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Low-dose rivaroxaban is often given to patients with atrial fibrillation (AF) around the world, but the rationale for its use remains unclear. We aimed to compare the efficacy and safety of standard- or low-dose rivaroxaban in patients with AF through systematic review of literature with meta-analysis.We searched PubMed, Web of Science, EMBASE, Clinical Trials.gov, the Cochrane Library, and Bayer trial website from inception of each database until June 2020. Randomized controlled trials (RCTs) and cohort studies were included in the meta-analysis. A random-effects model was employed to calculate the pooled effect estimates.Two RCTs and 17 cohort studies were included in the qualitative analysis. Indirect comparison of RCTs showed no significant difference between the two rivaroxaban dosages in risk of efficacy or safety outcomes (p 0.05). Indirect comparison of cohort studies showed a lower risk of MACE among Caucasians in standard-dose group (HR 0.779; 95% CI 0.687-0.884; p 0.001). Bleeding outcomes did not differ significantly between the two dosage regimens in Asian or Caucasian populations, except that the standard dose was associated with higher risk of major bleeding among elderly Caucasian patients (HR 1.329; 95% CI 1.141-1.547; p 0.001). The quality of evidence was rated ranging from very low to low for all the efficacy and safety outcomes.In Caucasians with AF, standard-dose rivaroxaban may prevent MACE significantly better than low-dose treatment. Further studies in Asians are needed to verify the advantages of the standard dose.

Background The critical shoulder angle (CSA), which helps to predict patients who are at risk of rotator cuff tears (RCTs) with large degree and who are susceptible to osteoarthritis with low angle, has been identified as one of the most vital acromial parameters; anterolateral and lateral acromioplasties have been proven to be valid ways to reduce CSA. However, no study has compared the effect of different acromioplasties on the reduction of the large CSA (≥33°) clinically. Additionally, either anterolateral or lateral acromioplasty could not precisely correct large CSAs to a favorable range (30–33°) in each patient. Thus, we will propose a novel precise acromioplasty technique for the purpose of reducing CSA accurately and effectively, and compare the effectiveness of different acromioplasties on the reduction of the CSA. Methods A total of 60 RCT patients who have indications for arthroscopic rotator cuff repair and with pre-operative CSA ≥33° will be recruited in outpatient center of Sun Yat-sen Memorial Hospital. Eligible participants will be randomly allocated to Group A (anterolateral acromioplasty), Group B (lateral acromioplasty) or Group C (precise acromioplasty) via a random, computer-generated number system. Three surgical plans will be made for each participant respectively by one professional surgeon according to the results of randomization allocation. The post-operative CSA will be measured 2 days post-operation. Follow-up will be maintained at 3, 6, and 12 months after surgery including the visual analog scale score, the University of California at Los Angeles score, the Constant Shoulder Score and the American Shoulder and Elbow Surgeon Shoulder Assessment Form. Finally, all outcomes will be assessed by two researchers who are blinded to the recruitment and allocation. Discussion This is the first clinical trial to evaluate the impact of different acromioplasties on the reduction of the CSA. Additionally, this study will provide a new precise acromioplasty technique, which is a novel precision and individualized treatment to prevent degenerative RCTs by reducing the CSA. Trial registration ChiCTR2000032343. Registered on April 26th, 2020.

Background Several suture repair techniques have been reported for radial tear close to the posterior lateral meniscal root (type II PLMRT). However, no study has evaluated the clinical results after repair using the FasT-Fix system. This paper describes a novel H-plasty surgical repair technique and reports its clinical results. Methods From January 2015 to January 2017, 47 patients underwent repair of type II PLMRT with concomitant anterior cruciate ligament reconstruction and were included in this study. Assessments performed preoperatively and at final follow-up included the Lysholm score, subjective International Knee Documentation Committee (IKDC) score, and knee stability assessments (pivot-shift test, Lachman test, KNEELAX arthrometer side-to-side difference). Magnetic resonance imaging was used to compare the lateral meniscal extrusion pre- versus postoperatively. Second-look arthroscopy was performed to evaluate the meniscal healing in 38 cases. Results Forty-seven patients were followed up for an average of 30.7 months (range 18–46 months). No patients experienced meniscal mechanical symptoms. At final follow-up, there were significant improvements in the Lysholm score, IKDC score, knee stability assessments, and lateral meniscal extrusion compared with the preoperative values. In the 38 of 47 patients that underwent second-look arthroscopy after an average of 17.5 months (range 14–19 months), all repairs (100%) were completely healed. Conclusions The novel H-plasty repair using the FasT-Fix system was an effective surgical treatment for type II PLMRT. Considering the satisfactory clinical results and the convenience of the surgery, H-plasty repair is recommended to be used preferentially.

Objective: At present, prostate cancer radical surgery still lacks an objective standard for predicting the anatomic difficulty of surgery through preoperative examination. Due to the poor prognosi...

Most studies have concentrated on the changes in contact pressure and area on the tibiofemoral joint. This study compared the contact mechanics underneath the medial meniscus of a repaired vertical longitudinal tear with that of the intact or the torn ones. In this controlled laboratory study, a 1000 N compressive axial load was applied to eight fresh-frozen cadaveric knees at four flexion angles and four loading conditions using a custom testing apparatus attached to a material testing machine. Intact knees, knees with a medial meniscus vertical longitudinal tear, and knees after meniscal repair were tested. The peak contact pressure and area underneath the meniscus were measured using Fuji pressure-sensitive film. A medial meniscus vertical longitudinal tear significantly increased the contact pressure and decreased contact area underneath the meniscus compared with those at the intact meniscus under all tested biomechanical conditions, and repair of the tear can restore the contact pressure and area in most conditions. While the repaired group showed a significantly higher or similar contact pressure compared with the tear group at 90° neutral knee position and at 60°, 90° 5 N·m-external rotation and 134 N-anterior tibial translation, and 5 N·m-internal rotation at all flexion angles. The contact area corresponding to the aberrant result of the contact pressure in the repaired group was lower than in the intact meniscus group. The contact mechanics underneath the meniscus of the repaired medial meniscus vertical longitudinal tear were significantly improved compared with the corresponding tear conditions in most cases, while the contact pressure and area at some certain status after repair were not significantly different from those of the corresponding tear conditions.

