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2.2.1. ADOS-2
ADOS-2 is a standard, semistructured diagnosis assessment of a range of activities focusing on reciprocal social interactions, communication and language, play, and restricted and repetitive, stereotyped interests and behaviours [
PMC9920098
2.2.2. SRS-2
repetitive behaviors
SRS-2 is a norm-referenced quantitative assessment measuring 65 items about children’s behaviour. Parents/caregivers rate five subdomains (social awareness, social cognition, social communication, social motivation subdomains, and restricted, repetitive behaviors) [
PMC9920098
2.2.3. ABC
irritability, hyperactivity/noncompliance, lethargy/social withdrawal
SECONDARY
ABC, a secondary rating scale, was originally developed to assess the effectiveness of psychotropic medication and measures the severity of a range of behaviour problems across five subscales. At each follow-up, parents/caregivers evaluated subdomains as follows: irritability, lethargy/social withdrawal, stereotypic be...
PMC9920098
2.3. Preparation of Sulforaphane-Rich Broccoli Sprouts and Placebo Powder
A sulforaphane-rich broccoli sprout/red radish sprout powder mix was prepared using BroccoPhaneThe placebo powder was prepared using spinach puree (Agro Jesenice, Zlatníky-Hodkovice, Czech Republic). The spinach puree was divided into aluminium dishes, cooled to −18 °C, lyophilized, and powdered. The placebo powder was...
PMC9920098
2.4. Statistics
All analyses were completed using MedCalc version 20.010 (MedCalc Software Ltd., Ostend, Belgium) and OriginPro 8.5.0 SR1 (OriginLab Corporation, Northampton, MA, USA). Descriptive statistics were used to characterize the variables. A one-way repeated measures analysis of variances (ANOVA) followed by a Tukey post hoc ...
PMC9920098
2.5. Ethics
All information was accessed in accordance with the applicable laws and ethical requirements for the study period concerned, and was compliant with the Declaration of Helsinki, revised in 2000. All parents/caregivers were thoroughly educated and consented at the screening visit. The study was approved by the Institutio...
PMC9920098
3. Results
PMC9920098
3.1. Study Population
A total of 40 children qualified for our study and were randomized (
PMC9920098
3.2. Changes in Symptoms
SRS
The changes in SRS and ABC scores over the study period are shown in Changes in the assessment of the ADOS-2 subscale scores are presented in Subjects’ scores at 18 or 36 weeks were subtracted from the same individual’s scores at the time of previous observation; differences were averaged and are presented as the means...
PMC9920098
3.3. Comparison of Parental and Trained Professional Ratings of Children’s ASD Symptoms or Feature Development
REGRESSION
We attempted to compare concordance and assess the eventual interchangeability of parents’ ratings of therapeutic efficacy in their children and the assessment of therapeutic efficacy performed by a trained professional. The parents’ impression scale was classified as follows: −1, the child worsened; 0, no noticeable c...
PMC9920098
4. Discussion
ADOS
No significant clinical improvement was demonstrated in the behavioural outcome measures evaluated in ASD children aged 3–7 years treated with sulforaphane (SFN) in our study. The mean total raw scores on ABC and SRS-2 improved in the SFN and placebo groups, but none of the changes reached statistical significance. Cha...
PMC9920098
5. Conclusions
autistic spectrum disorders
This investigation aimed to assess the effects of SFN on the reduction of ASD symptom severity. We examined a paediatric cohort of ASD patients aged three to seven years. We found no significant clinical improvement in the behavioural outcome measures evaluated in ASD children aged 3–7 years treated with sulforaphane (...
PMC9920098
Author Contributions
J.T.
M.M. had a leadership role in the preparation and organization of the clinical study, performed the clinical examinations, and wrote the first draft of the manuscript. K.T. was the leading psychologist; she provided the clinical evaluations, organized the data collection, and critically revised the draft together with ...
PMC9920098
Institutional Review Board Statement
All information was accessed in accordance with the applicable laws and ethical requirements for the study period concerned, and was compliant with the Declaration of Helsinki, revised in 2000. The study was approved by the Institutional Review Board (IRB) of the General University Hospital in Prague (Ethics Committee ...
PMC9920098
Informed Consent Statement
All parents/caregivers were thoroughly educated and consented at the screening visit. Informed consent was obtained from all subjects involved in the study.
