Improving difficult direct laryngoscopy prediction using deep learning and minimal image analysis: a single-center prospective study.

Accurate prediction of difficult direct laryngoscopy (DDL) is essential to ensure optimal airway management and patient safety. The present study proposed an AI model that would accurately predict DDL using a small number of bedside pictures of the patient's face and neck taken simply with a smartphone. In this prospective single-center study, adult patients scheduled for endotracheal intubation under general anesthesia were included. Patient pictures were obtained in frontal, lateral, frontal-neck extension, and open mouth views. DDL prediction was performed using a deep learning model based on the EfficientNet-B5 architecture, incorporating picture view information through multitask learning. We collected 18,163 pictures from 3053 patients. After under-sampling to achieve a 1:1 image ratio of DDL to non-DDL, the model was trained and validated with a dataset of 6616 pictures from 1283 patients. The deep learning model achieved a receiver operating characteristic area under the curve of 0.81-0.88 and an F1-score of 0.72-0.81 for DDL prediction. Including picture view information improved the model's performance. Gradient-weighted class activation mapping revealed that neck and chin characteristics in frontal and lateral views are important factors in DDL prediction. The deep learning model we developed effectively predicts DDL and requires only a small set of patient pictures taken with a smartphone. The method is practical and easy to implement.

Development and Validation of Deep Learning-Based Algorithms for Predicting Lumbar Herniated Nucleus Pulposus Using Lumbar X-rays.

Lumbar herniated nucleus pulposus (HNP) is difficult to diagnose using lumbar radiography. HNP is typically diagnosed using magnetic resonance imaging (MRI). This study developed and validated an artificial intelligence model that predicts lumbar HNP using lumbar radiography. A total of 180,271 lumbar radiographs were obtained from 34,661 patients in the form of lumbar X-ray and MRI images, which were matched together and labeled accordingly. The data were divided into a training set (31,149 patients and 162,257 images) and a test set (3512 patients and 18,014 images). Training data were used for learning using the EfficientNet-B5 model and four-fold cross-validation. The area under the curve (AUC) of the receiver operating characteristic (ROC) for the prediction of lumbar HNP was 0.73. The AUC of the ROC for predicting lumbar HNP in L (lumbar) 1-2, L2-3, L3-4, L4-5, and L5-S (sacrum)1 levels were 0.68, 0.68, 0.63, 0.67, and 0.72, respectively. Finally, an HNP prediction model was developed, although it requires further improvements.

Cancer-Cell-Derived Hybrid Vesicles from MCF-7 and HeLa Cells for Dual-Homotypic Targeting of Anticancer Drugs.

Here, as a proof of concept, hybrid vesicles (VEs) are developed from two types of cancer cells, MCF-7 and HeLa, for the dual targeting of the anticancer drug doxorubicin (Dox) to cancer cells via homotypic interactions. Hybrid VEs with a size of 181.8 ± 28.2 nm and surface charge of -27.8 ± 1.9 mV are successfully prepared by the fusion of MCF-7 and HeLa VEs, as demonstrated by the fluorescence resonance energy transfer assay. The hybrid VEs exhibit enhanced intracellular uptake both in MCF-7 and HeLa cells. Dox-encapsulated hybrid VEs (Dox-hybrid VEs) also exhibit promising anticancer and antiproliferative activities against MCF-7/multidrug-resistant cells and HeLa cells. In addition, compared to free Dox, the Dox-hybrid VEs exhibit low intracellular uptake and reduced cytotoxicity for RAW264.7 cells. Thus, hybrid VEs with dual-targeting activity toward two types of cancer cells may be useful for the specific targeting of anticancer drugs for improved anticancer effects with reduced nonspecific toxicity.

Comparison of Data Mining Methods for the Signal Detection of Adverse Drug Events with a Hierarchical Structure in Postmarketing Surveillance.

There are several different proposed data mining methods for the postmarketing surveillance of drug safety. Adverse events are often classified into a hierarchical structure. Our objective was to compare the performance of several of these different data mining methods for adverse drug events data with a hierarchical structure. We generated datasets based on the World Health Organization's Adverse Reaction Terminology (WHO-ART) hierarchical structure. We evaluated different data mining methods for signal detection, including several frequentist methods such as reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC), the likelihood ratio test-based method (LRT), and Bayesian methods such as gamma Poisson shrinker (GPS), Bayesian confidence propagating neural network (BCPNN), the new IC method, and the simplified Bayesian method (sB), as well as the tree-based scan statistic through an extensive simulation study. We also applied the methods to real data on two diabetes drugs, voglibose and acarbose, from the Korea Adverse event reporting system. Only the tree-based scan statistic method maintained the type I error rate at the desired level. Likelihood ratio test-based methods and Bayesian methods tended to be more conservative than other methods in the simulation study and detected fewer signals in the real data example. No method was superior to the others in terms of the statistical power and sensitivity of detecting true signals. It is recommended that those conducting drug‒adverse event surveillance use not just one method, but make a decision based on several methods.

