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Procedures
tumor, death, toxicity, blood coagulation, Cancer
ADVERSE EVENT, TUMOR, DISEASE, ADVERSE EVENT, CPS, CANCER
This study enrolled 26 eligible patients with RM-NPC. The patients received 250 mg of apatinib orally once a day and camrelizumab 200 mg was injected intravenously once every two weeks until the disease progressed, intolerable toxicity appeared, the study was completed, or consent was withdrawn. Reduction of the dose o...
PMC10795162
Endpoints and assessment
death
DISEASE, DISEASE PROGRESSION, SECONDARY
The major endpoint was the objective response rate (ORR), which was determined by the investigators as the percentage of patients who had a complete response (CR) or a partial response (PR) according to RECIST version 1.1.The secondary endpoints were: Progression-free survival (PFS), defined as the interval between tre...
PMC10795162
Sample size calculation
This clinical trial was a single-arm study with ORR as the primary endpoint. In accordance with Simon’s optimal two-stage design (one-sided α 5% and power 80%), the intended sample size was 26 patients. The response rate (RR) of nivolumab in RM-NPC was 20.5%.(
PMC10795162
Statistical analysis
All analyses were performed for all patients who were administered with at least one dose of the research treatment. The Clopper-Pearson method was used to determine the 95% confidence interval (CI) for ORR and DCR. PFS and OS were determined using the Kaplan-Meier technique. Statistics provided clinical and demographi...
PMC10795162
Study oversight
All participating centers’ institutional review committees gave their approval for the trial program, which was carried out in compliance with the Declaration of Helsinki and the guidelines for good clinical practice. Before participating in the trial, each patient gave their informed consent in Chinese.
PMC10795162
Role of the funding source
The funders of the study had no role in study design, data collection, data analysis, data interpretation, as well as writing the report. The corresponding author had the sole responsibility for choosing to submit the report for publication, and had complete access to all the data generated during the study.
PMC10795162
Results
PMC10795162
Patient characteristics
Cancer
ONCOLOGY, VIRUS, EPSTEIN, CANCER
In stage 1 of the trial, among the seven participating patients, three patients achieved an OR. Therefore, another 16 patients were recruited in the second phase. According to the assumed 10% loss to follow-up, finally, 26 eligible patients were registered between 14 January 2021 and 15 September 2021 ((ITT and safety ...
PMC10795162
Antitumor activity
Tumor
TUMOR
All patients were subjected to efficacy analysis. Fifteen patients (57.7%) in the efficacy evaluable population had smaller target lesions than those at baseline. Among these 15 patients, 10 achieved an OR according to RESIST1.1.(Tumor responses as assessed by the investigators or independent reviewers. Survival outcom...
PMC10795162
Safety
fatigue, anemia
ADVERSE EVENT, ANEMIA
All 26 (100%) patients experienced treatment-related AEs of any grade. The most frequent AEs were anemia (57.7%), increased alkaline phosphatase (34.6%), and fatigue (30.8%) (Treatment-Related Adverse Events in Total Treated Patients (n = 26).
PMC10795162
EBV DNA, PD-L1, VEGFR-2, CD4 and CD8 expression
tumor, tumors, PD-L1-positive tumors
CPS, TUMOR, TUMORS
Plasma EBV DNA was detectable before treatment in 22 of the 26 patients, but not in 4 patients. Of the 22 detectable patients, 9 were positive and 13 were negative. Their ORRs were 55.6% (5/9) and 38.5% (5/13), respectively, and there was no significant difference (P=0.666).Among the 26 patients, 21(80.8%) had evaluabl...
PMC10795162
Discussion
tumor, cancers, bleeding
ADVERSE REACTIONS, TUMOR, INFILTRATION, CANCERS, BLEEDING, ADVERSE EVENTS
In this multicenter, single-arm, phase II, prospective clinical trial, we reported the efficacy and safety of the VEGFR2-targeting apatinib combined with PD-1 inhibitor camrelizumab in patients with RM-NPC. Our findings revealed that the ORR of patients with RM-NPC treated with apatinib plus camrelizumab was 38.5% (10/...
PMC10795162
Conclusions
toxicity
Our findings indicated that in patients with RM-NPC, camrelizumab plus apatinib exhibited promising antitumor efficacy and acceptable toxicity. These results support the view that anti-angiogenic drugs combined with immunosuppressants represent a new and promising anti-tumor combination regimen for RM-NPC. To confirm o...
PMC10795162
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.
