title
stringlengths
1
1.19k
keywords
stringlengths
0
668
concept
stringlengths
0
909
paragraph
stringlengths
0
61.8k
PMID
stringlengths
10
11
INFORMED CONSENT
Informed consent was obtained from all individual participants included in the study.
PMC10315327
TRIAL REGISTRATION
Iranian Registry of Clinical Trial (registered prospectively: IRCT20191112045424N1; available at:
PMC10315327
ACKNOWLEDGMENTS
We are tankful to all study participants. We would like to thank the Clinical Research Development Unit, Imam Reza Hospital, Mashhad University of Medical Sciences, for their assistance in this manuscript.
PMC10315327
DATA AVAILABILITY STATEMENT
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
PMC10315327
REFERENCES
PMC10315327
Objective
NONALCOHOLIC FATTY LIVER DISEASE, TYPE 2 DIABETES
Academic Editor: Ferdinando Carlo Sasso The aim of study was to evaluate the effect and safety of pioglitazone-metformin combined treatment in the newly diagnosed type 2 diabetes patients with nonalcoholic fatty liver disease.
PMC10250100
Methods
nonalcoholic fatty liver disease
NONALCOHOLIC FATTY LIVER DISEASE, TYPE 2 DIABETES
A total of 120 newly diagnosed type 2 diabetes patients with nonalcoholic fatty liver disease from 8 centers were randomly divided into the control group (metformin hydrochloride) and the test group (pioglitazone hydrochloride and metformin hydrochloride).
PMC10250100
Results
fatty liver
FATTY LIVER
Compared to the control group, after treatment, the proportion of people with mild and moderate fatty liver increased, and the proportion of people with severe fatty liver decreased, and this change was more obvious in the population with moderate and severe fatty liver. The level of
PMC10250100
Conclusion
diabetic
ADVERSE EVENTS, NONALCOHOLIC FATTY LIVER DISEASE
Combined treatment with pioglitazone-metformin can effectively reduce liver fat content and gamma-GT level in newly diagnosed diabetic patients with nonalcoholic fatty liver disease, and adverse events do not increase compared with the control group, showing good safety and tolerance. This trial is registered with Cli...
PMC10250100
1. Introduction
NAFLD, fatty liver, weight gain, hypoglycemic, type 2 diabetes, diabetes
ADVERSE EVENTS, FATTY LIVER, CHRONIC DISEASES, INSULIN RESISTANCE, TYPE 2 DIABETES, DIABETES
As one of the most common chronic diseases, the prevalence rate of diabetes in China has skyrocketed, and the estimated prevalence of diabetes in Chinese adults is 11.6%, with type 2 diabetes predominating [Clinically, NAFLD is currently treated with multiple drugs, one of which is insulin sensitizer. Many literature r...
PMC10250100
2. Materials and Methods
PMC10250100
2.1. Study Design and Participants
This study was a randomized, double-blind, double-simulation, and positive drug control multicenter clinical trial (ClinicalTrials.gov registration number: Inclusion criteria are as follows: according to WHO criteria, age 18-70 years old, BMI between 21 and 35 kg/m
PMC10250100
2.2. Randomization and Masking
LIVER
Through a computer-generated centralized management program, all participants were randomized by a stratified computed randomization procedure to account for age, sex, and BMI to test group or control group at a ratio of 1 : 1 and were masked to the treatment assignment. The test group received pioglitazone-metformin c...
PMC10250100
2.3. Procedures
thirst, gastrointestinal tolerance, overdose, hypoglycemia, weight loss
HYPOGLYCEMIA, CONCOMITANT DISEASE
In order to improve gastrointestinal tolerance, all patients in the group received a weekly dose titration. The initial dose of the test group was once a day, 500 mg metformin and 15 mg pioglitazone (both from Hangzhou Zhongmei Huadong Pharma Ceutical Co., Ltd.) were taken before breakfast or dinner, and after 1 week o...