To explore whether the critical shoulder angle (CSA) and acromion index (AI) on nonstandard anteroposterior (AP) radiographs could be used as parameters for rotator cuff tear (RCT) diagnosis and to determine the optimized parameters.This study included 174 patients with RCTs or intact rotator cuffs in whom AP radiographs were obtained at our hospital. The radiographs were assessed by 2 independent radiologists and were grouped according to the Suter-Henninger criteria. The CSA and AI were measured on all films. We performed receiver operating characteristic curve analysis by calculating the area under the curve (AUC) to compare the sensitivity and accuracy of both parameters.Of the 174 enrolled patients, only 47 (27%) met the requirements for standard AP films (types A1 and C1). On standard AP films, both the CSA and AI were significantly different between the RCT and control groups (P.001 for CSA and P.001 for AI), with AUCs of 0.86 and 0.80 for the CSA and AI, respectively. On nonstandard AP films (other radiograph types), the mean CSA value was not significantly different between the RCT and control groups (P = .536) whereas the AI showed a significant difference (P = .024). The AUCs were 0.57 for the CSA and 0.64 for the AI.On standard AP films, both the CSA and AI could predict rotator cuff disorders, and the CSA had a higher diagnostic accuracy than the AI. In contrast, on nonstandard AP films, the diagnostic efficacy of the AI was better than that of the CSA. On the basis of this study, we suggest an evaluation of the AP films of patients before diagnosis to confirm whether the AP films meet the criteria for standard AP films.Level I, diagnostic study.

BACKGROUND Osteoarthritis (OA) affects the health and wellbeing of the elderly. Shaoyao Gancao decoction (SGD) is used in traditional Chinese medicine (TCM) for the treatment of OA and has two active components, shaoyao (SY) and gancao (GC). This study aimed to undertake a network pharmacology analysis of the mechanism of the effects of SGD in OA. MATERIAL AND METHODS The active compounds and candidates of SGD were obtained from the Traditional Chinese Medicine (TCM) Databases@Taiwan, the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, the STITCH database, the ChEMBL database, and PubChem. The network pharmacology approach involved network construction, target prediction, and module analysis. Significant signaling pathways of the cluster networks for SGD and OA were identified using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS Twenty-three bioactive compounds were identified, corresponding to 226 targets for SGD. Also, 187 genes were closely associated with OA, of which 161 overlapped with the targets of SGD and were considered to be therapeutically relevant. Functional enrichment analysis suggested that SGD exerted its pharmacological effects in OA by modulating multiple pathways, including cell cycle, cell apoptosis, drug metabolism, inflammation, and immune modulation. CONCLUSIONS A novel approach was developed to systematically identify the mechanisms of the TCM, SGD in OA using network pharmacology analysis.

Objective To investigate the Young's modulus value of infraspinatus tendons using shear wave elastography (SWE) technique in normal adults, and to analyze the influence of gender, postures, exercise, and dominant side on Young's modulus of infraspinatus tendons. Methods This is a prospective cross‐sectional study. From January 2019 to July 2020, 14 healthy subjects were identified, including seven males and seven females aged between 24 to 34, with a mean age of 27.67 ± 3.08 years. The Young's modulus of their infraspinatus tendons was measured by two operators using SWE in neutral and maximum external rotation positions of both sides before exercise and the dominant side after exercise. The Young's modulus values in different sexes, different postures, before vs after exercise, and dominant vs non‐dominant side were statistically analyzed. Results All 14 subjects completed the data collection process. The mean Young's modulus values of infraspinatus tendon for dominant sides in neutral position were 33.04 ± 3.01 kPa for males and 28.76 ± 3.09 kPa for females. And for non‐dominant sides in the neutral position, the values were 33.02 ± 2.38 kPa for males and 28.86 ± 2.47 kPa for females. In the maximum external rotation position, the values for dominant sides were 50.19 ± 4.86 kPa for males and 42.79 ± 4.44 kPa for females, and for non‐dominant sides were 50.95 ± 3.24 kPa for males and 42.42 ± 3.66 kPa for females. After exercise, the mean Young's modulus values of infraspinatus tendon for dominant sides in neutral position were 54.56 ± 3.76 kPa for males and 46.66 ± 5.99 kPa for females. And for the maximum external rotation position, the values were 59.13 ± 3.78 kPa for males and 54.49 ± 5.67 kPa for females. The Young's modulus of infraspinatus tendon in the neutral and maximum external rotation positions showed statistically significant differences in males and females, as well as before and after exercise (P 0.05). Intergroup reliability between both operators was excellent (ICC > 0.85). Conclusion There are gender‐related differences and post‐exercise increase in Young's modulus, yet such a difference cannot be witnessed between the dominant and non‐dominant sides., The Young's modulus value of normal adults' infraspinatus tendons can be obtained with SWE. Our study showed no significant difference in hardness of infraspinatus tendons between the dominant side and the non‐dominant side. The hardness increases significantly after exercise, and there is a hardness difference between men and women.

Objective. The mechanism of peach kernel-safflower in treating diabetic nephropathy (DN) was investigated using network pharmacology. Methods. Network pharmacology methodology was applied to screen the effective compounds of peach kernel-safflower in the SymMap and TCMSP databases. Potential targets were then screened in the ETCM, SEA, and SymMap databases to construct a compound-target network. This was followed by screening of DN targets in OMIM, Gene, and GeneCards databases. The common targets of drugs and diseases were selected for analysis in the STRING database, and the results were imported into Cytoscape 3.8.0 to construct a protein-protein interaction network. Next, GO and KEGG enrichment analyses were performed. Finally, Schrödinger molecular docking verified the reliability of the results. Results. A total of 23 effective compounds and 794 potential targets resulted from our screening process. Quercetin and luteolin were identified as the main effective ingredients in peach kernel-safflower. Furthermore, five key targets (VEGFA, IL6, TNF, AKT1, and TP53), AGE-RAGE, fluid shear stress and atherosclerosis, IL-17, and HIF-1 signaling pathways may be involved in the treatment of DN using peach kernel-safflower. Conclusions. This study embodies the complex network relationship of multicomponents, multitargets, and multipathways of peach kernel-safflower to treat DN and provides a basis for further research on its mechanism.

