A False Insulin Level in a Patient with Insulin Autoimmune Syndrome: a Case Report.

BACKGROUND: Insulin autoimmune syndrome (IAS) is a rare condition in which spontaneous severe hypoglycemia without previous exposure to exogenous insulin, and is characterized by hyperinsulinemia and high titers of insulin autoantibodies (IAA). METHODS: This paper reports a case of IAS with false insulin test results due to the hook effect. RESULTS: The patient's blood samples were collected at 0, 30, 60, 120, 180 minutes for measurement of serum insulin after a 3-hour oral glucose tolerance test (OGTT). The results of serum insulin levels were 1,698.6 pmol/L at fasting, 1,633.05 pmol/L at 30 minutes post load, 1,691.14 pmol/L at 60 minutes post load, 1,780.67 pmol/L at 120 minutes post load, and 1,807.93 pmol/L at 180 minutes post load. Dilution and re-analysis of the specimens revealed that the actual insulin concentrations were 217,516 pmol/L at fasting, 228,456 pmol/L at 30 minutes post load, 250,474 pmol/L at 60 minutes post load, 273,266 pmol/L at 120 minutes post load, and 291,232 pmol/L at 180 minutes post load. The insulin level results before and after the dilution had significant discrepancies. It was the hook effect caused by the high concentration of insulin in the serum that made the first test inaccurate. CONCLUSIONS: Serum insulin in patients with IAS is abnormally elevated, and extremely high concentrations of it may have a hook effect during assay resulting in inaccurate results. The laboratory should analyze and review the test results in combination with the patient's clinical case data, to detect interference in time and avoid erroneous diagnosis and treatment of patients.

Intermolecular 1,2-Difunctionalization of Terminal Alkynes to Access Trisubstituted Alkenes via Copper/Photoredox Dual Catalysis.

We report a copper metallaphotocatalytic 1,2-difunctionalization of terminal alkynes with N-hydroxyphthalimide (NHP) esters and readily available silyl reagents (TMSCN and TMSNCS) to access stereodefined trisubstituted alkenes, including (E)-alkenyl nitriles and thiocyanates. The reaction proceeds with excellent anti-stereoselectivity and demonstrates broad compatibility with a wide range of terminal alkynes and NHP esters as alkyl radical precursors. Experimental and computational studies have been performed to gain insight into the reaction mechanism.

Sub-Bowman keratomileusis versus femtosecond laser in situ keratomileusis on the long-term visual recovery: A comparative study.

Purpose: To explore the long-term visual quality of the same subjects after sub-Bowman keratomileusis (SBK) or femtosecond laser in situ keratomileusis (FS-LASIK). Methods: This prospective study included patients screened for corneal refractive surgery at the Refractive Surgery Center of our Hospital between November 2017 and March 2018. One eye underwent SBK, while the other eye underwent FS-LASIK. Total higher-order aberrations, coma aberrations, and clover aberrations were evaluated before and at 1 month and 3 years after the procedure. The visual satisfaction of both eyes was investigated, respectively. The participants completed a surgical satisfaction questionnaire. Results: Thirty-three patients were included. There were no significant differences in total higher-order aberrations, coma aberrations, and clover aberrations between the two procedures before and 1 month and 3 years after surgery (all P > 0.05), except for the total coma aberrations in FS-LASIK were significantly higher compared with the SBK group at 1 month after surgery [0.51 (0.18, 0.93) vs. 0.77 (0.40, 1.22), P = 0.019]. The surgical satisfaction questionnaire scores of the SBK group and the FS-LASIK group were 9.8 ± 0.8 and 9.8 ± 0.8, respectively, at 1 month, and 9.7 ± 0.9 and 9.7 ± 1.0, respectively, at 3 years (all P > 0.05). Conclusion: There were no differences in corneal aberrations and satisfaction between SBK and FS-LASIK procedures at 1 month and 3 years.

Magnetic field reversal in the turbulent environment around a repeating fast radio burst.

