Brain Atlas Guided Attention U-Net for White Matter Hyperintensity Segmentation.

White Matter Hyperintensities (WMH) are the most common manifestation of cerebral small vessel disease (cSVD) on the brain MRI. Accurate WMH segmentation algorithms are important to determine cSVD burden and its clinical con-sequences. Most of existing WMH segmentation algorithms require both fluid attenuated inversion recovery (FLAIR) images and T1-weighted images as inputs. However, T1-weighted images are typically not part of standard clinical scans which are acquired for patients with acute stroke. In this paper, we propose a novel brain atlas guided attention U-Net (BAGAU-Net) that leverages only FLAIR images with a spatially-registered white matter (WM) brain atlas to yield competitive WMH segmentation performance. Specifically, we designed a dual-path segmentation model with two novel connecting mechanisms, namely multi-input attention module (MAM) and attention fusion module (AFM) to fuse the information from two paths for accurate results. Experiments on two publicly available datasets show the effectiveness of the proposed BAGAU-Net. With only FLAIR images and WM brain atlas, BAGAU-Net outperforms the state-of-the-art method with T1-weighted images, paving the way for effective development of WMH segmentation. Availability: https://github.com/Ericzhang1/BAGAU-Net.

Preoperative identification of microvascular invasion in hepatocellular carcinoma by XGBoost and deep learning.

PURPOSE: Microvascular invasion (MVI) is a valuable predictor of survival in hepatocellular carcinoma (HCC) patients. This study developed predictive models using eXtreme Gradient Boosting (XGBoost) and deep learning based on CT images to predict MVI preoperatively. METHODS: In total, 405 patients were included. A total of 7302 radiomic features and 17 radiological features were extracted by a radiomics feature extraction package and radiologists, respectively. We developed a XGBoost model based on radiomics features, radiological features and clinical variables and a three-dimensional convolutional neural network (3D-CNN) to predict MVI status. Next, we compared the efficacy of the two models. RESULTS: Of the 405 patients, 220 (54.3%) were MVI positive, and 185 (45.7%) were MVI negative. The areas under the receiver operating characteristic curves (AUROCs) of the Radiomics-Radiological-Clinical (RRC) Model and 3D-CNN Model in the training set were 0.952 (95% confidence interval (CI) 0.923-0.973) and 0.980 (95% CI 0.959-0.993), respectively (p = 0.14). The AUROCs of the RRC Model and 3D-CNN Model in the validation set were 0.887 (95% CI 0.797-0.947) and 0.906 (95% CI 0.821-0.960), respectively (p = 0.83). Based on the MVI status predicted by the RRC and 3D-CNN Models, the mean recurrence-free survival (RFS) was significantly better in the predicted MVI-negative group than that in the predicted MVI-positive group (RRC Model: 69.95 vs. 24.80 months, p < 0.001; 3D-CNN Model: 64.06 vs. 31.05 months, p = 0.027). CONCLUSION: The RRC Model and 3D-CNN models showed considerable efficacy in identifying MVI preoperatively. These machine learning models may facilitate decision-making in HCC treatment but requires further validation.

Pairwise learning for medical image segmentation.

Fully convolutional networks (FCNs) trained with abundant labeled data have been proven to be a powerful and efficient solution for medical image segmentation. However, FCNs often fail to achieve satisfactory results due to the lack of labelled data and significant variability of appearance in medical imaging. To address this challenging issue, this paper proposes a conjugate fully convolutional network (CFCN) where pairwise samples are input for capturing a rich context representation and guide each other with a fusion module. To avoid the overfitting problem introduced by intra-class heterogeneity and boundary ambiguity with a small number of training samples, we propose to explicitly exploit the prior information from the label space, termed as proxy supervision. We further extend the CFCN to a compact conjugate fully convolutional network (C2FCN), which just has one head for fitting the proxy supervision without incurring two additional branches of decoders fitting ground truth of the input pairs compared to CFCN. In the test phase, the segmentation probability is inferred by the learned logical relation implied in the proxy supervision. Quantitative evaluation on the Liver Tumor Segmentation (LiTS) and Combined (CT-MR) Healthy Abdominal Organ Segmentation (CHAOS) datasets shows that the proposed framework achieves a significant performance improvement on both binary segmentation and multi-category segmentation, especially with a limited amount of training data. The source code is available at https://github.com/renzhenwang/pairwise_segmentation.

Efficient and Effective Training of COVID-19 Classification Networks With Self-Supervised Dual-Track Learning to Rank.

