Enhancing Endogenous Hyaluronic Acid in Osteoarthritic Joints with an Anti-Inflammatory Supramolecular Nanofiber Hydrogel Delivering HAS2 Lentivirus.

Osteoarthritis (OA) management remains challenging because of its intricate pathogenesis. Intra-articular injections of drugs, such as glucocorticoids and hyaluronic acid (HA), have certain limitations, including the risk of joint infection, pain, and swelling. Hydrogel-based therapeutic strategies have attracted considerable attention because of their enormous therapeutic potential. Herein, a supramolecular nanofiber hydrogel is developed using dexamethasone sodium phosphate (DexP) as a vector to deliver lentivirus-encoding hyaluronan synthase 2 (HAS2) (HAS2@DexP-Gel). During hydrogel degradation, HAS2 lentivirus and DexP molecules are slowly released. Intra-articular injection of HAS2@DexP-Gel promotes endogenous HA production and suppresses synovial inflammation. Additionally, HAS2@DexP-Gel reduces subchondral bone resorption in the anterior cruciate ligament transection-induced OA mice, attenuates cartilage degeneration, and delays OA progression. HAS2@DexP-Gel exhibited good biocompatibility both in vitro and in vivo. The therapeutic mechanisms of the HAS2@DexP-Gel are investigated using single-cell RNA sequencing. HAS2@DexP-Gel optimizes the microenvironment of the synovial tissue by modulating the proportion of synovial cell subpopulations and regulating the interactions between synovial fibroblasts and macrophages. The innovative nanofiber hydrogel, HAS2@DexP-Gel, effectively enhances endogenous HA production while reducing synovial inflammation. This comprehensive approach holds promise for improving joint function, alleviating pain, and slowing OA progression, thereby providing significant benefits to patients.

M2 macrophage-derived exosomal miR-26b-5p regulates macrophage polarization and chondrocyte hypertrophy by targeting TLR3 and COL10A1 to alleviate osteoarthritis.

Osteoarthritis (OA) is one of the most prevalent chronic musculoskeletal diseases among the elderly population. In this study, macrophage-derived exosomes were isolated and identified. Exosomes were subjected to microRNA (miRNA) sequencing and bioinformatic analysis, and differentially expressed miRNAs were verified. miR-26b-5p target genes were confirmed through target-site mutation combined with a dual-luciferase reporter assay. The effects of miR-26b-5p on macrophage polarization and chondrocyte hypertrophy were assessed in vitro. miR-26b-5p agomir was applied to mice with OA induced by anterior cruciate ligament transection (ACLT). The therapeutic effects of miR-26b-5p were evaluated via pain behavior experiments and histological observations. In vitro, miR-26b-5p repolarized M1 macrophages to an anti-inflammatory M2 type by targeting the TLR3 signaling pathway. miR-26b-5p could target COL10A1, further inhibiting chondrocyte hypertrophy induced by M1 macrophage-conditioned medium (M1-CM). In vivo, miR-26b-5p agomir ameliorated gait abnormalities and mechanical allodynia in OA mice. miR-26b-5p treatment attenuated synovitis and cartilage degeneration, thereby delaying OA progression. In conclusion, M2 macrophage-derived exosomal miR-26b-5p could protect articular cartilage and ameliorate gait abnormalities in OA mice by targeting TLR3 and COL10A1. miR-26b-5p further affected macrophage polarization and chondrocyte hypertrophy. Thus, this exosomal miR-26b-5p-based strategy might be a potential method for OA treatment.

Right ventricular global strain in patients with hypertrophic cardiomyopathy with and without right ventricular hypertrophy.