PMC9920098
Data Availability Statement
The data are available upon reasonable request to the corresponding author.
PMC9920098
Conflicts of Interest
Ladislav Jílek is a co-owner of the Pure Food Norway Company, a business focusing on food supplements. This ownership and the funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
PMC9920098
References
Autism
Enrollment, follow-up, and analysis of the clinical study.Effect of sulforaphane treatment on Aberrant Behaviour Checklist (ABC, upper panels) and Social Responsiveness Scale (SRS-2, lower panels) scores. SFN, sulforaphane group. Red dots represent score means.Effect of sulforaphane treatment on Autism Diagnostic Obser...
PMC9920098
Subject terms
The most common BRAF mutation is thymine (T) to adenine (A) missense mutation in nucleotide 1796 (T1796A, V600E). The BRAF
PMC10400539
Introduction
tumor
MALIGNANCIES, TUMOR, THYROID NODULES, PAPILLARY THYROID CANCER
The BRAFMore importantly, According to earlier research, BRAFWith the increasing popularity of tumor thermal ablation technology (microwave, radio frequency, and laser) in China, an increasing number of patients with PTC, particularly those with minimal papillary thyroid cancer (MPTC), are willing to accept thermal abl...
PMC10400539
Materials and methods
PMC10400539
Patients
PTC
PAPILLARY THYROID CARCINOMA
A retrospective analysis was performed on PTC patients who had undergone preoperative thyroid US elastography, BRAFSchematic diagram of the patient selection. PTC, papillary thyroid carcinoma.
PMC10400539
Strain elastography ultrasound examination
calcification
BLOOD, THYROID NODULES
There were two ultrasonic devices used: the Philips Q5 (both Healthcare, Eindhoven, Netherlands) and the GE LOGIC E20 (GE Medical Systems, American General) (L12-5 linear array probe, frequency: 10–14 MHz).To acquire longitudinal and transverse images of the thyroid nodules, continuous longitudinal and transverse scann...
PMC10400539
Region of interests (ROIs) segmentation
One week prior to surgery, thyroid US exams were conducted. US image segmentation was done manually. Using the ITK-SNAP program ((
PMC10400539
Radiomic feature extraction
Radiomic features were extracted using PyRadiomics (
PMC10400539
Radiomic feature selection
The retrieved features were normalized using a standard scalar to reduce bias and overfitting in the study. The dataset was divided into training and validation cohorts. To make each characteristic substantially independent, the row spatial dimension of the feature matrix was reduced using the Pearson correlation coeff...
PMC10400539
Development of machine learning-based models
NB
The Support Vector Machine with the linear kernel (SVM_L), Support Vector Machine with radial basis function kernel (SVM_RBF), LogisticRegression (LR), Naïve Bayes (NB), K-nearest Neighbors (KNN), and Linear Discriminant Analysis (LDA) classifiers were used to build the prediction models using the RFE’s key features. A...
PMC10400539
Statistical analysis
Python (version 3.7, A two‐sided P < 0.05 indicated statistically significant differences. PyRadiomics (version 2.2.0, Medcalc Statistical Software was used to calculate the six models’ AUCs and evaluate the predictions. The DeLong method was used to compare the AUCs of the six machine learning classifiers. To create c...
PMC10400539
Institutional review board statement
The study was conducted in accordance with the Declaration of Helsinki and approved by the Jiangsu University-Affiliated People’s Hospital and traditional Chinese medicine hospital of Nanjing Lishui District Ethics Committee.
PMC10400539
Informed consent
Patient consent was waived by the Jiangsu University-Affiliated People’s Hospital and traditional Chinese medicine hospital of Nanjing Lishui District ethics committee due to the retrospective nature of the study.
PMC10400539
Results
PMC10400539
Clinical characteristics
PTC, NB
REGRESSION, PAPILLARY THYROID CARCINOMA
There were 138 PTC patients in all, 87 of whom were women (mean age, 41.81 ± 11.23 [range, 25–57] years), and 51 of them were men (mean age, 43.82 ± 12.18 [range, 28–65] years). In Table Comparison of clinical and ultrasonic characteristics of the PTC patients in the training and validation dataset.The relationship bet...
