Unsupervised Machine Learning-Based Analysis of Clinical Features, Bone Mineral Density Features and Medical Care Costs of Rotator Cuff Tears.

PURPOSE: We aim to present unsupervised machine learning-based analysis of clinical features, bone mineral density (BMD) features, and medical care costs of Rotator cuff tears (RCT). PATIENTS AND METHODS: Fifty-three patients with RCT were reviewed, the clinical features, BMD features, and medical care costs were collected and analyzed by descriptive statistics. Furtherly, unsupervised machine learning (UML) algorithm was used for dimensionality reduction and cluster analysis of the RCT data. RESULTS: There were 26 males and 27 females. The patients were divided into four subgroups using the UML algorithm. There were significant differences among four subgroups regarding trauma exposure, full-thickness supraspinatus tendon tears, infraspinatus tendon tear, subscapularis tendon tear, BMD distribution, medial row anchors, lateral row anchors, total medical care costs, and consumables costs. We observed the highest frequency of trauma exposure, infraspinatus tendon tear, subscapularis tendon tear, osteoporosis, the highest number of medial row anchors, lateral row anchors, total medical care costs, and consumables costs in subgroup II. CONCLUSION: The unsupervised machine learning-based analysis of RCT can provide clinically meaningful classification, which shows good interpretability and contribute to a better understanding of RCT. The significance of the results is limited due to the small number of samples, a larger follow-up study is needed to confirm the encouraging results.

Postoperative Bone Marrow Lesions (BMLs) Are Associated with Pain Severity in Patients Undergoing Open Wedge High Tibial Osteotomy (OWHTO).

The purpose of the study was to investigate the relationship between postoperative bone marrow lesions (BMLs) and pain severity in patients undergoing open wedge high tibial osteotomy (OWHTO). We reviewed the patients undergoing OWHTO between April 2018 and April 2020. The demographic and clinical data of patients were collected. Clinically, VAS and Knee injury and Osteoarthritis Outcome Score (KOOS) were used to assess pain level and functional outcomes of patients. The MRI Osteoarthritis Knee Score (MOAKS) was used to assess the total BMLs size in medial tibiofemoral (MTF), lateral tibiofemoral (LTF), and patellofemoral (PF) joints. 98 patients were enrolled in the study, including 57 male and 41 female patients. The VAS scores improved significantly from 6.1 ± 0.8 to 1.5 ± 0.9 (p < 0.001), and all subscales of KOOS improved significantly after surgery (p < 0.001). There were no significant differences between the pre- and postoperative total BML size of PF and LTF joints (p > 0.05). We observed significant improvements in the total BML size of MTF joint (p < 0.001). The VAS scores and KOOS pain scores improved better in patients without postoperative MTF joint BMLs (p < 0.001). Postoperative MTF joint BMLs were correlated with postoperative VAS (p < 0.001) and KOOS pain (p < 0.001). Our study demonstrates that MTF joint BMLs improved significantly after OWTHO. We confirmed that the presence of postoperative MTF joint BMLs are strongly associated with pain severity. The greater the improvement in postoperative MTF joint BMLs, the less pain. Our findings provide valuable understandings of OWHTO in the treatment of knee osteoarthritis (KOA) and potential future directions for KOA treatment approaches.

A Novel Application of Unsupervised Machine Learning and Supervised Machine Learning-Derived Radiomics in Anterior Cruciate Ligament Rupture.

PURPOSE: We aim to present an unsupervised machine learning application in anterior cruciate ligament (ACL) rupture and evaluate whether supervised machine learning-derived radiomics features enable prediction of ACL rupture accurately. PATIENTS AND METHODS: Sixty-eight patients were reviewed. Their demographic features were recorded, radiomics features were extracted, and the input dataset was defined as a collection of demographic features and radiomics features. The input dataset was automatically classified by the unsupervised machine learning algorithm. Then, we used a supervised machine learning algorithm to construct a radiomics model. The t-test and least absolute shrinkage and selection operator (LASSO) method were used for feature selection, random forest and support vector machine (SVM) were used as machine learning classifiers. For each model, the sensitivity, specificity, accuracy, and the area under the curve (AUC) of receiver operating characteristic (ROC) curves were calculated to evaluate model performance. RESULTS: In total, 5 demographic features were recorded and 106 radiomics features were extracted. By applying the unsupervised machine learning algorithm, patients were divided into 5 groups. Group 5 had the highest incidence of ACL rupture and left knee involvement. There were significant differences in left knee involvement among the groups. Forty-three radiomics features were extracted using t-test and 7 radiomics features were extracted using LASSO method. We found that the combination of LASSO selection method and random forest classifier has the highest sensitivity, specificity, accuracy, and AUC. The 7 radiomics features extracted by LASSO method were potential predictors for ACL rupture. CONCLUSION: We validated the clinical application of unsupervised machine learning involving ACL rupture. Moreover, we found 7 radiomics features which were potential predictors for ACL rupture. The study indicated that radiomics could be a valuable method in the prediction of ACL rupture.