Fast radio bursts (FRBs) are brief, intense flashes of radio waves from unidentified extragalactic sources. Polarized FRBs originate in highly magnetized environments. We report observations of the repeating FRB 20190520B spanning 17 months, which show that the FRB's Faraday rotation is highly variable and twice changes sign. The FRB also depolarizes below radio frequencies of about 1 to 3 gigahertz. We interpret these properties as being due to changes in the parallel component of the magnetic field integrated along the line of sight, including reversing direction of the field. This could result from propagation through a turbulent magnetized screen of plasma, located 10-5 to [Formula: see text] parsecs from the FRB source. This is consistent with the bursts passing through the stellar wind of a binary companion of the FRB source.

Long-term environmental enrichment overcomes depression, learning, and memory impairment in elderly CD-1 mice with maternal sleep deprivation exposure.

Early-life stress disrupts central nervous system development and increases the risk of neuropsychiatric disorder in offspring based on rodent studies. Maternal sleep deprivation (MSD) in rodents has also been associated with depression and cognitive decline in adult offspring. However, it is not known whether these issues persist into old age. Environmental enrichment is a non-pharmacological intervention with proven benefits in improving depression and cognitive impairment; however, it is unclear whether these benefits hold for aging mice following MSD exposure. The aim of this study was to explore the effects of MSD on depression and cognition in elderly offspring CD-1 mice and to determine whether long-term environmental enrichment could alleviate these effects by improving neuroinflammation and synaptic plasticity. The offspring mice subjected to MSD were randomly assigned to either a standard environment or an enriched environment. At 18 months of age, the forced swimming and tail suspension tests were used to evaluated depression-like behaviors, and the Morris water maze test was used to evaluate cognitive function. The expression levels of hippocampal proinflammatory cytokines and synaptic plasticity-associated proteins were also measured. MSD increased depression-like behaviors and impaired cognition function in aging CD-1 offspring mice. These effects were accompanied by upregulated interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α expression, and downregulated brain-derived neurotrophic factor, tyrosine kinase receptor B, postsynaptic density-95, and synaptophysin expression in the hippocampus. All of these changes were reversed by long-term exposure to an enriched environment. These findings suggest that MSD exerts long-term effects on the behaviors of offspring in mice, leading to depression and cognitive impairment in older age. Importantly, long-term environmental enrichment could counteract the behavior difficulties induced by MSD through improving hippocampal proinflammatory cytokines and synaptic plasticity-associated proteins.

Copper-Catalyzed Monofluoroalkylation of Allyl Phosphates with Nucleophilic Ethyl 2-Fluoro-2-(trimethylsilyl)acetate.

An efficient method for C(sp3)-CHF bond formation was successfully developed by copper-catalyzed cross-coupling of allyl phosphate with 2-fluoro-2-(trimethylsilyl)acetate. Under moderate circumstances, the conversion was carried out in a good strategic range to provide a series of monofluoroalkylation products in high yields, which also demonstrates the practicality of gram-scale reactions.

Clonal evolution during metastatic spread in high-risk neuroblastoma.

Patients with high-risk neuroblastoma generally present with widely metastatic disease and often relapse despite intensive therapy. As most studies to date focused on diagnosis-relapse pairs, our understanding of the genetic and clonal dynamics of metastatic spread and disease progression remain limited. Here, using genomic profiling of 470 sequential and spatially separated samples from 283 patients, we characterize subtype-specific genetic evolutionary trajectories from diagnosis through progression and end-stage metastatic disease. Clonal tracing timed disease initiation to embryogenesis. Continuous acquisition of structural variants at disease-defining loci (MYCN, TERT, MDM2-CDK4) followed by convergent evolution of mutations targeting shared pathways emerged as the predominant feature of progression. At diagnosis metastatic clones were already established at distant sites where they could stay dormant, only to cause relapses years later and spread via metastasis-to-metastasis and polyclonal seeding after therapy.

Estimating Student Attrition in School-Based Prevention Studies: Guidance from State Longitudinal Data in Maryland.

Attrition is a critical concern for evaluating the rigor of prevention studies, and the current study provides rates of attrition for subgroups of students and schools who are often sampled for prevention science. This is the first study to provide practical guidance for expected rates of attrition using population-level statewide data; findings indicated that researchers using K-12 school-based samples should plan for attrition rates as high as 27% during middle school and 54% during elementary school. However, researchers should consider the grade levels initially sampled, the length of follow-up, and the specific student characteristics and schools available for sampling. Postsecondary attrition ranged from 45% for bachelor's degree seekers to 73% for associate degree seekers. This practical guidance can help researchers to proactively plan for attrition in the study design phase, limiting bias and increasing the validity of prevention studies.

