In Situ Fabrication of High Ionic and Electronic Conductivity Interlayers Enabling Long-Life Garnet-Based Solid-State Lithium Batteries.

Garnet-type Li6.75La3Zr1.75Ta0.25O12 (LLZTO) is a promising solid-state electrolyte (SSE) because of its fast ionic conduction and notable chemical/electrochemical stability toward the lithium (Li) metal. However, poor interface wettability and large interface resistance between LLZTO and Li anode greatly restrict its practical applications. In this work, we develop an in situ chemical conversion strategy to construct a highly conductive Li2S@C layer on the surface of LLZTO, enabling improved interfacial wettability between LLZTO and the Li anode. The Li/Li2S@C-LLZTO-Li2S@C/Li symmetric cell has a low interface impedance of 78.5 Ω cm2, much lower than the 970 Ω cm2 of a Li/LLZTO/Li cell. Moreover, the Li/Li2S@C-LLZTO-Li2S@C/Li cell exhibits a high critical current density of 1.4 mA cm-2 and an ultralong stability of 3000 h at 0.1 mA cm-2. When used in a LiFePO4 battery, the Li/Li2S@C-LLZTO/LiFePO4 battery exhibits a high initial discharge capacity of 150.8 mA h g-1 at 0.2 C without lithium storage capacity attenuation during 200 cycles. This work provides a novel and feasible strategy to address interface issues of SSEs and achieve lithium-dendrite-free solid-state batteries.

Hierarchical porous carbon materials for lithium storage: preparation, modification, and applications.

Secondary battery as an efficient energy conversion device has been highly attractive for alleviating the energy crisis and environmental pollution. Hierarchical porous carbon (HPC) materials with multiple sizes pore channels are considered as promising materials for energy conversion and storage applications, due to their high specific surface area and excellent electrical conductivity. Although many reviews have reported on carbon materials for different fields, systematic summaries about HPC materials for lithium storage are still rare. In this review, we first summarize the main preparation methods of HPC materials, including hard template method, soft template method, and template-free method. The modification methods including porosity and morphology tuning, heteroatom doping, and multiphase composites are introduced systematically. Then, the recent advances in HPC materials on lithium storage are summarized. Finally, we outline the challenges and future perspectives for the application of HPC materials in lithium storage.

Comparison between dynamic versus static models and real-time monitoring of neuronal dysfunction in an amyloid-ß induced neuronal toxic model on a chip platform.

Microfluidics-based organs-on-a-chip offer a promising method for dynamic and 3-dimensional (3D) cell culture to evaluate the cell behaviors within the biomimetic environment. The purpose of this study was to establish neural network connections in a 3D neural stem cell (NSC)-based system with an interstitial level of flow for simulating the brain microenvironment toward a dynamic amyloid-ß (Aß) induced neuronal toxic model on a chip and to compare the biological effects and neurite dysfunction between static and dynamic systems. The brain-on-a-chip system consisted of an impedance analyzing layer, a structured well with a connected channel, and an interface coating with polypeptide films fabricated with modification based on our previous study. The cytotoxicity and percentage of neuron/astrocyte differentiation were all compared in both static and dynamic brain-on-a-chip systems. Reactive oxygen species production, neuron marker expression and neurotransmitter-acetylcholine release were all compared to evaluate functional neurite losses in both static and dynamic systems with/without Aß addition. Moreover, real-time impedance recording was used to consecutively monitor the neurite connection/disconnection in both static and dynamic brain-on-a-chip systems. The NSC-based dynamic brain-on-a-chip may enable the application of different neurodegenerative disease in vitro models for pathogenesis studies, drug discovery and novel therapeutic method development.

5-aminolevulinic acid-based photodynamic therapy in combination with antifungal agents for adult kerion and facial ulcer caused by Trichophyton rubrum.

Dermatophytosis is the most common fungal infectious disease in the world, which is commonly caused by Trichophyton rubrum in China. The traditional therapies for treating dermatophytosis include topical and oral antifungal agents like terbinafine, griseofulvin, and azole antifungal drugs. However, 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT) as a new alternative therapy avoids the side effects and drug resistance of traditional antifungal agents. We report two cases diagnosed as kerion and tinea faciei secondary to ulcers with CARD 9 deficiency, both of whom were infected by T.rubrum. They were both successfully treated by ALA-PDT combined with antifungal drugs, providing a feasible strategy for therapeutic choice for adult kerion and ulcer treatment.

