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Trial Registration | ClinicalTrials.gov Identifier: | PMC10394570 |
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Introduction | aggressive disease | PROSTATE CANCER | Black patients present with more aggressive disease and experience higher mortality than White patients with prostate cancer. | PMC10394570 |
Methods | death, Prostate Cancer | SECONDARY, PROSTATE CANCER | This is a secondary analysis of a multicenter randomized, open-label, phase 3 study in which patients with mCSPC, enrolled between March 1, 2013, and July 15, 2017, were randomly assigned in a 1:1 ratio to receive either androgen deprivation therapy (ADT) with orteronel 300 mg orally twice daily (experimental group) or ADT with bicalutamide 50 mg orally daily (control group). This secondary analysis only included patients who identified themselves as either Black or White. The NCI’s central institutional review board approved the study. The study was conducted in accordance with the International Conference on Harmonization of Good Clinical Practice guidelines and the principles of the Declaration of Helsinki.The categorization of race was based on patient self-report. The primary end point was OS, defined as the time from randomization to death from any cause. Secondary end points included progression-free survival (PFS) and prostate-specific antigen (PSA) response rate at 7 months. PFS was defined as the time from randomization to biochemical, radiographic, or clinical progression (per Prostate Cancer Working Group 2 criteria) or death from any cause. PSA responses were categorized as complete response (CR; PSA below 0.2 ng/mL), partial response (PR; PSA between 0.2 and 4.0 ng/mL), and no response (NR; PSA above 4.0 ng/mL [to convert PSA to micrograms per liter, multiply by 1]). A detailed methodology and the primary results of the trial have been previously published ( | PMC10394570 |
Statistical Analysis | Baseline demographic and clinical characteristics were summarized using descriptive statistics, median (with IQR) for continuous characteristics and count and percentage for categorical characteristics. To test differences in baseline characteristics by race, a χ | PMC10394570 |
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Results | Of 1313 patients enrolled, 135 (10.3%) self-identified as Black and 1077 (82%) as White ( | PMC10394570 |
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Baseline Characteristics and PSA Responses | Abbreviation: PSA, prostate-specific antigen.Defined as greater than minimal involvement of vertebrae, pelvic bones, and/or lymph nodes.At a median follow-up of 4.9 years, the median OS for Black patients was 5.5 years (95% CI, 4.8 to not reached), compared with 6.3 years (95% CI, 5.7 to not reached) for White patients ( | PMC10394570 |
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Kaplan-Meier Estimates of Overall Survival (OS) and Progression-Free Survival (PFS) by Race in the Overall Population | Dashed lines indicate median time participants experienced OS (panel A) or PFS (panel B). | PMC10394570 |
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Multivariable Analysis of Progression-Free Survival (PFS) and Overall Survival (OS) | Abbreviations: NA, not applicable; PSA, prostate-specific antigen.Defined as greater than minimal involvement of vertebrae, pelvic bones, and/or lymph nodes.Among Black patients, 63 of 135 (55.8%) had a complete PSA response at 7 months and 16 (14.2%) had no PSA response at 7 months, compared with 558 (62.8%) and 94 (10.6%) of 1077 White patients, respectively. However, the difference was not statistically significant ( | PMC10394570 |
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Discussion | prostate cancer, aggressive disease | SECONDARY, METASTATIC PROSTATE CANCER, PROSTATE CANCER, PROSTATE | This secondary analysis of the SWOG 1216 trial found that ADT plus bicalutamide or ADT plus a novel androgen receptor pathway inhibitor (ARPI) elicited similar PFS, PSA response, and OS in Black and White patients with mCSPC, despite Black patients presenting with more aggressive disease features (younger age and higher baseline PSA level). In a race-stratified trial enrolling 100 patients with mCRPC (50 Black and 50 White patients), patients were treated with abiraterone acetate and prednisone as first-line therapy in addition to ongoing ADT.Historically, registration phase 3 clinical trials for metastatic prostate cancer have accrued disproportionately low numbers of Black patients, and this trend has worsened in the last 3 decades, especially in industry-sponsored trials.Our findings from the patient-level data from a prospective phase 3 trial validate the previous population-based research findings indicating that Black patients with advanced prostate cancer achieve comparable outcomes when health care access is equalized and treatment is standardized. A 2023 meta-analysis of more than 1 million patients with prostate cancer demonstrated that race was associated with prostate cancer-specific mortality and OS. | PMC10394570 |
Limitations | SECONDARY | This study had several limitations. In the SWOG 1216 trial, orteronel improved PFS but not OS, and therefore is not being used in the current practice, which may have limited the generalizability of this study in the clinical setting compared with other ARPIs. Also, while to our knowledge this trial enrolled the largest proportion of Black patients in the mCSPC setting to date, the sample size of the primary trial may not be sufficient for the subgroup analyses of Black patients or to detect small effect sizes. This can limit the statistical power of the secondary analysis. We acknowledge that this is an exploratory analysis in nature and should be interpreted with caution. | PMC10394570 |
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Conclusions | SECONDARY | In this secondary analysis of a large randomized, multicenter phase 3 clinical trial, we showed using high-quality patient-level data that Black patients had similar survival outcomes to White patients with mCSPC. These results support the hypothesis that equitable access to care as available in a clinical trial setting negates disparities in outcomes previously associated with Black patient populations. Possible avenues for action include accounting for variables linked to SDOH in research and tackling modifiable cultural, economic, and geographic factors in clinical settings. | PMC10394570 |
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Abstract | PMC10636424 |
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Objective | aMCI, amnestic mild, cognitive impairment | We aim to develop a radiomics model based on 3‐dimensional (3D)‐T1WI images to discriminate amnestic mild cognitive impairment (aMCI) patients from the normal population by measuring changes in frontal white matter. | PMC10636424 |
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Methods | aMCI | In this study, 126 patients with aMCI and 174 normal controls (NC) were recruited from the local community. All subjects underwent routine magnetic resonance imaging examination (including 3D‐T1WI ). Participants were randomly divided into a training set ( | PMC10636424 |
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Results | A total of 108 frontal lobe texture features were extracted from 3D‐T1WI images. LASSO selected 58 radiomic features for the final model, including log‐sigma ( | PMC10636424 |
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Conclusions | amnestic, aMCI, cognitive impairment | Textural features of white matter in the frontal lobe showed potential for distinguishing aMCI from the normal population, which could be a surrogate protocol to aid aMCI screening in clinical setting.(a) Drawing regions of interest in frontal lobe using ITK‐SNAP. (b) Strategy for frontal lobe extraction from high‐resolution structural magnetic resonance imaging. (c) Intensity features and textural features were extracted from the images, and used the least absolute shrinkage and selection operator to choose the optimized subset of features to construct the final model. (d) Statistical analysis was used to find radiomic features. aMCI, amnestic mild cognitive impairment.
