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Results | Eighty-two participants were included (PBT group n = 39), with a median age of 73 years (IQR 8 years). Median Mini-BESTest scores did not clinically relevantly improve and were not significantly different between groups post-intervention (p = 0.87). FES-I scores did not change in either group. | PMC10191085 | ||
Conclusions | Participation in a PBT program including multiple perturbation types and directions did not lead to different effects than usual care on clinical measures of balance control or fear of falling in community-dwelling older adults with a recent history of falls. More research is needed to explore how to modulate PBT train... | PMC10191085 | ||
Trial registration | Nederlands Trial Register NL7680. Registered 17-04-2019 – retrospectively registered. | PMC10191085 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12877-023-03988-x. | PMC10191085 | ||
Keywords | PMC10191085 | |||
Introduction | Falls annually affect one in three adults over 65 years [Balance training is reported to effectively improve balance control and reduce fall rates in older adults by approximately 24% [In recent years, perturbation-based balance training (PBT) has gained increasing interest as an intervention which is more task-specifi... | PMC10191085 | ||
Methods | PMC10191085 | |||
Study design and participants | A detailed description of the full study protocol was previously published [ | PMC10191085 | ||
Interventions | Participants were randomised to receive PBT as an add-on to usual care versus usual care alone. | PMC10191085 | ||
Usual care | Usual care consisted of physiotherapy referral by the medical doctor if indicated. As in usual clinical practice, it was ultimately up to the patient to decide whether or not to visit the physiotherapist. Both the content and duration of the physiotherapy treatment could vary based on the needs of each individual patie... | PMC10191085 | ||
Perturbation-based balance training | Participants referred to the experimental group received usual care as described above, and three 30-minute sessions of PBT additionally. The PBT sessions were given once a week for three consecutive weeks using the Computer Assisted Rehabilitation Environment (CAREN, MOTEK Medical BV). The CAREN is a dual-belt treadmi... | PMC10191085 | ||
Training procedures | cognitive and motor dual tasks | SAID | The first training session on the CAREN started with a familiarization procedure, where the participant could get used to the system by walking on the treadmill in the virtual environment. Participants reported a numeric rating scale (NRS) score for how comfortable they felt when walking on the CAREN before and during ... | PMC10191085 |
Gait adaptability | Participants walked in a virtual environment of a path through a forest, with various slopes and turns. Both the incline/decline of the slopes and the sharpness of the turns had a standardised starting level of 20% (out of 100%), which was then progressed in steps of 5–15%. Each 5% increase in difficulty level means an... | PMC10191085 | ||
Static reactive balance | standstill | Participants stood on the CAREN while the platform and treadmill belts provided sudden perturbations. The platform could shift (move in the horizontal plane) or tilt (move into a sloping position) to anterior, posterior, left and right. The treadmill belt could unilaterally accelerate from standstill. In the second and... | PMC10191085 | |
Dynamic reactive balance | Participants walked on the treadmill at their comfortable walking speed, while the above-mentioned platform and treadmill perturbations were applied. The treadmill perturbations consisted of unilaterally accelerating or decelerating the treadmill belt for short periods of time (0.2–0.7 s). | PMC10191085 | ||
Measurements | EVENT | Study outcomes were measured at baseline (T0) and after 4 weeks, which was one week after the final training session for the PBT group (T1), by an outcome assessor who was blinded to treatment allocation. Demographic data (age in years, sex, body height (cm) and weight (kg)) was collected at baseline, including retrosp... | PMC10191085 | |
Balance control | The main outcome in this study was balance control, assessed on the Mini-BESTest. The Mini-BESTest is a comprehensive measurement tool to assess balance in community-dwelling older adults [ | PMC10191085 | ||
Fear of falling | Fear of falling was measured with the Falls Efficacy Scale International (FES-I, Dutch version). This version of the falls efficacy scale is a 16-item questionnaire developed to determine if a person has confidence in their ability to perform a range of daily activities without falling. It has been adapted to be more s... | PMC10191085 | ||