Coronavirus Disease 2019 (COVID-19) has rapidly spread worldwide since first reported. Timely diagnosis of COVID-19 is crucial both for disease control and patient care. Non-contrast thoracic computed tomography (CT) has been identified as an effective tool for the diagnosis, yet the disease outbreak has placed tremendous pressure on radiologists for reading the exams and may potentially lead to fatigue-related mis-diagnosis. Reliable automatic classification algorithms can be really helpful; however, they usually require a considerable number of COVID-19 cases for training, which is difficult to acquire in a timely manner. Meanwhile, how to effectively utilize the existing archive of non-COVID-19 data (the negative samples) in the presence of severe class imbalance is another challenge. In addition, the sudden disease outbreak necessitates fast algorithm development. In this work, we propose a novel approach for effective and efficient training of COVID-19 classification networks using a small number of COVID-19 CT exams and an archive of negative samples. Concretely, a novel self-supervised learning method is proposed to extract features from the COVID-19 and negative samples. Then, two kinds of soft-labels ('difficulty' and 'diversity') are generated for the negative samples by computing the earth mover's distances between the features of the negative and COVID-19 samples, from which data 'values' of the negative samples can be assessed. A pre-set number of negative samples are selected accordingly and fed to the neural network for training. Experimental results show that our approach can achieve superior performance using about half of the negative samples, substantially reducing model training time.

Conquering Data Variations in Resolution: A Slice-Aware Multi-Branch Decoder Network.

Fully convolutional neural networks have made promising progress in joint liver and liver tumor segmentation. Instead of following the debates over 2D versus 3D networks (for example, pursuing the balance between large-scale 2D pretraining and 3D context), in this paper, we novelly identify the wide variation in the ratio between intra- and inter-slice resolutions as a crucial obstacle to the performance. To tackle the mismatch between the intra- and inter-slice information, we propose a slice-aware 2.5D network that emphasizes extracting discriminative features utilizing not only in-plane semantics but also out-of-plane coherence for each separate slice. Specifically, we present a slice-wise multi-input multi-output architecture to instantiate such a design paradigm, which contains a Multi-Branch Decoder (MD) with a Slice-centric Attention Block (SAB) for learning slice-specific features and a Densely Connected Dice (DCD) loss to regularize the inter-slice predictions to be coherent and continuous. Based on the aforementioned innovations, we achieve state-of-the-art results on the MICCAI 2017 Liver Tumor Segmentation (LiTS) dataset. Besides, we also test our model on the ISBI 2019 Segmentation of THoracic Organs at Risk (SegTHOR) dataset, and the result proves the robustness and generalizability of the proposed method in other segmentation tasks.

Microdialysis pharmacokinetic study of scopolamine in plasma, olfactory bulb and vestibule after intranasal administration.

The purpose of this study was to investigate the microdialysis pharmacokinetic of scopolamine in plasma, olfactory bulb and vestibule after intranasal administration. The pharmacokinetic study of subcutaneous and oral administration was also performed in rats. From the in vivo results, scopolamine intranasal administration can avoid hepatic first-pass effect. Tmax plasma samples after intranasal administration were significantly faster than oral administration and subcutaneous injection. The relative bioavailability of intranasal administrations was 51.8-70% when compared with subcutaneous injection. Moreover, one can see that in comparison with scopolamine subcutaneous administration, scopolamine intranasal gel and solutions can increased drug target index (DTI) with olfactory bulb 1.69 and 2.05, vestibule 1.80 and 2.15, respectively. The results indicated that scopolamine can be absorbed directly through the olfactory mucosa into the olfactory bulb, and then transported to various brain tissue after intranasal administration, with the characteristics of brain drug delivery.

A novel combined micellar system of lapatinib and Paclitaxel with enhanced antineoplastic effect against human epidermal growth factor receptor-2 positive breast tumor in vitro.

Lapatinib (LPT) could sensitize human epidermal growth factor receptor-2 (HER-2) positive breast cancer to paclitaxel (PTX) and induce synergetic action with PTX in preclinical test and phase II/III trial. In this study, LPT-conjugated poly (ethylene glycol) (PEG) and poly (lactic acid) (PLA) (LPT-PEG-PLA) was first synthesized and confirmed with ¹H Nuclear Magnetic Resonance and Matrix-Assisted Laser Desorption/ Ionization Time of Flight Mass Spectrometry, which was used for the preparation of a novel PEG-PLA combined micelles of LPT and PTX (PPM-LP). The obtained PPM-LP exhibited uniform, spherical shape with a size of 25.80 ± 0.47 nm and zeta potential of -3.17 ± 0.15 mv. PTX existed in molecular or amorphous forms in the micelles and superficial LPT could better delay PTX release. The cytotoxicity of PPM-LP with LPT conjugation against SKBr-3 cells (HER-2 positive) was found to be significantly increasing as compared with PPM-PTX, whereas there was no significant difference against MDA-MB-231 cells (HER-2 negative). PPM-LP could escape from endosomes and be distributed into cytoplasm and led to cell arrest in G2/M and G1/S phases simultaneously. Results of nucleus staining and flow cytometry confirmed that LPT could remarkably increase antineoplastic effect of PTX against SKBr-3 cells. All these results demonstrated that PPM-LP may be a promising drug delivery system for HER-2 positive breast cancer.