Wei Zheng, Ronghua Mu, and Fuzhen Liu have contributed equally to this work. | PMC10636424 |
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INTRODUCTION | cognitive impairment, MCI, dementia, Alzheimer's disease, dementia disorders, AD | ALZHEIMER'S DISEASE | Mild cognitive impairment (MCI) is a transitional state between normal aging and dementia disorders, especially Alzheimer's disease (AD; Petersen et al., MCI differs from dementia in many ways, and previous studies support better outcomes for early treatment or prevention of MCI (Pilipovich & Vorob'eva, Radiomics, as a rapidly advanced image analysis technique, has gained increasing attention in recent years. Radiomics extracts the high‐throughput features from segmented regions and quantitatively analyzes the lesion heterogeneity using appropriate models (Kumar et al., | PMC10636424 |
MATERIALS AND METHODS | This prospective study was approved by the local ethics committee, all recruited participants have signed informed consent. | PMC10636424 |
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Subjects | aMCI | From October 2020 to February 2021, 146 patients with aMCI and 189 healthy volunteers were recruited, all subjects were distributed a label that did not identify the group assignment. The gender, age, education, systolic pressure, and diastolic pressure of all subjects were collected for both groups. Body mass index (BMI, kg/m | PMC10636424 |
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MRI data acquisition | MR | All MRI protocols were performed using a 3.0T Magnetic Resonance (MR) scanner (Ingenia CX, Philips Healthcare) with a 32‐channel head coil. Scan sequences were listed below: three‐dimensional(3D) T1 fast field echo, repeat time (TR) = 6.4 ms, echo time (TE) = 3.0 ms, field of view (FOV) = 240 × 240 × 180 mm, reconstruction voxel size = 1.1 × 1.1 × 1.1, reconstruction matrix = 400 × 400, slice thickness = 1.1 mm; 3D T2 spin echo, TR = 2500 ms, TE = 232 ms, FOV = 250 × 25 × 180 mm, reconstruction voxel size = 1.1 × 1.1 × 1.1, reconstruction matrix = 512 × 512, slice thickness = 1.1 mm; 3D fluid attenuated inversion recovery, TR = 4800 ms, TE = 244 ms, FOV = 240 × 240 × 173 mm, reconstruction voxel size = 1.1 × 1.1 × 1.1, reconstruction matrix = 384 × 384, and slice thickness = 1.2 mm. Each subject underwent the above MRI sequences. | PMC10636424 |
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(ROI) delineated | amnestic, aMCI, cognitive impairment | The ROIs were manually delineated on the horizontal T1 images for segmentation using the ITK‐SNAP software (Version 3.6.0, Wikodeling for aMCI patients. (a) Drawing ROIs in frontal lobe using ITK‐SNAP. (b) Strategy for frontal lobe extraction from high‐resolution structural MRI. (c) Intensity features and textural features were extracted from the images, and used the LASSO to choose the optimized subset of features to construct the final model. (d) Statistical analysis was used to find radiomic features. aMCI, amnestic mild cognitive impairment; LASSO, least absolute shrinkage and selection operator; MRI, magnetic resonance imaging; ROIs, regions of interest.ROI delineation criteria are as follows: (i) the circular measurement tool was used to delineate the ten consecutive layers in the white matter of frontal lobe; (ii) the size of the bilateral ROI of all subjects remained the same, with an area of about 10 mmOne of the above‐mentioned radiologists randomly selected and drew 50 cases independently. After 1 month, radiologist A repeated the same procedure again. An intra‐class correlation coefficient (ICC) greater than 0.75 is considered to indicate good consistency. In our study, we obtained a good ICC result (see Results section for details). | PMC10636424 |
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Radiomic features extraction | In this study, radiomic features were extracted using pyradiomics, and 108 features were obtained from 3D MRI T1‐weighted images. Before feature selection, each feature value for all frontal lobes was normalized with Z‐scores (( | PMC10636424 |
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Features selection | REGRESSION | Due to the high complexity of the extracted features, there was a risk of overfitting in the analysis. Hence, the dimensions presented by these quantitative features needed to be reduced by prioritizing the features. The least absolute shrinkage and selection operator (LASSO) is a popular high‐dimensional data analysis method that can be used to improve both prediction accuracy and interpretation. This approach can estimate the regression coefficients for every feature and successively shrink them to avoid inflation of the estimated coefficients, resulting in superior predictive performance and irrelevant features. LASSO was conducted to choose the optimized subset of features to construct the final model.LASSO was first used to tune the regularization parameter λ using 10‐fold cross‐validation, and the optimized Texture feature selection using the least absolute shrinkage and the histogram of the Rad‐score based on the selected features. The optimal λ value of 0.026 was selected. | PMC10636424 |
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Prediction build and diagnostic validation | MCI | REGRESSION | A nomogram was formulated to predict MCI based on the results of LASSO regression. The sensitivity, specificity, accuracy, positive‐predictive value, and negative‐predictive value were obtained from the models. The predictive performance of the radiomics model was assessed using receiver operating characteristic (ROC) curve analysis (Figure ROC curves of the radiomics mode in training set and test set. AUC, the area under the ROC curve (AUC); ROC, receiver operating characteristic curve. | PMC10636424 |
Clinical usefulness | cognitive impairment, x‐axis, amnestic, y‐axis, aMCI | Decision curve analysis (DCA) was applied to justify the clinical usefulness of this study. The prediction model provided clinical consequences regarding the choice of the threshold probability from which the net benefit could be derived. DCA was performed to estimate the clinical value of the radiomics nomogram by quantifying the net benefits based on the threshold probabilities. Net benefit is defined as the ratio of true positives minus the fraction of false positives weighted by the relative harm of false‐positive and false‐negative results. This threshold probability, Decision curve analysis for the aMCI. The x‐axis represents the threshold probability, and the y‐axis represents the net benefit. aMCI, amnestic mild cognitive impairment. | PMC10636424 |