Sample size and randomisation | Sample size was calculated in G*power 3.1.9.2 and was based on the primary outcome of this study, difference between group means on balance measured with the Mini-BESTest post-intervention. The effect size Participants were randomised using a 1:1 ratio stratified block randomisation (block sizes 2 and 4). Randomisation... | PMC10191085 | ||
Statistical analysis | gait/balance | REGRESSION | Descriptive statistics are presented as means and standard deviations (SD) or as medians and interquartile ranges (IQR), depending on the normality of the data. Categorical data is presented as frequencies (n) or percentages (%). Data was analysed on an intention-to-treat basis (missing data imputed using single stocha... | PMC10191085 |
Results | Between March 27th, 2019 and July 8th, 2021, 82 participants were included, of which 39 were randomly assigned to the PBT group (8 men, 31 women) and 43 to the control group (9 men, 34 women). The median age of the participants was 73 years (IQR 8 years). Some 49 participants experienced 1 fall during the previous year... | PMC10191085 | ||
Training characteristics | knee pain | ADVERSE EVENT | Adherence to the training was 93.7% over all training sessions (104 out of 111 total scheduled sessions), of which 100 sessions were fully completed. Of the 37 participants who started PBT training, 31 (83.8%) attended all three training sessions. Six participants missed one or two training sessions, due to co-morbidit... | PMC10191085 |
Assumptions | All assumptions for statistical tests were met. An analysis of standard residuals showed that the data contained one outlier on the Mini-BESTest at T1. As this score accurately reflected the performance measured for this participant, this value was not removed from the analysis. | PMC10191085 | ||
Outcomes | REGRESSION | Table Multiple regression analysis was performed to explore and correct for potential interacting or confounding variables (age, sex, previous falls, FES-I at baseline, physiotherapy T0-T1 and Gait/Balance training T0-T1) in the association between group and ΔMini-BESTest, and between group and ΔFES-I. This analysis re... | PMC10191085 | |
Discussion | BBS | SECONDARY, ADVERSE EVENT | This study evaluated the effects of a PBT protocol in addition to usual care on balance control and fear of falling in older adults with a recent history of falls. We hypothesised that the PBT group would show greater improvements compared to the control group. While median Mini-BESTest scores increased slightly in bot... | PMC10191085 |
Limitations | This study was not without limitations. Firstly, restrictions related to the COVID-19 pandemic meant that some adjustments had to be made to the treatment protocol. The inclusion criterion of having experienced a fall in the previous 3 months was broadened to the previous 6 months to increase inclusion rates and reach ... | PMC10191085 | ||
Conclusions | Participation in a PBT program that includes multiple perturbation types and directions did not lead to significantly different effects than usual care on balance control measured with the Mini-BESTest in this population of community-dwelling older adults with a recent history of falls. Fear of falling measured with th... | PMC10191085 | ||
Acknowledgements | The authors would like to thank all research assistants who helped with the study measurements and data collection, and all involved doctors and nurses who helped inform potential participants about the study. | PMC10191085 | ||
Author Contribution | RS, MP | All authors were involved in the design of the study protocol. MG is the coordinating researcher, the main writer of the manuscript, involved in the data collection and training of the intervention group. RM was a major contributor in writing the manuscript and data collection, and involved in training of the intervent... | PMC10191085 | |
Funding | The authors received no specific funding for this research. | PMC10191085 | ||
Data Availability | The datasets used and analysed during the current study are available from the corresponding author on reasonable request. | PMC10191085 | ||
Declarations | PMC10191085 | |||
Ethics approval and consent to participate | Ethics approval was obtained from the Medical Ethics Committee azM/UM (METC18-049, Medical Ethics Committee of Maastricht University and Maastricht University Medical Center), and the study was conducted in accordance with the declaration of Helsinki. All participants provided written informed consent. | PMC10191085 | ||
Consent for publication | Not applicable. | PMC10191085 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10191085 | ||
Abbreviations | trialComputer | Perturbation-based balance trainingMini balance evaluation systems testFalls efficacy scale internationalInterquartile rangeOdds ratioBerg balance scaleRandomised controlled trialComputer assisted rehabilitation environmentNumeric rating scaleMeasurement time, baselineMeasurement time, post-interventionStandard deviati... | PMC10191085 | |