PMC10250100
2.4. Quantitative Ultrasound for Liver Steatosis
In our study, we mainly used controlled attenuation parameter (CAP) for liver fat quantification, which is best studied and clinically available technique for liver fat quantification, with the first clinical studies dating back to 2010 [
PMC10250100
2.5. Outcomes
fasting blood glucose, hypoglycemic, postprandial blood glucose
EVENTS, SECONDARY, INSULIN RESISTANCE
The primary end points are liver fat content (ultrasonic quantitative determination of liver fat content), ALT, AST, gamma-GT levels, and insulin resistance index. The secondary endpoints are HbA1c, intravenous fasting blood glucose, 2 h postprandial blood glucose, total cholesterol, triglyceride, HDL cholesterol, LDL ...
PMC10250100
2.6. Statistical Analysis
The statistical analysis was performed using SAS (9.1.3) statistical analysis software. The
PMC10250100
3. Results
PMC10250100
3.1. Baseline Characteristics
NAFLD
TYPE 2 DIABETES
This study enrolled a total of 120 type 2 diabetes patients with NAFLD from 8 hospitals in Shaanxi Province. As shown in the Consolidated Standards of Reporting Trials (CONSORT) diagram in
PMC10250100
3.2. Primary Endpoint Measurement
After 24 weeks of treatment, 8 (13%) of the 60 patients in the test group had substantial improvement in degree of liver fat content, and the degree of liver fat content decreased from moderate and severe grade to mild grade. In contrast, 4 of 60 patients (6%) in the metformin group saw their liver fat content drop fro...
PMC10250100
3.3. Secondary Endpoint Measurement
After 24 weeks of treatment, the HbA1c level of the pioglitazone-metformin combined treatment group and the metformin treatment group decreased significantly (pioglitazone-metformin combined treatment: 1.78% (95% CI: 1.53-2.04) and metformin treatment: 1.71% (95% CI: 1.46-1.96)), but there was no significant difference...
PMC10250100
3.4. Safety Evaluation
In this study, the compliance of pioglitazone-metformin combined treatment group was 95.79%, and that of the metformin group was 95.10%. As shown in
PMC10250100
4. Discussion
NAFLD, occult blood, diarrhea, fatty liver, adverse cardiovascular events, angina pectoris, liver cirrhosis, ALD, NAFL, hypoglycemic, metabolic stress liver injury, hypertension
ADVERSE REACTIONS, ALCOHOLIC LIVER DISEASE, HYPERTENSION, ADVERSE EVENTS, NONALCOHOLIC STEATOHEPATITIS (NASH), DISEASE, NONALCOHOLIC FATTY LIVER, FATTY LIVER, LIVER CIRRHOSIS, INSULIN RESISTANCE, HEPATOCELLULAR CARCINOMA, NONALCOHOLIC FATTY LIVER DISEASE, ALD, TYPE 2 DIABETES
Nonalcoholic fatty liver disease is a metabolic stress liver injury closely related to insulin resistance and genetic susceptibility. Except that the patient has no history of excessive drinking, its pathological changes are similar to alcoholic liver disease (ALD). The disease spectrum includes nonalcoholic fatty live...
PMC10250100
5. Limitation
NAFLD
Although our research is a randomized, double-blinded, double-simulated multicenter study, but our research still has some limitations. First of all, our study did not incorporate the gold standard of liver biopsy into our main results because of the expected early stages of NAFLD in these patients and the short durati...
PMC10250100
6. Conclusion
NAFLD, fatty liver
FATTY LIVER, TYPE 2 DIABETES
In conclusion, the results of this study showed that in the observation period of 24 weeks, in newly diagnosed type 2 diabetes patients with NAFLD, the pioglitazone-metformin combined treatment can effectively reduce liver fat content, especially in patients with moderate to severe fatty liver and
PMC10250100
Acknowledgments
We thank all the participants, investigators, and trial-site staff who were involved in the conduct of the study. We also thank Hangzhou Zhongmei Huadong Pharma Ceutical Co., Ltd. for providing free experimental drugs and placebos. This study was funded by the Xijing Hospital.
PMC10250100
Data Availability
The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.
PMC10250100
Ethical Approval
The research protocol was approved by the Ethics Committee of Xijing Hospital of Air Force Medical University (ClinicalTrials.gov registration number:
PMC10250100
Consent
Written informed consent was obtained from all the participants after a full explanation of the study.
PMC10250100
Disclosure
This trial represents independent academic research funded by Xijing Hospital. The trial drug and placebo were provided free of charge by Hangzhou Zhongmei Huadong Pharma Ceutical Co., Ltd., which did not participate in the design of the experiment, collection, analysis, and interpretation of data, report writing, and ...