PMC10795162
Ethics statement
CROSS
The studies involving humans were approved by Affiliated Hospital of Guilin Medical University, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Wuzhou Red Cross Hospital, Laibin people’s Hospital, Lingshan County people’s Hospital. The studies were conducted in accordance with the local legislation and institut...
PMC10795162
Author contributions
HC
YM: Writing – original draft, Writing – review & editing. YufP: Writing – original draft. BZ: Writing – original draft, Writing – review & editing. JZ: Writing – original draft, Writing – review & editing. YS: Writing – original draft, Writing – review & editing. ZL: Writing – original draft, Writing – review & editing...
PMC10795162
Acknowledgments
The authors are grateful to all patients and their families who participated in the study. The authors appreciate the support from Jiangsu Hengrui Pharmaceuticals.
PMC10795162
Abbreviations
Epstein-Barr virus
NASOPHARYNGEAL CARCINOMA, ADVERSE EVENT, NASOPHARYNGEAL CARCINOMA, SOLID TUMOR, CPS, DISEASE
RM-NPC, Recurrent/metastatic nasopharyngeal carcinoma; ORR, Objective response rate; PFS, Progression-free survival; OS, Overall survival; DCR, Disease control rate; NPC, Nasopharyngeal carcinoma; EBV, Epstein-Barr virus; PD-L1, Programmed death-ligand 1; VEGF, Vascular endothelial growth factor; RECIST, Response Evalu...
PMC10795162
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.
PMC10795162
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 ...
PMC10795162
References
PMC10795162
ABSTRACT
Chagas disease
CHAGAS DISEASE
The authors declare a conflict of interest. J.A. acted as a consultant to Bayer for the design, conduct and review of the CHICO and CHICO SECURE studies. U.G. is an employee of Bayer AG (Berlin, Germany). E.H. is an employee of Bayer US LLC (Whippany, New Jersey, USA). G.M. received personal fees from Bayer during the ...
PMC10112190
KEYWORDS
PMC10112190
INTRODUCTION
infection, Chagas disease, Chagasic cardiomyopathy
AMERICAN TRYPANOSOMIASIS, DISEASE, PARASITIC DISEASE, CHAGAS DISEASE, DISORDERS, CHRONIC CHAGAS DISEASE, INFECTION
Chagas disease (American trypanosomiasis) is a potentially life-threatening parasitic disease caused by the hemoflagellate protozoan Chagas disease has two phases: an initial acute phase of 6 to 8 weeks and then, if the patient is not treated, a chronic phase, which can be indeterminate, lasting years or decades, or sy...
PMC10112190
RESULTS
PMC10112190
Patient demographics and characteristics.
Of the 330 pediatric patients randomized and treated with nifurtimox in CHICO study (Demographic and patient characteristics at baseline (full analysis set)Age was defined as the patient's age at the time of randomization in CHICO (
PMC10112190
Duration of observation.
The median duration of observation, defined as the actual number of years an individual was at risk during the study, was 4.0 years for patients in both treatment groups (Duration of observation (full analysis set)Duration of observation was the actual number of years a patient was at risk in the study, i.e., the time ...
PMC10112190
Seronegative conversion.
During the 4-year posttreatment follow-up, seronegative conversion was observed in a total of 16 (8.12%) and 8 (8.16%) patients in the 60-day and 30-day nifurtimox regimens, respectively (Number and incidence rate of seronegative conversion with nifurtimox treatment (full analysis set)Total duration of observation is t...
PMC10112190
Seroreduction.
Optical density (OD) values measured by conventional ELISAs decreased over time in both treatment regimens during the study. At the 4-year posttreatment follow-up, the reduction in mean OD values from baseline was 23.72% and 18.68% by recombinant ELISA, and 23.81% and 19.08% by total purified antigen ELISA in the 60-da...
PMC10112190
Serological response and Chagas disease-related cardiomyopathy.
cardiomyopathy
CHAGAS, CARDIOMYOPATHY
More than 90% of patients in both treatment groups showed successive negative Parasitological response of patients according to follow-up visit (full analysis set), measured by quantitative PCRData shown are No patients showed signs of established Chagas disease-related cardiomyopathy as measured by electrocardiogram (...
PMC10112190
Safety.
The safety of the nifurtimox regimens during treatment and at the 1-year follow-up has been reported previously (
PMC10112190
DISCUSSION
Chagas disease, chronic Chagas disease
CHAGAS DISEASE, CHRONIC INFECTION, CHRONIC CHAGAS DISEASE
Establishing the efficacy of antitrypanosomal therapy in patients with Chagas disease using the currently accepted criterion of treatment response is challenging. In Chagas disease, it is widely acknowledged that treatment success is difficult to measure with the current diagnostic tools because the parasites are highl...