Background: Rotator cuff tear is one of the most common diseases in orthopedics, which seriously affects the quality of patients’ lives. And the arthroscopic repair of rotator cuff has recently become more and more popular. Systematic rehabilitation makes great significance for improving the prognosis of postoperative patients. Yet, the traditional outpatient rehabilitation is hard to popularize in developing countries like China due to the limitation of traffic and geography. Given this, we plan to develop a telerehabilitation system to facilitate doctors' remote guidance on patients' rehabilitation.Methods/design: Our study is a single-center, prospective randomized controlled trial. 124 patients who underwent arthroscopic rotator cuff repair will be recruited for the study. They will be randomly divided into 2 groups (62 cases in each group) based on the stratification factors of the operator, operation and preoperative diagnosis. The patients in the control group will get clinic and booklet based rehabilitation treatment after operation. However, patients in the experimental group will receive mobile phone and motion-capture device based programs for telerehabilitation after surgery. The primary outcome will be measured by the American Shoulder and Elbow Surgeons (ASES). Secondary outcomes include the Range of motion (ROM), Visual Analogue Scales (VAS), EuroQol-5 Dimension health questionnaire (EQ-5D), University of California at Los Angeles（UCLA）and the retear rate.Discussion: We hypothesize that patients who utilized mobile phone and motion-capture device based telerehabilitation will benefit more in the range of motion and shoulder function than those who received outpatient and manual based rehabilitation. If the hypothesize was confirmed, we could facilitate telerehabilitation for doctors and overcome the geographical and traffic limitations of traditional clinical based rehabilitation.Trial registration: ChiCTR.org.cn, ChiCTR2000030150, Registered on 24 February 2020

BackgroundSarcomas, cancers originating from mesenchymal cells, are comprehensive tumors with poor prognoses, yet their tumorigenic mechanisms are largely unknown. In this study, we characterize infiltrating immune cells and analyze immune scores to identify the molecular mechanism of immunologic response to sarcomas.MethodThe “CIBERSORT” algorithm was used to calculate the amount of L22 immune cell infiltration in sarcomas. Then, the “ESTIMATE” algorithm was used to assess the “Estimate,” “Immune,” and “Stromal” scores. Weighted gene co-expression network analysis (WGCNA) was utilized to identify the significant module related to the immune therapeutic target. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using the “clusterProfiler” package in R for annotation and visualization.ResultsMacrophages were the most common immune cells infiltrating sarcomas. The number of CD8 T cells was negatively associated with that of M0 and M2 macrophages, and positively associated with M macrophages in sarcomas samples. The clinical parameters (disease type, gender) significantly increased with higher Estimate, Immune, and Stromal scores, and with a better prognosis. The blue module was significantly associated with CD8 T cells. Functional enrichment analysis showed that the blue module was mainly involved in chemokine signaling and the PI3K-Akt signaling pathway.CD48, P2RY10andRASAL3were identified and validated at the protein level.ConclusionBased on the immune cell infiltration and immune microenvironment, three key genes were identified, thus presenting novel molecular mechanisms of sarcoma metastasis.

Background Osteosarcoma (OS) is a common malignant bone tumor originating in the interstitial tissues and occurring mostly in adolescents and young adults. Energy metabolism is a prerequisite for cancer cell growth, proliferation, invasion, and metastasis. However, the gene signatures associated with energy metabolism and their underlying molecular mechanisms that drive them are unknown. Methods Energy metabolism-related genes were obtained from the TARGET database. We applied the “NFM” algorithm to classify putative signature gene into subtypes based on energy metabolism. Key genes related to progression were identified by weighted co-expression network analysis (WGCNA). Based on least absolute shrinkage and selection operator (LASSO) Cox proportional regression hazards model analyses, a gene signature for the predication of OS progression and prognosis was established. Robustness and estimation evaluations and comparison against other models were used to evaluate the prognostic performance of our model. Results Two subtypes associated with energy metabolism was determined using the “NFM” algorithm, and significant modules related to energy metabolism were identified by WGCNA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) suggested that the genes in the significant modules were enriched in kinase, immune metabolism processes, and metabolism-related pathways. We constructed a seven-gene signature consisting of SLC18B1, RBMXL1, DOK3, HS3ST2, ATP6V0D1, CCAR1, and C1QTNF1 to be used for OS progression and prognosis. Upregulation of CCAR1, and C1QTNF1 was associated with augmented OS risk, whereas, increases in the expression SCL18B1, RBMXL1, DOK3, HS3ST2, and ATP6VOD1 was correlated with a diminished risk of OS. We confirmed that the seven-gene signature was robust, and was superior to the earlier models evaluated; therefore, it may be used for timely OS diagnosis, treatment, and prognosis. Conclusions The seven-gene signature related to OS energy metabolism developed here could be used in the early diagnosis, treatment, and prognosis of OS.

Objective Treatment of massive irreparable rotator cuff tears (RCT) has shown limited clinical success and a variety of subsequent complications. Superior capsule reconstruction (SCR) has been proved to reestablish superior stability but does not restore the dynamic force or shoulder kinematics. There are numerous reports of the short-term failure of SCR grafts at the glenoid side, which relate to the non-biological healing of grafts. To restore both dynamic and static stability and to provide biologic augmentation, an integrated procedure for massive irreparable RCT using an Achilles tendon-bone allograft (ATBA) was developed. Method This was a retrospect study completed between October 2019 and April 2020. A 71-year-old woman with massive and irreparable rotator cuff tears was enrolled in our study. The ATBA was folded into a double-layer structure. The superior layer (proximal portion) served as a bridge patch to dynamic the glenohumeral joint, while the inferior layer (distal portion) served as the superior capsule to restore static stability of glenohumeral joint. To enhance biologic healing on the glenoid side, we fixed the calcaneus of the graft on the superior-posterior side of the superior glenoid rim. The recovery of shoulder function (including strength, range of motion, acromiohumeral interval, and fatty infiltration) was assessed at 6 months postoperation. Result At 6-month follow-up, the patient's strength had improved significantly (from abduction of grade 3 preoperatively to grade 4 at 6 months). Radiographic analysis showed an increase in the acromiohumeral interval from 3 to 7 mm. Magnetic resonance imaging revealed an intact graft, with the thickness of the ligament part maintained (at 6-7 mm). Most importantly, recovery of atrophy and fatty infiltration of the supraspinatus were observed. No graft tears were observed on the glenoid side. Conclusion This technique could provide a preferable treatment option by restoring shoulder kinematics and augmentating biological healing for patients with massive irreparable RCT.