PMC10400539
Diagnostic performance of the machine learning models in the training and validation cohorts
NB
REGRESSION
After PCC and RFE with stratified tenfold cross-validation, 27 radiomic features were chosen in the training cohort (Figs. Boxplot of Selected features after RFE. Features were reduced to twenty-seven features during training of the machine learning models.Recursive feature elimination (RFE) with tenfold cross‐validati...
PMC10400539
Discussion
NB
REGRESSION, DISEASE, EVENT
The BRAF Real-time tissue strain elastography helps assess the anatomical structure and biological traits of PTC because it represents the relative hardness of the lesion and its surrounding tissues, whereas the hardness of PTC tissues is closely related to its internal pathological structure. Bojunga et al.In a previo...
PMC10400539
Conclusion
Finally, our study found that machine learning-based US elastography radiomic models performed well in predicting the potential of BRAF
PMC10400539
Author contributions
Conceptualization, E.A.A. and X.Q.; methodology, E.A.A.; software, E.A.A. and D.A.; validation, Y.-G.W., J.O.T., and Y.-Z.R.; formal analysis, E.A.A.; investigation, E.A.A. and F.-J.X.; resources, E.A.A., and Y.-G.W.; data curation, E.A.A., X.W., and X.W.; writing—original draft preparation, E.A.A.; writing—review and ...
PMC10400539
Funding
This study was financially supported by the National Natural Science Foundation of China (Project No.: 81971629). Jiangsu Provincial Health Commission research project (Z2021071), 2023 Medical Education Collaborative Innovation Fund of Jiangsu University (JDYY2023015).
PMC10400539
Data availability
The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding authors.
PMC10400539
Competing interests
The authors declare no competing interests.
PMC10400539
References
PMC10400539
1. Introduction
CVD
These authors contributed equally to this work.We hypothesized that consumption of high-fat (HF) ground beef (24% fat) would not affect plasma concentrations of high-density lipoprotein cholesterol (HDL-C) or low-density lipoprotein (LDL-C), whereas low-fat (LF) ground beef (5% fat) would decrease HDL-C and LDL-C conce...
PMC9861690
2. Materials and Methods
PMC9861690
2.1. Ethics Statements and Participant Recruitment
This randomized, controlled, 2-period crossover trial was conducted in accordance with the Declaration of Helsinki guidelines [Seventy-five healthy males between the ages of 25 and 60 years participated in one of two informational meetings (
PMC9861690
2.2. Inclusion Criteria
The participants had to be non-smoking males, not be on any restrictive diets or cholesterol-lowering medications, and not have a total cholesterol (TC) above 350 mg/dL. The participants were requested not to change their habitual diet or level of physical activity. Due to limited funding, we chose to recruit men only,...
PMC9861690
2.3. Study Design
The study design was a two-period, randomized crossover design in which each participant completed two 5-week ground beef interventions in a randomly assigned order, with a 4-week washout period [
PMC9861690
2.4. Source of Ground Beef
vacuum-packaged patties
The source of raw materials for the production of LF and HF patties were the beef pectoralis muscle and 75:25 coarse ground beef, respectively, purchased from a local supplier (Readfield Meats, Bryan, TX, USA). The muscle raw materials were ground, and 4-ounce (115 g) patties were formed in a patty maker, individually ...
PMC9861690
2.5. Diet Records
The participants were required to complete a 3-day diet record before the diet interventions and once during each intervention to establish nutrient intakes and encourage compliance. Daily intake of major nutrients and dietary exchanges were analyzed by a registered dietitian nutritionist (RDN) using ESHA’s Food Proces...
PMC9861690
2.6. Body Composition
The body composition of all subjects was assessed at the beginning and at the end of the study using dual-energy X-ray absorptiometry (DXA) (General Electric Lunar Prodigy Advance, Madison, WI, USA). Derived variables of interest from the DXA scans were total body mass, lean body mass, android fat, gynoid fat (all in k...
PMC9861690
2.7. General Blood Sampling and Analyses
BLOOD
Blood sampling and assay procedures were published previously [
PMC9861690
2.8. Lipoprotein Density Profiles
Density profiles for circulating lipoproteins were determined by imaging 6 μL serum following NBD-C6-ceramide labeling of lipoproteins, as described [The average percent relative standard deviation in AUC for different lipoprotein subfractions was 4.45% (within-day) and 7.37% (day-to-day). Data were also used to expres...
