was primarily explored using an inverse variance weighting approach. Multiple sensitivity analyses, including MR-Egger, weighted median, simple model, weighted model, and MR-PRESSO, were concurrently applied to bolster the final results. Results: The results showed that bFGF, IL-2 and IL2-RA were clinically causally associated with the risk of osteonecrosis (OR=1.942, 95% CI=1.13-3.35, p=0.017; OR=0.688, 95% CI=0.50-0.94, p=0.021; OR=1.386, 95% CI=1.04-1.85, p = 0.026). there was a causal relationship between SCF and drug-related osteonecrosis (OR=3.356, 95% CI=1.09-10.30, p=0.034). Conclusion: This pioneering Mendelian randomization study is the first to explore the causal link between osteonecrosis and 41 inflammatory cytokines. It conclusively establishes a causal association between osteonecrosis and bFGF, IL-2, and IL-2RA. These findings offer valuable insights into osteonecrosis pathogenesis, paving the way for effective clinical management. The study suggests bFGF, IL-2, and IL-2RA as potential therapeutic targets for osteonecrosis treatment.

Importance of CD8 Tex cell-associated gene signatures in the prognosis and immunology of osteosarcoma.

As a highly aggressive bone malignancy, osteosarcoma poses a significant therapeutic challenge, especially in the setting of metastasis or recurrence. This study aimed to investigate the potential of CD8-Tex cell-associated genes as prognostic biomarkers to reveal the immunogenomic profile of osteosarcoma and guide therapeutic decisions. mRNA expression data and clinical details of osteosarcoma patients were obtained from the TCGA database (TARGET-OS dataset). The GSE21257 dataset (from the GEO database) was used as an external validation set to provide additional information on osteosarcoma specimens. 84 samples from the TARGET-OS dataset were used as the training set, and 53 samples from the GSE21257 dataset served as the external validation cohort. Univariate Cox regression analysis was utilized to identify CD8 Tex cell genes associated with prognosis. The LASSO algorithm was performed for 1000 iterations to select the best subset to form the CD8 Tex cell gene signature (TRS). Final genes were identified using the multivariate Cox regression model of the LASSO algorithm. Risk scores were calculated to categorize patients into high- and low-risk groups, and clinical differences were explored by Kaplan-Meier survival analysis to assess model performance. Prediction maps were constructed to estimate 1-, 3-, and 5 year survival rates for osteosarcoma patients, including risk scores for CD8 Texcell gene markers and clinicopathologic factors. The ssGSEA algorithm was used to assess the differences in immune function between TRS-defined high- and low-risk groups. TME and immune cell infiltration were further assessed using the ESTIMATE and CIBERSORT algorithms. To explore the relationship between immune checkpoint gene expression levels and the two risk-defined groups. A CD8 Tex cell-associated gene signature was extracted from the TISCH database and prognostic markers including two genes were developed. The high-risk group showed lower survival, and model performance was validated by ROC curves and C-index. Predictive plots were constructed to demonstrate survival estimates, combining CD8 Tex cell gene markers and clinical factors. This study provides valuable insights into the molecular and immune characteristics of osteosarcoma and offers potential avenues for advances in therapeutic approaches.

Root Repair Has Superior Radiological and Clinical Outcomes Than Partial Meniscectomy and Nonoperative Treatment in the Management of Meniscus Root Tears: A Systematic Review.

