Reconstruction of Remodeling units reveals positive effects after 2 and 12 months of Romosozumab treatment.

Romosozumab treatment results in a transient early increase in bone formation and sustained decrease in bone resorption. Histomorphometric analyses revealed that the primary bone-forming effect of romosozumab is transient early stimulation of modeling-based bone formation on cancellous and endocortical surfaces; preclinical studies have demonstrated that romosozumab may affect changes in the remodeling unit resulting in positive bone balance. To further investigate the effects of romosozumab on bone balance, month 12 (M12) and M2 (to analyze early effects) unpaired bone biopsies from the FRAME clinical trial were analyzed using remodeling site reconstruction to assess whether positive changes in bone balance on cancellous/endocortical surfaces may contribute to the progressive improvement in bone mass/structure and reduced fracture risk in osteoporotic women at high fracture risk. At M12, bone balance was higher with romosozumab vs placebo on cancellous (+6.1 µm vs +1.5 µm; p = 0.012) and endocortical (+5.2 µm vs -1.7 µm; p = 0.02) surfaces; higher bone balance was due to lower final erosion depth (40.7 µm vs 43.7 µm; p = 0.05) on cancellous surfaces and higher completed wall thickness (50.8 µm vs 47.5 µm; p = 0.037) on endocortical surfaces. At M2, final erosion depth was lower on the endocortical surfaces (42.7 µm vs 50.7 µm; p = 0.021) and slightly lower on the cancellous surfaces (38.5 µm vs 44.6 µm; p = 0.11) with romosozumab vs placebo. Sector analysis of early endocortical formative sites revealed higher osteoid thickness (29.9 µm vs 19.2 µm; p = 0.005) and mineralized wall thickness (18.3 µm vs 11.9 µm; p = 0.004) with romosozumab vs placebo. These evolving bone packets may reflect early stimulation of bone formation that contributes to the increase in completed wall thickness at M12. These data suggest that romosozumab induces a positive bone balance due to its effects on bone resorption and formation at the level of the remodeling unit, contributing to the positive effects on bone mass, structure, and fracture risk.

Romosozumab treatment has a dual effect on bone, adding new bone and reducing bone loss. In the FRAME clinical trial, romosozumab increased bone mass and strength, and reduced fracture risk in postmenopausal women with osteoporosis. Addition of new bone occurs early in treatment and rapidly on cancellous and endocortical bone surfaces where bone resorption is not ongoing. However, it remains unclear if romosozumab affects bone loss or gain in areas where bone resorption is ongoing (remodeling units), contributing to a further positive bone balance. Here, we examined whether changes at the remodeling unit occur early (2 months) and/or late (12 months) in treatment, using bone biopsies from patients treated with romosozumab or placebo in FRAME. At month 2, a combination of lower bone resorption and higher bone gain on endocortical surfaces resulted in a positive bone balance with romosozumab versus placebo. At month 12, bone balance was positive with romosozumab versus placebo due to lower bone resorption on cancellous surfaces and greater bone gain on endocortical surfaces. This demonstrates that romosozumab induces a positive bone balance at remodeling units early in treatment leading to overall gains observed later, contributing to the positive effects of romosozumab on bone mass and structure.

A prognostic and immune related risk model based on zinc homeostasis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. The dysfunction of zinc homeostasis participates in the early and advancing malignancy of HCC. However, the prognostic ability of zinc homeostasis in HCC has not been clarified yet. Here, we showed a zinc-homeostasis related risk model in HCC. Five signature genes including ADAMTS5, PLOD2, PTDSS2, KLRB1, and UCK2 were screened out via survival analyses and regression algorithms to construct the nomogram with clinical characteristics. Experimental researches indicated that UCK2 participated in the progression of HCC. Patients with higher risk scores always had worse outcomes and were more associated with immune suppression according to the analyses of immune related-pathway activation, cell infiltration, and gene expression. Moreover, these patients were likely to exhibit more sensitivity to sorafenib and other antitumor drugs. This study highlights the significant prognostic role of zinc homeostasis and suggests potential treatment strategies in HCC.

Causal association of TSH with ischemic heart diseases and heart failure: A 2-sample Mendelian randomization study.

