A hierarchical opportunistic screening model for osteoporosis using machine learning applied to clinical data and CT images.

BACKGROUND: Osteoporosis is a common metabolic skeletal disease and usually lacks obvious symptoms. Many individuals are not diagnosed until osteoporotic fractures occur. Bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) is the gold standard for osteoporosis detection. However, only a limited percentage of people with osteoporosis risks undergo the DXA test. As a result, it is vital to develop methods to identify individuals at-risk based on methods other than DXA. RESULTS: We proposed a hierarchical model with three layers to detect osteoporosis using clinical data (including demographic characteristics and routine laboratory tests data) and CT images covering lumbar vertebral bodies rather than DXA data via machine learning. 2210 individuals over age 40 were collected retrospectively, among which 246 individuals' clinical data and CT images are both available. Irrelevant and redundant features were removed via statistical analysis. Consequently, 28 features, including 16 clinical data and 12 texture features demonstrated statistically significant differences (p < 0.05) between osteoporosis and normal groups. Six machine learning algorithms including logistic regression (LR), support vector machine with radial-basis function kernel, artificial neural network, random forests, eXtreme Gradient Boosting and Stacking that combined the above five classifiers were employed as classifiers to assess the performances of the model. Furthermore, to diminish the influence of data partitioning, the dataset was randomly split into training and test set with stratified sampling repeated five times. The results demonstrated that the hierarchical model based on LR showed better performances with an area under the receiver operating characteristic curve of 0.818, 0.838, and 0.962 for three layers, respectively in distinguishing individuals with osteoporosis and normal BMD. CONCLUSIONS: The proposed model showed great potential in opportunistic screening for osteoporosis without additional expense. It is hoped that this model could serve to detect osteoporosis as early as possible and thereby prevent serious complications of osteoporosis, such as osteoporosis fractures.

Foot drop as the initial symptom caused by thoracic disc herniation.

BACKGROUND: Foot drop is a syndrome resulting from weakness or paralysis of the tibialis anterior muscle. Some patients with thoracic disc herniation seek medical help complain of foot drop as the initial symptom. The study investigated the clinical characteristics of these patients and clarified the clinical efficacy after treatment. METHODS: A total of 13 patients with foot drop as the initial symptom arising from thoracic disc herniation were collected from January 2015 to December 2020. The average follow-up period was 20.5 months. We recorded neurological functions, the tibialis anterior muscle strength, Japanese Orthopedic Association score (JOA), location of the lesion, and occupation rate of herniation in the spinal canal preoperatively and at the final follow-up. RESULTS: None pathological reflex was found in the patients. Surgical treatment was performed in 12 of the 13 patients, and tibialis anterior functional recovery was observed in 83.4% (10/12) of the cases, with an average recovery rate of 52.8 ± 18.5%. The mean JOA score increased from 6.8 ± 1.9 points preoperatively to 8.9 ± 1.3 points postoperatively (p < 0.05), achieving a mean recovery rate of 52.3 ± 13.1%. The MRI showed the conus medullaris was obviously compressed at the level of T11-L1, and the occupation rate of herniation was more than 40% in all patients, with an average of 65.4 ± 16.3%. CT indicated that 84.6% of the cases had calcification in intervertebral discs. CONCLUSION: Foot drop can be the initial symptom caused by thoracic disc herniation at the T11-L1 level, especially for the calcified disc herniation. A satisfactory recovery rate can be achieved by surgical decompression with fixation.

Specific effects of neuregulin-1ß on the communication between DRG neurons and skeletal muscle cells in vitro.

The communication between primary afferent neuron and skeletal muscle (SKM) is one of the important factors on maintaining the structure and function of SKM cells. Neuregulin-1ß (NRG-1ß) signaling is essential for regulating synaptic neurotransmission. Here, we established a neuromuscular coculture model of dorsal root ganglion (DRG) sensory neurons and SKM cells to explore the nerve-muscle communication in the presence of exogenous NRG-1ß. The expression of three distinct subtypes (TrkA, TrkB, and TrkC) of tyrosine kinase receptors was monitored for the phenotypical alterations of the neurons. The aggregation extent of acetylcholine receptor (AChR) represents the specific changes of SKM cells after NRG-1ß incubation in this neuromuscular coculture model. The results showed that NRG-1ß not only enhanced neurite outgrowth of DRG neurons but also increased the length and branches of SKM cells. NRG-1ß treatment not only induced expression of all the three subtypes of Trk receptors in neurons but also promoted AChR aggregation on the surface of SKM cells. The effects of NRG-1ß could be blocked by administration of ERK1/2 inhibitor PD98059, PI3K inhibitor LY294002, and JAK2 inhibitor AG490, respectively. These data imply that NRG-1ß is essential for the nerve-muscle communication by enhancing growth and modifying phenotypes of the two different kinds of cells. The specific effects produced by NRG-1ß add novel interpretation for nerve-muscle communication between sensory neurons and SKM cells.