PURPOSE: Regardless of whether there are morphological abnormalities of right ventricle in hypertrophic cardiomyopathy (HCM) patients, the exact contribution of right ventricular (RV) global strains remains unresolved. We aimed to study the prognostic value of RV global strains in HCM patients with and without RV hypertrophy (RVH). METHOD: A total of 358 HCM patients who underwent the CMR examination and carried out the follow-up were finally included in this retrospective study. The endpoint was a composite of all-cause mortality, aborted SCD, and heart failure readmission. RV hypertrophy (RVH) was defined as maximal RVWT ≥ 5 mm at end-diastole. RV global strains (RV global longitudinal strain (GLS) and RV global circumferential strain (GCS) were measured in HCM patients by cardiac MRI feature tracking technique. The intraobserver and interobserver reproducibility were evaluated. Receiver-operating characteristic curves and Kaplan-Meier curves, cox proportional hazards regression, Likelihood ratio test and Integrated Discrimination Improvement (IDI) analysis were performed. P-value were corrected for multiple testing when using many covariables by a false discovery rate adjustment. RESULTS: Over a median follow-up of 25 (range 3-54) months, 49 patients reached the composite endpoints. HCM patients were divided into the RVH group and non-RVH groups. In the multivariate cox proportional hazards regression, after adjusting multiple clinical and imaging variables, RV GLS and RV GCS were independently associated with the composite endpoints in the RVH group (HR: 1.123; 95 % CI: 1.048-1.205; P = 0.002) and non-RVH group (HR: 1.174; 95 % CI: 1.031-1.337; P = 0.015), respectively. And The IDI index of models improved when adding RV GLS (IDI = 0.030, p < 0.001) and RV GLS (IDI = 0.056, p = 0.020), respectively. CONCLUSIONS: RV GLS and RV GCS are independent predictors of HCM with RVH and without RVH, respectively. RV GLS in the RVH group and RV GCS in the non-RVH group provide additional values for predicting the risk of adverse events.

Late gadolinium enhancement entropy as a new measure of myocardial tissue heterogeneity for prediction of adverse cardiac events in patients with hypertrophic cardiomyopathy.

OBJECTIVES: Entropy is a new late gadolinium enhanced (LGE) cardiac magnetic resonance (CMR)-derived parameter that is independent of signal intensity thresholds. Entropy can be used to measure myocardial tissue heterogeneity by comparing full pixel points of tissue images. This study investigated the incremental prognostic value of left ventricular (LV) entropy in patients with hypertrophic cardiomyopathy (HCM). METHODS: This study enrolled 337 participants with HCM who underwent 3.0-T CMR. The LV entropy was obtained by calculating the probability distribution of the LV myocardial pixel signal intensities of the LGE sequence. Patients who underwent CMR imaging were followed up for endpoints. The primary endpoint was defined as readmission to the hospital owing to heart failure. The secondary endpoint was the composite of the primary endpoint, sudden cardiac death and non-cardiovascular death. RESULTS: During the median follow-up of 24 months ± 13 (standard deviation), 43 patients who reached the primary and secondary endpoints had a higher entropy (6.20 ± 0.45, p < 0.001). The patients with increased entropy (≥ 5.587) had a higher risk of the primary and secondary endpoints, compared with HCM patients with low entropy (p < 0.001 for both). In addition, Cox analysis showed that LV entropy provided significant prognostic value for predicting both primary and secondary endpoints (HR: 1.291 and 1.273, all p < 0.001). Addition of LV entropy to the multivariable model improved model performance and risk reclassification (p < 0.05). CONCLUSION: LV entropy assessed by CMR was an independent predictor of primary and secondary endpoints. LV entropy assessment contributes to improved risk stratification in patients with HCM. CRITICAL RELEVANCE STATEMENT: Myocardial heterogeneity reflected by entropy the derived parameter of LGE has prognostic value for adverse events in HCM. The measurement of LV entropy helped to identify patients with HCM who were at risk for heart failure and sudden cardiac death. KEY POINTS: • Left ventricular entropy can reflect myocardial heterogeneity in HCM patients. • Left ventricular entropy was significantly higher in HCM patients who reached endpoint events. • Left ventricular entropy helps to predict the occurrence of heart failure and death in HCM patients.

A Comparison of Radiographic Outcomes after Total Hip Arthroplasty between the Direct Lateral Approach and Posterior Lateral Approach with EOS 2D/3D X-Ray Imaging System.