References | PMC10191085 | |||
Abstract | PMC10766135 | |||
Background | hypertensive | The benefits and safety of intensive blood pressure treatment in elderly hypertensive patients have been proved in the STEP trial. However, relevant mechanisms for intensive treatment are lacking. | PMC10766135 | |
Hypothesis | hypertensive, left ventricular systolic function | We aimed to explore whether intensive blood pressure treatment is associated with left ventricular systolic function changes as evaluated by myocardial work (MW) parameters in elderly hypertensive patients compared to the standard. | PMC10766135 | |
Methods | Patients were randomized to the intensive group ( | PMC10766135 | ||
Results | In phase 1, SBP was already significantly lower in the intensive treatment group than in the standard treatment group (126.5 vs. 132.1 mmHg, | PMC10766135 | ||
Conclusions | hypertensive | In elderly hypertensive patients, lower SBP was associated with decreased GWI and GCW and intensive BP treatment did not improve global MW efficiency.We investigated MW parameters and intensive antihypertensive treatment. We found that intensive antihypertensive treatment significantly reduced GWI and GCW from phase 1 ... | PMC10766135 | |
INTRODUCTION | Hypertensive, reduced cardiovascular events, Hypertension, ventricular hypertrophy | HYPERTENSIVE HEART DISEASE, DIASTOLIC DYSFUNCTION, HYPERTENSION, BLOOD, VENTRICULAR HYPERTROPHY | Hypertension sheds light on hypertensive heart disease (HHD) with ventricular hypertrophy processes, systolic and diastolic dysfunction, and a wider range of cardiac and vascular adaptive responses for performance.Left ventricular pressure‐strain loop (LV‐PSL) non‐invasively evaluates LV systolic function, which was fi... | PMC10766135 |
METHODS AND MATERIALS | PMC10766135 | |||
Study cohort | arrhythmia, congenital heart disease, valvular disease, hypertensive | MAY, ARRHYTHMIA, CARDIOMYOPATHY | We prospectively recruited elderly hypertensive patients from the Guangdong clinical center for the STEP trial between May 2017 and January 2018. Previous research detailed the trial protocol and main findings.When BP control was achieved, patients volunteered for an echocardiogram at the 1‐year (phase 1) and 3‐year (p... | PMC10766135 |
Anthropometry and biochemistry | Renal dysfunction, TG | RENAL DYSFUNCTION, HYPERTENSION, RECRUITMENT | Physicians gathered baseline demographic (age and sex) and anthropometric information (height and weight) during face‐to‐face recruitment visits. Standardized questionnaires were used to collect data on smoking status, duration of hypertension, medical history, and medication history. Weight in kilograms divided by hei... | PMC10766135 |
Conventional echocardiographic parameters | DECUBITUS | Echocardiography was performed using a Vivid ultrasound machine (GE Healthcare) with a Vivid Iq M4S‐RS Probe (GE Ving‐Med) connected to a 2.5‐ to 3.5‐MHz phased‐array probe. The patients were examined while at rest in the left lateral decubitus posture. According to the recommendations of the European Association of Ca... | PMC10766135 | |
LV GLS and MW parameters | brachial artery BP | WASTED | GLS and MW were evaluated on three consecutive cardiac cycles by Q‐analysis with EchoPAC software (EchoPAC Version 203, GE Healthcare). 2D‐STE collected data from three apical views (4, 2, and 3 chambers) at 50 and 80 frame/s. The gathered data were then used to assess the GLS of the LV myocardium. The operating doctor... | PMC10766135 |
Intra‐ and Interobserver variability | Fifty randomly chosen participant images were remeasured by two skilled sonographers specializing in echocardiography. Sonographers were blinded to both the clinical data and each other's consequences during the process. The same sonographer re‐examined the images a month later to evaluate the intra‐observer variabilit... | PMC10766135 | ||
Statistical analysis | SD | Continuous variables were expressed as mean ± SD or median with interquartile range and categorical data as absolute numbers and percentages. The Kolmogorov–Smirnov test evaluated continuous variables to assess the normality of distribution. Comparisons were made by independent samples | PMC10766135 | |
RESULTS | PMC10766135 | |||
Baseline characteristics | Sixty‐six participants were randomized to the intensive group and 50 to the standard treatment group. The median age was 66.0 (62.0–70.0) and 63.5 (61.0–69.0) years, respectively. The proportion of men in the intensive treatment group (42.4%) was larger than that in the standard treatment group (30.0%) without statisti... | PMC10766135 | ||
BP and conventional echocardiographic findings | BLOOD | SBP presented a statistically significant interaction between treatment and phase (interaction Blood pressure and conventional echocardiographic parameters between two groups and study phase.