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Calibration curves of the radiomics model | cognitive impairment, x‐axis, amnestic, y‐axis, aMCI | Calibration curves were plotted to evaluate the calibration of the radiomics model. Additionally, the Hosmer–Lemeshow test was conducted. Calibration curves show how well each model is calibrated by comparing the predicted risks of aMCI to the observed outcomes of aMCI (Figure Calibration curves of the radiomics model. The y‐axis represents the incidence rate of aMCI. The x‐axis represents the predicted risk of aMCI. The diagonal dotted line represents the prediction of an ideal model. The blue solid line represents the performance of the radiomics model. A closer fit to the diagonal dotted line indicates a more accurate prediction. aMCI, amnestic mild cognitive impairment. | PMC10636424 |
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Statistical analysis | aMCI | Statistical analyses were conducted with python software (Version 3.7; Variables for the normal control group and aMCI group were tested for normal distribution. In a two‐tailed analysis, a | PMC10636424 |
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RESULTS | PMC10636424 |
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Baseline characteristics of the patients | amnestic, aMCI, cognitive impairment | Fourteen subjects were excluded from the study because they could not cooperate for a normal examination; 19 subjects were excluded because their image quality did not meet the diagnostic requirements. Finally, 126 patients with aMCI and 176 normal controls (NC) were included in this study. Table Clinical characteristics.Abbreviations: aMCI, amnestic mild cognitive impairment; BMI, body mass index; MoCA, Montreal Cognitive Assessment; NC, normal controls.
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Feature selection and LASSO logistic regression results | REGRESSION | A total of 108 radiomic features were extracted from 3D‐T1WI imaging. Among the 108 extracted features, an ICC to or higher than 0.84 were included. To identify the relevant predictors, all explanatory features extracted from MR images of the training set were included in LASSO logistic regression. Features with regression coefficients of zero were eliminated. In the final feature selection with the LASSO method, 58 radiomic features were included from the T1‐weighted, including log‐sigma ( | PMC10636424 |
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Diagnostic performance of the radiomics model | aMCI | The diagnostic performance of the radiomics model to distinguish aMCI from normal subjects was evaluated using ROC analysis in both the training set and the test set. In the training set, the area under the ROC curve (AUC) was 1.00, and the accuracy, sensitivity, and specificity were 100%, 98%, and 100%, respectively. In the testing set, AUC was 0.82 (95% Confidence Interval(CI):0.69–0.95), and the accuracy, sensitivity, and specificity were 69%, 92%, and 55%, respectively (Table Model representation.Abbreviations: AUC, area under the receiver operating characteristic curve; NPV, negative‐predictive value; PPV, positive‐predictive value ;NA, not applicable. | PMC10636424 |
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Clinical usefulness | The DCA of the radiomics model is shown in Figure | PMC10636424 |
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Calibration curves of the radiomics model | y‐axis, aMCI, x‐axis | The y‐axis represents the incidence rate of aMCI. The x‐axis represents the predicted risk of aMCI. The diagonal dotted line represents the prediction of an ideal model. The blue solid line represents the performance of the radiomics model. A closer fit to the diagonal dotted line indicates a more accurate prediction. The Hosmer–Lemeshow test resulted in a | PMC10636424 |
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DISCUSSION | decline of cognitive function, MCI, aMCI, MR, AD | DISEASE, PATHOGENESIS, PATHOLOGY, DISEASES | Early diagnosis of MCI and timely clinical intervention may slow down further decline of cognitive function and progression to AD (Livingston et al., Radiomics is a promising technology that emerged in recent years, which improves the diagnosis and prediction efficiency of diseases by extracting a large number of radiomic features of target organs (H. Yang et al., Accumulating evidence suggests different imaging abnormalities related to AD follow a consistent trajectory during the pathogenesis of the disease, and that the first changes can be detected years before the disease manifests clinically (Pievani et al., Recently, automatic‐aided diagnoses of AD and MCI based on ROI techniques, voxel‐based morphometry and volumetric analysis, have gained increasing popularity (Chen et al., In clinical settings, as a conventional MR sequence, 3D‐T1 imaging is widely used in routine brain examination. Owing to the performing results of neuropsychological scales are unstable and require a high degree of patient cooperation (Guo et al., However, there are several limitations in the present study. First, this study was a single‐center study with small sample sizes, and multi‐center with large samples external validation is further needed. Second, this study is based on the Chinese community population, the results may not generalize to other ethnic groups due to ethnic differences. Although the study only examined the frontal lobe, available evidence indicates that the frontal lobe pathology occurs during aMCI and AD progression. Finally, the study lacked an AD patient group. | PMC10636424 |
CONCLUSION | aMCI | In this study, we identified significant alterations in radiomic features related to aMCI within the frontal lobe white matter. These alterations demonstrated the ability to discriminate aMCI from NC with a relatively high diagnostic efficacy as evidenced by an AUC of 0.82. The calibration curve of the radiomics model indicated that the predictions align well with an ideal model. Furthermore, DCA illustrated a high net benefit achieved by the radiomics model. In conclusion, the radiomics features of the 3D‐T1 frontal lobe white matter may serve as a surrogate imaging marker to aid clinicians in screening for aMCI. | PMC10636424 |
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AUTHOR CONTRIBUTIONS | Wei Zheng and Xiqi Zhu designed the study. Wei Zheng, Xiaoyan Qin, Ronghua Mu, and Xiaoyan Qin conducted the MRI data processing and statistical analyses. Wei Zheng, Ronghua Mu, Xin Li, JL, PY and Fuzhen Liu contributed to data collection and analyses. Wei Zheng and Ronghua Mu wrote the paper. Xiqi Zhu and Wei Zheng critically revised the manuscript. All authors approved the final draft. | PMC10636424 |