To compare tibiofemoral contact mechanics after horizontal or ripstop (horizontal plus vertical) sutures in inside-out and transtibial repair for meniscal radial tears with 10 porcine knees in each group.Ten matched pairs of porcine knees were tested under a 1500-N axial compressive load at 0°, 30°, 60°, and 90° of knee flexion. Each knee underwent 4 testing conditions consecutively: (1) intact, (2) medial meniscal radial tear, (3) horizontal suture repair configuration, and (4) ripstop suture repair configuration. Tekscan sensors measured tibiofemoral contact pressure and contact area in the medial and lateral compartments.All repair groups improved their contact mechanics when compared with the tear state among all flexion angles analyzed (all P.05). Furthermore, ripstop sutures with both inside-out and transtibial repairs restored intact knee contact area and pressures (peak and mean) in the medial compartment at all flexion angles, whereas the horizontal sutures alone failed to do so for contact pressures at 60° and 90° and for contact surface areas at all flexion angles. However, the aforementioned parameters were not significantly different between inside-out sutures and transtibial sutures, regardless of horizontal or ripstop configuration (P.05).Radial tears of the meniscus in a porcine model significantly decreased medial contact area and increased mean and peak contact pressure. Both inside-out and transtibial ripstop repairs for radial tears aid in restoring intact tibiofemoral contact mechanics at all assessed knee flexion angles.Our results suggest that both inside-out and transtibial ripstop repairs for radial tears can restore tibiofemoral contact mechanics to the intact state. Since the study were performed in an open fashion porcine model, the results should be carefully used in clinical practices, and the efficacy of the techniques through arthroscopic method should be further explored.

To investigate (1) whether measurement of the critical shoulder angle (CSA) is still reliable in some nonstandard anteroposterior radiographs; and (2) whether the ratio of the transverse to longitudinal diameter of the glenoid projection (RTL) could be used to determine the reliability of the CSA in nonstandard anteroposterior radiographs.The authors analyzed radiology records from 2017 to 2019 for patients with computed tomography (CT) scans of the shoulder. According to the Suter-Henninger classification system, each CT scan underwent 3-dimensional (3D) reconstructions to obtain 8 digitally reconstructed radiographs (DRRs), including 1 type A1 film and 7 type D1 films with different rotation angles. CSA and RTL were measured on all films, and 2 blinded reviewers evaluated DRRs. The relationship between RTL and CSA was determined by Pearson correlation test. The threshold value was determined by receiver operating characteristic (ROC) analyses using RTL as predictors and defined reliable CSA as criterion in the logistic regression. Intra- and inter-rater reliability were assessed by the intraclass correlation coefficient (ICC). Discriminative capacity was calculated with ROC analyses and area under the curve (AUC). An optimal measurement cutoff with resultant sensitivity and specificity was calculated.A total of 86 patients were included, mean age 40.70 ± 18.25 years, 19 of whom had rotator cuff tears (RCTs) and 67 without RCTs. Spearman's correlation test revealed that the deviation of CSA was positively correlated with RTL, correlation coefficient 0.544 (P.001) in all patients and 0.686 (P .001) only in patients with RCTs. ROC analysis of all patients showed that the AUC of the RTL was 0.90, and the optimal cutoff point was 0.25 (sensitivity 88%, specificity 87%). ROC analysis only of patients with RCTs showed that the AUC of the RTL was 0.95, and the optimal cutoff point was 0.22 (sensitivity 95%, specificity 92%).The ratio of the transverse to longitudinal diameter of the glenoid projection (RTL) is of good predictive value in defining the reliability of the CSA in malposition films. Based on the results, the CSA can be considered reliable if its RTL is0.25.III, retrospective cohort study investigating a diagnostic test.

This study compared the diagnostic accuracy of second-look arthroscopy, clinical assessment, and magnetic resonance imaging (MRI) in evaluating meniscal healing following repair. To explore the application of 3D-MRI sequences with signal-to-noise ratio (SNR) measurements and the analysis of sensitivity and accuracy in evaluating meniscal healing status after meniscal repair. This study included 75 patients (75 menisci; mean age, 25.4 ± 6.6 years) who underwent arthroscopic meniscal repair (medial menisci, 45; and lateral menisci, 29). Follow-up evaluation included clinical assessment, magnetic resonance imaging (MRI), and second-look arthroscopy (mean follow-up, 10.2 ± 3.4 months). The criteria defined for unhealed menisci were: on arthroscopy, presence of cleft; on clinical assessment, presence of joint-line tenderness, swelling, locking, or positive McMurray test; on MRI, grade III signal intensity at the site of repair. Finally, the SNR on 3D-MRI of the healed and the unhealed groups were compared. On second-look arthroscopy, 68 (90.7%) menisci were found to be completely healed. With the arthroscopic healing rate as the standard, the clinical healing rate was 69.3% (63 menisci) [sensitivity, 85.7%; specificity, 75.0%; accuracy, 76.0%; positive predictive value (PPV), 26.1%; negative predictive value (NPV), 98.1%]. Similarly, the sensitivity, specificity, accuracy, PPV and NPV, respectively, for MRI in four sequences were as follows: 2D-T2W-Sag: 71.4, 79.4, 78.7, 26.3, and 96.4%; 2D-T2W-Cor: 71.4, 82.4, 81.3, 29.4, and 96.6%; 3D-PDW-Sag: 100.0, 50.0, 54.7, 17.1, and 100.0%; 3D-PDW-Cor: 100.0, 58.8, 62.7, 20.0, and 100.0%. The mean SNRs of the healed group (3D-PDW-Sag, 66.7 ± 11.9; 3D-PDW-Cor, 63.9 ± 12.4) were significantly lesser than that of the unhealed group (3D-PDW-Sag, 89.2 ± 9.6; 3D-PDW-Cor, 82.2 ± 18.5) (P