PMC9861690
2.9. Statistics
Power calculations were conducted to estimate the required sample size based on HDL-C concentrations from our previous studies with normocholesterolemic men [Ground beef effects were analyzed using a repeated measures mixed model to assess the effects of diet (LF vs. HF), sequence (entry, first LF/HF intervention, wash...
PMC9861690
3. Results
PMC9861690
3.1. Ground Beef Composition and Participant Nutrient Intake
The LF patties did not lose a detectable amount of fat following pan frying, but the HF patties lost nearly 41% fat after frying. The drained, pan-fried HF patties contained more total SFA, MUFA, and polyunsaturated fatty acids (PUFA) than the pan-fried LF patties (Energy intake did not differ among treatment phases, a...
PMC9861690
3.2. Plasma Lipid Concentrations
TG
As indicated above, plasma LDL-C concentration was calculated by the Friedwald equation, which is based primarily on TC (LDL-C = TC − HDL-C − TG/5). For this reason, there was a high correlation between TC and LDL-C concentration (rPlasma TG concentration tended (
PMC9861690
3.3. Lipoprotein Density Distributions
TRL AUC was greater following the LF intervention than at entry (
PMC9861690
3.4. Pearson Correlation Coefficients
Plasma HDL-C concentration was negatively correlated with TRL AUC (r = −0.383;
PMC9861690
4. Discussion
PMC9861690
4.1. Energy and Macronutrient Intake and Composition of Patties
The primary outcome of this study was to document which voluntary changes in macronutrient intake were responsible for any observed changes in lipoprotein cholesterol concentrations. The current study confirmed significant increases in % energy from total fat, saturated fatty acids, and monounsaturated fatty acids duri...
PMC9861690
4.2. High-Density Lipoprotein Cholesterol Concentrations
HDL particles carry out reverse cholesterol transport and possess antioxidative and anti-inflammatory activities through associated proteins and bioactive lipids [Scott et al. [
PMC9861690
4.3. Low-Density Lipoprotein Cholesterol Abundance
Each LDL particle contains one apolipoprotein B (apoB), and the larger, less dense LDLWang et al. [
PMC9861690
4.4. Lipoprotein Area under the Curve
CVD
NBD-C6-ceramide labels the surface of lipoprotein particles and can be used to indicate particle diameter associated with a specific density interval [Wang et al. [Small, dense LDL particles have the strongest association with the risk for CVD [
PMC9861690
4.5. Nutrient Intake and Lipoprotein Cholesterol
The LF treatment increased % energy from protein, and the HF treatment increased % energy from fat and saturated fat, and decreased % energy from carbohydrate. However, the LF and HF treatments caused similar reductions in HDL-C and LDL-C concentrations from entry. This seemingly would rule out % energy from protein, f...
PMC9861690
4.6. Limitations
Several limitations of the present study should be considered. Because of the nature of the study treatments, the study staff were not blinded, which leads to the potential for bias associated with lack of blinding. The short duration of the intervention, 35 days, may also be considered a limitation, but previous resea...
PMC9861690
Author Contributions
Conceptualization, S.B.S., R.L.W. and S.F.C.; methodology, J.R.L., T.P. and D.R.S.; formal analysis, S.B.S.; writing, S.B.S., R.L.W., J.R.L., T.P. and D.R.S.; funding acquisition, S.B.S. and R.L.W. All authors have read and agreed to the published version of the manuscript.
PMC9861690
Institutional Review Board Statement
This study was conducted in accordance with the Guidelines of the Declaration of Helsinki guidelines and approved by the Texas A&M University Institutional Review Board for use of human participants in research (Protocol number IRB2018-0755). This trial was registered at
PMC9861690
Informed Consent Statement
Informed consent was obtained from all subjects involved in the registered trial NCT04841460.
PMC9861690
Data Availability Statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available as no appropriate public database is available.
PMC9861690
Conflicts of Interest
The authors declare no conflict of interest.