O3-Type Na0.95Ni0.40Fe0.15Mn0.3Ti0.15O2 Cathode Materials with Enhanced Storage Stability for High-Energy Na-Ion Batteries.

O3-type layered oxides with high initial sodium content are promising cathode candidates for Na-ion batteries. However, affected by the undesired transition metal slab sliding and reaction with H2O/CO2, their further application is typically hindered by unsatisfactory cycling stability upon charging to high voltage and poor storage stability under humid air. Herein, we demonstrate a Fe/Ti cosubstitution strategy to simultaneously enhance the electrochemical performance and storage stability of pristine O3-NaNi0.5Mn0.5O2 cathode material, via employing high redox potential and inactive stabilized dopants. The resultant Fe/Ti cosubstituted Na0.95Ni0.40Fe0.15Mn0.3Ti0.15O2 undergoes highly reversible O3-P3-OP2 phase transitions with a small cell volume change of 2.8%, instead of complex O3-O'3-P3-P'3-P3'-O1 phase transitions in NaNi0.5Mn0.5O2. Consequently, the cathode displays a high specific capacity of 161.6 mAh g-1 with an average working voltage of 3.28 V and 81.8% capacity retention after 200 cycles at 5C. Furthermore, the cathode material remains very stable after exposure to air for 7 days and even after soaking in water for 1 h, owing to the prohibition of sodium losing by elevating redox potential and contracting sodium layer spacing. This work proposes an effective method to enhance the electrochemical performance and storage stability of O3-type layered oxide cathodes and promises advancing Na-ion batteries toward large-scale industrialization.

Case report: Laparoscopic treatment of gastro-omental hemangioma with hemorrhage: two cases reports and review of literature.

Background: Spontaneous hemorrhage of gastro-omental hemangioma is a rare disease. The treatment strategy for this disease changes as it develops. In the acute stage, surgery is the first priority, among which laparoscopic treatment should be the most frequently considered option in large general hospitals. Due to the rarity of this disease, such cases have rarely been reported. Case description: We present the first report of two eldely cases with gastro-omental hemangioma with hemorrhage by laparoscopic treatment. Both cases were initially admitted with upper abdominal pain, and abdominal computed tomography (CT) scan revealed masses alongside the greater curvature of the stomach. Laparoscopic surgery was conducted immediately in both patients. The two cases recovered well after surgery, and no obvious abnormalities were observed in the follow-up period. Conclusion: Gastro-omental hemangioma rupture remains an uncommon cause of intraperitoneal hemorrhage. Timely diagnosis and surgery are paramount for treatment. Medical institutions with the correct technology and equipment should perform laparoscopic treatment to minimize surgical trauma and promote rapid recovery of patients with abdominal apoplexy.

Postoperative recovery after breast cancer surgery: A randomised controlled trial of opioid-based versus opioid-free anaesthesia with thoracic paravertebral block.

BACKGROUND: Perioperative use of opioids has revealed significant adverse effects associated with poor postoperative outcomes. OBJECTIVE: To determine whether opioid-free anaesthesia based on thoracic paravertebral block (TPVB) could improve postoperative recovery after breast cancer surgery. DESIGN: A randomised controlled trial. SETTING: A tertiary teaching hospital. PATIENTS: Eighty adult women undergoing breast cancer surgery were enrolled. Key exclusion criteria included remote metastasis (but not to axillary lymph nodes of the surgical side), contraindication to interventions or drugs and a history of chronic pain or chronic opioid use. INTERVENTIONS: Eligible patients were randomised at a 1 : 1 ratio to receive either TPVB-based opioid-free anaesthesia (OFA group) or opioid-based anaesthesia (control group). MAIN OUTCOME MEASURES: The primary outcome was the global score of the 15-item Quality of Recovery (QoR-15) questionnaire at 24 h after surgery. Secondary outcomes included postoperative pain and health-related quality of life. RESULTS: The QoR-15 global score was 140.3 ±â€Š5.2 in the OFA group and 132.0 ±â€Š12.0 in the control group (P < 0.001). The percentage of patients with good recovery (QoR-15 global score ≥118) was 100% (40/40) in the OFA group and 82.5% (33/40) in the control group (P = 0.012). Improved QoR in the OFA group was also evident in sensitivity analysis that rated QoR as excellent for a score of 136 to 150, as good at 122 to 135, as moderate at 90 to 121 and as poor at 0 to 89. The OFA group had higher scores in the domains of physical comfort (45.7 ±â€Š3.0 versus 41.8 ±â€Š5.7, P < 0.001) and physical independence (18.3 ±â€Š2.2 versus 16.3 ±â€Š4.5, P = 0.014). The two groups did not differ in pain outcomes or health-related quality of life. CONCLUSION: TPVB-based opioid-free anaesthesia improved early postoperative quality of recovery without compromising pain control in patients undergoing breast cancer surgery. TRIAL REGISTRATION: Clinicaltrials.gov; Identifier: NCT04390698.

