Optofluidic crystallithography for directed growth of single-crystalline halide perovskites.

Crystallization is a fundamental phenomenon which describes how the atomic building blocks such as atoms and molecules are arranged into ordered or quasi-ordered structure and form solid-state materials. While numerous studies have focused on the nucleation behavior, the precise and spatiotemporal control of growth kinetics, which dictates the defect density, the micromorphology, as well as the properties of the grown materials, remains elusive so far. Herein, we propose an optical strategy, termed optofluidic crystallithography (OCL), to solve this fundamental problem. Taking halide perovskites as an example, we use a laser beam to manipulate the molecular motion in the native precursor environment and create inhomogeneous spatial distribution of the molecular species. Harnessing the coordinated effect of laser-controlled local supersaturation and interfacial energy, we precisely steer the ionic reaction at the growth interface and directly print arbitrary single crystals of halide perovskites of high surface quality, crystallinity, and uniformity at a high printing speed of 102 µm s-1. The OCL technique can be potentially extended to the fabrication of single-crystal structures beyond halide perovskites, once crystallization can be triggered under the laser-directed local supersaturation.

Evaluation of Patient-Centric Sample Collection Technologies for Pharmacokinetic Assessment of Large and Small Molecules.

Low-volume sampling devices offer the promise of lower discomfort and greater convenience for patients, potentially reducing patient burden and enabling decentralized clinical trials. In this study, we determined whether low-volume sampling devices produce pharmacokinetic (PK) data comparable to conventional venipuncture for a diverse set of monoclonal antibodies (mAbs) and small molecules. We adopted an open-label, non-randomized, parallel-group, single-site study design, with four cohorts of 10 healthy subjects per arm. The study drugs, doses, and routes of administration included: crenezumab (15 mg/kg, intravenous infusion), etrolizumab (210 mg, subcutaneous), GDC-X (oral), and hydroxychloroquine (HCQ, 200 mg, oral). Samples were collected after administration of a single dose of each drug using conventional venipuncture and three low-volume capillary devices: TassoOne Plus for liquid blood, Tasso-M20 for dry blood, both applied to the arm, and Neoteryx Mitra® for dry blood obtained from fingertips. Serum/plasma concentrations from venipuncture and TassoOne Plus samples overlapped and PK parameters were comparable for all drugs, except HCQ. After applying a baseline hematocrit value, the dry blood concentrations and PK parameters for the two monoclonal antibodies were comparable to those obtained from venipuncture. For the two small molecules, two bridging strategies were evaluated for converting dry blood concentrations to equivalent plasma concentrations. A baseline hematocrit correction and/or linear regression-based correction was effective for GDC-X, but not for HCQ. Additionally, the study evaluated the bioanalytical data quality and comparability from the various collection methods, as well as patient preference for the devices.

Evaluation of partial volume correction and analysis of longitudinal [18F]GTP1 tau PET imaging in Alzheimer's disease using linear mixed-effects models.

Purpose: We evaluated the impact of partial volume correction (PVC) methods on the quantification of longitudinal [18F]GTP1 tau positron-emission tomography (PET) in Alzheimer's disease and the suitability of describing the tau pathology burden temporal trajectories using linear mixed-effects models (LMEM). Methods: We applied van Cittert iterative deconvolution (VC), 2-compartment, and 3-compartment, and the geometric transfer matrix plus region-based voxelwise methods to data acquired in an Alzheimer's disease natural history study over 18 months at a single imaging site. We determined the optimal PVC method by comparing the standardized uptake value ratio change (%ΔSUVR) between diagnostic and tau burden-level groups and the longitudinal repeatability derived from the LMEM. The performance of LMEM analysis for calculating %ΔSUVR was evaluated in a natural history study and in a multisite clinical trial of semorinemab in prodromal to mild Alzheimer's disease by comparing results to traditional per-visit estimates. Results: The VC, 2-compartment, and 3-compartment PVC methods had similar performance, whereas region-based voxelwise overcorrected regions with a higher tau burden. The lowest within-subject variability and acceptable group separation scores were observed without PVC. The LMEM-derived %ΔSUVR values were similar to the per-visit estimates with lower variability. Conclusion: The results indicate that the tested PVC methods do not offer a clear advantage or improvement over non-PVC images for the quantification of longitudinal [18F]GTP1 PET data. LMEM offers a robust framework for the longitudinal tau PET quantification with low longitudinal test-retest variability. Clinical trial registration: NCT02640092 and NCT03289143.