Activated Platelet-Derived Vesicles for Efficient Hemostatic Activity.

In this study, activated platelet-derived vesicles (Act-VEs) are developed as a novel hemostatic biomaterial. Spherical Act-VEs (114.40 ± 11.69 nm in size) with surface charges of -24.73 ± 1.32 mV are successfully prepared from thrombin-activated murine platelets with high surface expression of active glycoprotein IIb/IIIa (GP IIb/IIIa, also known as αIIbß3) and P-selectin. Although nanosized vesicles from resting platelets (VEs) and Act-VEs showed similar sizes and surface charges, Act-VEs formed much larger aggregates in the presence of thrombin and CaCl2 , compared to VEs. After incubation with fibrinogen, Act-VEs formed much denser fibrin networks compared to platelets or VEs, probably due to active αIIbß3 on the surfaces of the Act-VEs. After intravenous injection of the Act-VEs, tail bleeding time and the blood loss are greatly reduced by Act-VEs in vivo. In addition, Act-VEs showed approximately sevenfold lower release of pro-inflammatory interleukin-1ß (IL-1ß) during incubation for 4 days, compared to platelets. Taken together, the formulated Act-VEs can serve as a promising hemostatic biomaterial for the efficient formation of fibrin clots without releasing pro-inflammatory cytokine.

Byakangelicin as a modulator for improved distribution and bioactivity of natural compounds and synthetic drugs in the brain.

BACKGROUND: The elucidation of the biological roles of individual active compounds in terms of their in vivo bio-distribution and bioactivity could provide crucial information to understand how natural compounds work together as treatments for diseases. PURPOSE: We examined the functional roles of Byakangelicin (Byn) to improve the brain accumulation of active compounds, e.g., umbelliferone (Umb), curcumin (Cur), and doxorubicin (Dox), and consequently to enhance their biological activities. METHODS: Active compounds were administered intravenously to mice, with or without Byn, after which organs were isolated and visualized for their ex vivo fluorescence imaging to determine the bio-distribution of each active compound in vivo. For the in vivo bioactivity, Cur, either with or without Byn, was administered to a lipopolysaccharide (LPS)-induced neuro-inflammation model for 5 days, and its anti-inflammatory effects were examined by ELISA using a brain homogenate and serum. RESULTS: We successfully demonstrated that the levels of active compounds (Umb, Cur, and Dox) in the brain, lung, and pancreas were greatly elevated by the addition of Byn via direct ex vivo fluorescence monitoring. In addition, sufficient accumulation of the active compound, Cur, greatly reduced LPS-induced neuro-inflammation in vivo. CONCLUSION: Byn could serve as a modulator to allow improved brain accumulation of diverse active compounds (Umb, Cur, and Dox) and enhanced therapeutic effects.

PLGA Microspheres Coated with Cancer Cell-Derived Vesicles for Improved Internalization into Antigen-Presenting Cells and Immune Stimulation.

Microspheres (MS; 1-3 µm) with different degrees of surface roughness were prepared to assess the effects of surface topology on internalization into antigen-presenting cells (APCs; macrophages and dendritic cells). In this study, we demonstrated that the intracellular uptake of MS is readily enhanced by surface modification with nanoparticles or cancer cell-derived vesicles (VE) to modulate their surface topology. MS coated with nanovesicles (MS-VE) with high surface roughness was more successfully and efficiently engulfed by APCs, compared with bare MS and those with low surface roughness. Incorporated MPLA within MS-VEs (M/MS-VE) triggered greatly elevated release of immune stimulating cytokines, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), from macrophages and dendritic cells, compared to free MPLA. Taken together, this MS-VE could serve as a platform system for the delivery of immune stimulators and antigens to APCs with negligible toxicity.

Platelet-derived nanovesicles for hemostasis without release of pro-inflammatory cytokines.

Natural platelet-derived nanovesicles with a vacant core were prepared by hypotonic sonication. The nanovesicles efficiently formed platelet-like aggregates using membrane protein in the presence of thrombin and calcium chloride without a notable release of pro-inflammatory cytokines. These natural and biocompatible platelet-derived nanovesicles have great potential as biomaterials for inflammation-free injectable hemostasis.

Efficient Delivery of Tyrosinase Related Protein-2 (TRP2) Peptides to Lymph Nodes using Serum-Derived Exosomes.