Jianli Zhao,1,2,* Ying Wang,1,2,* Zengding Lao,3,* Siting Liang,3 Jingyi Hou,4 Yunfang Yu,1,2 Herui Yao,1,2 Na You,3 Kai Chen1,2 1Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; 2Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; 3School of Mathematics, Sun Yat-Sen University, Guangzhou, China; 4Department of Orthopedics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China *These authors contributed equally to this work Abstract: Breast cancer, the most common cancer among women, is a clinically and biologically heterogeneous disease. Numerous prognostic tools have been proposed, including gene signatures. Unlike proliferation-related prognostic gene signatures, many immune-related gene signatures have emerged as principal biology-driven predictors of breast cancer. Diverse statistical methods and data sets were used for building these immune-related prognostic models, making it difficult to compare or use them in clinically meaningful ways. This study evaluated successfully published immune-related prognostic gene signatures through systematic validations of publicly available data sets. Eight prognostic models that were built upon immune-related gene signatures were evaluated. The performances of these models were compared and ranked in ten publicly available data sets, comprising a total of 2,449 breast cancer cases. Predictive accuracies were measured as concordance indices (C-indices). All tests of statistical significance were two-sided. Immune-related gene models performed better in estrogen receptor-negative (ER-) and lymph node-positive (LN+) breast cancer subtypes. The three top-ranked ER- breast cancer models achieved overall C-indices of 0.62–0.63. Two models predicted better than chance for ER+ breast cancer, with C-indices of 0.53 and 0.59, respectively. For LN+ breast cancer, four models showed predictive advantage, with C-indices between 0.56 and 0.61. Predicted prognostic values were positively correlated with ER status when evaluated using univariate analyses in most of the models under investigation. Multivariate analyses indicated that prognostic values of the three models were independent of known clinical prognostic factors. Collectively, these analyses provided a comprehensive evaluation of immune-related prognostic gene signatures. By synthesizing C-indices in multiple independent data sets, immune-related gene signatures were ranked for ER+, ER-, LN+, and LN- breast cancer subtypes. Taken together, these data showed that immune-related gene signatures have good prognostic values in breast cancer, especially for ER- and LN+ tumors. Keywords: breast cancer, prognostic models, immune-related gene

Macrophage-related inflammatory response is one of the main biological factors resulting in failure of anterior cruciate ligament (ACL) reconstruction, although the specific pathomechanism remains to be clarified. Our aim was to investigate the association between graft loosening and macrophage-related inflammation in cases of loosening of reconstructed ACL autografts. Tissue samples were obtained from 21 patients who underwent a second-look arthroscopy within the first year after arthroscopic ACL reconstruction using single-bundle hamstring tendon autografts. Possible biological factors of graft loosening were analyzed using polymerase chain reaction, Western blot, and hematoxylin/eosin and immunohistochemical staining of graft tissue samples obtained during the second-look arthroscopy. Graft loosening was closely related to increased gene and protein expression of inflammatory cytokines (TNF-α, IL-6, and IL-8) and activation of the inflammation-related toll-like receptor (TLR) signaling (TLR2 and TLR4). The molecular expression of TGF-β and type I and III collagen was also inhibited to varying degrees, with decreased vascularization of the graft due to an inhibition of VEGF. iNOS, a marker of M1 macrophage activation, was highly expressed in cases of graft loosening, with no effect of M2 macrophages identified. The activation of M1 macrophages and aseptic inflammation signaling is an important biological factor of graft loosening after ACL reconstruction, affecting ligamentization and the health of grafts.

The underlying molecular characteristics of osteoarthritis (OA), a common age-related joint disease, remains elusive. Here, we aimed to identify potential early diagnostic biomarkers and elucidate underlying mechanisms of OA using weighted gene co-expression network analysis (WGCNA).We obtained the gene expression profile dataset GSE55235, GSE55457, and GSE55584, from the Gene Expression Omnibus. WGCNA was used to investigate the changes in co-expressed genes between normal and OA synovial membrane samples. Modules that were highly correlated to OA were subjected to functional enrichment analysis using the R clusterProfiler package. Differentially expressed genes (DEGs) between the two samples were screened using the "limma" package in R. A Venn diagram was constructed to intersect the genes in significant modules and DEGs. RT -PCR was used to further verify the hub gene expression levels between normal and OA samples.The preserved significant module was found to be highly associated with OA development and progression (P1e-200, correlation = 0.92). Functional enrichment analysis suggested that the antiquewhite4 module was highly correlated to FoxO signaling pathway, and the metabolism of fatty acids and 2-oxocarboxylic acid. A total of 13 hub genes were identified based on significant module network topology and DEG analysis, and RT-PCR confirmed that these genes were significantly increased in OA samples compared with that in normal samples.We identified 13 hub genes correlated to the development and progression of OA, which may provide new biomarkers and drug targets for OA.

Synovial-derived cells, found in the synovial membrane of human joints, were obtained by digestion of the synovial membrane and were subsequently expanded in vitro. The identity of synovial-derived cells has long been a topic of debate. The terms “type B synoviocytes,” “fibroblast-like synoviocytes (FLS),” “synovium-derived mesenchymal stem cells (MSCs),” and “synovial fibroblasts (SF)” appeared in different articles related to human synovial-derived cells in various disease models, yet they seemed to be describing the same cell type. However, to date, there is no clear standard to distinguish these terms; thus, the hypothesis that they represent the same cell type is currently inconclusive. Therefore, this review aims to clarify the similarities and differences between these terms and to diffuse the chaotic nomenclature of synovial-derived cells.