OBJECTIVE: The classical approaches for total hip arthroplasty (THA) are the direct lateral approach (DLA) and posterior lateral approach (PLA). There are few studies comparing implant orientation with these two approaches, and the impact of surgical approaches on implant orientation remains controversial. With the rise of the EOS imaging system, we aimed to use it to identify the differences between and factors associated with implant orientation after THA using DLA and PLA. METHODS: In our department from January 2019 to December 2021, 321 primary unilateral THAs that used PLA and DLA were enrolled. A total of 201 patients who received PLA and 120 patients who received DLA were included in this study. Two blinded observers measured each case using EOS imaging data. Postoperative imaging metrics and other relevant influencing factors of the two surgical approaches were compared. Postoperative imaging metrics, including the anteversion and inclination of the cup, anteversion of the stem, and combined anteversion were measured based on EOS. Other relevant influencing factors included age, approach, gender, laterality, BMI, anterior pelvic plane inclination, femoral head diameter, femoral offset, lateral pelvic tilt, pelvic incidence, pelvis axial rotation, sacral slope, sagittal pelvic tilt, and surgery time. Multiple linear regression analyses were performed to identify the predictors of acceptability for each imaging data point. RESULTS: No dislocation was found in the 321 patients who underwent primary THA during this period. The mean anteversion and combined anteversion of the cups using the DLA were 21.33° ± 17.31° (-51.7°-60.8°) and 33.71° ± 20.85° (-38.8°-77.6°) and PLA were 25.34° ± 12.76° (-5.5°-57.0°) and 42.37° ± 18.85° (-8.7°-84.7°), respectively. The DLA group had smaller anteversion (p = 0.038) and combined anteversion (p < 0.001). We found that surgical approach (p < 0.05), anterior pelvic plane inclination (p < 0.001), gender (p < 0.001), and femoral head diameter (p < 0.001) were important factors affecting acetabular cup anteversion (R2 = 0.375) and combined anteversion (R2 = 0.525). CONCLUSIONS: In total hip arthroplasty, different prosthesis installation directions should be made according to different surgical approaches. Compared with the direct lateral approach, the acetabular anteversion can be intentionally enlarged when using the posterolateral approach. Surgical approach, anterior pelvic plane inclination (APPI), gender, and femoral head diameter were significant predictors of prosthesis orientation. The anterior pelvic plane inclination may be a useful standard for assessing the position of the prosthesis using EOS.

Serum miR-4488 as a potential biomarker of lean nonalcoholic fatty liver disease.

Background: In lean individuals, nonalcoholic fatty liver disease (NAFLD) is not a benign disease, and these patients have long-term morbidity and mortality similar to those of their nonlean counterparts. Finding biomarkers for noninvasive and early detection is urgent and microRNAs (miRNAs) show potential. The aims of this study were to investigate the potential role of serum miRNAs in the detection of lean NAFLD and to explore the possible pathogenesis of lean NAFLD. Methods: A total of 498 patients with NAFLD and 98 healthy controls were included to compare the clinical characteristics of lean NAFLD patients [LNs: body mass index (BMI) <23 kg/m2], nonlean NAFLD patients (NLNs: BMI ≥23 kg/m2) and normal healthy individuals (HIs). A total of 14 serum samples were collected from 4 LNs, 6 NLNs and 4 HIs for high-throughput profiling to identify altered miRNA expression patterns in lean NAFLD. The candidate miRNA, miR-4488, was identified by filtering based on studies in a second independent cohort (31 LNs, 62 NLNs, 72 HIs) that included quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein-protein interaction network analyses were performed to investigate the potential molecular mechanism of miR-4488 in lean NAFLD. Results: LNs were older and had a smaller waist circumference, lower levels of alanine aminotransferase, glutamyl transpeptidase, fasting insulin, and uric acid, lower HOMA-IR score, and higher levels of total cholesterol, high-density lipoprotein cholesterol, and hemoglobin (P<0.05). The serum level of miR-4488 was increased in LNs compared with HIs (P<0.0001) and NLNs (P=0.025). miR-4488 had acceptable performance in predicting [area under the curve (AUC) =0.794, 0.698] lean NAFLD. Moreover, GO and KEGG enrichment analyses revealed that the differentially expressed target genes were mainly involved in choline metabolism in cancer, the tumor-necrosis factor (TNF) signaling pathway and the p53 signaling pathway. PPI analysis identified ARHGAP1, SLC10A1 and SIX5 as the hub genes. Conclusions: Taken together, our findings indicate that serum miR-4488 is a potential biomarker for diagnosing and predicting the pathogenetic mechanisms of lean NAFLD.

Arthroscopic Rotator Cuff Repair In Patients With Parkinson's Disease: A Propensity Score Matching Study With Minimum 2-Year Follow-up.

