Severe Hypocalcemia With Denosumab Among Older Female Dialysis-Dependent Patients.

Importance: Dialysis-dependent patients experience high rates of morbidity from fractures, yet little evidence is available on optimal treatment strategies. Chronic kidney disease-mineral and bone disorder is nearly universal in dialysis-dependent patients, complicating diagnosis and treatment of skeletal fragility. Objective: To examine the incidence and comparative risk of severe hypocalcemia with denosumab compared with oral bisphosphonates among dialysis-dependent patients treated for osteoporosis. Design, Setting, and Participants: Retrospective cohort study of female dialysis-dependent Medicare patients aged 65 years or older who initiated treatment with denosumab or oral bisphosphonates from 2013 to 2020. Clinical performance measures including monthly serum calcium were obtained through linkage to the Consolidated Renal Operations in a Web-Enabled Network database. Exposures: Denosumab, 60 mg, or oral bisphosphonates. Main Outcomes and Measures: Severe hypocalcemia was defined as total albumin-corrected serum calcium below 7.5 mg/dL (1.88 mmol/L) or a primary hospital or emergency department hypocalcemia diagnosis (emergent care). Very severe hypocalcemia (serum calcium below 6.5 mg/dL [1.63 mmol/L] or emergent care) was also assessed. Inverse probability of treatment-weighted cumulative incidence, weighted risk differences, and weighted risk ratios were calculated during the first 12 treatment weeks. Results: In the unweighted cohorts, 607 of 1523 denosumab-treated patients and 23 of 1281 oral bisphosphonate-treated patients developed severe hypocalcemia. The 12-week weighted cumulative incidence of severe hypocalcemia was 41.1% with denosumab vs 2.0% with oral bisphosphonates (weighted risk difference, 39.1% [95% CI, 36.3%-41.9%]; weighted risk ratio, 20.7 [95% CI, 13.2-41.2]). The 12-week weighted cumulative incidence of very severe hypocalcemia was also increased with denosumab (10.9%) vs oral bisphosphonates (0.4%) (weighted risk difference, 10.5% [95% CI, 8.8%-12.0%]; weighted risk ratio, 26.4 [95% CI, 9.7-449.5]). Conclusions and Relevance: Denosumab was associated with a markedly higher incidence of severe and very severe hypocalcemia in female dialysis-dependent patients aged 65 years or older compared with oral bisphosphonates. Given the complexity of diagnosing the underlying bone pathophysiology in dialysis-dependent patients, the high risk posed by denosumab in this population, and the complex strategies required to monitor and treat severe hypocalcemia, denosumab should be administered after careful patient selection and with plans for frequent monitoring.

Bufalin targeting BFAR inhibits the occurrence and metastasis of gastric cancer through PI3K/AKT/mTOR signal pathway.

Gastric cancer (GC) is the most common malignant tumor of digestive system. Bufalin extracted from Venenum Bufonis is one of the most effective anticancer monomers, which has been proved to play anticancer roles in a variety of cancers such as ovarian cancer, prostate cancer and neuroblastoma. However, there are few studies on bufalin in GC, and lack of clear targets. The effect of bufalin on the proliferation and migration of GC cells was detected by CCK-8, scratch wound healing assay, transwell assay and Western blotting. The potential direct interaction proteins of bufalin were screened by human proteome microarray containing 21,838 human proteins. The target protein was determined by bioinformatics, and the binding sites were predicted by molecular docking technique. Biological experiments in vitro and in vivo were conducted to verify the effect of bufalin directly interaction protein and the mechanism of bufalin targeting the protein to inhibit the development of GC. The results showed that bufalin inhibited the proliferation and migration of MKN-45 and HGC-27 GC cell lines in vitro. BFAR, a direct interaction protein of bufalin has several potential binding sites to bufalin. BFAR is highly expressed in GC and promotes the occurrence and metastasis of GC by activating PI3K/AKT/mTOR signal pathway in vitro and in vivo. Bufalin reversed the promoting effect of BFAR on the carcinogenesis and metastasis of GC by down-regulating the expression of BFAR. Our results show that bufalin targeting BFAR inhibits the occurrence and metastasis of GC through PI3K/AKT/mTOR signal pathway. These results provide a new basis for bufalin as a promising drug for the treatment of GC.

Three-dimensional theoretical model for effectively describing the effect of craniomaxillofacial structural factors on loading situation in the temporomandibular joint.