Abbreviations:
LVEDV decreased from phase 1 to phase 2 in both groups, with a significant treatment difference ( | PMC10766135 | |
GLS and MW analysis | WASTED | The analysis revealed a statistically significant phase×time interaction for GWI (GLS and myocardial work parameters between two groups and study phase.
Abbreviation: GCW, global constructive work; GLS, global longitudinal strain; GWE, global work efficiency; GWI, global work index; GWW, global wasted work.
Impact of ... | PMC10766135 | |
Regression analyses of the changes in GWI and GCW | REGRESSION | Univariate linear regression analysis showed the intensive treatment was significantly associated with ΔGCW (Univariate and multivariate linear regression analysis showing associations of clinical variables and the change of echocardiographic variables with the change of global work index and global constructive work.
... | PMC10766135 | |
Evaluation of intra‐ and interobserver variabilities | The Bland–Altman plots and ICC analysis of inter‐ and intraobserver agreement are shown in Supporting Information: Figure | PMC10766135 | ||
DISCUSSION | HF, cardiovascular death, LV systolic dysfunction, hypertensive, heart failure, hypertension | ACUTE MYOCARDIAL INFARCTION, HEART FAILURE, HYPERTENSION | We first examined the association of MW parameters and intensive BP treatment. Our findings indicated a significant reduction in GWI and GCW from phase 1 to phase 2 in the intensive treatment group. The standard treatment group exhibited no significant alterations in GWI and GCW. Intensive treatment was also independen... | PMC10766135 |
LIMITATIONS | EVENTS | This study's limitations need to be discussed. Our phase 2 data were insufficient to examine cardiovascular events and mortality. Therefore, we could not determine the MW parameters' prognostic threshold values, which prevented us from demonstrating how MW parameters would affect the study's endpoint. Otherwise, no ech... | PMC10766135 | |
CONCLUSIONS | hypertension, hypertensive | HYPERTENSION | Our study demonstrated that MW parameters were more sensitive to the changes of systolic function during intensive BP treatment than traditional parameters. Furthermore, intensive BP treatment was associated with reduced GWI and GCW in the elderly hypertensive patients. GWW increased and GWE declined in the both groups... | PMC10766135 |
AUTHOR CONTRIBUTIONS | All authors have made an important scientific contribution to the study. Yingqing Feng and Linghui Tang participated in study design. Xiaoxuan Feng, Mengqi Yan, Shiping Wu, and Yingqing Feng contributed to data analysis and interpretation. Xiaoxuan Feng, Mengqi Yan, Linghui Tang, Dan Zhou, and Yingqing Feng were respon... | PMC10766135 | ||
CONFLICT OF INTEREST STATEMENT | The authors declare no conflict of interest. | PMC10766135 | ||
Supporting information | Supporting information.Click here for additional data file.Supporting information.Click here for additional data file.Supporting information.Click here for additional data file. | PMC10766135 | ||
ACKNOWLEDGMENTS | Hypertensive | BLOOD, CARDIOVASCULAR DISEASE, CORONARY HEART DISEASE | We are grateful for the contributions made by each and every one of the people who work on the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial. We also appreciate the time and effort contributed by all participants in our study. This research was supported by the Key R&D Progra... | PMC10766135 |
DATA AVAILABILITY STATEMENT | All data relevant to the study are included in the article. The datasets used and/or analyzed during this investigation are available upon reasonable request from the corresponding author | PMC10766135 | ||
REFERENCES | PMC10766135 | |||
Objective | MPIM on infantile eczema | Edited by: Patricia C. Heyn, Marymount University, United StatesReviewed by: Mojtaba Vaismoradi, Nord University, Norway; Pernilla Garmy, Kristianstad University, SwedenThis article was submitted to Family Medicine and Primary Care, a section of the journal Frontiers in Public HealthTo observe the influence of MPIM on ... | PMC9875301 | |
Methods | eczema | ECZEMA | This trial was a randomized controlled study. Sixty-six full-term infants with eczema were randomly divided into eczema control group (EC group, | PMC9875301 |
Results | Overall, 31 cases in HC group, 31 in EC group and 32 in EM group were included for data analysis. There were no significant differences in the indexes of infantile growth among the three groups (all | PMC9875301 | ||