Lithium aluminum hydride Li3AlH6: new insight into the anode material for liquid-state lithium-ion batteries.

Metal hydrides have been demonstrated as one of the promising high-capacity anode materials for Li-ion batteries. Herein, we report the electrochemical properties and lithium storage mechanism of a Li-rich complex metal hydride (Li3AlH6). Li3AlH6 exhibits a lithiation capacity of ∼1729 mAh/g with a plateau potential of ∼0.33 V vs. Li+/Li at the first discharge cycle. Experimental results demonstrate that Li3AlH6 is converted into LiH and LiAl in the initial electrochemical lithiation process. In addition, Li3AlH6 also possesses a good cycling stability that 71 % of the second discharge capacity is retained after 20 cycles. More importantly, the cycling performance of Li3AlH6 can be improved to 100 cycles via adjusting electrolyte composition. This study provides a new approach for developing the lithium storage properties of anode materials for Li-ion batteries.

Effects of remote ischaemic preconditioning on myocardial injury after major abdominal surgery in patients at high risk for cardiovascular adverse events in China (RIPC-MAS): protocol for a randomised, sham-controlled, observer-blinded trial.

INTRODUCTION: Myocardial injury after non-cardiac surgery (MINS) caused by an ischaemic mechanism is common and is associated with adverse short-term and long-term prognoses. However, MINS is a recent concept, and few studies have prospectively used it as a primary outcome. Remote ischaemic preconditioning (RIPC) is a non-invasive procedure that induces innate cardioprotection and may reduce MINS. METHODS AND ANALYSIS: This is a multicentre, randomised, sham-controlled, observer-blinded trial. Patients with a high clinical risk of cardiovascular events who are scheduled to undergo major abdominal surgery will be enrolled. A total of 766 participants will be randomised (1:1 ratio) to receive RIPC or control treatment before anaesthesia. RIPC will comprise four cycles of cuff inflation for 5 min to 200 mm Hg and deflation for 5 min. In the controls, an identical-looking cuff will be placed around the arm but will not be actually inflated. The primary outcome will be MINS, defined as at least one postoperative cardiac troponin (cTn) concentration above the 99th percentile upper reference limit of the cTn assay as a result of a presumed ischaemic mechanism. This trial will test the concentration of high-sensitivity cardiac troponin T (hs-cTnT). The secondary outcomes will be hs-cTnT levels reaching/above the prognostically important thresholds, peak hs-cTnT and total hs-cTnT release during the initial 3 days after surgery, length of hospital stay after surgery, length of stay in the intensive care unit, myocardial infarction, major adverse cardiovascular events, cardiac-related death, all-cause death within 30 days, 6 months, 1 year and 2 years after surgery, and postoperative complications and adverse events within 30 days after surgery. ETHICS AND DISSEMINATION: This study protocol (version 5.0 on 7 April 2023) was approved by the Ethics Committee of Sixth Affiliated Hospital of Sun Yat-sen University. The findings will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05733208.

14-3-3ζ Participates in the Phase Separation of Phosphorylated and Glycated Tau and Modulates the Physiological and Pathological Functions of Tau.

Tau plays a major role in Alzheimer's disease (AD) and several other neurodegenerative diseases. Tau undergoing liquid-liquid phase separation (LLPS) performs specific physiological functions, induces pathological processes, and contributes to neurodegeneration. Regulating Tau phase separation helps maintain physiological functions of Tau and inhibits pathological aggregation. Here, we show that the 14-3-3 zeta isoform (14-3-3ζ) participates in Tau LLPS. 14-3-3ζ can undergo co-phase separation with WT Tau, participate in and stabilize Tau droplets, and inhibit Tau droplet-driven tubulin assembly. On the other hand, 14-3-3ζ disrupts the LLPS of phosphorylated and glycated Tau, thereby inhibiting the amyloid aggregation initiated by LLPS.

A Novel 3D Culture Scaffold to Shorten Development Time for Multicellular Tumor Spheroids.