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CONFLICT OF INTEREST STATEMENT | The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10636424 |
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PEER REVIEW | The peer review history for this article is available at | PMC10636424 |
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ACKNOWLEDGMENTS | We thank the Department of neurology, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, for their help and discussion. | PMC10636424 |
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DATA AVAILABILITY STATEMENT | The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. | PMC10636424 |
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REFERENCES | PMC10636424 |
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Abstract | Xin-Yi Gao and Yue-Ming Liu contributed equally to this work.Supplemental data for this article can be accessed online at | PMC9848225 |
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Purpose | bleeding | THROMBOEMBOLIC EVENT, NEPHROTIC SYNDROME, BLEEDING | The risk of thromboembolic events is elevated in patients with nephrotic syndrome, and warfarin use has been associated with an increased risk of bleeding. Indobufen, a selective cyclooxygenase-1 inhibitor, is currently being evaluated for the prevention of thromboembolic events in nephrotic syndrome. This study aimed to compare the efficacy and safety of indobufen with that of warfarin in patients with nephrotic syndrome. | PMC9848225 |
Materials and methods | thromboembolic, nephrotic syndrome, bleeding | BLEEDING, ADVERSE EVENTS, NEPHROTIC SYNDROME, SECONDARY, EVENTS | This multicenter, randomized, three-arm, open-label, parallel controlled trial involved a total of 180 adult patients with nephrotic syndrome from four centers in China. Patients were randomly assigned to receive 100 mg indobufen (bid), 200 mg indobufen (bid), and 3 mg warfarin (qd) daily for 12 weeks. The primary endpoints included thromboembolic and bleeding events, while laboratory results and adverse events constituted secondary endpoints. | PMC9848225 |
Results | bleeding | MINOR, THROMBOEMBOLIC EVENT, EVENTS, BLEEDING | No thromboembolic events occurred in the high-/low-dose indobufen and warfarin groups. Moreover, the use of a low dose of indobufen significantly reduced the risk of minor bleeding events compared with warfarin use (2% versus 18%, | PMC9848225 |
Conclusions | bleeding | EVENTS, THROMBOEMBOLIC EVENT, NEPHROTIC SYNDROME, BLEEDING | This study found that indobufen therapy provided equivalent effects in preventing thromboembolic events compared with warfarin therapy, while low dose of indobufen was associated with a reduced risk of bleeding events, thus it should be recommended for the prevention of thromboembolic events in clinical practice in patients with nephrotic syndrome. | PMC9848225 |
Trial registration number | ChiCTR-IPR-17013428. | PMC9848225 |
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Keywords | PMC9848225 |
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Introduction | hypoalbuminemia, bleeding, edema, Nephrotic syndrome | HYPOALBUMINEMIA, BLEEDING, EDEMA, NEPHROTIC SYNDROME, EVENTS | Nephrotic syndrome is characterized by a urine protein loss > 3.5 g/24 h, accompanied by hypoalbuminemia and edema, with an annual incidence of 1–3 per 100,000 adults [Currently, warfarin is widely used as a prophylactic anticoagulant; however, its risk of bleeding events is significantly high [ | PMC9848225 |
Methods | PMC9848225 |
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Trial design and oversight | This prospective, multicenter, randomized clinical trial was conducted at four centers in China. All patients provided written informed consent before participation, and the institutional review board of each center approved the protocol before the initiation of the study. The coauthors contributed to the first draft of the original manuscript and revision of the original manuscript. This study was registered at | PMC9848225 |
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Trial population | thrombosis, nephrotic syndrome | THROMBOSIS, HEART FAILURE, NEPHROTIC SYNDROME | Adult patients with nephrotic syndrome were eligible for inclusion in this study, and the inclusion criteria were as follows: (1) age between 18 and 75 years; (2) 24-h urinary protein excretion > 3.5 g and/or serum albumin < 30 g/L; and (3) exposure to thrombosis risk factors, such as recent abdominal surgery, prolonged immobilization, heart failure, and body mass index (BMI) > 35 kg/m | PMC9848225 |
Randomization and treatment protocol | thrombosis, nephrotic syndrome | THROMBOSIS, GROUP B, ADVERSE EVENTS, NEPHROTIC SYNDROME, REMISSION | After enrollment, patients were randomly assigned to three groups in a 1:1:1 ratio, and an observer-blinded approach was followed. Randomization was performed using a random number table with a central computerized system. Group A was administered an oral dose of 100 mg of indobufen twice daily. Group B was administered an oral dose of 200 mg of indobufen twice daily. Group C received 3 mg of warfarin orally once a day. Dose adjustment was based on the PT. The international normalized ratio (INR) was maintained between 1.5 and 3.0.Patients were followed-up for 12 weeks, and study visits occurred at baseline and at weeks 1, 4, 8, and 12. Patients or researchers had the option of discontinuing treatment early because of unacceptable serious adverse events (SAEs), any change in the patient’s condition that justified discontinuation (decided by the researcher; included the requirement for any drug that treats thrombosis, which was an exclusion criterion), withdrawal of consent (decided by the patient), and complete remission of nephrotic syndrome (24-h urinary protein < 0.3 g, serum albumin > 35 g/L). | PMC9848225 |
Collected variables | Baseline data included age, sex, weight, BMI, and pathological diagnosis from kidney biopsy samples. BMI is the weight in kilograms divided by the square of the height in meters. Baseline laboratory data obtained from the central laboratory included the following: hemoglobin (Hb), platelet count, serum albumin (Salb), blood urea nitrogen, serum creatinine, APTT, PT, thrombin time (TT), fibrinogen (FIB), and D-dimer. All laboratory examinations were performed at the central hospital laboratory. | PMC9848225 |