PURPOSE: To compile and analyze structural and clinical outcomes after meniscus root tear treatment as currently described in the literature. METHODS: A review was conducted to identify studies published since 2011 on efficacy of repair, meniscectomy, and nonoperative management in the treatment of meniscus root tears. Patient cohorts were grouped into treatment categories, with medial and lateral root tears analyzed separately; data were collected on patient demographics, structural outcomes including joint space width, degree of medial meniscal extrusion, progression to total knee arthroplasty, and patient-reported outcome measures. Risk of bias was assessed using the MINORS (methodological index for non-randomized studies) criteria. Heterogeneity was measured using the I-statistic, and outcomes were summarized using forest plots without pooled means. RESULTS: The 56 included studies comprised a total of 3,191 patients. Mean age among the included studies ranged from 24.6 to 65.6 years, whereas mean follow-up ranged from 12 to 125.9 months. Heterogeneity analysis identified significant differences between studies. Change in joint space width ranged from -2.4 to -0.6 mm (i.e., decreased space) after meniscectomy (n = 186) and -0.9 to -0.1 mm after root repair (n = 209); change in medial meniscal extrusion ranged from -0.6 to 6.5 mm after root repair (n = 521) and 0.2 to 4.2 mm after meniscectomy (n = 66); and event rate for total knee arthroplasty ranged from 0.00 to 0.22 after root repair (n = 205), 0.35 to 0.60 after meniscectomy (n = 53), and 0.27 to 0.35 after nonoperative treatment (n = 93). Root repair produced the greatest numerical increase in International Knee Documentation Committee and Lysholm scores of the 3 treatment arms. In addition, root repair improvements in Knee Injury and Osteoarthritis Outcome Score Pain (range: 22-32), Sports and Recreational Activities (range: 23-36), Quality of Life (range: 22-42), and Symptoms subscales (range: 10-19), in studies with low risk of bias. CONCLUSIONS: The literature reporting on the treatment of meniscus root tears is heterogenous and largely limited to Level III and IV studies. Current evidence suggests root repair may be the most effective treatment strategy in lessening joint space narrowing of the knee and producing improvements in patient-reported outcomes. LEVEL OF EVIDENCE: Level IV, systematic review of Level II-IV studies.

Exploring the ferroptosis-related gene lipocalin 2 as a potential biomarker for sepsis-induced acute respiratory distress syndrome based on machine learning.

BACKGROUND: Sepsis is a major cause of mortality in patients, and ARDS is one of the most common outcomes. The pathophysiology of acute respiratory distress syndrome (ARDS) caused by sepsis is significantly impacted by genes related to ferroptosis. METHODS: In this study, Weighted gene co-expression network analysis (WGCNA), protein-protein interaction (PPI) networks, functional enrichment analysis, and machine learning were employed to identify characterized genes and to construct receiver operating characteristic (ROC) curves. Additionally, DNA methylation levels were quantified and single-cell analysis was conducted. To validate the alterations in the expression of Lipocalin-2 (LCN2) and ferroptosis-related proteins in the in vitro model, Western blotting was carried out, and the changes in intracellular ROS and Fe2+ levels were detected. RESULTS: A combination of eight machine learning algorithms, including RFE, LASSO, RandomForest, SVM-RFE, GBDT, Bagging, XGBoost, and Boruta, were used with a machine learning model to highlight the significance of LCN2 as a key gene in sepsis-induced ARDS. Analysis of immune cell infiltration showed a positive correlation between neutrophils and LCN2. In a cell model induced by LPS, it was found that Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, was able to reverse the expression of LCN2. Knocking down LCN2 in BEAS-2B cells reversed the LPS-induced lipid peroxidation, Fe2+ levels, ACSL4, and GPX4 levels, indicating that LCN2, a ferroptosis-related gene (FRG), plays a crucial role in mediating ferroptosis. CONCLUSION: Upon establishing an FRG model for individuals with sepsis-induced ARDS, we determined that LCN2 could be a dependable marker for predicting survival in these patients. This finding provides a basis for more accurate ARDS diagnosis and the exploration of innovative treatment options.

Exploring the causal relationship between inflammatory cytokines and immunoinflammatory dermatoses: a Mendelian randomization study.

Objectives: Previous studies have shown that the onset and progression of several immunoinflammatory dermatoses are closely related to specific immune-inflammatory responses. To further assess the causal relationship between 41 inflammatory cytokines and immunoinflammatory dermatoses, we used a Mendelian randomization method. Methods: Mendelian two-sample randomization utilized inflammatory cytokines from a GWAS abstract containing 8,293 healthy participants as well as psoriasis (4,510 cases and 212,242 controls), atopic dermatitis (7,024 cases and 198,740 controls), and vitiligo (131 cases and 207,482 controls). The causal relationship between exposure and outcome was explored primarily using inverse variance weighting. In addition, multiple sensitivity analyses, including MR-Egger, weighted median, simple model, weighted model, and MR-PRESSO, were simultaneously applied to enhance the final results. Results: The results showed that in clinical practice, IL-4 and IL-1RA were suggestive indicators of atopic dermatitis risk (OR = 0.878, 95% CI = 0.78-0.99, p = 0.036; OR = 0.902, 95% CI = 0.82-1.00, p = 0.045). SCGF-b was a suggestive indicator of psoriasis risk (OR = 1.095, 95% CI = 1.01-1.18, p = 0.023). IL-4 is a suggestive indicator of vitiligo risk (OR = 2.948, 95% CI = 1.28-6.79, p = 0.011). Conclusion: Our findings suggest that circulating inflammatory cytokines may play a crucial role in the pathogenesis of chronic skin inflammation. IL-4 and IL-1RA may have inhibitory roles in the risk of developing atopic dermatitis, while SCGF-b may have a promoting role in the risk of developing psoriasis. Furthermore, IL-4 may contribute to the risk of developing vitiligo. These results provide insights into further understanding the mechanisms of chronic skin inflammation and offer new targets and strategies for the prevention and treatment of related diseases.