PMC10250100
Conflicts of Interest
All authors participating in this study reported no conflicts of interest.
PMC10250100
Authors' Contributions
±, fatty liver
ADVERSE EVENTS, FATTY LIVER
F.J.F and J.Q.H participated in the conception and design of this research, explained the data, and critically revised the manuscript. All authors have read and approved the final version. All authors participated in data collection, collation, and manuscript writing. All authors are guarantors of this work and are res...
PMC10250100
Supplementary Information
lymphopenia
LYMPHOPENIA, MYOCARDIAL INFARCTION (MI)
Myocardial infarction (MI) accelerates immune ageing characterised by lymphopenia, expansion of terminally differentiated CD8The online version contains supplementary material available at 10.1007/s11357-023-00794-6.
PMC10122201
Keywords
PMC10122201
Introduction
death
MYOCARDIAL INFARCTION (MI), ACUTE CORONARY SYNDROME, PROLIFERATION, INFLAMMATION, VIRAL INFECTION, EVENTS
Despite modern advances in therapy, myocardial infarction (MI) still carries a substantial risk of death or recurrent cardiovascular events [Immunosenescence is mainly linked to thymic involution and changes in cellular immunity as a response to pathogens, such as recurrent viral infections, throughout life [Lymphocyte...
PMC10122201
Methods
PMC10122201
Trial design and oversight
coronary heart disease
CORONARY HEART DISEASE
The TACTIC trial was a single-centre, randomized, double-blind, parallel-group, placebo-controlled phase IIa pilot trial comparing TA-65 with placebo in 90 participants with coronary heart disease who were diagnosed with myocardial infarction in the 6 months prior to enrolment. A total of 90 patients were randomized to...
PMC10122201
Trial population
comorbidity, substance addiction, obstructive coronary artery disease, malignancy, NSTEMI, epicardial vessel stenosis, arrhythmias, immunological dysfunction, hepatitis
ACUTE MYOCARDIAL INFARCTION, UNCONTROLLED HYPERTENSION, MYOCARDIAL INFARCTION, BLOOD, EVENT, DISEASE, CARDIOGENIC SHOCK, ARRHYTHMIAS, HEPATITIS, INSULIN-DEPENDENT DIABETES MELLITUS
Patients were eligible for the trial if they a) were aged 65 years or over with an index presentation of an acute myocardial infarction (either STEMI or NSTEMI) within the previous 6 months, b) had successfully completed revascularisation or were being managed medically following myocardial infarction, c) had evidence ...
PMC10122201
Randomization and blinding
NSTEMI
Randomisation was performed using a minimisation scheme to ensure patients randomised to each group were comparable at baseline. The minimisation scheme accounted for gender (male or female), type of MI (STEMI or NSTEMI) and proportion of terminally differentiated effector memory CD8
PMC10122201
Outcome measures
The primary outcome measure was the proportion of CD8
PMC10122201
Flow-cytometric assays
Two different assays were used for flow cytometric analysis of leucocytes. All measurements were performed on fresh blood within 4 h of collection. There was no significant amount of non-viable cells (< 1%) with this approach. The TruCount assay (containing CD45, CD3, CD4, CD8, CD19, CD16, CD56 fluorochrome-labelled mo...
PMC10122201
Telomerase activity
LYSED
Nuclear telomerase activity in peripheral blood mononuclear cells (PBMCs) was measured using the Telomerase Repeated Activation Protocol (TRAP) – quantitative polymerase chain reaction (qPCR) assay. Within 24 h of collection, whole blood was centrifuged to isolate PBMCs, which were cryopreserved at − 80 C. The cells we...
PMC10122201
Oxidative stress
OXIDATIVE STRESS
Oxidative stress was measured using the TBARS colorimetric assay. This assay is described in detail in the
PMC10122201
Endothelial function
hyperaemia
HYPERAEMIA, PAT
Endothelial function was evaluated using the EndoPAT device (Itamar Medical Ltd, Caesarea, Israel). This non-invasive operator-independent system consists of finger probes that measures peripheral arterial tone (PAT) for 5 min at rest and during reactive hyperaemia induced by 5-min forearm cuff occlusion. The reactive ...