Long non-coding RNA tumor suppressor candidate 7 functions as a tumor suppressor and inhibits proliferation in osteosarcoma.

Osteosarcoma is the most common malignant tumor of bone. Recent studies have proven long non-coding RNAs (lncRNAs) play important roles in the tumorigenesis and progression of cancer. However, few lncRNAs have been investigated in osteosarcoma. Here, we reported a novel lncRNA, tumor suppressor candidate 7 (TUSC7), was significantly downregulated in osteosarcoma tissues compared with paired non-tumor tissues and low expression of TUSC7 indicated poor survival (HR = 0.313, 95 % confidence interval (CI) 0.092-0.867) of osteosarcoma patients. Further analysis revealed that loss copy number of TUSC7 was correlated with low expression of TUSC7, and additionally, loss of TUSC7 copy number also indicated poor prognosis (HR = 3.994, 95 % CI 1.147-13.91) of osteosarcoma patients. Two osteosarcoma cell lines, HOS and MG63, were utilized to investigate biological function of TUSC7. Cell counting kit 8 (CCK-8) assay revealed that after silence of TUSC7, cell proliferation ability increased and the colony formation ability also increased. Further results showed that cell cycle was not affected by treatment of si-TUSC7, while the percentage of apoptotic cells decreased. Western blot showed that after silence of TUSC7, the proapoptotic Bcl2 expression was downregulated. Finally, we established xenograft tumor models in nude mice with MG63 cells. Compared with negative control group, silence of TUSC7 significantly promoted tumor growth in vivo. Thus, we demonstrated that TUSC7 could be a potential tumor suppressor in osteosarcoma.

Revealing the changes in signaling pathways caused by tofacitinib in patients with rheumatoid arthritis through RNA sequencing and the correlation with clinical parameters.

OBJECTIVES: The current study is to accelerate the understanding of how tofacitinib works in patients with rheumatoid arthritis (RA) due to the lack of relevant information. METHOD: We selected ten patients with active RA and obtained the expression profile for their peripheral blood mononuclear cells before and after the tofacitinib treatment by RNA sequencing. The gene set enrichment analysis was conducted, and the significantly enriched gene sets were identified. The hub gene highly correlated with clinical parameters in the gene set was selected. We constructed the weighted gene co-expression network, linked modules with clinical indicators, and screened hub genes. The expression of representative hub genes was validated by real-time quantitative PCR (qPCR). RESULTS: Gene set interferon (IFN) α and IFN ß signaling was the most significantly down-regulated after tofacitinib treatment. In this gene set, genes Oas2 and Oasl showed a significant positive correlation with morning stiffness. In co-expression network, gene Vgll3 from the violet module with the highest correlation coefficient, was positively correlated with morning stiffness. Among them, Oasl and Vgll3 have shown significant down-regulation in qPCR validation. CONCLUSIONS: Our results highlighted the role of type I IFN, mainly including IFN α and IFN ß, in the pathogenesis of RA and action for tofacitinib, and provided a new entry point for further elucidating the mechanism of morning stiffness. Key Points • Gene set IFN α and IFN ß signaling was the most significantly down-regulated after tofacitinib treatment in RA patients. • Gene Oasl and Vgll3 were correlated with morning stiffness and significantly down-regulated due to the action of tofacitinib. • Type I IFN system was highlighted in the action of tofacitinib.

Stress Distribution of Different Pedicle Screw Insertion Techniques Following Single-Segment TLIF: A Finite Element Analysis Study.