Multicellular tumor spheroids and tumoroids are considered ideal in vitro models that reflect the features of the tumor microenvironment. Biomimetic components resembling the extracellular matrix form scaffolds to provide structure to 3-dimensional (3D) culture systems, supporting the growth of both spheroids and tumoroids. Although Matrigel has long been used to support 3D culture systems, batch variations, component complexity, and the use of components derived from tumors are complicating factors. To address these issues, we developed the ACD 3D culture system to provide better control and consistency. We evaluated spheroid and tumoroid formation using the ACD 3D culture system, including the assessment of cell viability and cancer marker expression. Under ACD 3D culture conditions, spheroids derived from cancer cell lines exhibited cancer stem cell characteristics, including a sphere-forming size and the expression of stem cell marker genes. The ACD 3D culture system was also able to support patient-derived primary cells and organoid cell cultures, displaying adequate cell growth, appropriate morphology, and resistance to oxaliplatin treatment. These spheroids could also be used for drug screening purposes. In conclusion, the ACD 3D culture system represents an efficient tool for basic cancer research and therapeutic development.

Deep Learning-Based Construction and Processing of Multimodal Corpus for IoT Devices in Mobile Edge Computing.

Dialogue sentiment analysis is a hot topic in the field of artificial intelligence in recent years, in which the construction of multimodal corpus is the key part of dialogue sentiment analysis. With the rapid development of the Internet of Things (IoT), it provides a new means to collect the multiparty dialogues to construct a multimodal corpus. The rapid development of Mobile Edge Computing (MEC) provides a new platform for the construction of multimodal corpus. In this paper, we construct a multimodal corpus on MEC servers to make full use of the storage space distributed at the edge of the network according to the procedure of constructing a multimodal corpus that we propose. At the same time, we build a deep learning model (sentiment analysis model) and use the constructed corpus to train the deep learning model for sentiment on MEC servers to make full use of the computing power distributed at the edge of the network. We carry out experiments based on real-world dataset collected by IoT devices, and the results validate the effectiveness of our sentiment analysis model.

A Real-Time Sensing System for Monitoring Neural Network Degeneration in an Alzheimer's Disease-on-a-Chip Model.

Stem cell-based in vitro models may provide potential therapeutic strategies and allow drug screening for neurodegenerative diseases, including Alzheimer's disease (AD). Herein, we develop a neural stem cell (NSC) spheroid-based biochip that is characterized by a brain-like structure, well-defined neural differentiation, and neural network formation, representing a brain-on-a-chip. This system consisted of microelectrode arrays with a multichannel platform and allowed the real-time monitoring of network formation and degeneration by impedance analysis. The parameters of this platform for the real-time tracking of network development and organization were established based on our previous study. Subsequently, ß-amyloid (Aß) was added into the brain-on-a-chip system to generate an AD-on-a-chip model, and toxic effects on neurons and the degeneration of synapses were observed. The AD-on-a-chip model may help us to investigate the neurotoxicity of Aß on neurons and neural networks in real time. Aß causes neural damage and accumulates around neurites or inside neurospheroids, as observed by immunostaining and scanning electron microscopy (SEM). After incubation with Aß, reactive oxygen species (ROS) increased, synapse function decreased, and the neurotransmitter-acetylcholine (ACh) concentration decreased were observed. Most importantly, the real-time analysis system monitored the impedance value variation in the system with Aß incubation, providing consecutive network disconnection data that are consistent with biological data. This platform provides simple, real-time, and convenient sensing to monitor the network microenvironment. The proposed AD-on-a-chip model enhances the understanding of neurological pathology, and the development of this model provides an alternative for the study of drug discovery and cell-protein interactions in the brain.

Formation of soybean protein isolate-hawthorn flavonoids non-covalent complexes: Linking the physicochemical properties and emulsifying properties.