PMC10112190
Conclusions.
Chagas disease
CHAGAS DISEASE
This study confirms the efficacy and safety of a pediatric formulation of nifurtimox administered in an age- and weight-adjusted regimen for 60 days to treat Chagas disease in pediatric patients with 4-year follow-up data. Children younger than 2 years treated with nifurtimox are more likely to show seronegative conver...
PMC10112190
MATERIALS AND METHODS
PMC10112190
Ethics statement.
Approval from the ethics committee was obtained for all participating research sites, as described above (
PMC10112190
Study design.
This was a prospective, randomized, blinded, historically controlled, parallel-group, long-term follow-up study (Study design and schedule of follow-up visits. The schedule of study visits V1 to V10 are as previously reported (
PMC10112190
Study participants.
This study included patients who were randomized to treatment and received at least one dose of their assigned treatment with nifurtimox. Prior to enrollment, written informed consent was obtained from the patient and/or their parents or legally authorized representative(s) according to age and local regulations. Depen...
PMC10112190
Outcome measures.
cardiomyopathy
CHAGAS, CARDIOMYOPATHY
The primary outcome was the incidence rate of seronegative conversion measured and confirmed by recombinant ELISA (Secondary outcomes investigated included: the incidence rate of seronegative conversion confirmed by recombinant ELISA and IHA in patients who were randomized and received at least one dose of nifurtimox i...
PMC10112190
Follow-up assessments.
CHAGAS DISEASE
At annual follow-up visits, patients underwent a physical examination, including measurements of height, weight, and vital signs. Body mass index, treatment-related AEs, and AEs caused by procedures required by the protocol were also recorded. In addition, a standard 12-lead ECG was performed at the discretion of the i...
PMC10112190
Serological tests.
BLOOD
Blood samples for
PMC10112190
Parasitological tests.
BLOOD
Blood was also collected for qPCR tests to detect the presence of
PMC10112190
Statistical analyses.
cardiomyopathy
CARDIOMYOPATHY
In the primary outcome analysis, the difference in the incidence rate of patients treated with nifurtimox with seronegative conversion (60-day regimen) and the estimated seronegative rate from a historical placebo control group was tested using a Poisson two-sided 95% exact CI. The historical control group comprised ch...
PMC10112190
Data availability.
The authors confirm that all data underlying the findings are fully available without restriction. All data files are available from the
PMC10112190
ACKNOWLEDGMENTS
We thank the study participants and their families. The CHICO SECURE Study Group members are listed in the supplemental material. We sincerely thank LAT Research, Buenos Aires, Argentina, for excellent support in conducting the study. We also wish to thank the laboratory of Stamboulian Health Services, Buenos Aires, Ar...
PMC10112190
REFERENCES
PMC10112190
Key Points
PMC10403785
Question
depressive disorder, MDD
CORTEX
Is antidepressant treatment associated with volumetric and resting-state functional connectivity (rsFC) changes over time in the dorsolateral prefrontal cortex (DLPFC) in adolescents with major depressive disorder (MDD)?
PMC10403785
Findings
MDD, depressive
In this cohort study of 95 adolescents with MDD and 57 healthy control participants, responders with at least 40% depressive symptom improvement showed increased right DLPFC volume, decreased bilateral DLPFC rsFC with the superior frontal gyri, and decreased left DLPFC rsFC with the ventromedial PFC after treatment com...
PMC10403785
Meaning
depressive disorder, depressive
CORTEX
These findings suggest that DLPFC volumetric and rsFC changes after treatment may represent one set of potential neurobiological treatment markers that are associated with depressive symptom improvement in adolescents with MDD.This cohort study examines neurobiological changes associated with selective serotonin reupta...
PMC10403785
Importance
depression
Selective serotonin reuptake inhibitors (SSRIs) are considered a first-line pharmacological treatment for adolescent depression with moderate or higher levels of symptom severity. Thus, it is important to understand neurobiological changes related to SSRIs during the course of treatment for adolescents with depression.
PMC10403785
Objective
depressive disorder, MDD
CORTEX
To examine neurobiological changes associated with SSRI treatment in adolescents with major depressive disorder (MDD) by measuring longitudinal changes in volume and resting-state functional connectivity (rsFC) in the dorsolateral prefrontal cortex (DLPFC), a core region of cognitive control.