Flexible High-Temperature MoS2 Field-Effect Transistors and Logic Gates.

High-temperature-resistant integrated circuits with excellent flexibility, a high integration level (nanoscale transistors), and low power consumption are highly desired in many fields, including aerospace. Compared with conventional SiC high-temperature transistors, transistors based on two-dimensional (2D) MoS2 have advantages of superb flexibility, atomic scale, and ultralow power consumption. However, MoS2 cannot survive at high temperature and drastically degrades above 200 °C. Here, we report MoS2 field-effect transistors (FETs) with top/bottom hexagonal boron nitride (h-BN) encapsulation and graphene electrodes. With the protection of the h-BN/h-BN structure, the devices can survive at much higher temperature (≥500 °C in air) than those of the MoS2 devices ever reported, which provides us an opportunity to explore the electrical properties and working mechanism of MoS2 devices at high temperature. Unlike the relatively low-temperature situation, the on/off ratio and subthreshold swing of MoS2 FETs show drastic variation at elevated temperature due to the injection of thermal emission carriers. Compared with metal electrode, devices with a graphene electrode demonstrate superior performance at high temperature (∼1-order-larger current on/off ratio, 3-7 times smaller subthreshold swing, and 5-9 times smaller threshold voltage shift). We further realize that the flexible CMOS NOT gate based on the above technique, and demonstrate logic computing at 550 °C. This work may stimulate the fundamental research of properties of 2D materials at high temperature, and also creates conditions for next-generation flexible harsh-environment-resistant integrated circuits.

Rapid screening and identification of targeted and non-targeted illegal added drugs in functional foods by MRSIT-HRMS based on NIST screening database.

The last few decades have witnessed the increasing consumption of functional foods, leading to the expansion of the worldwide market. However, the illegal addition drugs in functional foods remains incessant despite repeated prohibition, making it a key focus of strict crackdowns by regulatory authorities. Effective analytical tools and procedures are desperately needed to rapidly screen and identify illegally added drugs in a large number of samples, given the growing amount and diversity of these substances in functional foods. The MRSIT-HRMS (Multiple Sample Rapid Introduction combined with High Resolution Mass Spectrometry) without chromatographic separation, after direct sampling, utilizes NIST software (National Institute of Standards and Technology) matching with a home-built library to target identification and non-targeted screen of illegal additives. When applied to 50 batches of suspicious samples, the targeted method detected illegal added drugs in 41 batches of samples, while the non-targeted method screened a new phosphodiesterase-5 (PDE-5) inhibitor type structural derivative. The positive results obtained by the targeted method were consistent with LC-MS/MS (QQQ). The novel MRSIT-HRMS with a limit of quantification (LOD) of 1 µg/mL achieved 100 % correct identification for all 50 batches of actual samples, demonstrating its potential as a highly promising and powerful tool for fast screening of illegally added drugs in functional food, especially when compared to traditional LC-MS/MS methods. This is essential for ensuring drug safety and public health.

Diagnostic CT of colorectal cancer with artificial intelligence iterative reconstruction: A clinical evaluation.

OBJECTIVES: To investigate the clinical value of a novel deep-learning based CT reconstruction algorithm, artificial intelligence iterative reconstruction (AIIR), in diagnostic imaging of colorectal cancer (CRC). METHODS: This study retrospectively enrolled 217 patients with pathologically confirmed CRC. CT images were reconstructed with the AIIR algorithm and compared with those originally obtained with hybrid iterative reconstruction (HIR). Objective image quality was evaluated in terms of the signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). Subjective image quality was graded on the conspicuity of tumor margin and enhancement pattern as well as the certainty in diagnosing organ invasion and regional lymphadenopathy. In patients with surgical pathology (n = 116), the performance of diagnosing visceral peritoneum invasion was characterized using receiver operating characteristic (ROC) analysis. Changes of diagnostic thinking in diagnosing hepatic metastases were assessed through lesion classification confidence. RESULTS: The SNRs and CNRs on AIIR images were significantly higher than those on HIR images (all p < 0.001). The AIIR was scored higher for all subjective metrics (all p < 0.001) except for the certainty of diagnosing regional lymphadenopathy (p = 0.467). In diagnosing visceral peritoneum invasion, higher area under curve (AUC) of the ROC was found for AIIR than HIR (0.87 vs 0.77, p = 0.001). In assessing hepatic metastases, AIIR was found capable of correcting the misdiagnosis and improving the diagnostic confidence provided by HIR (p = 0.01). CONCLUSIONS: Compared to HIR, AIIR offers better image quality, improves the diagnostic performance regarding CRC, and thus has the potential for application in routine abdominal CT.