[Efficacy of Stereotactic Body Radiotherapy versus Surgery for the Treatment 
of Early Non-small Cell Lung Cancer: A Meta-analysis].

BACKGROUND: To compare the clinical efficacy of stereotactic body radiotherapy (SBRT) versus surgery for early-stage non-small cell lung cancer through evidence based medicine analysis. METHODS: A systematic search was performed in the PubMed, EMBASE, CNKI and Wan Fang databases to find studies published before June 2020. Two authors independently extracted the data and assessed the eligibility. All of the statistical analyses were performed using Stata 13.0. Subgroup analysis were performed according to the score matching study and operation type (lobectomy, segmentectomy and thoracoscopic assisted surgery). RESULTS: Finally, 14 articles were included, including 15,841 cases in SBRT group and 17,708 cases in operation group. 10 articles used propensity score matching methods for survival analysis. Thirteen were retrospective cohort studies and one was randomized controlled trial. The results of meta-analysis showed that the overall survival rate of the surgery group and the SBRT group was statistically significant. The overall survival rate of the SBRT group (HR=1.51, 95%CI: 1.31-1.74) was inferior to that of the surgery group. In the subgroup analysis of the surgical type, there was no statistical difference between the SBRT group and each surgical type. The difference of overall survival rate between SBRT group and surgery group was statistically significant (HR=1.66, 95%CI: 1.45-1.90) in studies of propensity score matching. There was no statistically significant difference in cancer-specific survival between the surgery and SBRT groups (HR=1.12, 95%CI: 0.83-1.52). CONCLUSIONS: The overall survival rate of surgical treatment is better than that of SBRT, but it has no obvious advantages in cancer specific survival rate.

Tranexamic Acid Is Beneficial to Patients Undergoing Open-Wedge High Tibial Osteotomy.

The purpose of this study was to investigate the efficacy of tranexamic acid (TXA) in patients undergoing open-wedge high tibial osteotomy (OWHTO). Patients from August 2018 to May 2020 were retrospectively studied. Clinical data were obtained including gender, age, height, weight, body mass index (BMI), smoking, alcohol consumption, hypertension, diabetes, history of aspirin, prepostoperative hematocrit (Hct) and hemoglobin (Hb), thrombotic events, blood transfusion requirement, hospital length of stay, size of osteotomy gap, and wound complications such as wound hematoma and infection. 52 patients were enrolled in the tranexamic acid group (TA group), and 48 patients were enrolled in the nontranexamic acid group (NTA group); there were no significant differences between both groups in terms of gender, age, BMI, preoperative Hb, size of osteotomy gap, incidence of smoking, alcohol consumption, hypertension, diabetes, history of aspirin, thrombotic events, blood transfusion requirement, and wound hematoma and infection. The mean hospital length of stay was 9.4 ± 1.0 days in the TA group and 11.0 ± 1.2 days in the NTA group (P < 0.001), the blood loss was 296.0 ± 128.7 ml in the TA group and 383.3 ± 181.3 ml in the NTA group (P < 0.05), and the postoperative Hb level was 120.8 ± 15.0 g/l in the TA group and 109.5 ± 13.8 g/l in the NTA group (P < 0.001). In conclusion, the administration of TXA is beneficial to patients undergoing OWHTO via decreasing hospital length of stay, reducing blood loss, and maintaining higher postoperative Hb levels.

Patient Characteristics Related to Blood Loss in High Tibial Osteotomy in Novel Multiple Linear Regression Analysis.

The purpose of the study was to identify patient characteristics related to blood loss following high tibial osteotomy (HTO). We evaluated 48 patients undergoing HTO from August 2018 to August 2019. The data of 48 patients were collected, including gender, age, height, weight, body mass index (BMI), smoking, alcohol consumption, hypertension, diabetes, history of aspirin, and pre-postoperative hematocrit (Hct). Multiple linear regression analysis was used to analyze the risk factors related to blood loss in HTO. The mean age of patients was 56.6 ± 10.2 years, including 22 males and 26 females. The mean BMI was 28.5 ± 4.2 kg/m2, and the mean blood loss volume was 383.3 ± 181.3 mL, 13 patients with smoking (27.1%), 15 patients with alcohol consumption (31.3%), 23 patients with hypertension (47.9%), 10 patients with diabetes mellitus (20.8%), and 12 patients with history of aspirin (25.0%). Multiple linear regression model suggested alcohol consumption and BMI were associated with blood loss in HTO, R 2 = 0.451, F(9, 38) = 3.462 (P < 0.05). Our study indicates that alcohol consumption and BMI are important risk factors related to blood loss in HTO.

Discovery of dehydro-oxopiperazine acetamides as novel bradykinin B1 receptor antagonists with enhanced in vitro potency.