OBJECTIVES: At present, a variety of posterior lumbar internal fixation implantation methods have been developed, which makes it difficult for spine surgeons to choose. The stress distribution of the internal fixation system is one of the important indexes to evaluate these technologies. Common insertion technologies include Roy Camille, Magerl, Krag, AO, and Weinstein insertion techniques. This study aimed to compare the distribution of von Mises stresses in different screw fixation systems established by these insertion technologies. METHODS: Here, the three-dimensional finite element (FE) method was selected to evaluate the postoperative stress distribution of internal fixation. Following different pedicle screw insertion techniques, five single-segment transforaminal lumbar interbody fusion (TLIF) models were established after modeling and validation of the L1-S1 vertebrae FE model. RESULTS: By analyzing the data, we found that stress concentration phenomenon was in all the models. Additionally, Roy-Camille, Krag, AO, and Weinstein insertion techniques led to the great stress on lumbar vertebra, intervertebral disc, and screw-rod fixation systems. Therefore, we hope that the results can provide ideas for clinical work and development of pedicle screws in the future. It is worth noting that flexion, unaffected side lateral bending, and affected side axial rotation should be limited for the patients with cages implanted. CONCLUSIONS: Overall, our method obtained the results that Magerl insertion technique was the relatively safe approach for pedicle screw implantation due to its relatively dispersive stress in TLIF models.

Computational modeling of the cephalic arch with jugulocephalic vein variant predicts hemodynamic profiles in patients with brachiocephalic fistula.

BACKGROUND: The cephalic vein is often used in for arteriovenous fistula creation; however, the cephalic vein variation is common. This study will propose new theoretical explanations for a new discovered variation of cephalic vein draining into external jugular vein with "T-junction" shape by means of 3D computational hemodynamic modeling, which may provide reference for clinical practice. METHODS: The precise measurements were conducted for the variant right cephalic vein draining into external jugular vein and for a normal right cephalic vein as a control. After processing the anatomical data, 3D geometrical model was reconstructed. Then, the influent field inside the variant jugulocephalic vein was mathematically modeled to get a detailed description of hemodynamic environment. RESULTS: The anatomical parameters of the "T-junction" jugulocephalic vein variant were much more different from the normal right cephalic vein. The wall shear stress of variant cephalic vein at the corresponding position was higher and changed more rapidly than that of normal cephalic vein. The shear rate contour lines are disordered in several areas of the variant cephalic vein, indicating that the hemodynamic parameters in these areas are unstable. The hemodynamic characteristics at the confluence of the variant cephalic vein are more complex, with more areas where hemodynamic parameters are disrupted. CONCLUSIONS: The variation of cephalic arch in a "T-junction" with external jugular vein largely altered the fluid dynamics, especially in hemodialysis patients with brachiocephalic fistula in terms of the simulating flow in 3D computational model. This computational model provides hemodynamic profiles for stabilizing or modulating fluid dynamics in patients with jugulocephalic vein variant after brachiocephalic fistula.

In situ Co-Delivery of Doxorubicin and Cisplatin by Injectable Thermosensitive Hydrogels for Enhanced Osteosarcoma Treatment.

Purpose: Osteosarcoma is considered as the most common primary malignant bone tumor in children and adolescents, and the treatments including chemotherapy and surgery were far from satisfactory. Localized tumor treatments by hydrogels incorporating combined chemotherapeutic drugs have recently emerged as superior approaches for enhanced anti-tumor effects and reduced systemic toxicity. Methods: A novel injectable thermosensitive poly (lactide-co- glycolide)-poly (ethylene glycol)-poly(lactide-co-glycolide) triblock copolymer hydrogel containing doxorubicin and cisplatin for the localized chemotherapy of osteosarcoma were synthesized and characterized. The in vitro drug release properties of the drugs-loaded hydrogels were investigated. To study the anti-tumor efficacy of hydrogels depots in vitro, the cytotoxicity and apoptosis rate against Saos-2 and MG-63 cells were evaluated by MTT, Annexin V and PCR methods. The in vivo synergistic anti-tumor efficacy of the multi-drugs co-loaded hydrogels was investigated by human osteosarcoma xenografts. Additionally, the systemic toxic side effects were evaluated by ex vivo histological analysis of the major organs of the mice. Results: The PLGA-PEG-PLGA copolymer solution underwent a sol-gel transition at appropriate temperature and degraded in the PBS, presenting a friendly biocompatibility in vitro. The in vitro cell viability tests demonstrated that DOX and CDDP co-loaded hydrogels exhibited synergistic anti-proliferation effect, due to the sustained release of drugs from the drugs-loaded hydrogel. The treatment with DOX and CDDP co-loaded hydrogel led to the highest efficiency in inhibiting the tumor growth, enhanced tumor necrosis rate and increased regulation of the apoptosis-related gene expressions, indicating a synergistic anti-tumor efficacy in vivo. Additionally, ex vivo histological analysis of the nude mice exhibited low systemic toxicity. Conclusion: The combination treatment of osteosarcoma by localized, sustained co-delivery of DOX and CDDP by PLGA-PEG-PLGA hydrogel may serve as a promising strategy for efficient clinical treatment of osteosarcoma.