Monocyte alteration in elderly hip fracture healing: monocyte promising role in bone regeneration.

Individual aged with various change in cell and cellular microenvironments and the skeletal system undergoes physiological changes that affect the process of bone fracture healing. These changes are accompanied by alterations in regulating critical genes involved in this healing process. Unfortunately, the elderly are particularly susceptible to hip bone fractures, which pose a significant burden associated with higher morbidity and mortality rates. A notable change in older adults is the increased expression of activation, adhesion, and migration markers in circulating monocytes. However, there is a decrease in the expression of co-inhibitory molecules. Recently, research evidence has shown that the migration of specific monocyte subsets to the site of hip fracture plays a crucial role in bone resorption and remodeling, especially concerning age-related factors. In this review, we summarize the current knowledge about uniqueness characteristics of monocytes, and their potential regulation and moderation to enhance the healing process of hip fractures. This breakthrough could significantly contribute to the comprehension of aging process at a fundamental aging mechanism through this initiative would represent a crucial stride for diagnosing and treating age related hip fracture.

N-acetylneuraminic acid modulates SQSTM1/p62 sialyation-mediated ubiquitination degradation contributing to vascular endothelium dysfunction in experimental atherosclerosis mice.

Sialic acid (SIA) has been reported to be a risk factor for atherosclerosis (AS) due to its high plasma levels in such patients. However, the effect of increasing SIA in circulation on endothelial function during AS progression remains unclear. In the present study, ApoE-/- mice and endothelial cells line (HUVEC cells) were applied to investigate the effect of SIA on AS progression and its potential molecular mechanism. In vivo, mice were injected intraperitoneally with Neu5Ac (main form of SIA) to keep high-level SIA in circulation. ORO, H&E, and Masson staining were applied to detect the plaque progression. In vitro, HUVECs were treated with Neu5Ac at different times, CCK-8, RT-PCR, western blot, and immunoprecipitation methods were used to analyze its effects on endothelial function and the potential involved mechanism. Results from the present study showed that high plasma levels of Neu5Ac in ApoE-/- mice could aggravate the plaque areas as well as increase necrotic core areas and collagen fiber contents. Remarkably, Neu5Ac levels in circulation displayed a positive correlation with AS plaque areas. Furthermore, results from HUVECs showed that Neu5Ac inhibited cells viability in a time/dose-dependent manner, by then induced the activation of inflammation makers such as ICAM-1 and IL-1ß. Mechanism study showed that the activation of excessive autophagy medicated by SQSTM1/p62 displayed an important role in endothelium inflammatory injury. Neu5Ac could modify SQSTM1/p62 as a sialylation protein, and then increase its level with ubiquitin binding, further inducing ubiquitination degradation and being involved in the excessive autophagy pathway. Inhibition of sialylation by P-3Fax-Neu5Ac, a sialyltransferase inhibitor, reduced the binding of SQSTM1/p62 to ubiquitin. Together, these findings indicated that Neu5Ac increased SQSTM1/p62-ubiquitin binding through sialylation modification, thereby inducing excessive autophagy and subsequent endothelial injury. Inhibition of SQSTM1/p62 sialylation might be a potential strategy for preventing such disease with high levels of Neu5Ac in circulation.

No Differences in Exercise Performance, Perceptual Response, or Safety Were Observed Among 3 Blood Flow Restriction Devices.