In recent years, more and more attention had been paid to the combination of proteins and flavonoids, and several flavonoids had been reported to improve the physicochemical and emulsifying properties of proteins. This study investigated the effects of ultrasonic treatment (450 W for 10 min, 20 min, and 30 min) on the physicochemical properties, antioxidant activity, and emulsifying properties of soy protein isolate (SPI) -hawthorn flavonoids (HF) non-covalent complexes. The results showed that the addition of HF to SPI and 20 min of ultrasound could reduce α-helix and random coil, increase ß-sheet and ß-turn, and enhance fluorescence quenching. In addition, it decreased the particle size, zeta potential, surface hydrophobicity, and turbidity to 88.43 or 95.27 nm, -28.80 mV, 1250.42, and 0.23, respectively. The protein solubility, free sulfhydryl group, antioxidant activity, emulsifying activity index, and emulsifying stability index all increased to 73.93%, 15.07 µmol/g, 71.00 or 41.91%, 9.81 m2/g, and 67.71%, respectively. Moreover, high-density small and low-flocculation droplets were formed. Therefore, the combined ultrasound treatment and addition of HF to SPI is a more effective method for protein modification compared to ultrasound treatment alone. It provides a theoretical basis for protein processing and application in the future.

Effect of Echinococcus granulosus hydatid cyst fluid protein on allergic rhinitis induced by ovalbumin in mice / 中国血吸虫病防治杂志

Objective To investigate the protective effect of Echinococcus granulosus hydatid cyst fluid protein (HCFP) on ovalbumin (OVA)-induced allergic rhinitis (AR) in mice. Methods Twenty-four BALB/c mice at ages of 8 to 10 weeks, each weighing approximately 20 g, were randomly divided into four groups, including groups A (blank control group), B (blank intervention group), C (AR model group) and D (AR+HCFP intervention group), with 6 mice in each group. On days 0, 2, 4, 6, 8, 10 and 12, mice in groups A, B, C and D were injected with 200 μL sterile phosphate buffered saline (PBS), 200 μL sterile PBS containing 20 μg HCFP, 200 μL sterile PBS containing 50 μg OVA and 5 mg Al(OH)3 gel, and 200 μL sterile PBS containing 50 μg OVA, 5 mg Al(OH)3 gel and 20 μg HCFP, respectively. On days 14 to 20, mice in groups A, B, C and D were administered with 40 μL sterile PBS, 40 μL sterile PBS containing 20 μg HCFP, 40 μL sterile PBS containing 2 mg OVA and 40 μL sterile PBS containing 2 mg OVA and 20 μL HCFP by nasal drop, respectively. Mouse behavioral changes were observed and behavioral scores were estimated. The serum levels of interferon-γ (IFN-γ), interleukin-4 (IL-4), IL-5, IL-10, transforming growth factor-β (TGF-β) and OVA-specific IgE antibody (OVA-sIgE) were measured using enzyme-linked immunosorbent assay (ELISA), and the pathological changes of mouse nasal mucosa were observed by hematoxylin and eosin (HE) staining. Results The mean behavioral score was significantly greater in Group C (6.83 ± 0.50) than in groups A (1.17 ± 0.52) and B (1.33 ± 0.52) (P < 0.05), while a lower mean behavioral score was estimated in Group D (3.50 ± 0.50) than in Group C (P < 0.05). There were significant differences among the groups in terms of serum IFN-γ (F = 4.08, P < 0.05), IL-4 (F = 275.90, P < 0.05), IL-5 (F = 96.82, P < 0.05), IL-10 (F = 77.67, P < 0.05), TGF-β (F = 9.98, P < 0.05) and OVA-sIgE levels (F = 44.69, P < 0.05). The serum IFN-γ level was significantly lower in Group C than in groups A, B and C (P < 0.05), and the serum levels of IL-4, IL-5 and OVA-sIgE were significantly higher in Group C than in groups A, B and C (P < 0.05), while the serum IL-10 and TGF-β levels were significantly greater in Group D than in Group C (P < 0.05). Microscopy showed apparent loss of nasal mucosa cilia, increased number and enlargement of goblet cells, interstitial edema and submucous vascular dilation in Group C, while the pathological changes of nasal mucosa were alleviated in Group D relative to Group C. Conclusions E. granulosus HCFP has a protective activity against OVA-induced allergic rhinitis in mice.

Successful Surgical Salvage for a Patient with Ruptured Coronary Sinus during Percutaneous Ablation for Atrial Fibrillation: A Case Report.

Herein, we describe the rare anatomy of an abnormal shunt from the left atrium to the coronary sinus, which ruptured during a percutaneous ablation for atrial fibrillation. The iatrogenic lesion was successfully repaired after emergent extracorporeal membrane oxygenation set up followed by surgical exploration. The patient's postoperative course was uneventful, and she was regularly followed up without any complications.