Thyroid dysfunction is associated with the risk of cardiovascular disease; however, whether plasma thyroid-stimulating hormone (TSH) levels in subjects with euthyroidism affect the risk of cardiovascular disease remains unclear. This study aimed to investigate the causal association between plasma TSH levels and cardiovascular diseases, particularly ischemic heart disease and heart failure (HF). Summary statistics from the Integrative Epidemiology Unit Open genome-wide association studies Project and FinnGen consortium were used to investigate the causal relationship between plasma TSH levels and the risk of cardiovascular diseases. Two-sample Mendelian randomization analysis using inverse-variance weighting as the primary method was performed. The MR Pleiotropy RESidual Sum and Outlier and leave-one-out methods were used to ensure the robustness of our findings. Genetically determined plasma TSH levels were associated with major coronary heart disease events (OR 1.0557, 95% CI 1.0141-1.0991), all-cause HF (OR 0.9587, 95% CI 0.9231-0.9956), and HF + non-ischemic cardiomyopathy (OR 0.9318, 95% CI 0.8786-0.9882). After the Bonferroni correction, the causation described above disappeared. In the secondary analysis, genetically determined higher TSH levels were associated with a higher risk for unstable angina pectoris (OR 1.0913, 95% CI 1.0350-1.1507), but were associated with a lower risk for HF + overweight (OR 0.9265, 95% CI 0.8821-0.9731). These results were further validated using sensitivity analysis. Our findings show that increased plasma TSH levels in patients with euthyroidism may increase the risk of unstable angina pectoris but reduce the risk of HF in overweight patients. This evidence indicates that plasma TSH levels may need to be carefully controlled in specific patients.

3D-modeling from hip DXA shows improved bone structure with romosozumab followed by denosumab or alendronate.

Romosozumab treatment in women with postmenopausal osteoporosis increases bone formation while decreasing bone resorption, resulting in large BMD gains to reduce fracture risk within 1 yr. DXA-based 3D modeling of the hip was used to assess estimated changes in cortical and trabecular bone parameters and map the distribution of 3D changes in bone parameters over time in patients from 2 randomized controlled clinical trials: FRAME (romosozumab vs placebo followed by denosumab) and ARCH (romosozumab vs alendronate followed by alendronate). For each study, data from a subset of ~200 women per treatment group who had TH DXA scans at baseline and months 12 and 24 and had provided consent for future research were analyzed post hoc. 3D-SHAPER software v2.11 (3D-SHAPER Medical) was used to generate patient-specific 3D models from TH DXA scans. Percentage changes from baseline to months 12 and 24 in areal BMD (aBMD), integral volumetric BMD (vBMD), cortical thickness, cortical vBMD, cortical surface BMD (sBMD), and trabecular vBMD were evaluated. Data from 377 women from FRAME (placebo, 190; romosozumab, 187) and 368 women from ARCH (alendronate, 185; romosozumab, 183) with evaluable 3D assessments at baseline and months 12 and 24 were analyzed. At month 12, treatment with romosozumab vs placebo in FRAME and romosozumab vs alendronate in ARCH resulted in greater increases in aBMD, integral vBMD, cortical thickness, cortical vBMD, cortical sBMD, and trabecular vBMD (P < .05 for all). At month 24, cumulative gains in all parameters were greater in the romosozumab-to-denosumab vs placebo-to-denosumab sequence and romosozumab-to-alendronate vs alendronate-to-alendronate sequence (P < .05 for all). 3D-SHAPER analysis provides a novel technique for estimating changes in cortical and trabecular parameters from standard hip DXA images. These data add to the accumulating evidence that romosozumab improves hip bone density and structure, thereby contributing to the antifracture efficacy of the drug.

Osteoporosis is a chronic condition in which bones become weak and are more likely to break (fracture) with minimal force such as tripping or falling. A fracture, especially in the elderly, is a serious condition that affects daily activities and quality of life. Romosozumab, an approved medication for patients with osteoporosis, increases bone mass and bone strength thereby reducing fracture risk. In this study, 3D reproductions of patients' hip bones were generated from standard images of a bone density test with DXA from women in the FRAME clinical trial where they received romosozumab or placebo for 12 mo followed by 12 mo of denosumab or the ARCH clinical trial where they received romosozumab or alendronate for 12 mo, followed by 12 mo of alendronate. We found that patients treated with romosozumab for the first 12 mo had significantly greater increases in bone strength compared with those who received placebo or alendronate. After 24 mo, total gains in bone strength measurements were greater in patients treated with romosozumab first. Our study shows that DXA-based 3D modelling provides a novel technique for examining changes in bone strength and supports the use of romosozumab to improve hip bone strength and reduce fracture risk.