Purpose: To compare 3 separate blood flow restriction (BFR) systems in their capacity to reduce repetitions to failure, impact perceptual responses, and cause adverse events during a low-load free-flow exercise. Methods: The study included healthy subjects aged 18 years or older who presented to an ambulatory-care sports medicine clinic. On day 1, participants' demographic characteristics and anthropomorphic measurements were recorded. Each participant performed dumbbell biceps curl repetitions to failure using 20% of his or her 1-repetition maximum weight with each arm. Participants were exposed to 3 different tourniquet systems for familiarization. On day 2, each participant's arm was randomized to a cuff system, and the participant performed 2 sets of biceps curl repetitions to failure with the cuff inflated. Repetitions to failure, rating of perceived effort (RPE), rating of perceived discomfort, and pulse oxygenation levels were recorded after each set. On day 3, participants completed a survey of their perceived delayed-onset muscle soreness. Results: The final analysis was performed on 42 arms, with 14 limbs per system. The study population had a mean age of 28.7 ± 2.4 years and a mean body mass index of 24.9 ± 4.3. All 3 systems successfully reduced repetitions to failure compared with unrestricted low-load exercise from baseline to BFR set 1 and from baseline to BFR set 2. There were no significant between-group differences among BFR systems regarding the number of repetitions to failure performed at baseline versus BFR set 1 or BFR set 2. The Delfi Personalized Tourniquet System (PTS) cohort had the greatest reductions in repetitions to failure from BFR set 1 to BFR set 2 (P = .002) and reported the highest RPE after set 2 (P = .025). Conclusions: The Delfi PTS, SmartCuffs Pro, and BStrong BFR systems were each safe and were able to significantly reduce repetitions to failure compared with a low-load free-flow condition when used in a BFR exercise protocol. The Delfi PTS system may produce a higher RPE with prolonged use in comparison to the other systems. Level of Evidence: Level II, prospective cohort study.

Deep Learning Artificial Intelligence Tool for Automated Radiographic Determination of Posterior Tibial Slope in Patients With ACL Injury.

Background: An increased posterior tibial slope (PTS) corresponds with an increased risk of graft failure after anterior cruciate ligament (ACL) reconstruction (ACLR). Validated methods of manual PTS measurements are subject to potential interobserver variability and can be inefficient on large datasets. Purpose/Hypothesis: To develop a deep learning artificial intelligence technique for automated PTS measurement from standard lateral knee radiographs. It was hypothesized that this deep learning tool would be able to measure the PTS on a high volume of radiographs expeditiously and that these measurements would be similar to previously validated manual measurements. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: A deep learning U-Net model was developed on a cohort of 300 postoperative short-leg lateral radiographs from patients who underwent ACLR to segment the tibial shaft, tibial joint surface, and tibial tuberosity. The model was trained via a random split after an 80 to 20 train-validation scheme. Masks for training images were manually segmented, and the model was trained for 400 epochs. An image processing pipeline was then deployed to annotate and measure the PTS using the predicted segmentation masks. Finally, the performance of this combined pipeline was compared with human measurements performed by 2 study personnel using a previously validated manual technique for measuring the PTS on short-leg lateral radiographs on an independent test set consisting of both pre- and postoperative images. Results: The U-Net semantic segmentation model achieved a mean Dice similarity coefficient of 0.885 on the validation cohort. The mean difference between the human-made and computer-vision measurements was 1.92° (σ = 2.81° [P = .24]). Extreme disagreements between the human and machine measurements, as defined by ≥5° differences, occurred <5% of the time. The model was incorporated into a web-based digital application front-end for demonstration purposes, which can measure a single uploaded image in Portable Network Graphics format in a mean time of 5 seconds. Conclusion: We developed an efficient and reliable deep learning computer vision algorithm to automate the PTS measurement on short-leg lateral knee radiographs. This tool, which demonstrated good agreement with human annotations, represents an effective clinical adjunct for measuring the PTS as part of the preoperative assessment of patients with ACL injuries.

Genetic perspectives on the influence of circulating cytokines on acne: A Mendelian randomization study.

Previous studies have reported that the occurrence and development of acne are closely associated with immune-inflammatory responses. Mendelian randomization was performed to further assess the causal correlation between 41 inflammatory cytokines and acne. Mendelian two-sample randomization utilized genetic variants for acne from a large open genome-wide association study (1299 cases and 211,139 controls of European ancestry) and inflammatory cytokines from a genome-wide association study abstract containing 8293 healthy participants. The causal relationship between exposure and outcome was explored primarily using an inverse variance weighting approach. In addition, multiple sensitivity analyses including MR-Egger, weighted median, simple model, weighted model, and MR-PRESSO were applied simultaneously to enhance the final results. The results suggest that il-10, MIP-1A, and SCGF-ß are suggestive of the risk of acne in clinical practice (OR = 0.799, 95% CI = 0.641-0.995, P = .045; OR = 0.55, 95% CI = 0.388-0.787, P = .001; OR = 1. 152, 95% CI = 1.001-1.325, P = .048). Our study conclusively identified a causal relationship between il-10 and circulating levels of acne risk and a suggestive link between MIP-1A and SCGF-ß and acne. Our study may provide greater insight into the pathogenesis of acne and develop effective management strategies for the clinic. We believe that IL-10, MIP-1A, and SCGF-ß could be potential therapeutic targets for acne development.