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Endpoints | thrombosis, bleeding | THROMBOSIS, PULMONARY EMBOLISM, BLEEDING, DEEP VEIN THROMBOSIS, THROMBOEMBOLIC EVENTS, RENAL VEIN THROMBOSIS, EVENTS | The primary outcomes were the incidence rates of thrombosis and bleeding. Thromboembolic events were confirmed by ultrasound (for deep vein thrombosis), renal magnetic resonance venography (for renal vein thrombosis), or computed tomography pulmonary ventilation-perfusion scan (for pulmonary embolism). Major bleeding referred to any of the following: fatal bleeding, two symptomatic bleeding events at a critical site, bleeding causing the Hb level to drop by ≥ 20 g/L (1.24 mmol/L), or bleeding requiring the transfusion of two or more units of whole blood or red blood cells [ | PMC9848225 |
Statistical analysis | REGRESSION | Patient demographic, clinical, and laboratory data are described using (1) the mean (±SD) or median (range), depending on the underlying distribution, for continuous variables and (2) frequencies (percentages) for categorical variables. Continuous variables were compared using analysis of variance, while categorical variables were compared using the chi-square test. A mixed linear regression model was applied to assess the potential changes in laboratory data among the groups and various visit time points, and the intercept was random. The reported | PMC9848225 |
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Results | PMC9848225 |
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Patients | Between December 2017 and December 2020, 180 patients from four different centers were randomly assigned (59 in group A, 61 in group B, and 60 in group C) and followed up until February 2021. Nine patients discontinued treatment early during the COVID-19 lockdown. Of the 180 patients, 36 (20%) had missing primary-outcome data. Therefore, the baseline characteristics and primary-outcome analysis were based on the intention-to-treat set, which included 180 patients, while the pre-protocol analysis population included 144 patients (46 in group A, 51 in group B, and 47 in group C) (Flow chart for the study population. | PMC9848225 |
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Discussion | sudden cardiac arrest, thrombosis, bleeding, death, nephrotic syndrome, venous thromboembolism | SUDDEN CARDIAC ARREST, THROMBOSIS, THROMBOEMBOLIC EVENT, BLEEDING, HYPERCOAGULABILITY, MINOR, NEPHROTIC SYNDROME, EVENTS | Hypercoagulability, the main pathological change in nephrotic syndrome, is possibly caused by reduced anticoagulants (antithrombin III), increased liver procoagulant synthesis (FIB, factor V, and factor VIII), increased platelet activation and aggregability, and decreased fibrinolytic activity in the kidney [The current study was designed as a prospective, multicenter, randomized clinical trial, and it recruited 180 patients with nephrotic syndrome. This study found no thromboembolic events in the three groups, while low doses of indobufen were associated with a effectively reduced risk of minor bleeding events compared with warfarin. Moreover, APTT and PT levels in the warfarin group were higher than those in the low-dose indobufen group. Finally, one death occurred in the warfarin group; the patient died of sudden cardiac arrest between visits 3 and 4. Finally, other nonspecific AEs predominantly occurred in the warfarin group.This study did not observe any thromboembolic events in the three groups, suggesting that indobufen has an antithrombotic effect equivalent to that of warfarin, and it may be superior to warfarin owing to the significantly lower incidence of minor bleeding events. The trends in serum albumin and creatinine levels in the three groups were similar, suggesting that indobufen did not affect the efficacy of immunosuppressants in the treatment of nephrotic syndrome compared with warfarin. Moreover, the mean APTT and PT values were higher than normal (APTT:23–27 s; PT:11–15 s) after treatment with warfarin, suggesting that the warfarin dose was larger than expected, thus potentially increasing the risk of bleeding. Furthermore, D-dimer concentration decreased slightly in all three groups during the 12-week intervention. However, no statistically significant differences were observed among the three groups. Because D-dimer has a relatively high sensitivity in diagnosing thrombosis [To the best of our knowledge, our study is the first to provide evidence corroborating indobufen’s effectiveness and safety in preventing thromboembolic events in patients with nephrotic syndrome. Although no major bleeding occurred in any of the three groups, we recorded a numerically higher rate of clinically relevant minor bleeding (11/60 vs. 4/120) in the warfarin group than in the indobufen group. Moreover, this study found that treatment with warfarin requires frequent surveillance of INR and poses a higher risk of bleeding, whereas indobufen potentially offers a less burdensome treatment.Notwithstanding, this study has certain limitations. The sample size was relatively small and the duration of follow-up was 12 weeks. Considering the median number of days to the first venous thromboembolism in patients with nephrotic syndrome was 272 days [In conclusion, indobufen, an antiplatelet drug with an anticoagulation effect, provided equivalent effects to warfarin in preventing thromboembolic events and was associated with a reduced risk of bleeding events in adult patients with nephrotic syndrome. Therefore, indobufen is recommended for the prevention of thromboembolic events in patients with nephrotic syndrome. Nonetheless, further large-scale, randomized controlled trials should be performed to verify the efficacy and safety of indobufen in patients with nephrotic syndrome. | PMC9848225 |
Supplementary Material | PMC9848225 |
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Supplemental Material | Click here for additional data file. | PMC9848225 |
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Ethical approval | All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. | PMC9848225 |
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Author contributions | Research idea and study design: Li YW; data acquisition and centralized laboratory measurements: Zheng DN, Liu YM, Li H, Xiong XL, Chen HY, Wang H, Yu XY, Qu K; data analysis, statistical analysis, and manuscript drafting: Gao XY, Liu YM; supervision of the study or mentorship: Lin B, Jin J, He Q. | PMC9848225 |
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Disclosure statement | No potential conflict of interest was reported by the author(s). | PMC9848225 |
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Data availability statement | The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. | PMC9848225 |
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References | PMC9848225 |