Visible-Light-Mediated NHC and Tertiary Amine Catalysis Enabling α-H Acylation of Alkenes.

An intermolecular direct α-C-H acylation of alkenes was revealed by the visible-light-mediated N-heterocyclic carbene and quinuclidine catalysis. This convenient protocol provides a facile synthesis toward novel natural products and drug derivatives of α-substituted vinyl ketones. Mechanistic investigations indicated that the transformation proceeded via sequential radical addition, radical coupling, and an elimination process.

The role of childhood left-behind experience on childhood trauma exposure and mental health outcomes: a propensity score matching (PSM) analysis.

BACKGROUND: China has a significant number of left-behind families. This study focuses on the long-term effects of childhood left-behind experience on different type of childhood trauma and mental health outcomes in later life development. METHODS: participants were 67 795 Chinese young adults. Psychosocial characteristics were screened by sleep quality, the nine-item Patient Health Questionnaire for depressive symptoms, the generalized anxiety disorder-7 for anxiety symptoms, trauma screening questionnaire for post-traumatic stress, a short form of the Childhood Trauma Questionnaire for childhood trauma. Propensity score matching (PSM) and multivariate linear regression were applied to analyze the data. RESULTS: the results of the post-PSM analysis showed that the distributions of propensity scores for the two groups were approximately equal. And the total sample size in post-analysis dropped to 2358 (Nnuclear family = 1179, Nleft-behind family = 1179), with unmatched cases excluded. Post-matching results showed that the students from left-behind family were significantly associated with severer post-traumatic stress (b = 0.39, 95% CI = [0.15, 0.62]), loneliness (b = 0.29, 95% CI = [0.16, 0.42]), depressive symptoms (b = 0.44, 95% CI = [0.06, 0.82]) and CTQ-physical neglect (b = 0.34, 95% CI = [0.11, 0.58]). CONCLUSION: our study showed that childhood left-behind experiences are tightly related to childhood trauma experience and mental health issues (post-traumatic stress, loneliness and depression) in late adolescents.

Characteristic Features of Deep Brain Lymphatic Vessels and Their Regulation by Chronic Stress.

Studies have demonstrated that a functional network of meningeal lymphatic vessels exists in the brain. However, it is unknown whether lymphatic vessels could also extend deep into the brain parenchyma and whether the vessels could be regulated by stressful life events. We used tissue clearing techniques, immunostaining, light-sheet whole-brain imaging, confocal imaging in thick brain sections and flow cytometry to demonstrate the existence of lymphatic vessels deep in the brain parenchyma. Chronic unpredictable mild stress or chronic corticosterone treatment was used to examine the regulation of brain lymphatic vessels by stressful events. Western blotting and coimmunoprecipitation were used to provide mechanistic insights. We demonstrated the existence of lymphatic vessels deep in the brain parenchyma and characterized their features in the cortex, cerebellum, hippocampus, midbrain, and brainstem. Furthermore, we showed that deep brain lymphatic vessels can be regulated by stressful life events. Chronic stress reduced the length and areas of lymphatic vessels in the hippocampus and thalamus but increased the diameter of lymphatic vessels in the amygdala. No changes were observed in prefrontal cortex, lateral habenula, or dorsal raphe nucleus. Chronic corticosterone treatment reduced lymphatic endothelial cell markers in the hippocampus. Mechanistically, chronic stress might reduce hippocampal lymphatic vessels by down-regulating vascular endothelial growth factor C receptors and up-regulating vascular endothelial growth factor C neutralization mechanisms. Our results provide new insights into the characteristic features of deep brain lymphatic vessels, as well as their regulation by stressful life events.