Conclusion | depression, anxiety, infantile eczema | REMISSION, INFANTILE ECZEMA | MPIM could effectively promote the remission of infantile eczema and reduce its relapse, along with relieving maternal anxiety and depression mood. | PMC9875301 |
Clinical trial registration | Identifier: ChiCTR2200066246. | PMC9875301 | ||
Introduction | atopic eczema, xerosis, pruritus, Eczema, MPIM on infantile eczema, eczema | ATOPIC ECZEMA, ATOPIC DERMATITIS, XEROSIS, ECZEMA, ECZEMA | Eczema, also known as atopic eczema or atopic dermatitis, is a chronic relapsing inflammatory dermatosis characterized by pruritus, xerosis and a close association with immunoglobulin E (IgE)- mediated sensitization to aeroallergens and foods (It is noteworthy that eczema in infants also negatively influences maternal ... | PMC9875301 |
Methods | PMC9875301 | |||
Trial design | eczema | ECZEMA | The study used a prospective block-controlled randomized design shown in Flowchart of this study. MPIM, mother-performed infant massage; HC group, healthy control group; EC group, eczema control group; EM group, eczema MPIM group. | PMC9875301 |
Inclusion criteria | atopic, atopic dermatitis, eczema, infantile eczema | ATOPIC DERMATITIS, ATOPIC, INFANTILE ECZEMA, DISEASES, ECZEMA | For the infants with eczema:(1) full-term infant at or under 12 months old; (2) diagnosed as infantile eczema based on the clinical criteria for pediatric atopic dermatitis (For the healthy infants: (1) same as (1) and (3) for the infants with eczema above; (2) infants without any history of obvious visceral and functi... | PMC9875301 |
Exclusion criteria | infection, visceral disease or dysfunction, eczema | INFECTION, ECZEMA | For the infants with eczema: (1) preterm infants or infant over 1 year old; (2) infant with any visceral disease or dysfunction except for eczema; (3) infant with infection, or the history of topical and systemic application of corticosteroids, antihistamines, antibiotics agents, traditional Chinese herbs or other spec... | PMC9875301 |
Interventions | This study was a 5-month-long intervention study, which included the first 2-month intervention with regular supervision and the latter 3-month intervention without any supervision (shown in The protocol of the study.tif. | PMC9875301 | ||
Protocol in the HC group | Infants and mothers in the HC group received none of any specific intervention, except for the assessment at the three timepoints. | PMC9875301 | ||
Protocol in the EC group | skin irritants, infantile eczema | INFANTILE ECZEMA | The mothers in the EC group only received the instruction of routine care from one investigator for about half an hour in a small group of 3–5 mothers according to their convenience after the baseline observation. The tips of routine care for infantile eczema included the avoidance of skin irritants and allergens, avoi... | PMC9875301 |
Protocol in the EM group | The mothers in the EM group were also instructed with the same routine care as the EC group and infant massage. The mothers were instructed with infant massage by the investigator for about 1 h in a small group of 3–5 mothers according to their convenience after the baseline observation, following the instruction about... | PMC9875301 | ||
Outcome observation | PMC9875301 | |||
Weight, length, head circumference and BMI in infants | The weight, length and head circumference in infants were measured to assess infant's physical growth at the baseline, at the end of the 2- and 5-month intervention by one investigator, who was blinded from group division. The weight and length were measured by using an intelligent physical examination instrument (WS-R... | PMC9875301 | ||
Eczema severity | Eczema, eczema | ECZEMA, ECZEMA | Eczema severity was assessed by using the eczema area and severity index (EASI) at the baseline and the end of the 2-month intervention, which was conducted by one blinded investigator. EASI is a simple, reliable and easily understood system, which can be used by practitioners and investigators as a baseline evaluation... | PMC9875301 |
Quality of life in infants with eczema | dermatitis, eczema | DERMATITIS, ECZEMA | The quality of life (QOL) in infants with eczema was evaluated by their mothers using the infants' dermatitis quality of life index (IDQOL) at the baseline and the end of the 2-month intervention. IDQOL is an easy and sensitive method with good reproducibility for parents to assess QOL impairment in infants with eczema... | PMC9875301 |
