Cholesterol-Conjugated Supramolecular Multimeric siRNAs: Effect of siRNA Length on Accumulation and Silencing In Vitro and In Vivo.

Conjugation of small interfering RNA (siRNA) with lipophilic molecules is one of the most promising approaches for delivering siRNA in vivo. The rate of molecular weight-dependent siRNA renal clearance is critical for the efficiency of this process. In this study, we prepared cholesterol-containing supramolecular complexes containing from three to eight antisense strands and examined their accumulation and silencing activity in vitro and in vivo. We have shown for the first time that such complexes with 2'F, 2'OMe, and LNA modifications exhibit interfering activity both in carrier-mediated and carrier-free modes. Silencing data from a xenograft tumor model show that 4 days after intravenous injection of cholesterol-containing monomers and supramolecular trimers, the levels of MDR1 mRNA in the tumor decreased by 85% and 68%, respectively. The in vivo accumulation data demonstrated that the formation of supramolecular structures with three or four antisense strands enhanced their accumulation in the liver. After addition of two PS modifications at the ends of antisense strands, 47% and 67% reductions of Ttr mRNA levels in the liver tissue were detected 7 days after administration of monomers and supramolecular trimers, respectively. Thus, we have obtained a new type of RNAi inducer that is convenient for synthesis and provides opportunities for modifications.

General and local predictors of mandibular cortical bone morphology in adult females and males: the seventh survey of the Tromsø Study.

OBJECTIVES: To analyze factors predicting mandibular cortical width (MCW) and mandibular cortical index (MCI) in adult females and males. MATERIAL AND METHODS: Data on 427 females and 335 males aged 40-84 from The Tromsø study: Tromsø7 were used. T-score, age, menopausal status (for females), remaining teeth, and periodontal status were analyzed in linear and logistic regression analyses as predictors of MCW and MCI, respectively. RESULTS: T-score, age, and the number of remaining teeth significantly predicted MCW in females but not males. Standardized ß coefficients were 0.286, -0.231, and 0.131, respectively. The linear regression model explained 24% of MCW variation in females. MCI in females was significantly predicted by T-score, age, and remaining teeth with the Wald values of 9.65, 6.17, and 5.83, respectively. The logistic regression model explained 16.3-23% of the variation in MCI in females. In males, T-score was the only significant predictor of the eroded cortex, and the logistic model explained only 4.3-5.8% of the variation in MCI. CONCLUSIONS: The T-score demonstrated a stronger relationship with MCW and MCI than other factors in females, which supports the usefulness of those indices for osteoporosis screening. Conversely, the T-score exhibited no association with MCW and remained the only significant predictor of MCI in males, yet to a lesser extent than in females. CLINICAL RELEVANCE: Understanding factors affecting mandibular cortical morphology is essential for further investigations of MCW and MCI usefulness for osteoporosis screening in females and males.

Diagnostic efficacy of radiomorphometric indices for predicting osteoporosis in a Norwegian population in the Tromsø Study: Tromsø7.

OBJECTIVE: The aim of this study was to investigate the diagnostic efficacy of the radiomorphometric indices of mandibular cortical width (MCW) and mandibular cortical index (MCI) of cortical erosion for osteoporosis screening in adults (≥40 years) and older adults (≥65 years) to determine whether adding a fracture risk assessment tool (FRAX) would improve efficacy. STUDY DESIGN: One observer measured MCW and assessed MCI on dental panoramic radiographs acquired for patients in the Tromsø study. These indices, alone and with FRAX scores, were evaluated for efficacy in predicting osteoporosis, which was diagnosed by bone density measurement at the femoral necks with dual-energy X-ray absorptiometry. RESULTS: MCW ≤3 mm and MCI indicating heavily eroded cortices (C3) had accuracies of 68.8% and 83.6%, respectively, in identifying osteoporosis. In females >65 years, MCW ≤3 mm and C3 produced higher sensitivities but lower specificities, with slightly lower accuracies (61.4% and 79.8%, respectively) compared with all females. The addition of FRAX scores >15% improved the accuracy of MCW ≤3 mm (81.7%) and C3 (87.9%), resulting in high specificity (86.6% and 95.4%). Combining MCW ≤3 mm or C3 with FRAX >15% increased the probabilities of detecting osteoporosis by increasing positive likelihood ratios. CONCLUSIONS: MCW ≤3 mm or MCI C3, when combined with FRAX >15%, showed superior diagnostic efficacy, with high specificity in detecting females without osteoporosis.

Automatic detection of the mental foramen for estimating mandibular cortical width in dental panoramic radiographs: the seventh survey of the Tromsø Study (Tromsø7) in 2015-2016.

OBJECTIVE: To apply deep learning to a data set of dental panoramic radiographs to detect the mental foramen for automatic assessment of the mandibular cortical width. METHODS: Data from the seventh survey of the Tromsø Study (Tromsø7) were used. The data set contained 5197 randomly chosen dental panoramic radiographs. Four pretrained object detectors were tested. We randomly chose 80% of the data for training and 20% for testing. Models were trained using GeForce RTX 2080 Ti with 11 GB GPU memory (NVIDIA Corporation, Santa Clara, CA, USA). Python programming language version 3.7 was used for analysis. RESULTS: The EfficientDet-D0 model showed the highest average precision of 0.30. When the threshold to regard a prediction as correct (intersection over union) was set to 0.5, the average precision was 0.79. The RetinaNet model achieved the lowest average precision of 0.23, and the precision was 0.64 when the intersection over union was set to 0.5. The procedure to estimate mandibular cortical width showed acceptable results. Of 100 random images, the algorithm produced an output 93 times, 20 of which were not visually satisfactory. CONCLUSIONS: EfficientDet-D0 effectively detected the mental foramen. Methods for estimating bone quality are important in radiology and require further development.