BACKGROUND: Temporomandibular joint (TMJ) overloading is considered a primary cause of temporomandibular joint disorders (TMD). Accordingly, craniomaxillofacial structural parameters affect the loading situation in the TMJ. However, no effective method exists for quantitatively measuring the loading variation in human TMJs. Clinical statistics, which draws from general rules from large amounts of clinical data, cannot entry for exploring the underlying biomechanical mechanism in craniomaxillofacial system. The finite element method (FEM) is an effective tool for analyze the stress and load on TMJs for several cases in a short period of time; however, it is difficult to generalize general patterns through calculations between different cases due to the different geometric characteristics and occlusal contacts between each case. METHODS: (1) This study included 88 subjects with 176 unilateral data to measure angle (α) of the distance to the plane of occlusion. The bone destruction score was evaluated for clinical statistics. To rule out effects of the potential factors and ensure the generality of the study, one participant with no obvious bone destruction was selected as the standard case for establishing the three-dimensional (3D) theoretical model and FEM. (2) Three groups of forces, including biting, muscles and joint reaction forces on mandible, were adopted to establish a 3D theoretical model. (3) By modifying the sagittal α and coronal three types of deviation angle (φ) of the original model, nine candidate models were obtained for the FEM studies. RESULTS: (1) The static equilibrium equations, were used to establish a 3D theoretical model for describing the loading of the TMJ. The theoretical model was validated by monotonously modifying the structural parameter in comparison to two-dimensional theoretical models reported previously; (2) The force on the TMJ gradually decreased with α, and this trend was validated by both clinic statistics and FEM results; (3) The effects of the three types of deviation angle were different. The results of the case where only rotating biting forces were considered was consistent with clinical statistics, indicating that the side with lower α experiences higher TMJ load. (4) Changing the unilateral proportionality coefficients of biting and muscle force produced opposite effects, wherein the effects of the muscle force were stronger than those of the biting forces. CONCLUSIONS: A negative correlation was observed between the joint load and α. Among the three types of asymmetric deformities, occlusal deviations were the primary factors leading to TMD. Unilateral occlusion can result in a greater load on the ipsilateral joint and should be avoided when using the side corresponding to the TMD. This study provides a theoretical basis for the biomechanical mechanism of TMD and also enables the targeted mitigation and treatment of TMD through structural modification.

Effect of occlusal contact on TMJ loading during occlusion: An in silico study.

Alterations in occlusal features may have significant consequences, ranging from dental aesthetics to health issues. Temporomandibular joint disorders (TMDs) are often associated with joint overload, and the correlation between occlusal features and TMDs has been thoroughly discussed. In current work, we introduced a novel stomatognathic model that aligns well with in vivo experimental measurements, specifically designed to decouple the impact of occlusal contact and periodontal ligament (PDL) negative feedback on temporomandibular joint (TMJ) loading. Utilizing an in-silico approach, the simulation analysis included six symmetric occlusal contact scenarios. Furthermore, a biomechanical lever model was employed to clarify the mechanical mechanism and investigate the multi-factorial effects of TMJ overload. These findings indicate that anterior shifts in the occlusal centre lead to increased TMJ loading, particularly in occlusal contact cases with anteroposterior changes. Considering the symmetrical distribution of occlusal contact, mediolateral alterations had a more modest effect on TMJ loading. Additionally, potential negative feedback activated by principal strain of periodontal could not only alleviate joint load but also diminish occlusal force. These investigations enhance our understanding of the intricate interactions between masticatory muscles, occlusal forces, and joint contact forces, thereby providing motivation for future comprehensive studies on TMJ biomechanical overload.

Skin Comfort Sensation with Mechanical Stimulus from Electronic Skin.

The field of electronic skin has received considerable attention due to its extensive potential applications in areas including tactile sensing and health monitoring. With the development of electronic skin devices, electronic skin can be attached to the surface of human skin for long-term health monitoring, which makes comfort an essential factor that cannot be ignored in the design of electronic skin. Therefore, this paper proposes an assessment method for evaluating the comfort of electronic skin based on neurodynamic analysis. The holistic analysis framework encompasses the mechanical model of the skin, the modified Hodgkin-Huxley model for the transduction of stimuli, and the gate control theory for the modulation and perception of pain sensation. The complete process, from mechanical stimulus to the generation of pain perception, is demonstrated. Furthermore, the influence of different factors on pain perception is investigated. Sensation and comfort diagrams are provided to assess the mechanical comfort of electronic skin. The comfort assessment method proposed in this paper provides a theoretical basis when assessing the comfort of electronic skin.

A proposed novel digital condylar position adjustment technique to help restore a normal disc-condyle relationship.