Background Isolated rectus femoris (RF) contracture is encountered very rarely in orthopaedic practices. There are few reports on its imaging manifestations and no cases reported to be treated with arthroscopy. Case presentation A 11-year-old girl with a more than 7 years history of restricted left knee flexion was presented. The clinical assessment and magnetic resonance imaging (MRI) findings were detailed here. A strip-like induration was palpated in the left thigh, which tends to be more obvious with knee flexion. MRI demonstrated a hypointensity band connected the anterior inferior iliac spine with the patella, and marked atrophy of the left RF muscle. Fibrosis contracture band was confirmed with arthroscope, then divided by radiofrequency ablation (RFA) under arthroscopic observation. Followed by debridement of the fibrillar connective tissue and hemostasis around the broken ends. The movement of left knee joint significantly improved after the operation, and the patient recovered nearly full range of motion of this joint after 6 months. Conclusion The specific MRI findings could assist in confirming clinical early diagnosis of isolated RF contracture. Arthroscopic RFA treatment is an effective technique to treat this disorder with minimally incision. Electronic supplementary material The online version of this article (10.1186/s12891-019-2696-8) contains supplementary material, which is available to authorized users.

Interleukin-21 (IL-21) is a cytokine that plays a crucial role in pathogenesis and activity of the rheumatoid arthritis (RA). Meanwhile, genetic polymorphisms in the IL-21 gene may alter its expression. Previous studies have reported conflicting results assessing the association between the IL-21 rs6822844 G/T polymorphism and RA risk. Thus, it’s necessary to perform a meta-analysis to definite above relationship. PubMed database was searched for all papers published until October 20, 2019. Nine case–control studies with 9998 cases and 10742 controls were retrieved based on the search criteria at last. Odds ratio (95% confidence interval) was used to calculate the strength of this association. Publication bias was detected using both Begg’s and Egger’s tests. Overall, the IL-21 rs6822844 G/T polymorphism was found to be significantly associated with decreased RA risk (e.g. T-allele versus G-allele: OR = 0.81, 95% CI = 0.72–0.91, P < 0.001). In addition, decreased RA risk was also detected both in Asians (eg: TT+TG versus GG: OR = 0.42, 95% CI = 0.31–0.56, P < 0.001) and Caucasians (eg: TT+TG versus GG: OR = 0.85, 95% CI = 0.80–0.91, P < 0.001). A similar trend in association was found in the source of the control and genotype method subgroups. Furthermore, subgroup analysis of rheumatoid factor status revealed a protective relationship between the IL-21 rs6822844 G/T polymorphism and RF+/RF- RA risk. A similar relationship was noted in the anti-citrullinated protein antibody status subgroup. The results of the present study suggest that the IL-21 rs6822844 G/T polymorphism was significantly associated with decreased RA susceptibility.

Background: Rehabilitation is crucial for postoperative patients with low back pain (LBP). However, the implementation of traditional clinic-based programs is limited in developing countries, such as China, because of the maldistribution of medical resources. Mobile phone–based programs may be a potential substitute for those who have no access to traditional rehabilitation. Objective: The aim of this study was to examine the efficacy of mobile phone–based rehabilitation systems in patients who underwent lumbar spinal surgery. Methods: Patients who accepted spinal surgeries were recruited and randomized into 2 groups of rehabilitation treatments: (1) a mobile phone–based eHealth (electronic health) program (EH) or (2) usual care treatment (UC). The primary outcomes were (1) function and pain status assessed by the Oswestry Disability Index (ODI) and (2) the visual analog scale (VAS). Secondary outcomes were (1) general mental health and (2) quality of life (Likert scales, EuroQol-5 Dimension health questionnaire, and 36-item Short-Form Health Survey). All the patients were assessed preoperatively and then at 3, 6, 12, and 24 months postoperatively. Results: A total of 168 of the 863 eligible patients were included and randomized in this study. Our analysis showed that the improvement of primary outcomes in the EH group was superior to the UC group at 24 months postoperatively (ODI mean 7.02, SD 3.10, P

The authors wish to make the following correction to their paper [...]

Synovium-derived mesenchymal stromal cells (SMSCs) may play an important role in the pathogenesis of rheumatoid arthritis (RA) and show promise for therapeutic applications in RA. In this study, a whole-genome microarray analysis was used to detect differential gene expression in SMSCs from RA patients and healthy donors (HDs). Our results showed that there were 4828 differentially expressed genes in the RA group compared to the HD group; 3117 genes were upregulated, and 1711 genes were downregulated. A Gene Ontology analysis showed significantly enriched terms of differentially expressed genes in the biological process, cellular component, and molecular function domains. A Kyoto Encyclopedia of Genes and Genomes analysis showed that the MAPK signaling and rheumatoid arthritis pathways were upregulated and that the p53 signaling pathway was downregulated in RA SMSCs. Quantitative real-time polymerase chain reaction was applied to verify the expression variations of the partial genes mentioned above, and a western blot analysis was used to determine the expression levels of p53, p-JNK, p-ERK, and p-p38. Our study found that differentially expressed genes in the MAPK signaling, rheumatoid arthritis, and p53 signaling pathways may help to explain the pathogenic mechanism of RA and lead to therapeutic RA SMSC applications.

Background The American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) questionnaire is an effective tool for evaluating shoulder joint function. The development and usage of a mobile version of the ASES questionnaire has the potential to save time, money, and effort. Objective The aim of this study is to assess the equivalence between the paper and mobile versions of the ASES questionnaire and their acceptability among patients. Methods The paper and mobile versions of the ASES questionnaire were used to evaluate the shoulder joint function of 50 patients with shoulder pain. This study included patients from the shoulder clinic of Sun Yat-sen Memorial Hospital. The intraclass correlation coefficient (ICC) and Bland-Altman method were used to evaluate the agreement (reliability) of the scores obtained by the two methods (paper versus mobile). Results Of the 50 patients recruited from March 2018 to May 2019, 46 (92%) completed the study. There was a high agreement between the paper and mobile versions of the ASES questionnaire (ICC=0.979, 95% CI 0.943-0.987; P Conclusions Our study shows that the mobile version of the ASES questionnaire is comparable to the paper version, and has a higher patient preference. This could prove to be a useful tool for epidemiological studies and patient follow-up over longer periods of time.