Weak to no correlation between quantitative high-resolution computed tomography metrics and lung function change in fibrotic diseases.

Background: Identifying systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF) patients at risk of more rapid forced vital capacity (FVC) decline could improve trial design. The purpose of the present study was to explore the prognostic value of quantitative high-resolution computed tomography (HRCT) metrics derived by Imbio lung texture analysis (LTA) tool in predicting FVC slope. Methods: This retrospective study used data from patients who were not treated with investigational drugs with and without background antifibrotic therapies in tocilizumab phase 3 SSc, lebrikizumab phase 2 IPF, and zinpentraxin alfa phase 2 IPF studies conducted from 2015 to 2021. Controlled HRCT axial volumetric multidetector computed tomography scans were evaluated using the Imbio LTA tool. Associations between HRCT metrics and FVC slope were assessed through the Spearman correlation coefficient and adjusted R2 in a linear regression model adjusted by demographics and baseline clinical characteristics. Results: A total of 271 SSc and IPF patients were analysed. Correlation coefficients of highest magnitude were observed in the SSc study between the extent of ground glass, normal volume, quantification of interstitial lung disease, reticular pattern, and FVC slope (-0.25, 0.28, -0.28, and -0.33, respectively), while the correlation coefficients observed in IPF studies were in general <0.2. The incremental prognostic value of the baseline HRCT metrics was marginal after adjusting baseline characteristics and was inconsistent across study arms. Conclusion: Data from the SSc and IPF studies suggested weak to no and inconsistent correlation between quantitative HRCT metrics derived by the Imbio LTA tool and FVC slope in the studied SSc and IPF population.

Preclinical validation of a novel deep learning-based metal artifact correction algorithm for orthopedic CT imaging.

PURPOSE: To validate a novel deep learning-based metal artifact correction (MAC) algorithm for CT, namely, AI-MAC, in preclinical setting with comparison to conventional MAC and virtual monochromatic imaging (VMI) technique. MATERIALS AND METHODS: An experimental phantom was designed by consecutively inserting two sets of pedicle screws (size Φ 6.5 × 30-mm and Φ 7.5 × 40-mm) into a vertebral specimen to simulate the clinical scenario of metal implantation. The resulting MAC, VMI, and AI-MAC images were compared with respect to the metal-free reference image by subjective scoring, as well as by CT attenuation, image noise, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and correction accuracy via adaptive segmentation of the paraspinal muscle and vertebral body. RESULTS: The AI-MAC and VMI images showed significantly higher subjective scores than the MAC image (all p < 0.05). The SNRs and CNRs on the AI-MAC image were comparable to the reference (all p > 0.05), whereas those on the VMI were significantly lower (all p < 0.05). The paraspinal muscle segmented on the AI-MAC image was 4.6% and 5.1% more complete to the VMI and MAC images for the Φ 6.5 × 30-mm screws, and 5.0% and 5.1% for the Φ 7.5 × 40-mm screws, respectively. The vertebral body segmented on the VMI was closest to the reference, with only 3.2% and 7.4% overestimation for Φ 6.5 × 30-mm and Φ 7.5 × 40-mm screws, respectively. CONCLUSIONS: Using metal-free reference as the ground truth for comparison, the AI-MAC outperforms VMI in characterizing soft tissue, while VMI is useful in skeletal depiction.

Two-Dimensional Transition Metal Dichalcogenide Tunnel Field-Effect Transistors for Biosensing Applications.