PMC10122201
Echocardiography
Transthoracic echocardiography (TTE) was performed at baseline and 12 months to evaluate left ventricular function including global longitudinal strain (
PMC10122201
Adverse events
ADVERSE REACTIONS, ADVERSE EVENT, EVENT, ADVERSE EVENTS
Adverse events (AEs), adverse reactions (ARs), serious adverse events (SAEs), and serious adverse reactions (SARs) were assessed by a medical practitioner for severity and causality. The severity of each was classified as follows: grade 1—minor event not requiring medical intervention, grade 2—an event which is symptom...
PMC10122201
Statistical analysis
Continuous variables were reported by number, mean ± SD, median (IQR) or minimum and maximum, whereas number and percentages summarised categorical variables. The proportion of CD8
PMC10122201
Results
PMC10122201
Trial progress
All patients were recruited at The James Cook University Hospital, Middlesbrough, UK, between 21Consolidated Standards of Reporting Trials (CONSORT) diagram of patient enrolment. The diagram shows the number of patients who met the inclusion or exclusion criteria and their distribution among the two study groups. TA-65...
PMC10122201
Effect on telomerase activity and oxidative stress
Nuclear telomerase activity did not change significantly between baseline and 12 months in either group. The estimated change after 12 months in telomerase activity was + 22.9 (95% CI − 91.8–136.0) in the placebo group, and + 18.5 (95% CI: − 89.4–125.9) in the TA-65 group (Table
PMC10122201
Effect on endothelial function and cardiac function
There were no significant treatment effects of TA-65 on reactive hyperaemic index after 6 or 12 months compared to baseline (Table
PMC10122201
Discussion
MYOCARDIAL INFARCTION
In this novel clinical trial investigating TA-65 versus placebo in patients aged 65 years and over following myocardial infarction, we established four main results: there was no significant change in senescence-like CD8
PMC10122201
Reversal of lymphopenia under TA-65
lymphopenia, NSTEMI
LYMPHOPENIA
We demonstrated that TA-65 led to a reversal of relative lymphopenia. This was notable in NSTEMI but not STEMI patients. In STEMI, baseline lymphocytes are elevated between 24 and 72 h post reperfusion [
PMC10122201
Mitochondrial dysfunction in T cells as a driver of senescence and inflammageing
mitochondrial dysfunction
MITOCHONDRIAL DYSFUNCTION
Senescence can be driven directly by mitochondrial dysfunction [
PMC10122201
Mitochondrial telomerase activation as a potential mechanism of TA-65
Although there is no direct evidence to suggest that mitochondrial Tert protects against senescence induction, global TERT activation inhibits senescence [
PMC10122201
Inflammation as a residual risk post ACS
hypercholesterolemia, myocardial infarction, TA-65, impaired innate immunity, inflammation, infections, sepsis, platelet aggregation, coronary artery disease
HYPERCHOLESTEROLEMIA, MYOCARDIAL INFARCTION, ADVERSE EVENTS, INFLAMMATION, INFECTIONS, EVENTS, SEPSIS, CORONARY ARTERY DISEASE
Secondary prevention in patients who have undergone revascularisation after myocardial infarction aims to reduce their residual risk, predominantly by targeting hypercholesterolemia (with cholesterol-lowering agents) and platelet aggregation (with antiplatelet therapy). Recently, inflammation, as quantified by hsCRP, h...
PMC10122201
Limitations
Our trial did not have an age matched healthy control. It is not clear whether TA-65 preserves lymphocyte count for the age group or accelerates its return to normal after MI. While a reduction in hsCRP is demonstrated, measurement of systemic cytokine levels is needed to elucidate the impact of TA-65 on SASP. We used ...
PMC10122201
Conclusion
myocardial infarction, TA-65
MYOCARDIAL INFARCTION
Our pilot trial suggests that activation of telomerase could be a promising new drug target for patients following MI. Given the significant findings in lymphocyte increase, the trend in hsCRP reduction, as well as the extremely favourable safety profile, we propose as a next step a larger phase II clinical trial with ...
PMC10122201
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 11827 KB)
PMC10122201
Acknowledgements
HEART
The trial was funded by TA-Sciences Inc (New York, US) as an investigator-led grant to I.S.BK is supported by a British Heart Foundation personal chair (CH//13/2/30154). K. Stellos is supported by grants from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (...