Unilateral pedicle screw fixation of lumber spine: A safe internal fixation method.

Background: Unilateral pedicle screw fixation several advantages, including reduced trauma and low cost. However, its stability and safety have not been widely recognized. In this study, the biomechanical differences in the vertebral body and screw-rod system after unilateral and bilateral pedicle screw fixation were compared using both the finite element model and calf lumbar model. Method: We used the verified finite element model to establish unilateral and bilateral posterior lumbar surgery models. The biomechanical data of different parts of the models were recorded under different working states. Then, three calf lumbar models were selected to simulate different working states with the help of a universal testing machine and other instruments. Finally, the biomechanical data of the screw-rod system were obtained from a static strain test and analysis system. Results: By analyzing and comparing biomechanical data obtained using two different methods, this study found that unilateral pedicle screw fixation does not bring excessive loads to the lumbar spine and screw-rod system. Conclusion: From the perspective of biomechanics, unilateral pedicle screw fixation is considered a safe and reliable implantation technique.

Long non-coding RNA TUSC7 suppresses osteosarcoma by targeting miR-211.

Long non-coding RNAs (lncRNAs) play a critical role in regulating cancer progression and metastasis. LncRNA tumor suppressor candidate 7 (TUSC-7) was shown to be a tumor suppressor in osteosarcoma. However, the regulation mechanism of TUSC-7 in osteosarcoma is unknown. Bioinformatics analysis showed that TUSC7 specifically binds to miR-211. MiR-211 was up-regulated in osteosarcoma and negatively correlated with the expression of TUSC7. miR-211 expression was inhibited remarkably by TUSC7 overexpression and the reciprocal inhibition exists between TUSC7 and miR-211. RNA pull-down and luciferase reporter assays were used to validate the sequence-specific correlation between miR-211 and TUSC7. TUSC7 inhibited the proliferation, migration of osteosarcoma cells and promoted cellular apoptosis, which is largely mediated by miR-211. We conclude that the TUSC7 acted as a tumor suppressor gene, which is negatively regulated by miR-211. Our study could suggest a potentially novel therapeutic strategy against osteosarcoma.

The effects of neuregulin-1ß on intrafusal muscle fiber formation in neuromuscular coculture of dorsal root ganglion explants and skeletal muscle cells.

BACKGROUND: The formation of intrafusal muscle (IM) fibers and their contact with afferent proprioceptive axons is critical for construction, function, and maintenance of the stretch reflex. Many factors affect the formation of IM fibers. Finding new factors and mechanisms of IM fiber formation is essential for the reconstruction of stretch reflex arc after injury. METHODS: We established a coculture system of organotypic dorsal root ganglion (DRG) explants and dissociated skeletal muscle (SKM) cells. The formation of IM fibers was observed in this coculture system after neuregulin-1ß (NRG-1ß) incubation. RESULTS: We found that NRG-1ß promoted outgrowth of neurites and migration of neurons from the organotypic DRG explants and that this correlated with an induction of growth-associated protein 43 (GAP-43) expression. NRG-1ß also increased the amount of nuclear bag fibers and nuclear chain fibers by elevating the proportion of tyrosine kinase receptor C (TrkC) phenotypic DRG neurons. In addition, we found that the effects of NRG-1ß could be blocked by inhibiting ERK1/2, PI3K/Akt, and JAK2/STAT3 signaling pathways. CONCLUSION: These data imply that NRG-1ß promoted neurite outgrowth and neuronal migration from the organotypic DRG explants and that this correlated with an induction of GAP-43 expression. The modulating effects of NRG-1ß on TrkC DRG neuronal phenotype may link to promote IM fiber formation. The effects produced by NRG-1ß in this neuromuscular coculture system provide new data for the therapeutic potential on IM fiber formation after muscle injury.