In vivo behavior and safety of lapatinib-incorporated lipid nanoparticles.

To improve the solubility, bioavailability and anti-tumor effect of lapatinib, lapatinib-incorporated lipid nanoparticles (LTNPs) were prepared and characterized. The particle size of LTNPs was 88.6 nm with a zeta potential of 20 mV. Laptinib was loaded into LTNPs with a non-crystal structure as determined by FT-IR. In vitro, LTNPs could be effectively uptaken into C6 glioma cells at a concentration-dependent manner. In vivo, LTNPs showed a relative higher AUC, which was 5.27- and 3.21-fold as that of Tykerb and lapatinib suspension (LTS) group. LTNPs also showed highest glioma concentration, which may benefit from the enhanced permeability and retention effect and active targeting ability. In toxicity studies, LTNPs displayed a half lethal dose over 250 mg/kg. Repeated administering 30 mg/kg of LTNPs could led to toxicity to hematology which might owe to the bovine serum albumin, a foreign protein to mice. However, there was no organic change observed through HE staining. In conclusion, LTNPs could target to glioma with high concentration and low side effect.

Incorporation of lapatinib into core-shell nanoparticles improves both the solubility and anti-glioma effects of the drug.

PURPOSE: Lapatinib is a dual EGFR and HER2 inhibitor that is used to treat HER2-overexpressing cancers. However, its poor water solubility hinders its clinical use. Proteobionics is a promising way to solve this problem. METHODS: Lapatinib-incorporated core-shell nanoparticles (LTNPs) were prepared and characterized by cryo-transmission electron micrograph. Then, in vitro cellular uptake and in vivo glioma targeting effect were determined by both qualitative and quantitative studies. After that, anti-glioma effect of LTNPs was determined by cytotoxicity and life-span study. Finally, the mechanism was elucidated by western blot. RESULTS: LTNPs elevated the water solubility of the drug from 0.007 mg/mL to over 10 mg/mL, which was better than most commercially available injection solvents. Glioma is an increasing threat to humans' health. Here, we evaluated the treatment effects of LTNPs on glioma and explored their mechanism. LTNPs were taken up by U87 cells, inhibiting their proliferation and causing a G2 phase arrest. The uptake was energy-, time- and concentration-dependent, and several pathways were involved. LTNPs inhibited the phosphorylation of the survival (phosphatidylinositol 3-kinase/Akt) pathways, which caused the anti-proliferative effect. In vivo experiments determined that LTNPs were distributed to and accumulated in glioma by the enhanced permeation and retention effect. The distribution was colocalized with SPARC expression, which may mediate endocytosis. In pharmacokinetics and glioma distribution study, LTNPs displayed a higher blood AUC, glioma concentration and glioma/brain ratio than Tykerb. A pharmacodynamics study confirmed that LTNPs could significantly expand the median survival time of glioma-bearing mice at a cumulative dose of 40 mg/kg, which was only 5% of the dose of the commercially available lapatinib tablet (Tykerb). CONCLUSION: LTNPs effectively increased the solubility of lapatinib and improved the treatment of glioma.

Incorporation of lapatinib into lipoprotein-like nanoparticles with enhanced water solubility and anti-tumor effect in breast cancer.

AIM: The poor water solubility of many active compounds is a serious deterrent to their use as commercial drugs. Lapatinib is a dual inhibitor of the EGF receptor and EGF receptor 2 approved by the US FDA to treat advanced breast cancer. This study prepares lapatinib-incorporated lipoprotein-like nanoparticles (LTNPs) to enhance the water solubility and elevate the anti-tumor effect of lapatinib. MATERIALS & METHODS: Bovine albumin was used to bind with lapatinib, and egg yolk lecithin was used to stabilize the conjugation of bovine albumin and lapatinib. The characteristics of LTNPs were evaluated by several experiments. Cell uptake and toxicity were performed on BT-474 cells. In vivo anti-tumor effect was performed on BT-474 xenograft-bearing mice. RESULTS: LTNPs contained a lipid corona and a core of lapatinib and albumin. LTNPs could be effectively taken up by BT-474 cells and induced apoptosis. An in vivo study demonstrated that LTNPs could passively distribute into a tumor via the enhanced permeability and retention effect and induce anti-tumor activity in breast cancer. CONCLUSION: The authors present a convenient nanoformulation with improved anti-tumor effect, which is a promising candidate for clinical trials.