PMC10122201
Data availability
Data are available upon request and following approval by the trial steering committee.
PMC10122201
Declarations
PMC10122201
Conflict of interest
The authors declare no competing interests.
PMC10122201
References
PMC10122201
Background
mental illness
Some children of parents with mental illness need support. This study aimed to develop and test the effectiveness of an e-learning program for training elementary schoolteachers to support children of parents with mental illness.
PMC10024023
Methods
mental illness
The program, which included a 30-min video-based e-learning program, aimed to help schoolteachers gain basic knowledge about mental illness and children of parents with mental illness, recognize children in need of support, and gain confidence in supporting them. A school-based cluster randomized controlled trial was c...
PMC10024023
Results
Baseline responses were collected from 87 participants in the intervention group and 84 in the control group. The total score of the Sense of Coping Difficulty subscale at T3 was significantly lower in the intervention group than in the control group (
PMC10024023
Conclusions
mental illness
The program was effective for schoolteachers in supporting children of parents with mental illness.
PMC10024023
Trial registration
UMIN000045483; 14/09/2021.
PMC10024023
Keywords
PMC10024023
Background
mental illness
Mental illness is an important public health issue affecting many people, with one in five Japanese individuals reportedly being affected during their lifetime [In Japan, it has only been about 15 years since the existence of children raised by parents with mental illness became known to society [Even if the children t...
PMC10024023
Methods
PMC10024023
Design
A school-based cluster randomized controlled trial (RCT) was conducted to test the effectiveness of the program. Contamination of the information provided across groups within the same school may have occurred. Therefore, the RCTs of schoolteachers could use schools as clusters [The program, which was offered online on...
PMC10024023
Study participants
Requests for research participation were sent to 322 public elementary schools in three Japanese prefectures. Only schools that were willing to cooperate were included in the study.A maximum of 10 schoolteachers participated from each school. The inclusion criterion was full-time schoolteachers, and the exclusion crite...
PMC10024023
Program development
mental illness
DISORDERS
The program was called the WATASHI-KOKO (“We are here” in Japanese) PROGRAM. It involved a 30-min video-based e-learning program for elementary schoolteachers, which was designed to help them support children of parents with mental illness. It aimed to help schoolteachers gain basic knowledge about mental illness and c...
PMC10024023
Outcome measures
The outcomes were measured at the individual level. The questionnaire was developed by multidisciplinary experts who were research members of this project. The pre-test was conducted among 18 elementary schoolteachers. After watching the video of the program, they were asked to answer the questionnaire and also asked t...
PMC10024023
Confidence in supporting children
The Sense of Coping Difficulty subscale was used to assess confidence in supporting children (Purpose 3 of the program). The Sense of Coping Difficulty/Possibility Scale refers to analogous concepts of self-efficacy, which is the expectation that professionals can deal with difficult situations [
PMC10024023
Actual behaviors and attitude
Three self-developed questions were used at T1 and T3 in order to assess the effects of program Purposes 2 and 3 on behaviors and attitudes. The program introduced the life situations of children in need of support and highlighted certain signs to look out for when identifying such children. The first question asked sc...
PMC10024023
Knowledge
mental illness
Knowledge questions, with responses that could be correct or incorrect, were administered to the schoolteachers; they were developed in order to assess program Purpose 1 (gaining basic knowledge about mental illness and children of parents with mental illness). The five items related to parental mental illness were lif...
PMC10024023
Program goals achievement
mental illness, illness
The degree to which the participants had achieved the eight items representing the program goals was measured using a seven-point scale ranging from “not at all” (1 point) to “very well” (7 points). The following goals were set as an assessment for achieving program Purpose 1: 1) be able to describe the impact of paren...
PMC10024023
Process and feasibility evaluation measures
The process and feasibility evaluation measures were as follows: program satisfaction (very satisfied, somewhat satisfied, not very satisfied, not satisfied at all); whether the participants would recommend the program to other schoolteachers (would recommend, would not recommend); length of the program (long, just rig...
PMC10024023
Basic characteristics
mental illness
The basic characteristics included age, gender, years of experience, job title, experience in special needs teaching, experience of supporting parents with mental illness, experience of supporting students with mental illness, experience of learning about mental illness, and the history of someone close, who has, or is...