Polychromatic fluorescent MoS2 quantum dots: fabrication and off-on sensing for fluorine ions in water.

Recently, MoS2 quantum dots (QDs) have receive widespread attention as a promising luminescent material. However, so far, little effort has been made on the multicolor emission of MoS2 QDs. Herein, an in situ iodine doping strategy is presented and used to synthesize tunable-photoluminescent (PL) MoS2 QDs. By fine iodine doping, the PL of the MoS2 QDs (I-MoS2 QDs) can be tuned in the range from 423 nm to 529 nm, which exceeds the as-reported emission wavelength range. Studies using controlled experiments and density functional theory (DFT) reveal that the change in electronic state of MoS2 QDs is responsible for the changing PL due to iodine doping. As-synthesized I-MoS2 QDs combined with Fe3+ is developed as a "turn-off-on" fluorescence sensor for F- ions in water. The fluorescence probe has a fine linear response to F- ions in the concentration range of 2.5-80 µM, and the limit of detection is 1.4 µM (S/N = 3).

Transabdominal ultrasound alleviates LPS-induced neuroinflammation by modulation of TLR4/NF-κB signaling and tight junction protein expression.

AIM: Inflammatory bowel disease (IBD) may be a risk factor in the development of brain inflammation. It has been demonstrated noninvasive neuromodulation through sub-organ ultrasound stimulation. The purpose of this study was to investigate whether abdominal low-intensity pulsed ultrasound (LIPUS) alleviates lipopolysaccharide (LPS)-induced cortical inflammation via inhibition of colonic inflammation. MATERIALS AND METHODS: Colonic and cortical inflammation was induced in mice by LPS (0.75 mg/kg, i.p. injection) for 7 days, followed by application of LIPUS (0.5 and 1.0 W/cm2) to the abdominal area for 6 days. Biological samples were collected for Western blot analysis, gelatin zymography, colon length measurement, and histological evaluation. KEY FINDINGS: LIPUS treatment significantly attenuated LPS-induced increases in IL-6, IL-1ß, COX-2, and cleaved caspase-3 expression in the colon and cortex of mice. Moreover, LIPUS significantly increased the levels of tight junction proteins in the epithelial barrier in the mouse colon and cortex with LPS-induced inflammation. Compared to the group treated only with LPS, the LIPUS-treated groups showed decreased muscle thickness and increased crypt length and colon length. Furthermore, LIPUS treatment reduced inflammation by inhibiting the LPS-induced activation of TLR4/NF-κB inflammatory signaling in the brain. SIGNIFICANCE: We found that LIPUS alleviated LPS-induced colonic and cortical inflammation through abdominal stimulation of mice. These results suggest that abdominal LIPUS stimulation may be a novel therapeutic strategy against neuroinflammation via enhancement of tight junction protein levels and inhibition of inflammatory responses in the colon.

3D Lanthanide Neodymium Porphyrin Metal-Organic Framework for Photocatalytic Oxidation of Styrene.

A novel three-dimensional lanthanide porphyrin-based MOF (Nd-PMOFs) was synthesized by using tetracarboxyphenyl porphyrin as the ligand and the lanthanide Nd as the coordination metal. Its specific crystal structure information was obtained by single-crystal diffraction with the space group C2/c and the empirical formula C72H45N6Nd2O15.25. This new Nd porphyrin-based MOF with an organic framework formed by a unique coordination method enables the effective separation of photogenerated electrons and holes under photoluminescence, giving it excellent photocatalytic property which could be verified by the characterization data. The photocatalytic performance was examined by taking tert-butyl hydroperoxide as the oxidant and Nd-PMOFs as the catalyst for photocatalytic oxidation of styrene to benzaldehyde with 91.4% conversion and 81.2% benzaldehyde selectivity under optimal reactions, which surpasses most of the results reported in the literature. Several styrenes with other substituents were screened to explore the general applicability of Nd-PMOF for photocatalysis of styrene, among which Nd-PMOFs also exhibited excellent photocatalytic performance. This work offers the possibility to apply lanthanide organometallic frameworks, which are widely used in fluorescent materials, to photocatalysis. In addition, it also provides a new method for the catalytic generation of benzaldehyde from styrene that is consistent with the needs of modern green development.