Field-effect transistor (FET) biosensors based on two-dimensional (2D) materials have drawn significant attention due to their outstanding sensitivity. However, the Boltzmann distribution of electrons imposes a physical limit on the subthreshold swing (SS), and a 2D-material biosensor with sub-60 mV/dec SS has not been realized, which hinders further increase of the sensitivity of 2D-material FET biosensors. Here, we report tunnel FETs (TFETs) based on a SnSe2/WSe2 heterostructure and observe the tunneling effect of a 2D material in aqueous solution for the first time with an ultralow SS of 29 mV/dec. A bilayer dielectric (Al2O3/HfO2) and graphene contacts, which significantly reduce the leakage current in solution and contact resistance, respectively, are crucial to the realization of the tunneling effect in solution. Then, we propose a novel biosensing method by using tunneling current as the sensing signal. The TFETs show an extremely high pH sensitivity of 895/pH due to ultralow SS, surpassing the sensitivity of FET biosensors based on a single 2D material (WSe2) by 8-fold. Specific detection of glucose is realized, and the biosensors show a superb sensitivity (3158 A/A for 5 mM), wide sensing range (from 10-9 to 10-3 M), low detection limit (10-9 M), and rapid response rate (11 s). The sensors also exhibit the ability of monitoring glucose in complex biofluid (sweat). This work provides a platform for ultrasensitive biosensing. The discovery of the tunneling effect of 2D materials in aqueous solution may stimulate further fundamental research and potential applications.

A Survey of the Landscape Visibility Analysis Tools and Technical Improvements.

Visual perception of the urban landscape in a city is complex and dynamic, and it is largely influenced by human vision and the dynamic spatial layout of the attractions. In return, landscape visibility not only affects how people interact with the environment but also promotes regional values and urban resilience. The development of visibility has evolved, and the digital landscape visibility analysis method allows urban researchers to redefine visible space and better quantify human perceptions and observations of the landscape space. In this paper, we first reviewed and compared the theoretical results and measurement tools for spatial visual perception and compared the value of the analytical methods and tools for landscape visualization in multiple dimensions on the principal of urban planning (e.g., complex environment, computational scalability, and interactive intervention between computation and built environment). We found that most of the research was examined in a static environment using simple viewpoints, which can hardly explain the actual complexity and dynamic superposition of the landscape perceptual effect in an urban environment. Thus, those methods cannot effectively solve actual urban planning issues. Aiming at this demand, we proposed a workflow optimization and developed a responsive cross-scale and multilandscape object 3D visibility analysis method, forming our analysis model for testing on the study case. By combining the multilandscape batch scanning method with a refined voxel model, it can be adapted for large-scale complex dynamic urban visual problems. As a result, we obtained accurate spatial visibility calculations that can be conducted across scales from the macro to micro, with large external mountain landscapes and small internal open spaces. Our verified approach not only has a good performance in the analysis of complex visibility problems (e.g., we defined the two most influential spatial variables to maintain good street-based landscape visibility) but also the high efficiency of spatial interventions (e.g., where the four recommended interventions were the most valuable), realizing the improvement of intelligent landscape evaluations and interventions for urban spatial quality and resilience.

All-Optical Reconfigurable Excitonic Charge States in Monolayer MoS2.

Excitons are quasi-particles composed of electron-hole pairs through Coulomb interaction. Due to the atomic-thin thickness, they are tightly bound in monolayer transition metal dichalcogenides (TMDs) and dominate their optical properties. The capability to manipulate the excitonic behavior can significantly influence the photon emission or carrier transport performance of TMD-based devices. However, on-demand and region-selective manipulation of the excitonic states in a reversible manner remains challenging so far. Herein, harnessing the coordinated effect of femtosecond-laser-driven atomic defect generation, interfacial electron transfer, and surface molecular desorption/adsorption, we develop an all-optical approach to manipulate the charge states of excitons in monolayer molybdenum disulfide (MoS2). Through steering the laser beam, we demonstrate reconfigurable optical encoding of the excitonic charge states (between neutral and negative states) on a single MoS2 flake. Our technique can be extended to other TMDs materials, which will guide the design of all-optical and reconfigurable TMD-based optoelectronic and nanophotonic devices.

The endometrial microbiota profile influenced pregnancy outcomes in patients with repeated implantation failure: a retrospective study.