PMC9861690
Abbreviations
CVD, CARDIOVASCULAR DISEASE
AUC, area under the curve; BMI, body mass index; CVD, cardiovascular disease; DXA, dual-energy X-ray adsorptiometry; HDL-C, high-density lipoprotein cholesterol; HF, high-fat; LDL-C, low-density lipoprotein cholesterol; LF, low-fat; MUFA, monounsaturated fatty acids; PUFA, polyunsaturated fatty acids; RDN, registered d...
PMC9861690
Materials and methods
jaundice
This randomized controlled clinical trial was performed on 106 full-term neonates with jaundice who were admitted to the neonatal ward of 17 Shahrivar Hospital in Rasht, Iran. The neonates were randomly assigned to two groups of intervention (10 mg/kg UDCA+phototherapy) and control (phototherapy alone). Total serum bil...
PMC10715657
Results
Results showed that in the intervention group, 28 (52.8%) of neonates were boys with the mean age of 5.1±1.25 days. While, in the control group 29 (54.7%) of them were boys with the mean age of 5.19±2.26 days. Bilirubin levels in both groups decreased significantly after hospitalization (at 12, 24 and 48 hours) (P <0.0...
PMC10715657
Conclusions
NEONATAL HYPERBILIRUBINEMIA
Administering UDCA plus phototherapy reduced TSB and length of hospital stay with proper safety and efficacy. Therefore, it seems that this combination can be an appropriate treatment modality in neonatal hyperbilirubinemia.
PMC10715657
Data Availability
“All data are available within the manuscript and/or
PMC10715657
Introduction
primary bile acid chenodeoxycholic acid, Hyperbilirubinemia
NEONATAL DISORDERS, NEONATAL HYPERBILIRUBINEMIA, HYPERBILIRUBINEMIA
Hyperbilirubinemia is one of the most common neonatal disorders, especially in the first week after birth, which occurs in half of term and most preterm infants [Ursodeoxycholic Acid (UDCA) is a type of hydrophilic bile acid that accounts for about 4% of bile acids in humans and is synthesized by bacterial enzymes in t...
PMC10715657
Materials and methods
PMC10715657
Patients and settings
Gilbert’s syndromes, Crigler-Najjar, hyperbilirubinemia, sepsis, breast milk
HYPOTHYROIDISM, GLUCOSE 6 PHOSPHATE DEHYDROGENASE DEFICIENCY, MATERNAL DIABETES, CHRONIC DISEASES, LIVER DISEASE, DIRECT HYPERBILIRUBINEMIA, HYPERBILIRUBINEMIA, SEPSIS, DISEASES
The present study is a paralleled randomized single-blinded controlled clinical trial that was performed from 10 April 2021 to 10 October 2021 for 6 months. In this study, 106 term neonates were admitted for at least 48 hours due to indirect hyperbilirubinemia in the neonatal ward of 17 Shahrivar Hospital in Rasht, Ira...
PMC10715657
Data gathering
bloating, constipation, rash, nausea, vomiting
SECONDARY
Data were gathered by a checklist including baseline and post randomization variables. Baseline characteristics were age, sex, gestational age, and baseline blinrubin level. Also, bilirubin level at 12, 24, and 48 hours after admission and side effects including nausea, vomiting, constipation, bloating, and skin rash w...
PMC10715657
Statistical analysis
Data were analyzed using IBM SPSS Statistics for Windows, version 20 (IBM Corp., Armonk, N.Y., USA). Data were reported by frequency, percent, mean, and standard deviation. Qualitative variables were also described based on number and percent. At first, the normality of the data was evaluated using the Kolmogorov-Smirn...
PMC10715657
Results
In the present study, 198 admitted neonates were assessed for eligibility from 10 April 2021 to 10 October 2021 for 6 months. Among them, 106 were enrolled in two groups of 53 neonates (
PMC10715657
Flow chart of participants.
PMC10715657
Baseline demographic characteristics in the intervention and control groups.
* Mann-Whitney U test.** Independent samples T-test.*** Chi-Squared test.According to the results, a statistically significant difference was observed between the total bilirubin levels at the time of admission and discharge in both groups (P <0.001).As
PMC10715657
Comparing bilirubin level at admission and discharge in the intervention and control groups.
*Wilcoxon signed-rank test.** Mann-Whitney U test.In addition, bilirubin levels in both groups were measured during 12, 24, and 48 hours after admission, and the results were obtained by Friedman test. We intended to investigate the difference in bilirubin levels in these three time periods, the neonates studied at thi...