SuperUDF: Self-supervised UDF Estimation for Surface Reconstruction.

Learning-based surface reconstruction based on unsigned distance functions (UDF) has many advantages such as handling open surfaces. We propose SuperUDF, a self-supervised UDF learning which exploits a learned geometry prior for efficient training and a novel regularization for robustness to sparse sampling. The core idea of SuperUDF draws inspiration from the classical surface approximation operator of locally optimal projection (LOP). The key insight is that if the UDF is estimated correctly, the 3D points should be locally projected onto the underlying surface following the gradient of the UDF. Based on that, a number of inductive biases on UDF geometry and a pre-learned geometry prior are devised to learn UDF estimation efficiently. A novel regularization loss is proposed to make SuperUDF robust to sparse sampling. Furthermore, we also contribute a learning-based mesh extraction from the estimated UDFs. Extensive evaluations demonstrate that SuperUDF outperforms the state of the arts on several public datasets in terms of both quality and efficiency. Code will be released after accteptance.

Romosozumab Efficacy in Postmenopausal Women With No Prior Fracture Who Fulfill Criteria for Very High Fracture Risk.

OBJECTIVE: We evaluated the efficacy of romosozumab in women from FRAME who had no prior fracture but met other criteria for very high fracture risk (VHFR). METHODS: In FRAME, postmenopausal women received romosozumab or placebo for 12 months (year 1) followed by denosumab for 12 months (year 2). In this post hoc analysis, we applied the following criteria from the American Association of Clinical Endocrinology to define VHFR: lumbar spine or total hip T-score <-3.0 and/or Fracture Risk Assessment Tool probability of major osteoporotic fracture >30% or hip fracture >4.5% to women with no fracture history at baseline (no fracture-VHFR [NF-VHFR]). Incidence of new vertebral, clinical, and nonvertebral fractures and mean bone mineral density (BMD) percentage change from baseline were assessed at years 1 and 2. RESULTS: Of the 7180 women in FRAME, 2825 were included in the NF-VHFR subgroup analysis. At year 1, romosozumab versus placebo reduced the incidence of new vertebral fracture (relative risk reduction [RRR]: 76%), clinical fracture (RRR: 60%), and nonvertebral fracture (RRR: 54%) (all P <.05). This fracture reduction was maintained through year 2 in women receiving the romosozumab-to-denosumab sequence versus the placebo-to-denosumab sequence for new vertebral, clinical, and nonvertebral fractures (RRR: 77%, 54%, and 46%, respectively; all P <.05). The mean BMD changes in both treatment groups were similar to those in the overall FRAME population at years 1 and 2. CONCLUSION: Romosozumab significantly reduced vertebral, clinical, and nonvertebral fracture risk and increased the BMD more than placebo in women at VHFR.

RayMVSNet++: Learning Ray-Based 1D Implicit Fields for Accurate Multi-View Stereo.

Learning-based multi-view stereo (MVS) has by far centered around 3D convolution on cost volumes. Due to the high computation and memory consumption of 3D CNN, the resolution of output depth is often considerably limited. Different from most existing works dedicated to adaptive refinement of cost volumes, we opt to directly optimize the depth value along each camera ray, mimicking the range (depth) finding of a laser scanner. This reduces the MVS problem to ray-based depth optimization which is much more light-weight than full cost volume optimization. In particular, we propose RayMVSNet which learns sequential prediction of a 1D implicit field along each camera ray with the zero-crossing point indicating scene depth. This sequential modeling, conducted based on transformer features, essentially learns the epipolar line search in traditional multi-view stereo. We devise a multi-task learning for better optimization convergence and depth accuracy. We found the monotonicity property of the SDFs along each ray greatly benefits the depth estimation. Our method ranks top on both the DTU and the Tanks & Temples datasets over all previous learning-based methods, achieving an overall reconstruction score of 0.33 mm on DTU and an F-score of 59.48% on Tanks & Temples. It is able to produce high-quality depth estimation and point cloud reconstruction in challenging scenarios such as objects/scenes with non-textured surface, severe occlusion, and highly varying depth range. Further, we propose RayMVSNet++ to enhance contextual feature aggregation for each ray through designing an attentional gating unit to select semantically relevant neighboring rays within the local frustum around that ray. This improves the performance on datasets with more challenging examples (e.g., low-quality images caused by poor lighting conditions or motion blur). RayMVSNet++ achieves state-of-the-art performance on the ScanNet dataset. In particular, it attains an AbsRel of 0.058m and produces accurate results on the two subsets of textureless regions and large depth variation.