Preparation of nasal temperature-sensitive in situ gel of Radix Bupleuri and evaluation of the febrile response mechanism.

OBJECTIVE: This study developed a nasal temperature-sensitive in situ gel system for Radix Bupleuri. METHOD: Using 20% Poloxamer 407 as the gel base and 6% PEG 4000 adjusting the gelation temperature. RESULTS: The system is liquid at 4 degrees C. It can change its phase to gel above 30 degrees C, which is close to the temperature in nasal cavity. The antipyretic effect produced by Radix Bupleuri in situ gel formulation was investigated in fevered rabbits. The results show that it can prolong the effective time to 24 hours compared with 4-6 hours in Radix Bupleuri intranasal solution. The antipyretic response mechanism was researched by evaluating the relationship between body temperature and concentrations of cyclic adenosine monophosphate in cerebrospinal fluid. The results showed that the two parameters were positively correlated (r = 0.9435, P < 0.05). Six hours later after given in situ gel, the concentrations of cAMP were significantly lower than those in the solution group. It confirmed that temperature-sensitive Radix Bupleuri in situ gel applied in the nasal sprays had a longer residence and release time. CONCLUSION: Radix Bupleuri nasal temperature-sensitive in situ gel has a higher medical effect and a longer effective time. Compared to the traditional nasal spray, it is more applicable for the treatment of fever.

In situ gel based on gellan gum as new carrier for nasal administration of mometasone furoate.

The main purpose of this study was to prepare a novel in situ gel system for nasal delivery of MF and study its efficacy on allergic rhinitis model. An ion-activated in situ gel was developed and characterized with gellan gum as a carrier. The system was stable kept at 40+/-2 degrees C for 6 months, and the micrographic results showed that in situ gel was safety without mucosa irritation when given at 20 microg once daily for 1 month to rats with allergic rhinitis. MF in gellan gum produced obviously effect on allergic rhinitis at the doses of 20 microg/body following intranasal administration, and the efficacy was significantly superior to that of the common suspension (P<0.01). The in situ gel system is a promising approach for the intranasal delivery of MF for the therapeutic effects improvement.

A novel arthroscopic procedure for fixation of avulsion fracture of tibial attachment of anterior cruciate ligament guided by meniscal stitching needle.

OBJECTIVE: To introduce a novel technique in which meniscal stitching needle is used as a puller to induct steel wire to secure the tibial eminence avulsion under arthroscopic visualization, and evaluate the clinical results. METHODS: From 1999 to 2005, fifteen cases of tibial eminence avulsion were treated with this new technique. Lysholm scoring scale system was used to assess knee function before and after surgery. Regular plain anteroposterior and lateral X-ray films were undertaken to detect the bony healing of avulsed fragment. RESULTS: The operating time could be controlled within 30 minutes. No complications such as intraarticular infection, iatrogenic injury, fibroarthritis or nonunion of fracture occurred in this group. X-ray film revealed that bony healing in all 15 cases was achieved from 6 weeks to 12 weeks postoperatively. Lysholm score was improved from 19.1+/-15.2 (ranging from 10 to 56) preoperatively to 97.5+/-3.7 (ranging from 91 to 100) postoperatively on average in 12-54 months follow up (mean 23 months). The statistically significant difference was shown in Student's t test (t equal to 18.483, P equal to 3.100 x 10(-11), P < 0.01). Wire breakage was found in two patients whose wires were removed 8 months and 14 months after initial operation, respectively. CONCLUSION: This technique has many advantages, such as simplicity, wide indications from type II to type IV fractures, minimal invasion, short operating time and predictable satisfactory results.

A novel nasal delivery system of a Chinese traditional medicine, Radix Bupleuri, based on the concept of ion-activated in situ gel.