OBJECTIVES: To investigate the association between the pregnancy outcomes of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) patients with repeated implantation failure (RIF) and their endometrial microbiota profiles. METHODS: One hundred and forty-one RIF patients were recruited in this retrospective study. Endometrial tissues were sampled using a disposable sterile endometrium sampler. Comprehensive next-generation sequencing techniques were used to detect the endometrial bacteria status, and the pregnancy outcomes were analyzed. RESULTS: Endometrial pathogenic bacteria were detected in 125 patients (88.70%, the pathogenic group) while no relevant pathogen was found in the remaining 16 (11.30%, the no-pathogen group). All the 125 patients received the treatment of oral antibiotics for 14 days. Clinical pregnancy rates and ongoing pregnancy rates were higher in the pathogenic group than in the no-pathogen group without statistical significance (50.40% vs. 37.50%, P＞0.05; 42.40% vs. 25%, P＞0.05). CONCLUSION: In the endometrium of most RIF patients existed pathogenic bacteria, among which Streptococcus, Staphylococcus, Neisseria, and Klebsiella were most frequently observed, and the sensitive antibiotic therapy might improve clinical outcomes of the RIF patients in subsequent embryo transfer cycles.

Development of a 3D-printed pelvic CT phantom combined with fresh pathological tissues of bone tumor.

Background: Computed tomography (CT) imaging is the most important and common means of detecting and diagnosing pelvic bone tumors. While phantoms with sufficient flexibility and anatomical realism are useful in CT research, using phantoms has been difficult for pelvic bone tumors because of the tumors' relatively large size and highly variable shape. By combining medical 3D printing technology and fresh tumor specimens, this study aimed to design such a hybrid phantom, test its imaging properties, and demonstrate its usefulness in optimizing the CT protocols. Methods: Two phantoms were designed for 2 patients with pelvic bone tumors who underwent surgical resection. One phantom was scanned with a routine pelvic CT protocol and compared against the patient image to test the imaging properties. We optimized the imaging protocol by assessing a series of varied settings on tube voltage (80, 100, 120, and 140 kVp), tube current (80, 120, and 160 to 200 mAs), and pitch factor (0.5, 0.8, 1.1, and 1.4) using the other phantom. These were assessed in comparison to the clinical reference of 140 kVp, 240 mAs, and 1.0 pitch, respectively. Image quality was quantified in terms of CT value, image noise, signal to noise ratio (SNR), and contrast to noise ratio (CNR) in various regions of interest. Results: With the routine protocol, the phantom image showed no significant difference in CT values of the bone and soft tissues and image noise compared to the patient image (all P values >0.05). With a lower tube voltage (80, 100, and 120 kVp) than the reference protocol, the CT value of bone tissue showed significant differences (all P values <0.001). No significant difference was found when applying a reduced tube current (all P values >0.05). With an increased helical pitch, pitches of 0.5, 0.8 and 1.1 were found to be comparable to those using the reference protocol (all P values >0.05). Conclusions: The 3D-printed phantom can simulate the radiological properties of tumors in the pelvis and was successfully used in imaging studies of pelvic bone tumors. According to our preliminary findings, a low-dose pelvic CT protocol with acceptable image quality is achievable using reduced tube current or increased pitch.

Investigation of the Pharmacological Effect and Mechanism of Jinbei Oral Liquid in the Treatment of Idiopathic Pulmonary Fibrosis Using Network Pharmacology and Experimental Validation.

Overview: Idiopathic pulmonary fibrosis (IPF) is a disease caused by many factors, eventually resulting in lung function failure. Jinbei oral liquid (JBOL) is a traditional Chinese clinical medicine used to treat pulmonary diseases. However, the pharmacological effects and mechanism of the action of JBOL on IPF remain unclear. This study investigated the protective effects and mechanism of the action of JBOL on IPF using network pharmacology analysis, followed by in vivo and in vitro experimental validation. Methods: The components of JBOL and their targets were screened using the TCMSP database. IPF-associated genes were obtained using DisGeNET and Drugbank. The common targets of JBOL and IPF were identified with the STRING database, and a protein-protein interaction (PPI) network was constructed. GO and KEGG analyses were performed. Sprague-Dawley rats were injected with bleomycin (BLM) to establish an IPF model and treated orally with JBOL at doses of 5.4, 10.8, and 21.6 ml/kg. A dose of 54 mg/kg of pirfenidone was used as a control. All rats were treated for 28 successive days. Dynamic pulmonary compliance (Cdyn), minute ventilation volume (MVV), vital capacity (VC), and lung resistance (LR) were used to evaluate the efficacy of JBOL. TGF-ß-treated A549 cells were exposed to JBOL, and epithelial-to-mesenchymal transition (EMT) changes were assessed. Western blots were performed. Results: Two hundred seventy-eight compounds and 374 targets were screened, and 103 targets related to IPF were identified. Core targets, including MAPK1 (ERK2), MAPK14 (p38), JUN, IL-6, AKT, and others, were identified by constructing a PPI network. Several pathways were involved, including the MAPK pathway. Experimentally, JBOL increased the levels of the pulmonary function indices (Cdyn, MVV, and VC) in a dose-dependent manner and reduced the RL level in the BLM-treated rats. JBOL increased the epithelial marker E-cadherin and suppressed the mesenchymal marker vimentin expression in the TGF-ß-treated A549 cells. The suppression of ERK1/2, JNK, and p38 phosphorylation by JBOL was validated. Conclusion: JBOL had therapeutic effects against IPF by regulating pulmonary function and EMT through a systemic network mechanism, thus supporting the need for future clinical trials of JBOL.