Fabrication of bio-inspired anisotropic structures from biopolymers for biomedical applications: A review.

The anisotropic features play indispensable roles in regulating various life activities in different organisms. Increasing efforts have been made to learn and mimic various tissues' intrinsic anisotropic structure or functionality for broad applications in different areas, especially in biomedicine and pharmacy. This paper discusses the strategies for fabricating biomaterials using biopolymers for biomedical applications with the case study analysis. Biopolymers, including different polysaccharides, proteins, and their derivates, that have been confirmed with sound biocompatibility for different biomedical applications are summarized, with a special focus on nanocellulose. Advanced analytical techniques for understanding and characterizing the biopolymer-based anisotropic structures for various biomedical applications are also summarized. Challenges still exist in precisely constructing biopolymers-based biomaterials with anisotropic structures from molecular to macroscopic levels and fitting the dynamic processes in native tissue. It is foreseeable that with the advancement of biopolymers' molecular functionalization, biopolymer building block orientation manipulation strategies, and structural characterization techniques, developing anisotropic biopolymer-based biomaterials for different biomedical applications would significantly contribute to a friendly disease-curing and healthcare experience.

Resistance Risk and Resistance-Related Point Mutation in SdhB and SdhC1 of Cyclobutrifluram in Fusarium pseudograminearum.

Cyclobutrifluram is a novel succinate dehydrogenase inhibitor (SDHI) developed by Syngenta and helps to inhibit Fusarium pseudograminearum. Here, the potential for cyclobutrifluram resistance in F. pseudograminearum and the resistance mechanism involved were evaluated. Baseline sensitivity of F. pseudograminearum to cyclobutrifluram was determined with a mean EC50 value of 0.0248 µg/mL. Fungicide adaption generated five resistant mutants, which possess a comparable or a slightly impaired fitness compared to corresponding parental isolates. This indicates that the resistance risk of F. pseudograminearum to cyclobutrifluram might be moderate. Cyclobutrifluram-resistant isolates also demonstrated resistance to pydiflumetofen but sensitivity to carbendazim, phenamacril, tebuconazole, fludioxonil, or pyraclostrobin. Additionally, point mutations H248Y in FpSdhB and A83V or R86K in FpSdhC1 were found in cyclobutrifluram-resistant F. pseudograminearum mutants. Molecular docking and overexpression transformation assay revealed that FpSdhBH248Y and FpSdhC1A83V or FpSdhC1R86K confer the resistance of F. pseudograminearum to cyclobutrifluram.

Learning to Detect 3D Symmetry From Single-View RGB-D Images With Weak Supervision.

3D symmetry detection is a fundamental problem in computer vision and graphics. Most prior works detect symmetry when the object model is fully known, few studies symmetry detection on objects with partial observation, such as single RGB-D images. Recent work addresses the problem of detecting symmetries from incomplete data with a deep neural network by leveraging the dense and accurate symmetry annotations. However, due to the tedious labeling process, full symmetry annotations are not always practically available. In this work, we present a 3D symmetry detection approach to detect symmetry from single-view RGB-D images without using symmetry supervision. The key idea is to train the network in a weakly-supervised learning manner to complete the shape based on the predicted symmetry such that the completed shape be similar to existing plausible shapes. To achieve this, we first propose a discriminative variational autoencoder to learn the shape prior in order to determine whether a 3D shape is plausible or not. Based on the learned shape prior, a symmetry detection network is present to predict symmetries that produce shapes with high shape plausibility when completed based on those symmetries. Moreover, to facilitate end-to-end network training and multiple symmetry detection, we introduce a new symmetry parametrization for the learning-based symmetry estimation of both reflectional and rotational symmetry. The proposed approach, coupled symmetry detection with shape completion, essentially learns the symmetry-aware shape prior, facilitating more accurate and robust symmetry detection. Experiments demonstrate that the proposed method is capable of detecting reflectional and rotational symmetries accurately, and shows good generality in challenging scenarios, such as objects with heavy occlusion and scanning noise. Moreover, it achieves state-of-the-art performance, improving the F1-score over the existing supervised learning method by 2%-11% on the ShapeNet and ScanNet datasets.