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Objective | non-alcoholic fatty liver disease, NAFLD, TCM | METABOLIC DISEASE, NON-ALCOHOLIC FATTY LIVER DISEASE | Edited by: Xinhua Shu, Glasgow Caledonian University, United KingdomReviewed by: Tianhao Liu, Affiliated Hospital of Jiangnan University, China; Kangxiao Guo, Central South University Forestry and Technology, China; Haoqing Shao, Hunan University of Medicine, China†These authors have contributed equally to this workThis article was submitted to Gut Endocrinology, a section of the journal Frontiers in EndocrinologyAs a metabolic disease, one important feature of non-alcoholic fatty liver disease (NAFLD) is the disturbance of the intestinal flora. Spleen-strengthening and liver-draining formula (SLF) is a formula formed according to the theory of “One Qi Circulation” (Qing Dynasty, 1749) of Traditional Chinese Medicine (TCM), which has shown significant therapeutic effect in patients with NAFLD in a preliminary clinical observation. In this study, we aim to explore the mechanism of SLF against NAFLD, especially its effect on glucolipid metabolism, from the perspective of intestinal flora. | PMC9892935 |
Methods | NAFLD | A prospective, randomized, controlled clinical study was designed to observe the efficacy and safety of SLF in the treatment of NAFLD. The study participants were randomly and evenly divided into control group and treatment group (SLF group). The control group made lifestyle adjustments, while the SLF group was treated with SLF on top of the control group. Both groups were participated in the study for 12 consecutive weeks. Furthermore, the feces of the two groups were collected before and after treatment. The intestinal flora of each group and healthy control (HC) were detected utilizing 16S rRNA gene sequencing. | PMC9892935 |
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Results | NAFLD, liver stiffness | INSULIN RESISTANCE | Compared with the control group, the SLF group showed significant improvements in liver function, controlled attenuation parameter (CAP), and liver stiffness measurement (LSM), meanwhile, patients had significantly lower lipid and homeostasis model assessment of insulin resistance (HOMA-IR) with better security. Intestinal flora 16S rRNA gene sequencing results indicated reduced flora diversity and altered species abundance in patients with NAFLD. At the phylum level, | PMC9892935 |
Conclusions | NAFLD | SLF can improve liver function and glucolipid metabolism in patients with NAFLD and lower down liver fat content to some extent. SLF could be carried out by regulating the disturbance of intestinal flora, especially | PMC9892935 |
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Introduction | NAFLD, Radix glehniae, obesity, Paeoniae Radix Alba, Radix Bupleuri, Fuling, metabolic diseases, liver reaction, Atractylodis Macrocephalae Rhizoma, metabolic syndrome, steatosis, TCM, diabetes | OBESITY, DISEASE, NON-ALCOHOLIC FATTY LIVER DISEASE, METABOLIC DISEASES, METABOLIC SYNDROME, STEATOSIS, DIABETES | Non-alcoholic fatty liver disease (NAFLD), is common disease characterized by steatosis in more than 5% of hepatocytes with no excessive alcohol consumption, and is a form of liver reaction to a metabolic syndrome (In recent years, Traditional Chinese Medicine (TCM) has been favored by a growing number of patients because of its good efficacy with few side effects. There is a promising development and application prospect in the prevention and treatment of NAFLD with TCM, and definite curative clinical efficacy has been achieved. Spleen-strengthening and liver-draining formula (SLF) is a formula formed according to the theory of “One Qi Circulation” of TCM, which originated in the Qing Dynasty (in 1749). SLF is composed of Radix Bupleuri (Chaihu) 9g, Paeoniae Radix Alba (Baishao) 10g, Radix glehniae (Beishashen) 15g, Atractylodis Macrocephalae Rhizoma (Baizhu) 10g, Poria cocos (Fuling) 10g, Citrus Reticulata (Chenpi) 9g, Radix Glycyrrhizae preparate (Gancao) 6g, Sedum sarmentosum (Chuipencao) 15g, Carbonized hawthorn (Shanzhatan) 9g, Salvia miltiorrhiza (Danshen) 15g. In a preliminary clinical observation, SLF showed significant therapeutic effects in patients with NAFLD, including their levels of liver function, blood glucose, and lipids, as well as TCM symptoms.Recent studies have shown that the imbalance of intestinal flora was closely related to metabolic diseases such as NAFLD, diabetes, and obesity (In this study, we observed the clinical therapeutic result of SLF based on a prospective, randomized, controlled clinical study, and the effect of SLF on intestinal flora of NAFLD was analyzed by 16S rRNA gene sequencing, to further clarify the mechanism of SLF in the treatment of NAFLD. | PMC9892935 |
Material and methods | PMC9892935 |
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Ethical approval | The study was conducted in conformity with the guidelines set out in the declaration of Helsinki. The study protocol and informed consent were approved by the Institutional Review Board of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (Ethics No. 2020-863-72-01). All the patients who agreed to participate in the trial signed informed consent forms before the trial, and the participants could withdraw from the study at any time freely. | PMC9892935 |
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Study design and participants | NAFLD, fatty liver disease | DRUG-INDUCED LIVER DISEASE, VIRUS, AUTOIMMUNE LIVER DISEASE, METABOLIC DISEASE, HEPATITIS B, DISEASES | This study was designed as a randomized, controlled trial. Participants were recruited from Shuguang Hospital Affiliated to the Shanghai University of Traditional Chinese Medicine from September 2020 to September 2021 who meet the diagnostic of NAFLD. The diagnostic criteria are as follows: (1) No history of alcohol consumption or consumption of less than 30 g of alcohol per day in men (less than 20 g per day in women). (2) Except for certain diseases that can lead to NAFLD including Hepatitis B and C virus, autoimmune liver disease, drug-induced liver disease, genetic metabolic disease, etc. (3) Imaging features of the liver conform with the diagnostic criteria for diffuse fatty liver disease (Eligible patients were between 18 and 70 years old, consistent with the diagnosis of NAFLD; ALT, AST and GGT<5×upper limit of normal (ULN); BMI ≤ 30kg/m | PMC9892935 |