A two-dimensional calcium (II) coordination polymer constructed from 2,2'-[terephthaloylbis(azanediyl)]diacetate: synthesis, structure and properties.

A new two-dimensional (2D) coordination polymer, namely, poly[[diaqua-[µ4-2,2'-[terephthaloylbis(azanediyl)]diacetato]calcium(II)] monohydrate], {[Ca(C12H10N2O6)(H2O)2]·H2O}n, (I), has been synthesized by the reaction of CaCl2 with 2,2'-[terephthaloylbis(azanediyl)]diacetic acid (H2L). The title compound was structurally characterized by single-crystal X-ray diffraction analysis, elemental analysis and IR spectroscopy. In the crystal structure of (I), each CaII cation binds to six carboxylate groups from four symmetry-related L2- dianions. The hexadentate L2- ligand links four symmetry-related calcium cations into a 2D layer-like structure, which can be simplified as a uninodal SP 2-periodic (3,6)III net with the point symbol (43·63). In the lattice, all layers pack in parallel arrays through weak interlayer hydrogen bonding and π-π interactions. The thermal stability and photoluminescence properties of (I) have been investigated. Thermogravimetric analysis reveals the different thermal stabilities of the two coordinated water molecules due to their different hydrogen-bonding interactions. The title coordination polymer exhibits an excitation-wavelength-dependent fluorescence in the solid state.

Peptides for disrupting and degrading amyloids.

Amyloid proteins can aggregate into insoluble fibrils and form amyloid deposits in the human brain, which is the hallmark of many neurodegenerative diseases. Promising strategies toward pathological amyloid proteins and deposition include investigating inhibitors that can disrupt amyloid aggregation or induce misfolding protein degradation. In this review, recent progress of peptide-based inhibitors, including amyloid sequence-derived inhibitors, designed peptides, and peptide mimics, is highlighted. Based on the increased understanding of peptide design and precise amyloid structures, these peptides exhibit advanced inhibitory activities against fibrous aggregation as well as enhanced druggability.

Unprecedented Self-Healing Effect of Li6 PS5 Cl-Based All-Solid-State Lithium Battery.

Argyrodite Li6 PS5 Cl with high Li+ conductivity is a promising material for solid-state electrolytes (SSEs) in all-solid-state lithium batteries (ASSLBs). However, the narrow electrochemical window of Li6 PS5 Cl limits its applications in ASSLBs with high energy densities, and those that consist of high-voltage cathode materials and metallic lithium anodes. Unstable lithium deposition and stripping at interfaces is also a factor that restricts its industrialization. Herein, the authors investigated the electrochemical stability of Li6 PS5 Cl using it as both the cathode and electrolyte. The Li6 PS5 Cl-C/Li6 PS5 Cl/Li cell and symmetric Li/Li6 PS5 Cl/Li cells failed after a certain number of cycles, and subsequently healed electrochemically. This failure/healing phenomenon recurred during the cycling process. The self-healing behavior is closely related to the electrochemical window, which suggests that it can be controlled by the charge-discharge voltage range. In-depth X-ray photoelectron spectroscopy, in situ Raman spectroscopy, and in situ electrochemical impedance spectroscopy revealed the reversible Li6 PS5 Cl decomposition and metallic lithium growth inside the electrolyte during the cycling process. This self-healing behavior is mainly attributed to the reciprocating lithium growth and reversible redox reaction of the Li6 PS5 Cl decomposition. The proposed self-healing mechanism is a key aspect for sulfide-based SSEs, guiding the interface modification, and material design of ASSLBs.

Integrating Transcriptome-Wide Association Study and mRNA Expression Profiling Identifies Novel Genes Associated With Osteonecrosis of the Femoral Head.