Crystallization and Structural Properties of Oleogel-Based Margarine.

Interest in oleogel as a promising alternative to traditional hydrogenated vegetable oil has increasingly grown in recent years due to its low content of saturated fatty acids and zero trans fatty acids. This study aimed to develop wax-based margarine to replace traditional commercial margarine. The wax-based margarine was prepared and compared with commercial margarine in texture, rheology, and microscopic morphology. The possibility of preparing margarine at room temperature (non-quenched) was also explored. The results showed that the hardness of oleogel-based margarine increased as the BW concentration increased. Denser droplets and crystal network structure were observed with the increase in BW content. XRD patterns of oleogel-based margarine with different content BW were quite similar and structurally to the ß' form. However, the melting temperature of oleogel-based margarine was over 40 °C at each concentration, which represented a poor mouth-melting characteristic. In addition, the unique, improved physical properties of oleogel-based margarine were obtained with binary mixtures of China lacquer wax (ZLW) and Beeswax (BW), due to the interaction of the ZLW and BW crystal network. The rapid cooling process improved the spreadability of oleogel-based margarine. The margarine prepared by 5% BW50:ZLW50 had similar properties to commercial margarine in texture and melting characteristics (37 °C), which had the potential to replace commercial margarine.

Trueness of One Stationary and Two Mobile Systems for Three-Dimensional Facial Scanning.

PURPOSE: To evaluate the trueness of one stationary and two mobile systems for 3D facial scanning. MATERIALS AND METHODS: Twenty participants were included in this study. After marking facial soft tissue landmarks, their faces were scanned using three facial scanning systems: the Bellus3D Dental Pro app on an iPad Pro 2020 (Apple; IP); the ARC-7 Face Scanning System (Bellus3D; BA); and the EinScan Pro 2X Plus (Shining 3D Tech; EP) following the manufacturers' operating instructions. Three-dimensional images were reconstructed with corresponding software and saved in object (OBJ) file format. The interlandmark distances were measured and compared to direct caliper measurements, and absolute error (AE) was chosen as the measurement to determine the trueness of the three scanners. The normal distribution and variance of homogeneity were measured, and then the data were analyzed using one-way ANOVA or Kruskal-Wallis H test. The significance level was set at P = .05. RESULTS: For the measurement of interlandmark distances, no significant differences were found among the four measuring techniques, and the mean AEs of the IP, BA, and EP systems were 1.17 ± 0.80 mm, 0.76 ± 0.61 mm, and 0.69 ± 0.65 mm. CONCLUSION: The three facial scanning systems tested provided a reliable 3D facial reconstruction. The portable IP system could meet the clinical requirements for facial scanning, but it is suggested to select the EP and BA systems when a higher trueness is required.

Functionalization of nanocellulose applied with biological molecules for biomedical application: A review.

Nanocellulose has great potential in the biomedical field due to its biocompatibility, large specific surface area, and customizable surface chemistry. However, due to the bioinert nature and mismatch of the mechanical strength, nanocellulose itself has no cell adhesion ability and cannot directly promote cell growth and reproduction. Recently, surface functionalization of nanocellulose has been reported as an indispensable strategy for improving its bioactivities or other physic-chemical properties. In this paper, functionalization strategies of nanocellulose based on its inherent hydroxyl, aldehyde, carboxyl, and sulfate group reactions are reviewed. Biomacromolecules, such as peptides, proteins, and DNA that are commonly used in functionalization for different biomedical applications are summarized. Prospects and ongoing challenges of nanocellulose-based biomaterials application, as well as these advanced processing technologies such as additive manufacturing, nanomanufacturing, and bio-manufacturing are also discussed. This review is supposed to serve as a guideline for the development of nanocellulose-based biomaterials in biomedical applications.

On the spurious resonance modes of time domain integral equations for analyzing acoustic scattering from penetrable objects.