Scaffolds with antioxidant capability have attracted considerable interests for wound healing. For enhanced wound healing, new antioxidant materials are still highly needed. In this study, new antioxidant materials, arginine derivatives (AD), were introduced into dopamine-functionalized hyaluronic acid (HA-DA) to develop novel hydrogels (HA-DA/AD) with enhanced antioxidant activity. The HA-DA/AD hydrogels showed greater DPPH and hydroxyl radical scavenging rates than the HA-DA hydrogel. Moreover, the HA-DA/AD hydrogels exhibited significantly better protection for cells against external oxidative stress (decreased ROS and MDA levels and increased SOD and GPx enzyme activity) and better wound healing (enhanced VEGF and CD 31 expression and enhanced tissue remodeling). This study confirmed that AD could assist wound healing scaffolds to have enhanced antioxidant properties.

In this study, the network pharmacology analysis method was used to explore the bioactive components and targets of Xianlinggubao (XLGB) and further elucidate its potential biological mechanisms of action in the treatment of osteoporosis (OP). The bioactive compounds and predictive targets of XLGB were collected from the traditional Chinese medicine systems pharmacology databases and analysis platform(TCMSP), the Encyclopeida of traditional Chinese medicine (ETCM), traditional Chinese medicine Databse@Taiwan, ChEMBL, STITCH, and SymMap database. The targets corresponding to OP were obtained by using Online Mendelian Inheritance in Man® (OMIM), GeneCards, the National Center for Biotechnology Information-Gene database. The XLGB-OP targets were obtained by intersecting with the targets of XLGB and OP. Protien-Protien interaciton (PPI) network was constructed using STRING online database and analyzed using Cytoscape 3.7.0 software to screen out hub genes. Gene ontology (GO) and KEGG enrichment analysis of the target in the PPI network was conducted using the ClusterProfiler package in R with adjusted p-value

SUMMARYA century ago, influenza A virus (IAV) infection caused the 1918 flu pandemic and killed an estimated 20-40 million people. Pandemic IAV outbreaks occur when strains from animal reservoirs acquire the ability to infect and spread among humans. The molecular details of this species barrier are incompletely understood. We combined metabolic pulse labeling and quantitative shotgun proteomics to globally monitor protein synthesis upon infection of human cells with a human-and a bird-adapted IAV strain. While production of host proteins was remarkably similar, we observed striking differences in the kinetics of viral protein synthesis over the course of infection. Most importantly, the matrix protein M1 was inefficiently produced by the bird-adapted strain at later stages. We show that impaired production of M1 from bird-adapted strains is caused by increased splicing of the M segment RNA to alternative isoforms. Experiments with reporter constructs and recombinant influenza viruses revealed that strain-specific M segment splicing is controlled by the 3’ splice site and functionally important for permissive infection. Independentin silicoevidence shows that avian-adapted M segments have evolved different conserved RNA structure features than human-adapted sequences. Thus, our data identifies M segment RNA splicing as a viral determinant of host range.

Although the suture-hook technique remains popular for meniscal ramp lesions, which frequently occur after anterior cruciate ligament (ACL) injury, it is unclear whether the all-inside FasT-Fix technique (Smith & Nephew, Andover, MA) is appropriate for the repair of ramp lesions. This study evaluated results of arthroscopic FasT-Fix meniscal ramp lesion repair using second-look arthroscopy. From August 2010 to December 2014, 46 knees diagnosed with combined ACL injury and ramp lesion underwent ACL reconstruction with meniscal repair using the FasT-Fix technique. We classified ramp lesions into three types according to tear pattern: meniscotibial ligament tear, meniscocapsular tear, and combined meniscotibial/meniscocapsular tear. Second-look arthroscopy was performed postoperatively. The healing capacity of the ramp lesion was evaluated retrospectively. At the final follow-up (mean = 32 months), the Lysholm knee score and the International Knee Documentation Committee (IKDC) objective score were compared with preoperative scores. All patients (n = 46) underwent a second-look arthroscopy, with 45 (97.8%) exhibiting complete or partial healing after the FasT-Fix technique was used in conjunction with ACL reconstruction. The Lysholm knee score and IKDC objective score were significantly better than preoperative scores at final follow-up. The FasT-Fix technique for meniscal ramp lesion repair—when performed with concomitant ACL reconstruction—exhibits excellent healing results.

This study compared knee stability and alterations in the composition of synovial fluid among patients who underwent arthroscopic anterior cruciate ligament (ACL) reconstruction with either a hamstring autograft or a hamstring allograft. This prospective cohort study enrolled 175 patients. Of these patients, 90 underwent hamstring tendon autograft ACL reconstruction. The remaining patients (n=85) underwent hamstring tendon allograft ACL reconstruction. All of the patients had a minimum of 1 year of follow-up (mean, 2.5 years). Side-to-side differences and the proportion of mononuclear cells in knee joint synovial fluid were measured at 5 time points (preoperatively and at postoperative weeks 1, 3, 6, and 12). During the early postoperative phase, side-to-side knee laxity was greater among the allograft group compared with the autograft group ( P P >.05). These findings showed that, in the early postoperative phase, ACL reconstruction with a hamstring allograft resulted in greater knee laxity and immunologic response compared with the hamstring autograft group. However, at relatively long-term follow-up, both grafts achieved similar objective and subjective outcomes. [ Orthopedics. 2017; 40(5):e892–e897.]