Interventions description | DISEASE | A screening test had to be conducted for all patients who meet the inclusion criteria during the screening period in clinic. It included the general status of patients, symptoms, and signs associated with the disease, and laboratory detection, including the following: liver function, HOMA-IR, hemorrheologic, FibroTouch, and other examinations. The control group was treated by lifestyle modifications, including diet and exercise. Here, brisk walking was recommended to the patients in this group, and the exercise time had to be ≥150 min per week ( | PMC9892935 |
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Outcomes evaluation | ADVERSE EVENTS | The outcomes included liver function, hepatic fat, blood glucose and lipids, and HOMA-IR. In addition, we recorded the compliance and adverse events of participants, and monitored participants’ health status through blood and urine tests, including kidney function checks and electrocardiogram. | PMC9892935 |
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Stool sample collection | Stool samples were collected from all patients who were recruited with genetic testing sample collectors before and after treatment. Samples were collected only once from HC. All patients were required not to take antibiotics or probiotic preparations in the two weeks preceding the study, and they had to stop eating after 8 PM, before the collection of specimens. They then kept specimens until the next morning in a designated area in the hospital. After collection, specimens were stored at -80°C immediately until further processing. And the stool samples of 11 patients in the SLF group and the control group were randomly selected for subsequent intestinal flora sequencing. | PMC9892935 |
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16S rRNA gene sequencing analysis | When the raw sequencing data were completed, FastQC was used to check the length and quality of sequencing data control, and errors and low-quality sequences was removed simultaneously. After that, DADA2 ( | PMC9892935 |
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Statistical analysis | All data were statistically analyzed using Graphpad Prism 9.4.0 and R 4.2.1. Measurement data followed a normal distribution, with mean ± standard deviation ( | PMC9892935 |
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Results | PMC9892935 |
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Baseline comparison | NAFLD | After strict inclusion and exclusion criteria, a total of 88 patients were enrolled in this study, with 44 in each group, which made up the intent-to-treat population. In the control group 4 patients were lost to follow up and 2 patients in the treatment group. The final 82 patients (40 in the control group and 42 in the SLF group) were included in the efficacy and safety evaluation, which constituted the per-protocol population (Flow chart of the study. A total of 88 NAFLD patients who were assessed to be eligible were made up of the intent-to-treat population. These patients were randomly divided into the control group and the SLF group, and 1 patient was lost to follow up and 3 patients withdrew due to COVID-19 in the control group, whereas 2 patients in the SLF group. The remaining 82 patients made up the per-protocol population.Baseline of the NAFLD in the control group and SLF group. | PMC9892935 |
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SLF had a clinical efficacy on improving the liver function and FibroTouch, as well as relieving symptoms of fatigue | NAFLD, fatigue | LIVER | Liver function was tested for normality in both groups, and ALT, AST, and gamma glutamyl transpeptidase (GGT) did not conform to a normal distribution (SLF had a clinical efficacy on improving the liver function and FibroTouch, as well as relieving symptoms of fatigue. ALT, AST, GGT, CAP, LSM and FS-14 was compared in the two groups to evaluate the efficacy of SLF in liver function and FibroTouch, as well as the symptoms of fatigue. We also compared FibroTouch before and after treatment in both groups. There was no statistical difference in CAP between the two groups pre-treatment (In our clinical practice, we found that patients with NAFLD are often accompanied with fatigue symptoms. Therefore, we use the fatigue scale-14 (FS-14) to assess the fatigue symptoms of patients, which includes physical fatigue and mental fatigue ( | PMC9892935 |
SLF could improve glycolipid metabolism with a good security | NAFLD, TG | In order to investigate the effects of SLF on blood lipids, we conducted a statistical analysis of total cholesterol (TC) and triglyceride (TG) of the two groups. After treatment in the control group, TC (SLF could improve glycolipid metabolism. TC, TG, FPG, HOMA-IR, and BMI were compared to evaluate the efficacy of SLF on metabolism, especially glycolipid metabolism. IR is closely related to the development of NAFLD, and we compared the correlation between HOMA-IR and CAP and found that they had a positive correlation (r=0.46 in the control group and r=0.32 in the SLF group) (We compared the safety indicators between the control group and SLF group, and found that the white blood cell (WBC), red blood cell (RBC), platelet (PLT), neutrophil granulocyte (GRA), hemoglobin (Hb), urea nitrogen (BUN), creatinine (Cr) and glomerular filtration rate (GFR) within groups had no statistically significant difference (Comparison of safety indicators between the control group and SLF group. | PMC9892935 |
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Reduced species diversity and altered intestinal flora abundance were observed in NAFLD | NAFLD | We randomly selected 11 patients, each from the control group and SLF group, and stool specimens were collected from these patients before and after treatment and sent for examination. A total of 53 stool samples (44 NAFLD and 9 HC) were detected utilizing 16S rRNA gene sequencing to analyze the changes of intestinal flora for the mechanism of the potential therapeutic effect of NAFLD by SLF. Alpha diversity was used to observe the diversity of the flora between the HC and NAFLD. We found that there were significant differences in chao1 (Reduced species diversity and altered intestinal flora abundance were observed in NAFLD. We then compared the abundance percentages of HC and NAFLD groups at the phylum to genus levels, and found that there were varying degrees of alterations in each level (Altered intestinal flora abundance at genus level was observed in NAFLD. At the genus level, the levels of | PMC9892935 |