PMC10024023
Randomization and blinding
mental illness
BLIND
When school-based applications were received by the research office, a random number table was prepared by a person who was unrelated to the implementation process, and independent allocations were made to either the intervention or control group in the order of arrival of the applications. After the school application...
PMC10024023
Analyses
As the primary population, the full analysis set (FAS), excluding the scores of those who did not respond to T1 from all randomized participants, was used in all analyses, except process and feasibility evaluation. The per-protocol set (PPS), which excluded participants who did not respond on time, those who did not co...
PMC10024023
Ethical procedures
ADVERSE EVENTS
This study was approved by the Ethics Committee for the Intervention Study of Osaka University Hospital (approval no. 21144; 5/10/2021). Written informed consent was obtained from all the participants. This study was conducted in accordance with the principles of the Declaration of Helsinki. This project has been regis...
PMC10024023
Results
PMC10024023
Study participants
infection
MAY, INFECTION
This study was conducted between October 2021 and May 2022. The flow of study participants is shown in Fig. Flow of study participantsEighty-six participants in the intervention group and 82 in the control group completed T3. Of the 86 participants in the intervention group, 73 became PPS, excluding 8, who responded af...
PMC10024023
Process and feasibility evaluations
In the intervention group, 83 of 86 participants were "very satisfied" or "somewhat satisfied" with the program, and three were "not very satisfied." Regarding whether they would recommend the program to other schoolteachers, 85 were "willing to recommend" and 1 was "unwilling to recommend.” The length of the program w...
PMC10024023
Discussion
PMC10024023
Study participants
mental illness, illness
The intervention and control groups had approximately the same number of clusters and schoolteachers, with no significant baseline differences. The mean age of the study participants was 43.6 years (intervention group) and 41.1 years (control group), similar to the mean age of public elementary schoolteachers in Japan,...
PMC10024023
Effectiveness of the program
mental illness
The program was effective in reducing schoolteachers’ difficulty in supporting children of parents with mental illness. The effect sizes were as large as –0.90 (FAS) and –0.86 (PPS). Goal attainment was also effective for over one month. Few studies on mental health interventions for schoolteachers have been conducted ...
PMC10024023
Program feasibility and adaptation to practice
Although Japanese schoolteachers are very busy, 168 of the 171 baseline participants remained in the study until the end. This may have been due to the short duration of the program (30 min) and the easy participation in the e-learning format, which was not restricted to any location and allowed them to choose their ow...
PMC10024023
Study limitations
This study had several limitations. First, the program assessed the understanding and behaviors of individual schoolteachers but not the organizational response of the school as a whole. There were opinions that in order to identify and support children, not only the efforts of individual schoolteachers, but also the w...
PMC10024023
Conclusion
mental illness
We developed a 30-min video-based e-learning program to help elementary schoolteachers support children of parents with mental illness and evaluated its effectiveness using a school-based cluster randomized controlled trial. It was observed that it was significantly effective, over one month, in reducing difficulties i...
PMC10024023
Acknowledgements
mental illness
We thank all elementary schoolteachers who contributed to our research. I would like to thank the core group members of the self-help group for adult children of parents with mental illness, “KODOMO-PEER.” We also thank Prof. Yoshie Hamashima (Osaka Dental University) and Ms. Natsumi Asada (Taanto Life) for their advic...
PMC10024023
Authors’ contributions
RS
Design of the study: MK, AM; development of the program: MK, AK, TS, YE, AM, SS, HK, SI, KY; development of question items: MK, YE, SS, AM; coordination with research fields: AM, KY, MK; quantitative analysis: RS; qualitative analysis: MK, KK; data management: MK, KK, HK; manuscript preparation: MK. All the authors hav...
PMC10024023
Funding
This study was supported by JSPS KAKENHI (grant numbers JP 19H03960 and 20K10788).
PMC10024023
Availability of data and materials
The materials for this program are openly available (
PMC10024023
Declarations
PMC10024023
Ethics approval and consent to participate
ADVERSE EVENTS
This study was approved by the Ethics Committee for the Intervention Study of Osaka University Hospital (approval no. 21144; 5/10/2021). Written informed consent was obtained from all the participants. This study was conducted in accordance with the principles of the Declaration of Helsinki. This project has been regis...
PMC10024023