High-temperature flexible WSe2 photodetectors with ultrahigh photoresponsivity.

The development of high-temperature photodetectors can be beneficial for numerous applications, such as aerospace engineering, military defence and harsh-environments robotics. However, current high-temperature photodetectors are characterized by low photoresponsivity (<10 A/W) due to the poor optical sensitivity of commonly used heat-resistant materials. Here, we report the realization of h-BN-encapsulated graphite/WSe2 photodetectors which can endure temperatures up to 700 °C in air (1000 °C in vacuum) and exhibit unconventional negative photoconductivity (NPC) at high temperatures. Operated in NPC mode, the devices show a photoresponsivity up to 2.2 × 106 A/W, which is ~5 orders of magnitude higher than that of state-of-the-art high-temperature photodetectors. Furthermore, our devices demonstrate good flexibility, making it highly adaptive to various shaped surfaces. Our approach can be extended to other 2D materials and may stimulate further developments of 2D optoelectronic devices operating in harsh environments.

Protective effect of Du-Zhong-Wan against osteoporotic fracture by targeting the osteoblastogenesis and angiogenesis couple factor SLIT3.

ETHNOPHARMACOLOGICAL RELEVANCE: Du-Zhong-Wan (DZW) is a traditional Chinese medicine (TCM) composed of Eucommia ulmoides Oliv. and Dipsacus asper Wall. ex C.B. Clarke in the ratio 1:1. Based on the TCM theory, DZW nourishes the kidney to strengthen the bones. The literature research revealed that DZW possesses anti-fatigue, anti-depressant, and anti-osteoporotic properties. However, the action and mechanism of DZW on osteoporotic fracture remains slightly unclear. AIM OF THE STUDY: To evaluate the pharmacological effect of DZW on ovariectomized mice with an open femoral fracture and reveal the underlying mechanism. MATERIALS AND METHODS: We conducted ovariectomy for 5 weeks, followed by unilateral open transverse femoral fracture for another 3 weeks in C57BL/6 mice; during this process, DZW was administrated. The femur bone and vertebra tissues were collected and analyzed by micro-computed tomography, histomorphometry, mechanical strength testing, immunohistochemistry staining, and qRT-PCR analyses. In addition, alkaline phosphatase (ALP) and Alizarin red S (ARS) staining were performed to determine the extent of osteoblastogenesis from bone marrow mesenchymal stem cells (BMSCs). Western blotting was performed to examine the protein expression. RESULTS: DZW treatment significantly improved the bone histomorphometric parameters in mice undergoing ovariectomy when combined with the femoral fracture, including an increase in the bone volume, trabecular number, and bone formation rate and a decrease in the bone erosion area. Simultaneously, DZW treatment histologically promoted fractured callus formation. Mechanical strength testing revealed significantly higher stiffness and an ultimate load after treatment with DZW. The angiogenesis of H-type vessels was enhanced by DZW, as evidenced by increased levels of CD31 and endomucin (EMCN), the H-type vessel endothelium markers, at the fractured endosteum and metaphysis regions. Relative to the osteoporotic fracture mice, the DZW treatment group showed an increased proangiogenic factor SLIT3 level. The increased level of SLIT3 was also recorded during the process of DZW-stimulated osteoblastogenesis from BMSCs. CONCLUSIONS: For the first time, we demonstrated that DZW promoted osteoporotic fracture healing by enhancing osteoblastogenesis and angiogenesis of the H-type vessels. This enhanced combination of osteoblastogenesis and angiogenesis was possibly related to the production of proangiogenic factor SLIT3 induced by DZW.