The interior resonance problem of time domain integral equations (TDIEs) formulated to analyze acoustic field interactions on penetrable objects is investigated. Two types of TDIEs are considered: The first equation, which is termed the time domain potential integral equation (TDPIE), suffers from the interior resonance problem, i.e., its solution is replete with spurious modes that are excited at the resonance frequencies of the acoustic cavity in the shape of the scatterer. Numerical experiments demonstrate that, unlike the frequency-domain integral equations, the amplitude of these modes in the time domain could be suppressed to a level that does not significantly affect the solution. This is achieved by increasing the numerical solution accuracy through the use of a higher-order discretization in space and the band limited approximate prolate spheroidal wave function with high interpolation accuracy as basis function in time. The second equation is obtained by linearly combining TDPIE with its normal derivative. The solution of this equation, which is termed the time domain combined potential integral equation (TDCPIE), does not involve any spurious interior resonance modes but it is not as accurate as the TDPIE solution at non-resonance frequencies. In addition, TDCPIE's discretization calls for treatment of hypersingular integrals.

Development of Cellulose Nanofibril/Casein-Based 3D Composite Hemostasis Scaffold for Potential Wound-Healing Application.

Excessive bleeding in traumatic hemorrhage is the primary concern for natural wound healing and the main reason for trauma deaths. The three-dimensional (3D) bioprinting of bioinks offers the desired structural complexity vital for hemostasis activity and targeted cell proliferation in rapid and controlled wound healing. However, it is challenging to develop suitable bioinks to fabricate specific 3D scaffolds desirable in wound healing. In this work, a 3D composite scaffold is designed using bioprinting technology and synergistic hemostasis mechanisms of cellulose nanofibrils (TCNFs), chitosan, and casein to control blood loss in traumatic hemorrhage. Bioinks that consist of casein bioconjugated TCNF (with a casein content of 104.5 ± 34.1 mg/g) using the carbodiimide cross-linker chemistry were subjected to bioprinting for customizable 3D scaffold fabrication. Further, the 3D composite scaffolds were in situ cross-linked using a green ionic complexation approach. The covalent conjugation among TCNF, casein, and chitosan was confirmed by Fourier transform infrared (FTIR) spectroscopy, nuclear magnetic resonance (NMR), X-ray photoelectron spectroscopy (XPS), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and X-ray diffraction (XRD) studies. The in vitro hemostasis activity of the 3D composite scaffold was analyzed by a human thrombin-antithrombin (TAT) assay and adsorption of red blood cells (RBCs) and platelets. The 3D composite scaffold had a better swelling behavior and a faster whole blood clotting rate at each time point than the 3D TCNF scaffold and commercial cellulose-based dressings. The TAT assay demonstrated that the 3D composite scaffold could form a higher content of thrombin (663.29 pg/mL) and stable blood clot compared to a cellulosic pad (580.35 pg/mL), 3D TCNF (457.78 pg/mL), and cellulosic gauze (328.92 pg/mL), which are essential for faster blood coagulation. In addition, the 3D composite scaffold had a lower blood clotting index (23.34%) than the 3D TCNF scaffold (41.93%), suggesting higher efficiencies for RBC entrapping to induce blood clotting. The in vivo cytocompatibility was evaluated by a 3D cell culture study, and results showed that the 3D composite scaffold could promote growth and proliferation of NIH 3T3 fibroblast cells, which is vital for wound healing. Cellulase-based in vitro deconstruction of the 3D composite scaffold showed significant weight loss (80 ± 5%) compared to the lysozyme hydrolysis (22 ± 5%) after 28 days of incubation, suggesting the biodegradation potential of the composite scaffold. In conclusion, this study proposes efficient prospects to develop a 3D composite scaffold from bioprinting of TCNF-based bioinks that can accelerate blood clotting and wound healing, suggesting its potential application in reducing blood loss during traumatic hemorrhage.

Modeling-Based Bone Formation After 2 Months of Romosozumab Treatment: Results From the FRAME Clinical Trial.