PMC10715657
The trend of bilirubin levels of all, intervention, and control groups from baseline to discharge.
PMC10715657
Inter and intra group analyses of bilirubin level in 12, 24, and 48 hours after hospitalization.
SECONDARY
*Friedman test.*** Mann-Whitney U test.Using the Mann-Whitney U test, the length of hospital stay as the secondary outcome was significantly reduced in the intervention compared to the control group (P = 0.038) (
PMC10715657
Comparing duration of hospitalization in the intervention and control groups.
bloating, constipation, rash, nausea, vomiting
* Mann-Whitney U test.No side effects including nausea, vomiting, constipation, bloating, and skin rash were observed in the two groups.
PMC10715657
Discussion
diabetic mothers might, retinal damage, constipation, dehydration, skin rash, nausea, vomiting
DEHYDRATION, HYPOCALCEMIA, RETINAL DAMAGE
Phototherapy is a cheap, simple, non-invasive method with appropriate effectiveness. This treatment has side effects such as changes in circadian rhythm, dehydration, hypocalcemia, skin rash, and retinal damage [In the present study, we compared TSB at the beginning of hospitalization and at the time of discharge betwe...
PMC10715657
Conclusions
NEONATAL JAUNDICE, NEONATAL HYPERBILIRUBINEMIA
Based on the findings, administering UDCA plus phototherapy reduced TSB and length of hospital stay with appropriate safety and efficacy. Therefore, it seems that this combination can be an appropriate treatment modality in neonatal hyperbilirubinemia. Besides, further studies can be recommended to evaluate the efficac...
PMC10715657
Supporting information
PMC10715657
Consort checklist: CONSORT 2010 Checklist dr aghili.
(DOC)Click here for additional data file.
PMC10715657
Data set: Dr aghili–analysis.
(XLSX)Click here for additional data file.
PMC10715657
Persian protocol: Trials persian dr aghili.
(PDF)Click here for additional data file.
PMC10715657
English protocol: Trials english dr aghili.
(PDF)Click here for additional data file.
PMC10715657
Persian and English protocol summary: Protocol dr aghili revised.
(DOCX)Click here for additional data file.
PMC10715657
Consort flow diagram: CONSORT 2010 flow diagram dr aghili.
(DOC)Click here for additional data file.This was the proposal accepted by the Vice-Chancellor of Research at Guilan University of Medical Sciences. It was the thesis of the Dr. Safoora Aghili resident of pediatrics (third Author). We appreciate all colleagues and parents/guardians for their valuable cooperation.
PMC10715657
Abstract
PMC10097047
Introduction
PHN, Herpes zoster
POSTHERPETIC NEURALGIA, PHN, HERPES ZOSTER, COMPLICATIONS
Postherpetic neuralgia (PHN) is one of the most common complications of Herpes zoster (HZ), yet the mechanism and the treatment for PHN remains elusive. We first performed this feasibility study to verify the safety and efficiency of autologous fat grafting into the paravertebral space in early HZ to prevent PHN.
PMC10097047
Methods
PHN, rash, pain
PHN
Patients suffering from HZ with a rash in chest, back, or abdomen were arranged for autologous fat grafting to the paravertebral space. The primary endpoint was the incidence of PHN, which was defined as persistence pain in the affected dermal area in 12 weeks after fat grafting. Secondary endpoints including patient‐r...
PMC10097047
Results
PHN, pain
ADVERSE EVENTS, EVENTS, PHN
Eight patients accept the intervention and completed all follow‐ups. Most patients report immediate pain relief after injection, one patient has a mild to moderate dizzy symptom after injection. No other short‐ or long‐term adverse events occurred. For primary outcome, all patients have a timely reduced pain intensity,...
PMC10097047
Discussion
PHN, rash
PHN
Autologous fat transplantation to the paravertebral space is a safe and feasible technique in preventing PHN from HZ in a rash. Further randomized controlled trial to investigate the actual long‐term benefice of autologous fat grafting to the paravertebral space in preventing PHN is needed.
PMC10097047
Trial registration
ChiCTR, (ChiCTR1900025416); registered August 26, 2019. Xiujuan Li, Ran Tao, and Xiaoyan Meng contributed equally to this work.
PMC10097047