OBJECTIVE: This study aims to identify novel candidate genes associated with osteonecrosis of the femoral head (ONFH). METHODS: A transcriptome-wide association study (TWAS) was performed by integrating the genome-wide association study dataset of osteonecrosis (ON) in the UK Biobank with pre-computed mRNA expression reference weights of muscle skeleton (MS) and blood. The ON-associated genes identified by TWAS were further subjected to gene ontology (GO) analysis by the DAVID tool. Finally, a trans-omics comparative analysis of TWAS and genome-wide mRNA expression profiling was conducted to identify the common genes and the GO terms shared by both DNA-level TWAS and mRNA-level expression profile for ONFH. RESULTS: TWAS totally identified 564 genes that were with P TWAS value <0.05 for MS and blood, such as CBX1 (P TWAS = 0.0001 for MS), SRPK2 (P TWAS = 0.0002 for blood), and MYO5A (P TWAS = 0.0005 for blood). After comparing the genes detected by TWAS with the differentially expressed genes identified by mRNA expression profiling, we detected 59 overlapped genes, such as STEAP4 [P TWAS = 0.0270, FC (fold change)mRNA = 7.03], RABEP1 (P TWAS = 0.010, FCmRNA = 2.22), and MORC3 (P TWAS = 0.0053, FCmRNA = 2.92). The GO analysis of TWAS-identified genes discovered 53 GO terms for ON. Further comparing the GO results of TWAS and mRNA expression profiling identified four overlapped GO terms, including cysteine-type endopeptidase activity (P TWAS = 0.0006, P mRNA = 0.0227), extracellular space (P TWAS = 0.0342, P mRNA = 0.0012), protein binding (P TWAS = 0.0112, P mRNA = 0.0106), and ATP binding (P TWAS = 0.0464, P mRNA = 0.0033). CONCLUSION: Several ONFH-associated genes and GO terms were identified by integrating TWAS and mRNA expression profiling. It provides novel clues to reveal the pathogenesis of ONFH.

Capturing protein droplets: label-free visualization and detection of protein liquid-liquid phase separation with an aggregation-induced emission fluorogen.

We developed a new method for protein droplet visualization by means of a droplet probe (DroProbe) based on an aggregation-induced emission (AIE) fluorogen. A simple method for viscosity comparison of the protein condensed phase based on the lifetime of the DroProbe was also developed.

Electrocatalytic performance of Sb-modified Bi25FeO40 for nitrogen fixation.

The Haber-Bosch N2 fixation method suffers from the power-consuming and harsh conditions. In contrast, the electrochemical conversion of N2 (NRR) at room temperature and atmospheric pressure is considered a promising alternative route. In this study, we synthesized Sb-modified with Bi25FeO40 (BFSO/BFO) by using one-step hydrothermal treatment. The BFSO/BFO catalyst has higher selectivity to NRR than Bi25FeO40 (BFO) under the same applied voltage. Such large interfacial interaction area plays a critical role in transfer electron and enhances the density of current. The resulting BFSO/BFO heterojunction showed significant electrocatalytic activity under controllable voltage, which exhibited favorable average ammonia (NH3) yield as high as 2.62 µg·h-1·cm-2 at -0.2 V versus RHE. Moreover, the stability of the BFSO/BFO composite was evaluated for six cycles and the results were desirable. This study provides a new insight into the design of composite catalysts using BFO, which has high activity and selectivity toward NRR.

Acupuncture for persistent atrial fibrillation after catheter ablation: study protocol for a pilot randomized controlled trial.

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia, which is closely related to cardiovascular morbidity and mortality. Although acupuncture is used in the treatment of AF, the evidence is insufficient. The objective of this pilot trial is to evaluate the feasibility, preliminary efficacy, and safety of acupuncture in reducing AF burden for persistent AF after catheter ablation (CA). METHODS AND DESIGN: This will be a multi-center, 3-arm, pilot randomized controlled trial in China. Sixty patients in total will be randomly assigned to the specific acupoints group, the non-specific acupoints group, or the non-acupoints group in a 1:1:1 ratio. The whole study period is 6 months, including a 3-month treatment period and a 3-month follow-up period. All patients will receive 18 sessions of acupuncture over 12 weeks after CA and appropriate post-ablation routine treatment. The primary outcome is AF burden at 6 months after CA measured by electrocardiography patch that can carry out a 7-day continuous ambulatory electrocardiographic monitoring. The secondary outcomes include AF burden at 3 months after CA, recurrence of AF, quality of life, etc. The adverse events will also be recorded. DISCUSSION: This pilot study will contribute to evaluating the feasibility, preliminary efficacy, and safety of acupuncture in reducing AF burden for persistent AF after CA. The results will be used for the sample size calculation of a subsequent large-scale trial. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000030576 . Registered on 7 March 2020.