Exosomes (EXO) are considered to be versatile carriers for biomolecules; however, the delivery of therapeutic peptides using EXOs poses several challenges. In this study, the efficiency of serum-derived EXOs in delivering tyrosinase-related protein-2 (TRP2) peptides to lymph nodes is determined. TRP2 peptides are successfully incorporated into EXOs, which show a uniform and narrow size distribution of around 45 nm. The TRP2-incorporated exosomes (EXO-TRP2) are efficiently internalized into macrophages and dendritic cells, and are seen to display a punctate distribution. EXOs loaded with TRP2 together with MPLA, (EXO-MPLA-TRP2) result in a strong release of proinflammatory cytokines (TNF-α and IL-6) from both RAW264.7 and DC2.4 cells. Finally, subcutaneous injection of fluorescently labeled EXO-TRP2 followed by ex vivo imaging using in vivo imaging system (IVIS) show a strong fluorescent signal in the lymph nodes after only 1 h, which is maintained until at least 4 h after injection. Taken together, the findings suggest that serum-derived EXOs can serve as promising carriers to deliver therapeutic peptides to lymph nodes for immunotherapy.

Comparative evaluation of cell- and serum-derived exosomes to deliver immune stimulators to lymph nodes.

To determine whether exosomes are efficient carriers for immune stimulating molecules into lymph nodes, comparative studies of exosomes (EXOs) derived from different origins (cells and serums) in terms of physicochemical properties and delivery efficiency were performed. Serum-derived EXOs were of a preferable size and generated higher yields than RAW264.7 cell-derived exosomes (RAW-EXO). In particular, fetal bovine serum-derived exosomes (bo-EXO), with a size below 50 nm, were delivered not only to surface zones (subcapsular sinus (SCS) macrophage zone) but also to inner paracortex zones (T cell zone) of lymph nodes, which allowed an efficient delivery of immune stimulating molecules to antigen presenting cells and T cells. The encapsulation of immune stimulating biomolecules (monophosphoryl lipid A (MPLA) and CpG oligodeoxynucleotides (CpG ODN)) within EXOs greatly increased intracellular delivery to macrophages via phagocytic pathways, which induced higher TNF-α and IL-6 secretion than free MPLA and free CpG ODN. MPLA-incorporated exosomes activated and differentiated T cells after subcutaneous injection, which elevated cytokine IFN-γ and TNF-α induction for CD3+ T cells. Taken together, bo-EXOs might serve as efficient carrier systems of immune stimulators to lymph nodes for desired immune responses.

Multivalent Aptamer-RNA Conjugates for Simple and Efficient Delivery of Doxorubicin/siRNA into Multidrug-Resistant Cells.

Multivalent aptamer-siRNA conjugates containing multiple mucin-1 aptamers and BCL2-specific siRNA are synthesized, and doxorubicin, an anthracycline anticancer drug, is loaded into these conjugates through intercalation with nucleic acids. These doxorubicin-incorporated multivalent aptamer-siRNA conjugates are transfected to mucin-1 overexpressing MCF-7 breast cancer cells and their multidrug-resistant cell lines. Doxorubicin-incorporated multivalent aptamer-siRNA conjugates exert promising anticancer effects, such as activation of caspase-3/7 and decrease of cell viability, on multidrug-resistant cancer cells because of their high intracellular uptake efficiency. Thus, this delivery system is an efficient tool for combination oncotherapy with chemotherapeutics and nucleic acid drugs to overcome multidrug resistance.

Complexation of curcumin with 2-aminoethyl diphenyl borate and implications for spatiotemporal fluorescence monitoring.

In this study, we successfully determined spatiotemporal distribution of curcumin in mice via simple and fast fluorescence detection of native curcumin and stabilized curcumin. We used 2-aminoethyl diphenyl borate (DPBA) as a stabilizer of curcumin, which binds to curcumin and enhances its aqueous stability. After intravenous injection, curcumin and DPBA-curcumin complexes showed similar fluorescence intensities in the brain, pancreas, lungs, and kidneys at 15min. However, stabilized DPBA-curcumin complexes exhibited much stronger fluorescent signals at metabolically active sites such as liver tissues than native curcumin. After incubation for 1-3h, native curcumin showed significantly rapid reduction of fluorescent signals, compared to DPBA-curcumin complexes, probably due to degradation and reduction. In addition, complicate extraction procedures inhibited precise fluorescent monitoring of unstable curcumin, which result in different biodistribution of curcumin before and after extraction. Direct fluorescent monitoring could allow evaluation of in vivo distribution and fate of curcumin, which could be also applied to diverse natural polyphenols with fluorescent signals.