Clinical validation of an AI-based motion correction reconstruction algorithm in cerebral CT.

OBJECTIVES: To evaluate the clinical performance of an artificial intelligence (AI)-based motion correction (MC) reconstruction algorithm for cerebral CT. METHODS: A total of 53 cases, where motion artifacts were found in the first scan so that an immediate rescan was taken, were retrospectively enrolled. While the rescanned images were reconstructed with a hybrid iterative reconstruction (IR) algorithm (reference group), images of the first scan were reconstructed with both the hybrid IR (motion group) and the MC algorithm (MC group). Image quality was compared in terms of standard deviation (SD), signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), the mean squared error (MSE), peak signal-to-noise ratio (PSNR), structural similarity index (SSIM), and mutual information (MI), as well as subjective scores. The diagnostic performance for each case was evaluated accordingly by lesion detectability or the Alberta Stroke Program Early CT Score (ASPECTS) assessment. RESULTS: Compared with the motion group, the SNR and CNR of the MC group were significantly increased. The MSE, PSNR, SSIM, and MI with respect to the reference group were improved by 44.1%, 15.8%, 7.4%, and 18.3%, respectively (all p < 0.001). Subjective image quality indicators were scored higher for the MC than the motion group (p < 0.05). Improved lesion detectability and higher AUC (0.817 vs 0.614) in the ASPECTS assessment were found for the MC to the motion group. CONCLUSIONS: The AI-based MC reconstruction algorithm has been clinically validated for reducing motion artifacts and improving diagnostic performance of cerebral CT. KEY POINTS: • An artificial intelligence-based motion correction (MC) reconstruction algorithm has been clinically validated in both qualitative and quantitative manner. • The MC algorithm reduces motion artifacts in cerebral CT and increases the diagnostic confidence for brain lesions. • The MC algorithm can help avoiding rescans caused by motion and improving the efficiency of cerebral CT in the emergency department.

Effects of inhaled JAK inhibitor GDC-4379 on exhaled nitric oxide and peripheral biomarkers of inflammation.

BACKGROUND: Janus Kinases (JAKs) mediate activity of many asthma-relevant cytokines. GDC-0214, an inhaled small molecule JAK1 inhibitor, has previously been shown to reduce fractional exhaled nitric oxide (FeNO) in patients with mild asthma, but required an excessive number of inhalations. AIM: To assess whether GDC-4379, a new inhaled JAK inhibitor, reduces FeNO and peripheral biomarkers of inflammation. METHODS: This study assessed the activity of GDC-4379 in a double-blind, randomized, placebo-controlled, Phase 1 study in patients with mild asthma. Participants included adults (18-65y) with a diagnosis of asthma for ≥6 months, forced expiratory volume in 1 s (FEV1)> 70% predicted, FeNO >40 ppb, using as-needed short-acting beta-agonist medication only. Four sequential, 14-day, ascending-dose cohorts (10 mg QD, 30 mg QD, 40 mg BID, and 80 mg QD) of 12 participants each were randomized 2:1 to GDC-4379 or placebo. The primary activity outcome was percent change from baseline (CFB) in FeNO to Day 14 compared to the pooled placebo group. Safety, tolerability, pharmacokinetics, and pharmacodynamic biomarkers, including blood eosinophils, serum CCL17, and serum CCL18, were also assessed. RESULTS: Of 48 enrolled participants, the mean age was 25 years and 54% were female. Median (range) FeNO at baseline was 79 (41-222) ppb. GDC-4379 treatment led to dose-dependent reductions in FeNO. Compared to placebo, mean (95% CI) percent CFB in FeNO to Day 14 was: -6 (-43, 32) at 10 mg QD, -26 (-53, 2) at 30 mg QD, -55 (-78, -32) at 40 mg BID and -52 (-72, -32) at 80 mg QD. Dose-dependent reductions in blood eosinophils and serum CCL17 were also observed. Higher plasma drug concentrations corresponded with greater FeNO reductions. No serious AEs occurred. The majority of AEs were mild to moderate. The most common AEs were headache and oropharyngeal pain. Minor changes in neutrophils were noted at 80 mg QD, but were not considered clinically meaningful. CONCLUSIONS: In patients with mild asthma, 14-day treatment with GDC-4379 reduced FeNO levels and peripheral biomarkers of inflammation. Treatment was well tolerated without any major safety concerns. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12619000227190.