Objectives: To demonstrate a novel digital technique that enables real-time visualisation of occlusal transfer and adjustment of condyle position, to (1) improve the repeatability of occlusal transfer and the accuracy of condyle position adjustment and (2) be clinically effective in helping to restore the disc-condyle relationship. Materials and methods: Three participants were included in the study and underwent facebow transfers using two different methods. The digital method used patient-related three-dimensional imaging data matched with digital dental casts for occlusal transfer. The conventional method used anatomical facebows. The condylar position was adjusted based on occlusal transfer results. The results were evaluated and compared in three dimensions. In addition, clinical application data from 36 patients were analysed before and after condylar position adjustment. Statistical significance was set at p < 0.05. Results: Differences in the spatial positions of the three anatomical structures reproduced by both methods were statistically significant (p = 0.000). After adjusting the rotation of the condylar position, the positional deviation of the condylar point along the X- and Z-axes was significantly lower in the digital group (p < 0.05). After adjustment for translation (X and Z), the positional deviation showed no difference along the X- and Z-axes (p > 0.05) but a significant difference along the Y-axis (p < 0.001). Conclusion: A novel digital technique for occlusal transfer and condylar position adjustment was presented. This technique simplifies clinical practice, improves the accuracy of results, and can help restore a normal disc-condyle relationship.

Variation in stress distribution modified by mandibular material property: a 3D finite element analysis.

BACKGROUND: Temporomandibular joint disorder (TMD) is a common oral and maxillary facial disease. Finite element method (FEM) has been widely used in TMD studies. Material assignment significantly affects FEM results. The differences in the methods of material assignment used in previous studies have not been comprehensively assessed for further calculations. METHODS: The mandible material modelling approaches were of four types, namely: uniform modelling with (A) cortical bone; and (B) cancellous bone; (C) semi-uniform modelling with division of cortical and cancellous bone; and (D) non-uniform modelling with Computed tomography (CT) gray value related modulus. Meanwhile, the Young's modulus of values ranging from 20 to 300 GPa were considered for the teeth. Ten modellings were used to analyze and discuss the differences in contact pressure and contact force. RESULTS: (1) The increase in teeth elastic modulus increased the maximum contact pressure on the alveolar bone and contact force on teeth, but induced insignificant stress variation on the temporomandibular joint; (2) The location of the maximum contact pressure was steady for all four modelling approaches of the mandibular material. However, the maximum contact pressure and contact force exhibited an insignificant difference. CONCLUSIONS: Teeth with a higher elastic modulus significantly enhanced the stress concentration in the alveolar bone; in contrast, it induced minor variations in the temporomandibular joint stress states. The extreme stress regions predicted by the four mandibular models were consistent with the actual damaged regions. However, non-uniform modellings based on CT values could better describe the mechanical properties of the human bone, which should be primarily considered.

Research progress in protein microarrays: Focussing on cancer research.

Although several effective treatment modalities have been developed for cancers, the morbidity and mortality associated with cancer continues to increase every year. As one of the most exciting emerging technologies, protein microarrays represent a powerful tool in the field of cancer research because of their advantages such as high throughput, small sample usage, more flexibility, high sensitivity and direct readout of results. In this review, we focus on the research progress in four types of protein microarrays (proteome microarray, antibody microarray, lectin microarray and reversed protein array) with emphasis on their application in cancer research. Finally, we discuss the current challenges faced by protein microarrays and directions for future developments. We firmly believe that this novel systems biology research tool holds immense potential in cancer research and will become an irreplaceable tool in this field.

Condyle bone destruction: the association between temporomandibular joint vibration and finite element analysis.

OBJECTIVE: The objective of the study is to investigate the stress distributions of condyle and articular disc at different mandibular plane angles and the association between the temporomandibular joint (TMJ) vibration and anatomical relationship. SETTING AND SAMPLE POPULATION: Data from 195 untreated patients were analyzed. Patients were, respectively, divided into 3 groups, based on cone-beam computed tomography (CBCT): Group 0 presenting normal condyles, Group 1 presenting mild bone change, and Group 2 presenting severe bone change; based on magnetic resonance imaging (MRI): normal disc position (N), disc displacement with reduction (DDR) and disc displacement without reduction (DDNR); based on the mandibular plane angle: low, normal and high. METHODS: (1) According to peak frequency, average amplitude, and occurrence phase, association was assessed between TMJ condition and TMJ vibration; (2) A three-dimensional finite element model of masticatory system was established and the relationship between mandibular plane angle and condyle bone destruction was described. RESULTS: The average amplitude of TMJ vibration negatively correlated with pathological condition of the articular disc (p < 0.01). The angle of SN-MP was strongly relevant to bone destruction of condyle (p < 0.01), and the biomechanical analysis showed that with the increase of SN-MP angle, the area of stress concentration in the posterior slope of condyle rose. CONCLUSIONS: The average amplitude of TMJ vibration decreased with the pathological position state of articular disc, and condyle bone destruction was positively associated with SN-MP angle.