In a series of bradykinin B1 antagonists, we discovered that replacement of oxopiperazine acetamides with dehydro-oxopiperazine acetamides provided compounds with enhanced activity against the B1 receptor. The synthesis and SAR leading to potent analogs with reduced molecular weight will be discussed.

3-Oxo-2-piperazinyl acetamides as potent bradykinin B1 receptor antagonists for the treatment of pain and inflammation.

The discovery of novel and highly potent oxopiperazine based B1 receptor antagonists is described. Compared to the previously described arylsulfonylated (R)-3-amino-3-phenylpropionic acid series, the current compounds showed improved in vitro potency and metabolic stability. Compound 17, 2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide, showed EC(50) of 10.3 nM in a rabbit biochemical challenge model. The practical syntheses of chiral arylsulfonylated oxopiperazine acetic acids are also described.

Novel vanilloid receptor-1 antagonists: 1. Conformationally restricted analogues of trans-cinnamides.

The vanilloid receptor-1 (VR1 or TRPV1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role as an integrator of multiple pain-producing stimuli. From a high-throughput screening assay, measuring calcium uptake in TRPV1-expressing cells, we identified an N-aryl trans-cinnamide (AMG9810, compound 9) that acts as a potent TRPV1 antagonist. We have demonstrated the antihyperalgesic properties of 9 in vivo and have also reported the discovery of novel, orally bioavailable cinnamides derived from this lead. Herein, we expand our investigations and describe the synthesis and biological evaluation of a series of conformationally constrained analogues of the s-cis conformer of compound 9. These investigations resulted in the identification of 4-amino- and 4-oxopyrimidine cores as suitable isosteric replacements for the trans-acrylamide moiety. The best examples from this series, pyrimidines 79 and 74, were orally bioavailable and exhibited potent antagonism of both rat (IC50 = 4.5 and 0.6 nM, respectively) and human TRPV1 (IC50 = 7.4 and 3.7 nM, respectively). In addition, compound 74 was shown to be efficacious at blocking a TRPV1-mediated physiological response in vivo in the capsaicin-induced hypothermia model in rats; however, it was ineffective at preventing thermal hyperalgesia induced by complete Freund's adjuvant in rats.

Novel vanilloid receptor-1 antagonists: 2. Structure-activity relationships of 4-oxopyrimidines leading to the selection of a clinical candidate.

A series of novel 4-oxopyrimidine TRPV1 antagonists was evaluated in assays measuring the blockade of capsaicin or acid-induced influx of calcium into CHO cells expressing TRPV1. The investigation of the structure-activity relationships in the heterocyclic A-region revealed the optimum pharmacophoric elements required for activity in this series and resulted in the identification of subnanomolar TRPV1 antagonists. The most potent of these antagonists were thoroughly profiled in pharmacokinetic assays. Optimization of the heterocyclic A-region led to the design and synthesis of 23, a compound that potently blocked multiple modes of TRPV1 activation. Compound 23 was shown to be effective in a rodent "on-target" biochemical challenge model (capsaicin-induced flinch, ED50 = 0.33 mg/kg p.o.) and was antihyperalgesic in a model of inflammatory pain (CFA-induced thermal hyperalgesia, MED = 0.83 mg/kg, p.o.). Based on its in vivo efficacy and pharmacokinetic profile, compound 23 (N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide; AMG 517) was selected for further evaluation in human clinical trials.

Discovery of potent, orally available vanilloid receptor-1 antagonists. Structure-activity relationship of N-aryl cinnamides.

The vanilloid receptor-1 (TRPV1 or VR1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role in regulating the function of sensory nerves. A growing body of evidence demonstrates the therapeutic potential of TRPV1 modulators, particularly in the management of pain. As a result of our screening efforts, we identified (E)-3-(4-tert-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide (1), an antagonist that blocks the capsaicin-induced and pH-induced uptake of (45)Ca(2+) in TRPV1-expressing Chinese hamster ovary cells with IC(50) values of 17 +/- 5 and 150 +/- 80 nM, respectively. In this report, we describe the synthesis and structure-activity relationship of a series of N-aryl cinnamides, the most potent of which (49a and 49b) exhibit good oral bioavailability in rats (F(oral) = 39% and 17%, respectively).

N-Aryl-gamma-lactams as integrin alphavbeta3 antagonists.

Novel alphavbeta3 antagonists based on the N-aryl-gamma-lactam scaffold were prepared. SAR studies led to the identification of potent antagonists for alphavbeta3 receptor with excellent selectivity against the structurally related alpha(IIb)beta3 receptor. Additional interactions of N-aryl-gamma-lactam derivatives with alphavbeta3 were found when compared to c(-RGDf[NMe]V-) peptide antagonist. The effects of the conformation and configuration of the gamma-lactam core on the binding were also assessed.