The purpose of this study was to develop a nasal in situ gel system for Radix Bupleuri employing gellan gum as a polymer. Radix Bupleuri in situ gel containing 0.2 mL essential oil extracted from 450 g Radix Bupleuri, proper solubilizing agents and gellan gum (0.5% w/v) was prepared and characterized. The antipyretic effect produced by in situ gel formulation was investigated in fevered rabbits and compared to an intranasal solution. The resulting in situ gel was a clear and light-yellow liquid, with viscosity of 346 mPa x s and caproic acid content of 1.31 +/- 0.01 mg/mL. Intranasal administration of this preparation to fevered rabbits decreased body temperature markedly (1.1 degree C at the doses of oil from 1.5 g Bupleuri/body) and the effect could last for 20-30 h. The results suggest that Radix Bupleuri in situ gel can be greater effective than the solution in the treatment of fever.

Preparation of ion-activated in situ gel systems of scopolamine hydrobromide and evaluation of its antimotion sickness efficacy.

AIM: To develop a novel, in situ gel system for nasal delivery of scopolamine hydrobromide (SCOP) and study its efficacy on motion sickness. METHODS: SCOP in situ gels at 0.2%, 0.5%, and 1.0% gellan gum concentration (w/v) were prepared, respectively, and characterized in terms of viscosity, in vitro release, and nasal ciliotoxicity. Single photon emission computing tomography technique was used to evaluate the nasal residence time of gel containing (99m)Tc tracer. The antimotion sickness efficacy produced by the in situ gel formulation was investigated in rats and compared with those achieved after subcutaneous and oral administration. RESULTS: The viscosity of the gellan gum formulations either in solution or in gel increased with increasing concentrations of gellan gum. Its release in vitro was moderate in artificial nasal fluid. The micrographic results showed that in situ gels were safe, without nasal ciliotoxicity. In comparison with phosphate buffer saline, a prolonged radioactivity of (99m)Tc in the rabbit nasal cavity was observed after administration of the gellan gum formulation. Intranasal SCOP in situ gel at a dose of 100 microg/kg decreased symptoms of motion sickness significantly in comparison with subcutaneous and oral administration (P<0.01). CONCLUSION: SCOP nasal in situ gel is a safe and promising therapeutic alternative to existing medications for motion sickness.

Preparation of bupleurum nasal spray and evaluation on its safety and efficacy.

Radix Bupleuri is widely used in traditional medicine for the treatment of fever, pain, and inflammation associated with influenza or the common cold. The essential oil extracted from the herb is generally claimed to play the major role in the efficacious treatment of fever. The purpose of the present study was to formulate an intranasal delivery system for the essential oil in an aqueous solution used in the form of nasal spray. From 450 g Radix Bupleuri was extracted the essential oil in the amount of about 0.2 ml, which was slightly water-soluble and viscous with low-fluidity. In order to dissolve the essential oil evenly in the aqueous solution, tween-80 (TW-80, used in 10% (w/v) solution), propylene glycol (PG) and diethylene glycol monoethyl ether (TC) were selected as the favorable solubilizing agents, whose amount was respectively determined by L16(4(5)) orthogonal design. An aqueous solution with clarity and no ciliotoxicity was prepared when TW-80 8% (v/v), PG 14.4% (v/v) and TC 14.4% (v/v) were added. Employed to evaluate the acute toxicity, the rats grew well and were kept active and healthy within 14 d after an intranasal administration of this preparation at the dose of oil from 10 g Bupleuri/kg (50-fold higher than the clinical dose), indicating that there would be no serious toxicity at the normal dose. Intranasal administration of this preparation to 2 kg rabbits with fever induced by subcutaneous injection of turpentine decreased body temperature markedly (0.5, 0.8 and 1.0 degrees C respectively at the dose of oil from 1, 2 and 4 g Bupleuri/body). In addition, the administration significantly reduced fever in 200 g rats induced by intramuscular injection of colicine suspension (0.6 degrees C at the dose of oil from 0.8 g Bupleuri/body). The results suggest that the formulation of nasal spray for the essential oil from Radix Bupleuri can be potentially effective in the treatment of fever.

Determination of apovincaminic acid in human plasma by high-performance liquid chromatography using solid-phase extraction and ultraviolet detection.

A new, simple and rapid high-performance liquid chromatography (HPLC) method with UV detection has been developed for the determination of apovincaminic acid in human plasma. Apovincaminic acid and internal standard were isolated from plasma samples by solid-phase extraction with OASIS HLB cartridges. The chromatographic separation was accomplished on a reversed-phase C(18) column and UV detection was set at 311 nm. The calibration curves were linear in the concentration range of 2.4-240.0 ng/ml, and the limits of quantification was 2.4 ng/ml. The precision and accuracy ranged from 0.84 to 8.54% and 91.5 to 108.3%, respectively. The developed method was subsequently applied to study the pharmacokinetics of apovincaminic acid in a group of 20 human subjects at a single oral dose of 10mg of vinpocetine tablet.