PMC10403785
Design, Setting, and Participants
MDD
This cohort study was conducted with an open-label design. Adolescents with MDD and healthy controls were recruited at the Seoul National University Hospital (Seoul, South Korea). Adolescents with MDD were treated with escitalopram for 8 weeks. Data analysis was conducted between April 2021 and February 2022.
PMC10403785
Main Outcomes and Measures
Depressive, Depression, depressive symptoms
Depressive symptoms were assessed using the Children’s Depression Rating Scale–Revised. The outcome measure was defined as the change in Children’s Depression Rating Scale–Revised scores from week 0 (before treatment) to week 8 (after treatment) or upon termination. Participants completed structural and resting-state f...
PMC10403785
Results
MDD
Ninety-five adolescents with MDD and 57 healthy controls were initially recruited. The final analyses of volume included 36 responders (mean [SD] age, 15.0 [1.6] years; 25 girls [69.4%]) and 26 nonresponders (mean [SD] age, 15.3 [1.5] years; 19 girls [73.1%]). Analyses of rsFC included 33 responders (mean [SD] age, 15....
PMC10403785
Conclusions and Relevance
MDD
The preliminary results of this cohort study suggest that the DLPFC volumetric and rsFC changes may serve as potential neurobiological treatment markers that are associated with symptom improvement in adolescents with MDD.
PMC10403785
Introduction
MDD, depression, depressive, adolescence
PATHOPHYSIOLOGY
Antidepressants are widely used to treat depression in adolescents. Selective serotonin reuptake inhibitors (SSRIs) are known to be the most frequently prescribed antidepressantsThe literature suggests that neurobiological markers associated with the pathophysiology of depression can be targets for depression treatment...
PMC10403785
Methods
PMC10403785
Participants
MDD
Adolescents aged 12 to 17 years were recruited by the Seoul National University Hospital. Adolescents with MDD were included if they had a current diagnosis of MDD according to the
PMC10403785
SSRI Treatment Procedures
MDD
All adolescents with MDD were treated with escitalopram in an 8-week, open-label trial.
PMC10403785
Depressive Symptom Assessment
depression, Depressive, Depression
Depressive symptoms were assessed using the Children’s Depression Rating Scale–Revised (CDRS-R), which is used to evaluate depression severity in children and adolescents.
PMC10403785
Structural MRI and rsfMRI Acquisition
T1-weighted structural MRI (sMRI) and rsfMRI data were collected using a 3-T scanner (Trio; Siemens Healthineers). T1-weighted images were obtained using a T1-weighted, 3-dimensional gradient-echo pulse sequence with magnetization-prepared rapid gradient-echo sequencing. The rsfMRI data were acquired with interleaved T...
PMC10403785
sMRI and rsfMRI Preprocessing
T1 and rsfMRI data were preprocessed using FreeSurfer imaging software version 6.0 (Harvard University) and Analysis of Functional NeuroImages imaging software version 21.3.09 (National Institute of Mental Health), respectively. Details of sMRI and rsfMRI data preprocessing and all analytical methods are described in e...
PMC10403785
Examples of Dorsolateral Prefrontal Cortex (DLPFC) Seed Regions Segmented by FreeSurfer
Images show segmented DLPFC seed regions of 3 separate patients.
PMC10403785
Statistical Analysis
We calculated the volumes of the DLPFC seed regions. The extracted DLPFC volumes were exported to SPSS software version 25.0 (SPSS, Inc). We examined whether DLPFC volumes would differ between responders and nonresponders over time (week 0 vs week 8). We also extracted the average time series from the DLPFC seed region...
PMC10403785
Results
PMC10403785
Demographic and Clinical Characteristics
MDD
A total of 152 adolescents, including 95 adolescents with MDD and 57 healthy controls, were initially recruited (eTable 1 in
PMC10403785
Longitudinal Changes (Before vs After Treatment) by SSRI Treatment in Adolescents With MDD
PMC10403785
DLPFC Volumes
We found a significant group (responders vs nonresponders) by time (week 0 vs week 8) interaction in the right DLPFC volume, controlling for intracranial volume (
PMC10403785
rsFC: DLPFC Seed-Based Analysis
Group by time interactions were found on the right DLPFC rsFC with the left superior frontal gyrus (SFG) and left middle frontal gyrus (MFG) (eTable 3 in
PMC10403785
Correlations Between DLPFC Volumetric Changes and DLPFC rsFC Changes After vs Before SSRI Treatment
Given the significant longitudinal associations of SSRI treatment with volume and rsFC in the right DLPFC, we investigated how volumetric changes (week 8 minus week 0) in the right DLPFC were associated with changes in DLPFC rsFC, with 6 regions reported in eTable 3 in
PMC10403785
Correlation Between the Right Dorsolateral Prefrontal Cortex (DLPFC) Volume Change and DLPFC–Left Superior Frontal Gyrus (SFG) Resting-State Functional Connectivity (rsFC) Change in Adolescents With Major Depressive Disorder
A greater increase in the right DLPFC volume was significantly correlated with a greater reduction in rsFC between the right DLPFC and left SFG.