BACKGROUND: Although the effectiveness of arthroscopic rotator cuff repair (ARCR) for structural and functional outcomes has been widespread proven, few researchers investigated the impact of ARCR on patients with Parkinson's Disease (PD), which may have previously been viewed as a relative contraindication to ARCR. METHODS: Data were collected retrospectively for all patients who underwent ARCR for small- to large-sized rotator cuff tears between September 2014 and May 2019. Patients were eligible for the study if they indicated that they diagnosed with rotator cuff repair and had minimum 2-year postoperative outcome scores for the range of motion (ROM), the Western Ontario Rotator Cuff Index (WORC), the Constant-Murley Score (CMS), the University of California, Los Angeles (UCLA), Pittsburgh Sleep Quality Index (PSQI), Hospital Anxiety and Depression Scale (HADS), and the visual analog scale (VAS) for pain. Propensity score matching (PSM), a statistical method, was used to screen a control group without PD matched 1:1 with similar age, sex, tear size, preoperative stiffness, and fatty infiltration, which have previously been identified as important factors influencing success rates. RESULTS: Three hundred and eighty-nine patients met all study criteria including required follow-up, of whom 31 and 358 with PD and without PD, respectively. After adjusting for confounders, the propensity score matched indicators were compared, patients with PD experienced significantly more pain (4.45 ± 2.43 vs. 0.52 ± 1.18; P<.001) and had lower WORC (49.10 ± 21.22 vs. 78.90 ± 17.54; P<.001), CMS (46.77 ± 22.24 vs. 79.45 ± 14.74; P<.001) and UCLA (21.11 ± 8.54 vs. 28.16 ± 6.16; P<.001) scores respectively than the matched control group. They also exhibited higher sleep disturbance (10.04 ± 5.36 vs. 5.19 ± 3.28; P<.001), as well as higher anxiety and depression psychological status at 24 months (P<.001; P<.001). Overall clinical outcomes from preoperatively to postoperatively were not improved significantly for patients with PD vs. without PD. CONCLUSION: Patients with PD experienced significantly more pain, resulted in worse shoulder functional outcomes, and reported persistently diminished mental and physical health status. Shoulder surgeons should be cognizant of PD as an outcome-modifying variable when treating patients with rotator cuff tears. This finding suggested that the need for ARCR in patients with PD should be carefully considered in the light of personalized needs and physical conditions.

Short-term clinical effectiveness of 5% lidocaine patch after arthroscopic rotator cuff repair: study protocol for a randomized, double-blinded, placebo-controlled clinical trial.

BACKGROUND: Arthroscopic rotator cuff repair (ARCR) often causes unbearable postoperative pain, even more severe than before surgery. Opioids are the drugs of choice for temporary postoperative analgesia. However, this conventional approach also has some side effects and potential for drug abuse. The aims of this study are expected to verify the effect of 5% lidocaine patch (LP5) on the intensity of early postoperative pain, functional recovery and quality of life in patients undergoing ARCR. METHODS: In this randomized, double-blind, and placebo-controlled clinical trial, a total of 102 postoperative patients undergoing ARCR will be randomly assigned to either the LP5 group, receiving topical lidocaine analgesia, or the placebo control group. The primary outcome measure will be the change in the American Shoulder Elbow Surgeons score from pre-operation to 90 days post-operation. Secondary outcomes will include pain scores, range of motion, opioid use, safety indicators, blinding assessment and several shoulder function score questionnaires. The effect of the allocated treatment will be assessed at preoperative baseline and at 7-, 14-, 30- and 90-day postoperatively. DISCUSSION: In this study, the efficacy and safety of the 5% lidocaine patch will be evaluated in terms of short-term clinical symptoms in patients undergoing ARCR. The results of this study will help determine whether LP5 is effective in early functional recovery in ARCR and whether it relieves pain and reduces opioid consumption. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( http://www.chictr.org.cn ) ChiCTR2200060108. Registered on 19 May 2022.

Comparative outcomes of patient-specific instrumentation, the conventional method and navigation assistance in open-wedge high tibial osteotomy: A prospective comparative study with a two-year follow up.