The bone-forming agent romosozumab is a monoclonal antibody that inhibits sclerostin, leading to increased bone formation and decreased resorption. The highest levels of bone formation markers in human patients are observed in the first 2 months of treatment. Histomorphometric analysis of bone biopsies from the phase 3 FRAME trial (NCT01575834) showed an early significant increase in bone formation with concomitant decreased resorption. Preclinical studies demonstrated that most new bone formation after romosozumab treatment was modeling-based bone formation (MBBF). Here we analyzed bone biopsies from FRAME to assess the effect of 2 months of romosozumab versus placebo on the surface extent of MBBF and remodeling-based bone formation (RBBF). In FRAME, postmenopausal women aged ≥55 years with osteoporosis were randomized 1:1 to 210 mg romosozumab or placebo sc every month for 12 months, followed by 60 mg denosumab sc every 6 months for 12 months. Participants in the bone biopsy substudy received quadruple tetracycline labeling and underwent transiliac biopsies at month 2. A total of 29 biopsies were suitable for histomorphometry. Using fluorescence microscopy, bone formation at cancellous, endocortical, and periosteal envelopes was classified based on the appearance of underlying cement lines as modeling (smooth) or remodeling (scalloped). Data were compared using the Wilcoxon rank-sum test, without multiplicity adjustment. After 2 months, the median percentage of MBBF referent to the total bone surface was significantly increased with romosozumab versus placebo on cancellous (18.0% versus 3.8%; p = 0.005) and endocortical (36.7% versus 3.0%; p = 0.001), but not on periosteal (5.0% versus 2.0%; p = 0.37) surfaces, with no significant difference in the surface extent of RBBF on all three bone surfaces. These data show that stimulation of bone formation in the first 2 months of romosozumab treatment in postmenopausal women with osteoporosis is predominately due to increased MBBF on endocortical and cancellous surfaces. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

The effect of denosumab and alendronate on trabecular plate and rod microstructure at the distal tibia and radius: A post-hoc HR-pQCT study.

BACKGROUND: Age-related trabecular microstructural deterioration and conversion from plate-like trabeculae to rod-like trabeculae occur because of unbalanced rapid remodeling. As denosumab achieves greater remodeling suppression and lower cortical porosity than alendronate, we hypothesized that denosumab might also preserve trabecular plate microstructure, bone stiffness and strength more effectively than alendronate. METHODS: In this post hoc analysis of a phase 2 study, postmenopausal women randomized to placebo (P, n = 74), denosumab (D, n = 72), or alendronate (A, n = 68). HR-pQCT scans of the distal radius and tibia were performed at baseline and Month-12 (M12). Trabecular compartment was subjected to Individual Trabecula Segmentation while finite element analysis was performed to estimate stiffness and strength. Percent change from baseline at M12 of each parameter was compared between patient groups. RESULTS: At the distal tibia, in the placebo group, plate surface area (pTb.S, -1.3%) decreased while rod bone volume fraction (rBV/TV, +4.5%) and number (rTb.N, +2.1%) increased. These changes were prevented by denosumab but persisted despite alendronate therapy (pTb.S: -1.7%; rBV/TV: +6.9%; rTb.N: +3.0%). Both treatments improved whole bone stiffness (D: +3.1%; A: +1.8%) and failure load (D: +3.0%; A: +2.2%); improvements using denosumab was significant compared to placebo (stiffness: p = 0.004; failure load: p = 0.003). At the distal radius, denosumab increased total trabecular bone volume fraction (BV/TV, +3.4%) and whole bone failure load (+4.0%), significantly different from placebo (BV/TV: p = 0.044; failure load: p = 0.046). Significantly different effects of either drug on plate and rod microstructure were not detected. CONCLUSIONS: Denosumab preserved trabecular plate microstructure. Alendronate did not. However, estimated strength did not differ between denosumab and alendronate treated groups.

Electrochemical Biosensor Based on Well-Dispersed Boron Nitride Colloidal Nanoparticles and DNA Aptamers for Ultrasensitive Detection of Carbendazim.