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Intestinal flora correlated with clinical indicators of NAFLD, and SLF might play a role in regulating | NAFLD | To further investigate whether intestinal flora affected the severity of NAFLD, we investigated the correlation between Intestinal flora were correlated with clinical indicators of NAFLD, and SLF might play a role in regulating Our clinical trial results showed that SLF ameliorated the condition of NAFLD patients. Whether SLF played a therapeutic role of altering the disturbance of the intestinal flora was still unclear. Consequently, we observed the changes in intestinal flora before and after treatment. Surprisingly, we found that SLF may regulate | PMC9892935 |
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SLF exerted its effect by regulating the disturbance of specific intestinal flora genera | At the genus level, some of the intestinal flora abundances altered. In our study, we found SLF exerted its effect by regulating the disturbance of specific intestinal flora genera. We applied PICRUSt2 to predict the metabolic function of intestinal flora. Metacyc pathway enrichment analysis showed enhanced super pathway of polyamine biosynthesis II ( | PMC9892935 |
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Discussion | NAFLD, metabolic diseases, HC | DISORDER, DISORDERS, METABOLIC DISEASES, HOT SPOT, PATHOGENESIS | NAFLD is often accompanied with disorders of glucolipid metabolism (The study of intestinal flora has become a hot spot in the study of metabolic diseases and microorganisms has grown rapidly in the past few decades. The intestinal flora participates in the absorption and metabolism of nutrients (including the metabolism of carbohydrates, lipids, and amino acids) in the human body, which plays a strong part in maintaining fitness (As a consequence, we speculate there is a link between abnormal intestinal flora and NAFLD. With the increased understanding of the “gut-liver axis” and the popularity of fecal amplicon sequencing, the gut microbiome seems to occupy an undisputed position in the pathogenesis of NAFLD. Similar to our study, the diversity and abundance of intestinal flora in NAFLD have been shown to change to varying degrees in both animal and human studies (The clinical investigations and animal experiments have showed that TCM could reverse the dysregulation of intestinal flora and maintain the balance of intestinal micro-ecological system (We collected the stool samples of patients who were diagnosed with NAFLD and HC to examine the composition and abundance of the intestinal flora In our study, significant changes occurred in Nonetheless, our study has some shortcomings. The treatment course of NAFLD patients is relatively short, and the sample size is not enough, which leads to not obvious differences and incomplete recovery of the disorder flora after SLF treatment. In subsequent studies, we will expand the sample size to further confirm the effect of SLF on intestinal flora in NAFLD patients. In addition, we only observed the effect of SLF on different classification levels of intestinal flora in patients. In future research, we will further study the potential mechanisms of different strains of SLF. | PMC9892935 |
Conclusion | NAFLD | Our study suggested that NAFLD had relations with disturbances in the intestinal flora, which manifested as the levels of | PMC9892935 |
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Data availability statement | The data presented in the study are deposited in the NCBI repository, accession number PRJNA921570. | PMC9892935 |
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Ethics statement | The studies involving human participants were reviewed and approved by the Institutional Review Board of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (Ethics No. 2020-863-72-01). The patients/participants provided their written informed consent to participate in this study. | PMC9892935 |
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Author contributions | DH: Project management, Methodology, Writing manuscript. LL: Conceptualization, Investigation, Methodology. NA:Conceptualization, Revision. JS, YH and WX: Visualization. CW,DX and YJ: Revision. YB: Supervision, Methodology. MS: Funding acquisition, Writing – review and editing. All authors contributed to the article and approved the submitted version. | PMC9892935 |
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Conflict of interest | The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC9892935 |
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Publisher’s note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC9892935 |
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Supplementary material | NAFLD | The Supplementary Material for this article can be found online at:
Click here for additional data file.Differentially abundant taxa between HC and NAFLD samples analyzed by linear discriminant analysis effect size (LEfSe).Click here for additional data file. | PMC9892935 |
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References | PMC9892935 |
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Background | UEs | Umbilical artery serum-derived exosomes (UEs) serve as messengers for maternal–fetal information exchange and cellular regulation. Intravenous remifentanil could be considered as an effective adjunct to epidural anesthesia in providing a favorable analgesia effect for cesarean section (C-section), but its effects on UEs are currently unknown. | PMC9840320 |
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Methods | visceral pain | NEONATAL ASPHYXIA, COMPLICATIONS | From 01/12/2021 to 30/06/2022, eligible parturients scheduled for repeated C-section at the First Affiliated Hospital of Wenzhou Medical University were randomized to receive either an intravenous bolus (0.15 μg/kg) followed by a continuous infusion (0.075 μg/kg/min) of remifentanil or normal saline throughout the procedure. The primary outcome was the number of UEs. Secondary outcomes included the size and protein amount of UEs, the vital signs, visceral pain score, sedation score, maternal satisfaction score, Apgar score, the incidence of neonatal asphyxia, umbilical arterial pH, and the presence of complications. | PMC9840320 |
Results | Nanoparticle tracking analysis indicated similar size of UEs between the two groups, but the number and protein amount of UEs were increased in the remifentanil group compared to the control group ( | PMC9840320 |
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Conclusion | COMPLICATIONS | The intravenous administration of remifentanil increased the number of UEs in parturients undergoing repeated C-section under epidural anesthesia, with improved birth experience and minimal neonatal complications. | PMC9840320 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s12884-023-05360-8. | PMC9840320 |
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