BACKGROUND: To compare and analyze the correction precision, clinical outcomes and complications among the three methods of performing open-wedge high tibial osteotomy (HTO), including patient-specific instrumentation (PSI), conventional method and navigation assistance. METHODS: In this prospective, single-center study, we randomly assigned patients with knee osteoarthritis in a 1:1:1 ratio to undergo Open-wedge high tibial osteotomy (OWHTO) with conventional method, navigation assistance or PSI. The primary outcome was the target/observed hip-knee-ankle (HKA) angle difference at 1 month postoperatively. Secondary outcomes were changes in the postoperative posterior tibial slope (PTS) at 1 month and clinical outcomes including knee pain on a visual analogue scale (ranging from 0 to 100, with higher scores indicating more severe pain), Lysholm and Western Ontario and McMaster Universities Osteoarthritis Index (ranging from 0 to 240) scores at 1 month, 6 months, 12 months, and 24 months. RESULTS: From 2017 through 2019, a total of 608 patients were screened; of those patients, 144 were enrolled, with 48 in each group. The primary outcome of the HKA difference was 2.6 ± 2.0° in the conventional group, 2.3 ± 1.5° in the navigation group and 0.6 ± 1.0° in the PSI group (P < 0.001). Secondary outcomes including changes in the postoperative PTS and clinical outcomes at 1 month, 6 months, and 12 months were in the same direction as the primary outcome. There were no significant differences in the complications among the three groups. CONCLUSIONS: In the present study, none of the three methods showed superiority in objective correction precision and clinical outcomes at 2 years.

New insights into natural products that target the gut microbiota: Effects on the prevention and treatment of colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignant carcinomas. CRC is characterized by asymptomatic onset, and most patients are already in the middle and advanced stages of disease when they are diagnosed. Inflammatory bowel disease (IBD) and the inflammatory-cancer transformation of advanced colorectal adenoma are the main causes of CRC. There is an urgent need for effective prevention and intervention strategies for CRC. In recent years, rapid research progress has increased our understanding of gut microbiota. Meanwhile, with the deepening of research on the pathogenesis of colorectal cancer, gut microbiota has been confirmed to play a direct role in the occurrence and treatment of colorectal cancer. Strategies to regulate the gut microbiota have potential value for application in the prevention and treatment of CRC. Regulation of gut microbiota is one of the important ways for natural products to exert pharmacological effects, especially in the treatment of metabolic diseases and tumours. This review summarizes the role of gut microbiota in colorectal tumorigenesis and the mechanism by which natural products reduce tumorigenesis and improve therapeutic response. We point out that the regulation of gut microbiota by natural products may serve as a potential means of treatment and prevention of CRC.

Research progress in the role and mechanism of LPCAT3 in metabolic related diseases and cancer.

Lysophosphatidylcholine acyltransferases (LPCATs) are among the lysophopholipid acyltransferases (LPLATs) that specifically regulate the abundance of different phosphatidylcholine (PC) species in a variety of cell and tissue types, thereby playing an important role in lipid metabolism and homeostasis. Lysophosphatidylcholine acyltransferase 3 (LPCAT3, MBOAT5) is a member of the LPCAT family that primarily regulates the levels of arachidonic PC species. LPCAT3 is regulated by the liver X receptor, which plays an important role in lipoprotein production in the liver and small intestine. Increasing lines of research have demonstrated that LPCAT3 plays important roles in the occurrence and development of many diseases, such as atherosclerosis, intestinal tumors, and nonalcoholic steatohepatitis (NASH). The development of many diseases has been linked to the proinflammatory effects of LPCAT3. This review focuses on the current knowledge of LPCAT3, including its function and mechanism in different diseases. We aim to provide a comprehensive and in-depth understanding of LPCAT3 and to provide new ideas for the treatment of some diseases.

Can Natural Products be Used to Overcome the Limitations of Colorectal Cancer Immunotherapy?

Colorectal cancer (CRC) is a common cancer of the digestive system that endangers human health. Immunotherapy is widely used in the treatment of patients with cancer. Some patients with dMMR/MSI-H CRC benefit from treatments that use immune checkpoint inhibitors, but most CRC patients are not sensitive to immunotherapy. Furthermore, internal resistance and immune escape lead to a reduced immunotherapy response. Therefore, the development of an effective combination therapy to improve the response rate to immunotherapy is a goal of cancer research. Natural products are potential candidates for comprehensive cancer treatments due to their wide range of immunomodulatory effects through multifactorial underlying mechanisms. In this review, we summarize the challenges in the treatment of CRC and assess the immunomodulatory effects of natural products and their active components. Our work suggests that natural products represent potential options for combined CRC immunotherapy.