Risk factors for short-term mortality in elderly hip fracture patients with complicated heart failure in the ICU: A MIMIC-IV database analysis using nomogram.

BACKGROUND: Hip fracture is a prevalent and hazardous injury among the elderly population that often results in intensive care unit (ICU) admission due to various complications, despite advanced medical science. One common complication experienced in the ICU by elderly hip fracture patients is heart failure, which significantly impacts short-term survival rates. Currently, there is a deficit of adequate predictive models to forecast the short-term risk of death following heart failure for elderly hip fracture patients in the ICU. This study aims to identify independent risk factors for all-cause mortality within 30 days for elderly patients with hip fractures and heart failure while in the ICU in order to develop a predictive model. METHOD: A total of 641 elderly patients with hip fractures combined with heart failure were recruited from the Medical Information Mart for Intensive Care IV dataset and randomized to the training and validation sets. The primary outcome was all-cause mortality within 30 days. The least absolute shrinkage and selection operator regression was used to reduce data dimensionality and select features. Multivariate logistic regression was used to build predictive models. Consistency index (C-index), receiver operating characteristic curve, and decision curve analysis (DCA) were used to measure the predictive performance of the nomogram. RESULT: Our results showed that these variables including MCH, MCV, INR, monocyte percentage, neutrophils percentage, creatinine, and combined sepsis were independent factors for death within 30 days in elderly patients with hip fracture combined with heart failure in the ICU. The C-index was 0.869 (95% CI 0.823-0.916) and 0.824 (95% CI 0.749-0.900) for the training and validation sets, respectively. The results of the area under the curve and decision curve analysis (DCA) confirmed that the nomogram performed well in predicting elderly patients with hip fractures combined with heart failure in the ICU. CONCLUSION: We developed a new nomogram model for predicting 30-day all-cause mortality in elderly patients with hip fractures combined with heart failure in the ICU, which could be a valid and useful clinical tool for clinicians for targeted treatment and prognosis prediction.

Decoding the immune landscape following hip fracture in elderly patients: unveiling temporal dynamics through single-cell RNA sequencing.

BACKGROUND: Hip fractures in the elderly have significant consequences, stemming from the initial trauma and subsequent surgeries. Hidden blood loss and stress due to concealed injury sites could impact the whole osteoimmune microenvironment. This study employs scRNA-seq technique to map immune profiles in elderly hip fracture patients from post-trauma to the recovery period, investigating the dynamic changes of immune inflammation regulation subgroups. METHODS: We collected peripheral blood samples from four elderly hip fracture patients (two males and two females, all > 75 years of age) at three different time points (24 h post-trauma, 24 h post-operation, and day 7 post-operation) and applied scRNA-seq technique to analyze the cellular heterogeneity and identify differentially expressed genes in peripheral blood individual immune cells from elderly hip fracture patients. RESULTS: In this study, we analyzed the composition and gene expression profiles of peripheral blood mononuclear cells (PBMCs) from elderly hip fracture patients by scRNA-seq and further identified new CD14 monocyte subpopulations based on marker genes and transcriptional profiles. Distinct gene expression changes were observed in various cell subpopulations at different time points. C-Mono2 monocyte mitochondria-related genes were up-regulated and interferon-related and chemokine-related genes were down-regulated within 24 h post-operation. Further analysis of gene expression profiles at day 7 post-operation showed that C-Mono2 monocytes showed downregulation of inflammation-related genes and osteoblast differentiation-related genes. However, the expression of these genes in cytotoxic T cells, Treg cells, and B cell subsets exhibited a contrasting trend. GZMK+CD8+ cytotoxic T cells showed downregulation of chemokine-related genes, and Treg cells showed upregulation of genes related to the JAK/STAT signaling pathway. Furthermore, we examined interactions among diverse immune cell subsets, pinpointing specific ligand-receptor pairs. These findings imply cross-talk and communication between various cell types in the post-traumatic immune response. CONCLUSIONS: Our study elucidates the notable alterations in immune cell subpopulations during different stages of hip fracture in elderly patients, both in terms of proportions and differential gene expressions. These changes provide significant clinical implications for tissue repair, infection prevention, and fracture healing in clinic.