Wedelolactone, a Component from Eclipta prostrata (L.) L., Inhibits the Proliferation and Migration of Head and Neck Squamous Cancer Cells through the AhR Pathway.

BACKGROUND: Ecliptae prostrata (L.) L. has been widely used in East Asia with reported biological activities, including anti-cancer properties. OBJECTIVES: We aimed to investigate the effect of ethyl acetate extract of Ecliptae prostrata (L.) L. (EAE) and its component wedelolactone on the proliferation and migration of head and neck squamous cancer cells. METHODS: The proliferation of human SCC-4 and mouse CU110-1 tongue squamous carcinoma cells was assessed using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) method. Scratch wound assays were performed to assess cell migration rates. The levels of Ecadherin and vimentin were used as markers of the epithelial-to-mesenchymal transition (EMT). AhR, CYP1A1, and CYP1B1 levels were examined to uncover the mechanism of inhibition of cell migration by wedelolactone. RESULTS: We found that EAE and wedelolactone decreased the proliferation of human SCC-4 cells and mouse CU110-1 cells at doses of EAE at > 25 µg/ml and wedelolactone at > 6.25 µg/ml. Similarly, both EAE and wedelolactone produced inhibitory effects against migration, but the effective doses that significantly inhibited migration were lower than those affecting proliferation. Wedelolactone below 12.5 µg/ml inhibited the epithelial-to-mesenchymal transition (EMT) with increased expression of E-cadherin and decreased expression of vimentin in SCC-4 and CU110-1 cells. Further analysis showed wedelolactone inhibited the expression of AhR and its downstream target molecules CYP1A1 and CYP1B1 in both squamous carcinoma cells at the same doses inhibiting cell migration. The addition of benzo (a)pyrene [B(a)P], an agonist of AhR, stimulated migration, especially in the CU110-1 cells with reported cancer stem cell-like characteristics. Instructively, B(a)P reversed the inhibitory effects of wedelolactone on AhR expression and cell migration, suggesting that wedelolactone antagonizes cell migration through the AhR pathway. Moreover, the higher activity of EAE and wedelolactone against the migration of cancer stem-like CU110-1 cells relative to SCC-4 cells suggests selective activity against cancer stem cells. CONCLUSION: Our study identifies wedelolactone as a major active component of Ecliptae prostrata (L.) L. with promising anti-cancer properties against head and neck squamous cancer cells.

Phase I and scintigraphy studies to evaluate safety, tolerability, pharmacokinetics, and lung deposition of inhaled GDC-0214 in healthy volunteers.

Several inflammatory cytokines that promote inflammation and pathogenesis in asthma signal through the Janus kinase 1 (JAK1) pathway. This phase I, randomized, placebo-controlled trial assessed the pharmacokinetics and safety of single and multiple ascending doses up to 15 mg twice daily for 14 days of a JAK1 inhibitor, GDC-0214, in healthy volunteers (HVs; n = 66). Doses were administered with a dry powder, capsule-based inhaler. An accompanying open-label gamma scintigraphy study in HVs examined the lung deposition of a single dose of inhaled Technetium-99m (99m Tc)-radiolabeled GDC-0214. GDC-0214 plasma concentrations were linear and approximately dose-proportional after both single and multiple doses. Peak plasma concentrations occurred at 15-30 min after dosing. The mean apparent elimination half-life ranged from 32 to 56 h across all single and multiple dose cohorts. After single and multiple doses, all adverse events were mild or moderate, and none led to treatment withdrawal. There was no clear evidence of systemic toxicity due to JAK1 inhibition, and systemic exposure was low, with plasma concentrations at least 15-fold less than the plasma protein binding-corrected IC50 of JAK1 at the highest dose. Scintigraphy showed that approximately 50% of the emitted dose of radiolabeled GDC-0214 was deposited in the lungs and was distributed well to the peripheral airways. 99m Tc-radiolabeled GDC-0214 (1 mg) exhibited a mean plasma Cmax similar to that observed in phase I at the same dose level. Overall, inhaled GDC-0214 exhibited pharmacokinetic properties favorable for inhaled administration.