Mixed Micelles for Targeted and Efficient Doxorubicin Delivery to Multidrug-Resistant Breast Cancer Cells.

For efficient treatment of multidrug-resistance (MDR) breast cancer cells, design of biocompatible mixed micelles with diverse functional moieties and superior stability is needed for targeted delivery of chemical drugs. In this study, polypropylene glycol (PPG)-grafted hyaluronic acid (HA) copolymers (PPG-g-HA) are used to make mixed micelles with different amounts of pluronic L61, named PPG-g-HA/L61 micelles. Optimized PPG-g-HA/L61 micelles with 3% pluronic L61 exhibit great stability in aqueous solution, superior biocompatibility, and significantly increased uptake into MCF-7 MDR cells via HA-CD44-specific interactions when compared to free doxorubicin (DOX) and other types of micelles. In addition, DOX in PPG-g-HA/L61 micelles with 3% pluronic L61 have toxicity in MCF-7 MDR cells but significantly lower toxicity in fibroblast L929 cells compared to free DOX. Thus, PPG-g-HA/L61 micelles with 3% pluronic L61 content can be a promising nanocarrier to overcome MDR and release DOX in a hyaluronidase-sensitive manner without any toxicity to normal cells.

Bridging the Nanogap with Light: Continuous Tuning of Plasmon Coupling between Gold Nanoparticles.

The control of nanogaps lies at the heart of plasmonics for nanoassemblies. The plasmon coupling sensitively depends on the size and the shape of the nanogaps between nanoparticles, permitting fine-tuning of the resonance wavelength and near-field enhancement at the gap. Previously reported methods of molecular or lithographic control of the gap distance are limited to producing discrete values and encounter difficulty in achieving subnanometer gap distances. For these reasons, the study of the plasmon coupling for varying degrees of interaction remains a challenge. Here, we report that by using light, the interparticle distance for gold nanoparticle (AuNP) dimers can be continuously tuned from a few nanometers to negative values (i.e., merged particles). Accordingly, the plasmon coupling between the AuNPs transitions from the classical electromagnetic regime to the contact regime via the nonlocal and quantum regimes in the subnanometer gap region. We find that photooxidative desorption of alkanedithiol linkers induced by UV irradiation causes the two AuNPs in a dimer to approach each other and eventually merge. Light-driven control of the interparticle distance offers a novel means of exploring the fundamental nature of plasmon coupling as well as the possibility of fabricating nanoassemblies with any desired gap distance in a spatially controlled manner.

Survival analysis of Korean end-stage renal disease patients according to renal replacement therapy in a single center.

This study was to investigate clinical characteristics and any differential trends in survival among renal replacement therapy (hemodialysis [HD], peritoneal dialysis [PD], and kidney transplantation [KT]) in Korean end-stage renal disease (ESRD) population. We tried to analyze retrospectively the survival rate adjusted by risk factors and the relative risk stratified by key risk factors among 447 ESRD patients who began dialysis or had a kidney transplant at Ajou University Hospital from 1994 to 2004. In adjusted Cox survival curves, the KT patients had the best survival rate, and the HD patients had better survival than PD patients. The consistent trends in different subgroups stratified by age and diabetes were as following: 1) The risk of death for PD and HD was not proportional over time, 2) The relative risk of PD was similar or lower than that of HD for the first 12 months, but it became higher at later period. The significant predictors for mortality were age (over 55 yr), presence of diabetes, cerebrovascular accident at ESRD onset, and more than one time of hospitalization caused by malnutrition. Further large-scaled, multicenter-based comparative study is needed in Korean ESRD patients and more meticulous attention is required in high-risk patients.

Discrimination of metastatic from acute osteoporotic compression spinal fractures with MR imaging.

A study was performed to determine which magnetic resonance (MR) imaging findings are useful in discrimination between metastatic compression fractures and acute osteoporotic compression fractures of the spine. The MR imaging findings in 27 patients with metastatic compression fractures and 55 patients with acute osteoporotic compression fractures were compared by using the chi(2) test. MR imaging findings suggestive of metastatic compression fractures were as follows: a convex posterior border of the vertebral body, abnormal signal intensity of the pedicle or posterior element, an epidural mass, an encasing epidural mass, a focal paraspinal mass, and other spinal metastases. MR imaging findings suggestive of acute osteoporotic compression fractures were as follows: a low-signal-intensity band on T1- and T2-weighted images, spared normal bone marrow signal intensity of the vertebral body, retropulsion of a posterior bone fragment, and multiple compression fractures. The signal intensity on fast spin-echo T2-weighted images obtained without fat suppression played little role in distinguishing between metastatic compression fractures and acute osteoporotic compression fractures.