Background: We introduce a novel method of combining the standard anteromedial and anterolateral approaches and dual posterolateral approaches in the arthroscopic treatment of posterior and anterior ankle impingement syndrome and compare the postoperative outcomes with conventional anteromedial/anterolateral and posteromedial/posterolateral approaches. Methods: From January 2013 to January 2015, we treated 28 patients with posterior and anterior ankle impingement syndrome by arthroscopy. The patients were divided into the conventional group (n = 13) and the modified group (n = 15) according to the surgical approaches used in the operation. Preoperative and postoperative American Orthopaedic Foot & Ankle Society (AOFAS) score, visual analog scale (VAS) score, range of ankle motion, and operation time were recorded. The average follow-up was 16 months (range 6-24 months). Results: Posterior and anterior ankle impingement syndrome was confirmed arthroscopically in all patients. After the operation, the range of ankle motion in all patients was restored. There was no significant difference in postoperative AOFAS score, VAS score, dorsiflexion, and plantarflexion between the conventional group and the modified group. Moreover, the operation time was significantly reduced in the modified group compared with the conventional group. There was no recurrence of osteophyte and no complications such as infection, neurovascular injury, or delayed healing of surgical incision in the modified group. Conclusions: Dual posterolateral approaches combined with standard anteromedial and anterolateral approaches was a novel method for arthroscopic treatment of posterior and anterior ankle impingement syndrome. It proved to be safe and effective, and significantly reduced the operation time. Reposition, repeated prep and drape, and limb distraction were avoided. Level of Evidence: Level IV, retrospective case series.

Supplemental Digital Content is available in the text, Human bladder cancer (BCa) is one of the most commonly diagnosed malignancies worldwide. It has high recurrence rates and low-grade malignancy, thus representing an important public health concern. An increasing number of studies suggest that long-noncoding RNAs (lncRNAs) play important roles in various biological processes and disease pathologies, including cancer. We analyzed the expression profiles of lncRNA, miRNA, and mRNA, along with the clinical information of BCa patients collected from the Cancer Genome Atlas database to identify lncRNA biomarkers for prognosis. We also constructed an lncRNA–miRNA–mRNA global triple network (competitive endogenous RNA network) by bioinformational approach. This BCa lncRNA–miRNA–mRNA network consisted of 23 miRNA nodes, 52 mRNA nodes, 59 lncRNA nodes, and 365 edges. Subsequent gene ontology (GO) and pathway analyses were performed using BinGO for Cytoscape and Database for Annotation, Visualization, and Integration Discovery, respectively, highlighting important GO terms and pathways that were enriched in the network. Subnetworks were created using 3 key lncRNAs (MAGI2-AS3, ADAMTS9-AS2, and LINC00330), revealing associations with BCa-linked mRNAs and miRNAs. Finally, an analysis of significantly differentiating RNAs found 6 DElncRNAs (AC112721.1, ADAMTS9-AS1, ADAMTS9-AS2, HCG22, MYO16-AS1, and SACS-AS1), 1 DEmiRNA (miRNA-195), and 6 DEmRNAs (CCNB1, FAM129A, MAP1B, TMEM100, AIFM3, and HOXB5) that correlated with BCa patient survival. Our results provide a novel perspective from which to study the lncRNA-related ceRNA network in BCa, contributing to the development of future diagnostic biomarkers and therapeutic targets.

Supplemental Digital Content is available in the text, Rheumatoid arthritis (RA) and osteoarthritis (OA) comprise the most common forms of arthritis. The aim of this study was to identify differentially expressed genes (DEGs) and associated biological processes between RA and OA using a bioinformatics approach to elucidate their potential pathogenesis. The gene expression profiles of the GSE55457 datasets, originally produced through use of the high-throughput Affymetrix Human Genome U133A Array, were downloaded from the Gene Expression Omnibus (GEO) database. The GSE55457 dataset contains information from 33 samples, including 10 normal control (NC) samples, 13 RA samples, and 10 OA samples. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were performed to identify functional categories and associated molecular and biochemical pathways, respectively, for the identified DEGs, and a protein-protein interaction (PPI) network of the DEGs was constructed using Cytoscape software. GO and KEGG results suggested that several biological pathways (ie, “immune response,” “inflammation,” and “osteoclast differentiation”) are commonly involved in the development of both RA and OA, whereas several other pathways (eg, “MAPK signaling pathway,” and “ECM-receptor interaction”) presented significant differences between these disorders. This study provides further insights into the underlying pathogenesis of RA and OA, which may facilitate the diagnosis and treatment of these diseases.

Circular RNAs (circRNAs) have re-emerged as an interesting RNA species. Here, by deep RNA profiling in different mouse tissues, we observed that circRNAs are significantly enriched in brain.and a disproportionate fraction of them is derived from host genes that code for synaptic proteins. Moreover, based on separate profiling of the RNAs localized in neuronal cell bodies and neuropil, on average, circRNAs are more enriched in the neuropil than their host gene mRNA isoforms. Using high resolution in situ hybridization we, for the first time, visualized circRNA punctae in the dendrites of neurons. Consistent with the idea that circRNAs might regulate synaptic function, during development, many circRNAs change their abundance abruptly at a time corresponding to synaptogenesis. In addition, following a homeostatic downscaling of neuronal activity many circRNAs exhibit significant up or down-regulation. Together, our data indicate that brain circRNAs are positioned to respond to and regulate synaptic function.

Our objective was to evaluate the feasibility, safety, and efficacy of intravenous (IV) infusion of allogenic mesenchymal stem cells (MSCs) in ankylosing spondylitis (AS) patients who are refractory to or cannot tolerate the side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). AS patients enrolled in this study received four IV infusions of MSCs on days 0, 7, 14, and 21. The percentage of ASAS20 responders (the primary endpoint) at the fourth week and the mean ASAS20 response duration (the secondary endpoint) were used to assess treatment response to MSC infusion and duration of the therapeutic effects. Ankylosing Spondylitis Disease Activity Score Containing C-reactive Protein (ASDAS-CRP) and other preestablished evaluation indices were also adopted to evaluate the clinical effects. Magnetic resonance imaging (MRI) was performed to detect changes of bone marrow edema in the spine. The safety of this treatment was also evaluated. Thirty-one patients were included, and the percentage of ASAS20 responders reached 77.4% at the fourth week, and the mean ASAS20 response duration was 7.1 weeks. The mean ASDAS-CRP score decreased from 3.6 ± 0.6 to 2.4 ± 0.5 at the fourth week and then increased to 3.2 ± 0.8 at the 20th week. The average total inflammation extent (TIE) detected by MRI decreased from 533,482.5 at baseline to 480,692.3 at the fourth week ( p > 0.05) and 400,547.2 at the 20th week ( p < 0.05). No adverse effects were noted. IV infusion of MSCs is a feasible, safe, and promising treatment for patients with AS.