A selective electrochemical biosensor was developed for detecting carbendazim (CBZ) based on well-dispersed colloidal boron nitride (BN) nanocrystals and gold nanoparticles (Au NPs). BN was synthesized by "solvent cutting" to modify a glassy carbon electrode (GCE), and Au NPs were then electrodeposited. A single-stranded oligonucleotide with methylene blue (MB) was modified to the electrode surface through gold-sulfur bonds. A double-stranded DNA was formed in the presence of an aptamer. The aptamer chain can specifically bind to the target CBZ. When the aptamer binds to CBZ, the electroactive substance MB labeled at one end of the complementary chain can effectively contact the electrode surface. Detection of CBZ is realized by simultaneously monitoring the MB signal enhancement. The CBZ concentration was determined in a wide linearity range from 0.1 ng mL-1 to 100 µg mL-1, with a low detection limit of 0.019 ng mL-1. This biosensor exhibited excellent selectivity and acceptable repeatability and was applied in cucumber, kiwifruit, and water samples with good recoveries, demonstrating that the strategy has remarkable potential and offers a good platform for CBZ detection.

Gelation behavior and crystal network of natural waxes and corresponding binary blends in high-oleic sunflower oil.

Wax-based oleogels attract considerable attention for their perfect gelation properties, but the waxy mouthfeel severely limits their implementation in food. Herein, we developed a novel strategy via designing the crystal network to produce wax-based oleogels with a suitable mouthfeel. Four natural waxes with different melting points were selected as oleogelators to investigate the gelation behavior. All waxes at 5 wt% concentrations could form stable oleogels with low-frequency dependence. Especially, rice bran wax (RBW) and beeswax (BW) with high oil-binding capacity indicated that the ordered crystal network with fiber or needle-like morphology is more suitable for trapping liquid oil. Interestingly, China lacquer wax (ZLW) presented satisfactory oral melting characteristics according to the melting properties. Subsequently, to enhance the structure of ZLW-oleogel, RBW and BW with desirable crystal networks were added at varying mass ratios (100:0, 75:25, 50:50, 25:75, and 0:100). The binary oleogels exhibited monotectic behavior from thermodynamic phase diagrams. The polarization microscope indicated that similar needle-like crystals in BW/ZLW system enhanced the order of network structure, while long fiber-like crystals by RBW dominated the crystallization of RBW/ZLW binary oleogels. Finally, the BW/ZLW binary oleogels with ratios of 25:75 and 50:50 showed no-waxy mouthfeels in sensory analysis. These findings provide strong theoretical support for the application of wax-based oleogels in plastic fats replacement. PRACTICAL APPLICATION: Natural wax-based oleogel has been widely investigated due to the high oil binding capacity and perfect gelation properties. But its waxy mouthfeel severely limits the application in the food industry. In this study, oleogels with no-waxy an mouthfeel were obtained by designing wax-blend crystalline network. These findings provide strong theoretical support for the application of wax-based oleogels in plastic fats replacement.

Skeletal responses to romosozumab after 12 months of denosumab.

Romosozumab, a monoclonal anti-sclerostin antibody that has the dual effect of increasing bone formation and decreasing bone resorption, reduces fracture risk within 12 months. In a post hoc, exploratory analysis, we evaluated the effects of romosozumab after 12 months of denosumab in postmenopausal women with low bone mass who had not received previous osteoporosis therapy. This phase 2 trial (NCT00896532) enrolled postmenopausal women with a lumbar spine, total hip, or femoral neck T-score ≤ -2.0 and ≥ -3.5. Individuals were randomized to placebo or various romosozumab dosing regimens from baseline to month 24, were re-randomized to 12 months of denosumab or placebo (months 24-36), and then all received romosozumab 210 mg monthly for 12 months (months 36-48). Results for the overall population have been previously published. Here, we present results for changes in bone mineral density (BMD) and levels of procollagen type I N-terminal propeptide (P1NP) and ß-isomer of the C-terminal telopeptide of type I collagen (ß-CTX) from a subset of women who were randomized to placebo for 24 months, were re-randomized to receive denosumab (n = 16) or placebo (n = 12) for 12 months, and then received romosozumab for 12 months. In women who were randomized to placebo followed by denosumab, romosozumab treatment for 12 months maintained BMD gained during denosumab treatment at the total hip (mean change from end of denosumab treatment of 0.9%) and further increased BMD gains at the lumbar spine (mean change from end of denosumab treatment of 5.3%). Upon transition to romosozumab (months 36-48), P1NP and ß-CTX levels gradually returned to baseline from their reduced values during denosumab administration. Transitioning to romosozumab after 12 months of denosumab appears to improve lumbar spine BMD and maintain total hip BMD while possibly preventing the rapid increase in levels of bone turnover markers above baseline expected upon denosumab discontinuation. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.