Translation and validation of a Chinese version of the body talk scale for women and men.

Body talk has received increasing research attention in recent years, with accumulating evidence supporting the link between body talk and eating and body image disturbances. However, research on body talk in China is still relatively scarce and generally focused on fat talk, especially in women, and much remains unknown about muscle talk and positive body talk for both Chinese women and men. To promote a better understanding of body talk in the Chinese context, the present study adapted the Body Talk Scale (BTS) into Chinese Mandarin (i.e., C-BTS) and evaluated the factor structure and psychometric properties of the C-BTS in Chinese adult women and men. The English version of the BTS was translated into Chinese Mandarin with standard procedures. With 300 Chinese women (Mage = 29.48 years, SD = 7.26) and 300 men (Mage = 29.36 years, SD = 6.81), we examined the factor structure and gender invariance of the C-BTS, as well as internal consistency reliability, test-retest reliability, and construct validity, including convergent, concurrent, and incremental validity of the C-BTS. The results indicated that, consistent with the development study of the BTS, the C-BTS had three subscales (i.e., Negative Fat Talk, Negative Muscle Talk, and Positive Body Talk) and good reliability and validity. The findings demonstrate that the C-BTS can be a useful measure of body talk in both Chinese women and men.

The Body Talk Scale (BTS) measures three types of body talk, including negative fat talk, negative muscle talk, and positive body talk. The present study adapted the English version of the BTS into Chinese Mandarin and examined its psychometric properties in Chinese adult women and men. Results showed that the BTS had adequate reliability and validity in Chinese adults and could be used to assess body talk in Chinese women and men.

Metabolite Neu5Ac triggers SLC3A2 degradation promoting vascular endothelial ferroptosis and aggravates atherosclerosis progression in ApoE-/-mice.

Background: Atherosclerosis (AS) is still the major cause of cardiovascular disease (CVD) as well as stroke. Endothelial metabolic disorder has been found to be activated and then promote endothelial cells (ECs) injury, which is regarded to initiate AS progression. N-acetylneuraminic acid (Neu5Ac), a metabolite produced by hexosamine-sialic acid pathway branching from glucose metabolism, was presented as a notable biomarker of CVD and is positively correlated with ECs function. However, few studies explain whether Neu5Ac regulate AS progression by affecting EC function as well as its involved mechanisms are still unknown. Methods: Here, we mimicked an animal model in ApoE-/- mice which displaying similar plasma Neu5Ac levels with AS model to investigate its effect on AS progression. Results: We found that Neu5Ac exacerbated plaques area and increased lipids in plasma in absence of HFD feeding, and ECs inflammatory injury was supposed as the triggering factor upon Neu5Ac treatment with increasing expression of IL-1ß, ICAM-1, and promoting ability of monocyte adhesion to ECs. Mechanistic studies showed that Neu5Ac facilitated SLC3A2 binding to ubiquitin and then triggered P62 mediated degradation, further leading to accumulation of lipid peroxidation in ECs. Fer-1 could inhibit ECs injury and reverse AS progression induced by Neu5Ac in ApoE-/- mice. Interestingly, mitochondrial dysfunction was also partly participated in ECs injury after Neu5Ac treatment and been reversed by Fer-1. Conclusions: Together, our study unveils a new mechanism by which evaluated metabolite Neu5Ac could promote SLC3A2 associated endothelial ferroptosis to activate ECs injury and AS plaque progression, thus providing a new insight into the role of Neu5Ac-ferroptosis pathway in AS. Also, our research revealed that pharmacological inhibition of ferroptosis may provide a novel therapeutic strategy for premature AS.

Nano-calcipotriol as a potent anti-hepatic fibrosis agent.

Calcipotriol (CAL) has been widely studied as a fibrosis inhibitor and used to treat plaque psoriasis via transdermal administration. The clinical application of CAL to treat liver fibrosis is bottlenecked by its unsatisfactory pharmacokinetics, biodistribution, and side effects, such as hypercalcemia in patients. The exploration of CAL as a safe and effective antifibrotic agent remains a major challenge. Therefore, we rationally designed and synthesized a self-assembled drug nanoparticle encapsulating CAL in its internal hydrophobic core for systematic injection (termed NPs/CAL) and further investigated the beneficial effect of the nanomaterial on liver fibrosis. C57BL/6 mice were used as the animal model, and human hepatic stellate cell line LX-2 was used as the cellular model of hepatic fibrogenesis. Immunofluorescence staining, flow cytometry, western blotting, immunohistochemical staining, and in vitro imaging were used for evaluating the efficacy of NPs/CAL treatment. We found NPs/CAL can be quickly internalized in vitro, thus potently deactivating LX-2 cells. In addition, NPs/CAL improved blood circulation and the accumulation of CAL in liver tissue. Importantly, NPs/CAL strongly contributed to the remission of liver fibrosis without inducing hypercalcemia. Overall, our work identifies a promising paradigm for the development of nanomaterial-based agents for liver fibrosis therapy.