Characterization of RBD-specific cross-neutralizing antibodies responses against SARS-CoV-2 variants from COVID-19 convalescents.

Introduction: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been posing a severe threat to global public health. Although broadly neutralizing antibodies have been used to prevent or treat corona virus disease 2019 (COVID-19), new emerging variants have been proven resistant to these antibodies. Methods: In this study, we isolated receptor binding domain (RBD)-specific memory B cells using single-cell sorting method from two COVID-19 convalescents and expressed the antibody to test their neutralizing activity against diverse SARS-CoV-2 variants. Then, we resolved antibody-RBD complex structures of potent RBD-specific neutralizing antibodies by X-ray diffraction method. Finally, we analyzed the whole antibody repertoires of the two donors and studied the evolutionary pathway of potent neutralizing antibodies. Results and discussion: We identified three potent RBD-specific neutralizing antibodies (1D7, 3G10 and 3C11) from two COVID-19 convalescents that neutralized authentic SARS-CoV-2 WH-1 and Delta variant, and one of them, 1D7, presented broadly neutralizing activity against WH-1, Beta, Gamma, Delta and Omicron authentic viruses. The resolved antibody-RBD complex structures of two antibodies, 3G10 and 3C11, indicate that both of them interact with the external subdomain of the RBD and that they belong to the RBD-1 and RBD-4 communities, respectively. From the antibody repertoire analysis, we found that the CDR3 frequencies of the light chain, which shared high degrees of amino acid identity with these three antibodies, were higher than those of the heavy chain. This research will contribute to the development of RBD-specific antibody-based drugs and immunogens against multiple variants.

Efficient cobalt hydroxide nanosheets for enhanced electrochemical sensing of Hg (II) ion.

A sensitive electrochemical device was suggested via the modification of a simple graphite rod electrode (GRE) with cobalt hydroxide (Co(OH)2) nanosheets. After closed circuit process on the modified electrode, the anodic stripping voltammetry (ASV) technique was used for measuring of Hg(II). In optimal experimental conditions, the suggested assay depicted a linear response over a broad range in the range 0.25-30 µg L-1, with the lowest detection limit of 0.07 µg L-1. Besides good selectivity, the sensor also indicated excellent reproducibility with a relative standard deviation (RSD) value of 2.9%. Moreover, the Co(OH)2-GRE showed satisfactory sensing performance in real water samples with appropriate recovery values (96.0-102.5%). Additionally, possible interfering cations were examined, but no significant interference was found. By taking some merits such high sensitivity, remarkable selectivity and good precision, this strategy is expected to provide an efficient protocol for the electrochemical measuring of toxic Hg(II) in environmental matrices.

"Huoling Shengji granule" for amyotrophic lateral sclerosis: protocol for a multicenter, randomized, double-blind, riluzole parallel controlled clinical trial.

Background: There is still a large demand for effective treatments to delay disease deterioration in amyotrophic lateral sclerosis (ALS). Typical symptoms of ALS are considered "flaccidity syndrome" in traditional Chinese medicine (TCM). Huoling Shengji Granule (HLSJ) is a TCM formula used to treat flaccidity syndrome. Results of preclinical tests and a previous clinical study support HLSJ as a novel drug for ALS patients. This trial proposed to examine whether a 48-week course of HLSJ is effective and safe for ALS patients diagnosed with the Chinese medicine syndrome of spleen qi insufficiency and kidney yang deficiency. Methods and analysis: In this phase II, multicenter, randomized, double-blind, riluzole parallel-controlled, superiority-design study, eligible participants had the equal opportunity to be assigned to receive either HLSJ or riluzole randomly. Eleven specialized ALS centers in Mainland China will recruit 144 patients for this trial. The primary and secondary outcomes included the change in the ALSFRS-R score and the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) from baseline to Week 48. Discussion: Here, we endeavored to evaluate TCM for ALS using a standard evidence-based approach for the first time. In addition, the ROADS, a self-report linear-weighted questionnaire, was selected as a secondary outcome measure. We expect to offer a new reference for the outcome evaluation of ALS trials.Clinical trial registration:http://www.Chictr.org.cn, identifier ChiCTR2100044085.