Mental state in mothers | depression, anxiety | Maternal anxiety and depression levels were evaluated, respectively by using SAS and SDS to investigate their mental state. Mothers in the three groups completed SAS and SDS questionnaires at the baseline and the end of the 2-month intervention. SAS and SDS were designed to quantify the severity of anxiety and depressi... | PMC9875301 | |
Adverse event | impairment of skin, continuous crying, eating and bowel movement | ADVERSE EVENTS | During the study, the mothers and investigators observed whether there were any adverse events in the infants after intervention, including any local impairment of skin, continuous crying, any abnormal change in sleep, eating and bowel movement. | PMC9875301 |
Observation on the relapse of eczema | infantile eczema | INFANTILE ECZEMA | Since infantile eczema is a chronic relapsing inflammatory dermatosis ( | PMC9875301 |
Statistical analysis | The one-way ANOVA and χ2 test were performed to compare baseline data among groups. The repeated-measures ANOVA was performed to compare infantile growth data among groups. The student's | PMC9875301 | ||
Results | PMC9875301 | |||
Demographical data of infant-mother dyads | eczema | ECZEMA | Thirty-one dyads and 63 dyads completed the study. The demographical profile of these infant-mother dyads is shown in Demographical data of infant-mother dyads.Data are presented as the mean ± standard deviation or n/n.HC, healthy control; EC, eczema control; EM, eczema with mother-performed infant massage. | PMC9875301 |
Weight, length, head circumference and BMI in infants | As shown in Comparison of infantile growth indexes at three timepoints. | PMC9875301 | ||
Safety observation of MPIM | ADVERSE EVENTS | During the study, none of any obviously adverse events was observed and reported following MPIM or routine care except for temporal crying during BP only on the first several days in 4 cases in the EM group. | PMC9875301 | |
Adherence in routine care or MPIM | This study was also designed to observe maternal adherence condition during the latter 3-month intervention without any supervision from investigators. The investigator asked about (1) whether the mothers persisted in following instructed routine care in the EC and EM groups; (2) how often MPIM was conducted in the EM ... | PMC9875301 | ||
Discussion | anxious mood, impaired infantile, anxiety, allergic manifestation, depression, depressive, infantile eczema, MPIM on infantile eczema, eczema | INFANTILE ECZEMA, REMISSION, ECZEMA, INFANTILE ECZEMA | This study aimed to observe the potentially positive effect of MPIM on infantile eczema, growth and the mental state in mothers. This study indicated that infantile eczema impaired infantile quality of life and negatively influenced maternal mental state. Infantile eczema improved over time after mothers followed the i... | PMC9875301 |
Limitations | eczema | ECZEMA | There are some limitations in this study. Firstly, for the convenient implementation in this pilot study, it was designed to enroll participants from one community, which might influence the real intervention effects. Secondly, this study was designed not to supervise the implementation of MPIM during the latter 3 mont... | PMC9875301 |
Conclusion | depression, anxiety, eczema | REMISSION, ECZEMA, INFANTILE ECZEMA | In conclusion, this study demonstrated for the first time that MPIM enhanced the remission of infantile eczema, reduced the relapse rate and improved maternal depression and anxiety mood. Given its safety, cost-effectiveness and feasibility, MPIM may be recommended as a routine home healthcare method for infants with e... | PMC9875301 |
Data availability statement | The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author. | PMC9875301 | ||
Ethics statement | The studies involving human participants were reviewed and approved by Ethics Committee of Jiangsu Provincial Hospital of Intergrated Chinese and Western Medicine. Number of ethics approval: 2020LWKY010. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. | PMC9875301 | ||
Author contributions | YX contributed to the conception and design of the study. LY and JL participated in the design of the manuscript and collected data. LL and YX drafted the manuscript. LL and SZ analyzed data. All authors contributed to manuscript revision, read, and approved the submitted version.We would like to thank the staffs in th... | PMC9875301 | ||
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. | PMC9875301 |
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