Artificial Intelligence Can Define and Predict the "Optimal Observed Outcome" After Anterior Shoulder Instability Surgery: An Analysis of 200 Patients With 11-Year Mean Follow-Up.

Purpose: The purpose of this study was to use unsupervised machine learning clustering to define the "optimal observed outcome" after surgery for anterior shoulder instability (ASI) and to identify predictors for achieving it. Methods: Medical records, images, and operative reports were reviewed for patients <40 years old undergoing surgery for ASI. Four unsupervised machine learning clustering algorithms partitioned subjects into "optimal observed outcome" or "suboptimal outcome" based on combinations of actually observed outcomes. Demographic, clinical, and treatment variables were compared between groups using descriptive statistics and Kaplan-Meier survival curves. Variables were assessed for prognostic value through multivariate stepwise logistic regression. Results: Two hundred patients with a mean follow-up of 11 years were included. Of these, 146 (64%) obtained the "optimal observed outcome," characterized by decreased: postoperative pain (23% vs 52%; P < 0.001), recurrent instability (12% vs 41%; P < 0.001), revision surgery (10% vs 24%; P = 0.015), osteoarthritis (OA) (5% vs 19%; P = 0.005), and restricted motion (161° vs 168°; P = 0.001). Forty-one percent of patients had a "perfect outcome," defined as ideal performance across all outcomes. Time from initial instability to presentation (odds ratio [OR] = 0.96; 95% confidence interval [CI], 0.92-0.98; P = 0.006) and habitual/voluntary instability (OR = 0.17; 95% CI, 0.04-0.77; P = 0.020) were negative predictors of achieving the "optimal observed outcome." A predilection toward subluxations rather than dislocations before surgery (OR = 1.30; 95% CI, 1.02-1.65; P = 0.030) was a positive predictor. Type of surgery performed was not a significant predictor. Conclusion: After surgery for ASI, 64% of patients achieved the "optimal observed outcome" defined as minimal postoperative pain, no recurrent instability or OA, low revision surgery rates, and increased range of motion, of whom only 41% achieved a "perfect outcome." Positive predictors were shorter time to presentation and predilection toward preoperative subluxations over dislocations. Level of Evidence: Retrospective cohort, level IV.

Machine learning can accurately predict risk factors for all-cause reoperation after ACLR: creating a clinical tool to improve patient counseling and outcomes.

PURPOSE: Identifying predictive factors for all-cause reoperation after anterior cruciate ligament reconstruction could inform clinical decision making and improve risk mitigation. The primary purposes of this study are to (1) determine the incidence of all-cause reoperation after anterior cruciate ligament reconstruction, (2) identify predictors of reoperation after anterior cruciate ligament reconstruction using machine learning methodology, and (3) compare the predictive capacity of the machine learning methods to that of traditional logistic regression. METHODS: A longitudinal geographical database was utilized to identify patients with a diagnosis of new anterior cruciate ligament injury. Eight machine learning models were appraised on their ability to predict all-cause reoperation after anterior cruciate ligament reconstruction. Model performance was evaluated via area under the receiver operating characteristics curve. To explore modeling interpretability and radiomic feature influence on the predictions, we utilized a game-theory-based method through SHapley Additive exPlanations. RESULTS: A total of 1400 patients underwent anterior cruciate ligament reconstruction with a mean postoperative follow-up of 9 years. Two-hundred and eighteen (16%) patients experienced a reoperation after anterior cruciate ligament reconstruction, of which 6% of these were revision ACL reconstruction. SHapley Additive exPlanations plots identified the following risk factors as predictive for all-cause reoperation: diagnosis of systemic inflammatory disease, distal tear location, concomitant medial collateral ligament repair, higher visual analog scale pain score prior to surgery, hamstring autograft, tibial fixation via radial expansion device, younger age at initial injury, and concomitant meniscal repair. Pertinent negatives, when compared to previous studies, included sex and timing of surgery. XGBoost was the best-performing model (area under the receiver operating characteristics curve of 0.77) and outperformed logistic regression in this regard. CONCLUSIONS: All-cause reoperation after anterior cruciate ligament reconstruction occurred at a rate of 16%. Machine learning models outperformed traditional statistics and identified diagnosis of systemic inflammatory disease, distal tear location, concomitant medial collateral ligament repair, higher visual analog scale pain score prior to surgery, hamstring autograft, tibial fixation via radial expansion device, younger age at initial injury, and concomitant meniscal repair as predictive risk factors for reoperation. Pertinent negatives, when compared to previous studies, included sex and timing of surgery. These models will allow surgeons to tabulate individualized risk for future reoperation for patients undergoing anterior cruciate ligament reconstruction. LEVEL OF EVIDENCE: III.

Examining an integrated sociocultural and objectification model of thinness- and muscularity-oriented disordered eating in Chinese older men and women.

OBJECTIVE: We tested an integrated model of three prominent theories of disordered eating (tripartite influence theory, objectification theory, and social comparison theory) in a sample of older Chinese men and women. METHOD: Chinese older men (n = 270) and women (n = 160) completed questionnaires assessing the tripartite influence, objectification, and social comparison theories and thinness- and muscularity-oriented disordered eating. Two structural equation models were tested in Chinese older men and women. RESULTS: The integrated model showed good model fit and described meaningful variance in thinness- and muscularity-oriented disordered eating in Chinese older men and women. Higher appearance pressures were uniquely related to higher muscularity-oriented disordered eating in men. Across both gender groups, higher thinness internalization was uniquely related to higher thinness- and muscularity-oriented disordered eating, and in women only, higher muscularity internalization was uniquely related to lower thinness-oriented disordered eating. In men, higher upward and downward body image comparisons were uniquely related to higher and lower, respectively, muscularity-oriented disordered eating. In women, higher upward body image comparisons were only uniquely related to higher muscularity-oriented disordered eating while higher downward body image comparisons were uniquely related to both outcomes. Higher body shame was uniquely related to higher thinness-oriented disordered eating across both groups and in men alone, higher body shame was also uniquely related to higher muscularity-oriented disordered eating. DISCUSSION: Findings, which tested the integration of tripartite influence, objectification, and social comparison theories, inform the prevention and treatment of disordered eating in Chinese older populations. PUBLIC SIGNIFICANCE: The present study is the first to describe theories of disordered eating (tripartite influence, objectification, and social comparison) in Chinese older adults. Findings suggested good model fit and the integrated models described meaningful variance in thinness- and muscularity-oriented disordered eating in Chinese older women and men. Findings extend existing theories of disordered eating and, pending further study, may inform theory-driven prevention and treatment approaches in Chinese older adults.

Defining Clinically Meaningful Subgroups for Risk Stratification in Patients Undergoing Revision Total Hip Arthroplasty: A Combined Unsupervised and Supervised Machine Learning Approach.

BACKGROUND: Studies developing predictive models from large datasets to risk-stratify patients under going revision total hip arthroplasties (rTHAs) are limited. We used machine learning (ML) to stratify patients undergoing rTHA into risk-based subgroups. METHODS: We retrospectively identified 7,425 patients who underwent rTHA from a national database. An unsupervised random forest algorithm was used to partition patients into high-risk and low-risk strata based on similarities in rates of mortality, reoperation, and 25 other postoperative complications. A risk calculator was produced using a supervised ML algorithm to identify high-risk patients based on preoperative parameters. RESULTS: There were 3,135 and 4,290 patients identified in the high-risk and low-risk subgroups, respectively. Each group significantly differed by rate of 30-day mortalities, unplanned reoperations/readmissions, routine discharges, and hospital lengths of stay (P < .05). An Extreme Gradient Boosting algorithm identified preoperative platelets < 200, hematocrit > 35 or < 20, increasing age, albumin < 3, international normalized ratio > 2, body mass index > 35, American Society of Anesthesia class ≥ 3, blood urea nitrogen > 50 or < 30, creatinine > 1.5, diagnosis of hypertension or coagulopathy, and revision for periprosthetic fracture and infection as predictors of high risk. CONCLUSION: Clinically meaningful risk strata in patients undergoing rTHA were identified using an ML clustering approach. Preoperative labs, demographics, and surgical indications have the greatest impact on differentiating high versus low risk. LEVEL OF EVIDENCE: III.