PMC10403785
Discussion
MDD, depression
PATHOPHYSIOLOGY
To the best of our knowledge, this cohort study is one of the first to investigate neurobiological treatment markers after SSRI treatment that are associated with clinical symptom improvement in adolescents with MDD. We also examined the associations between neurobiological treatment markers, such as DLPFC volume and D...
PMC10403785
Limitations
MDD, trauma
This study has some limitations. First, this study was conducted with an open-label design, which made it difficult to disentangle the effects of SSRI treatment from the effects of nonspecific factors (eg, expectation of improvement or knowledge of treatment). Second, this study treated all adolescents with MDD with 1 ...
PMC10403785
Conclusions
MDD
This study found longitudinal associations of SSRI treatments with both volume and rsFC in the DLPFC of adolescents with MDD using a relatively large sample. More significant longitudinal changes in the DLPFC volume and rsFC in responders may be potential treatment markers of neural plasticity that can mediate the effe...
PMC10403785
Background
SECONDARY
Serum albumin concentrations are frequently used to monitor nutritional therapy in the hospital setting but supporting studies are largely lacking. Within this secondary analysis of a randomized nutritional trial (EFFORT), we assessed whether nutritional support affects short-term changes in serum albumin concentration...
PMC10564620
Methods
We analyzed patients with available serum albumin concentrations at baseline and day 7 included in EFFORT, a Swiss-wide multicenter randomized clinical trial that compared individualized nutritional therapy with usual hospital food (control group).
PMC10564620
Results
SD
Albumin concentrations increased in 320 of 763 (41.9%) included patients (mean age 73.3 years (SD ± 12.9), 53.6% males) with no difference between patients receiving nutritional support and controls. Compared with patients that showed a decrease in albumin concentrations over 7 days, those with an increase had a lower ...
PMC10564620
Conclusion
inflammation
INFLAMMATION, SECONDARY
Results from this secondary analysis indicate that nutritional support did not increase short-term concentrations of albumin over 7 days, and changes in albumin did not correlate with response to nutritional interventions. However, an increase in albumin concentrations possibly mirroring resolution of inflammation was ...
PMC10564620
Trail Registration
ClinicalTrials.gov Identifier: NCT02517476.
PMC10564620
Subject terms
PMC10564620
Introduction
Malnutrition, Frailty
MALNOURISHED, MALNUTRITION, NUTRITIONAL DEFICIENCIES
Historically, serum albumin concentration was considered to be a marker of nutritional status and physicians monitored albumin concentrations in patients during their hospital stay. This assumption was based on the pathophysiological grounds that albumin concentration reflects circulating proteins in plasma, with lower...
PMC10564620
Material & Methods
PMC10564620
Study design and setting
SECONDARY
This is a secondary analysis of EFFORT [
PMC10564620
Patient population and management
NRS
DISEASE
EFFORT enrolled adult ( ≥ 18 years of age) medical inpatients at nutritional risk with an anticipated hospital stay of at least 5 days who were willing to give informed consent within the first 48 hours after admission. Nutritional risk was defined as a Nutritional Risk Screening (NRS 2002) score of 3 points or more. T...
PMC10564620
Research objective and outcomes
gastrointestinal failure
GASTROINTESTINAL FAILURE, RESPIRATORY FAILURE, EVENT, ACUTE RENAL FAILURE, NOSOCOMIAL INFECTION, COMPLICATIONS
We had three main goals for this analysis: first, to investigate how nutritional therapy impacts on the short-term changes in serum albumin concentrations from baseline to 7 days in the overall population and within subgroups of patients with high and low baseline albumin concentrations ( < 30 g/L or ≥ 30 g/L) [Our pri...
PMC10564620
Statistical analyses
Continuous variables are shown as means and standard deviation. Categorical and binary data are expressed as counts and percentages. Baseline characteristics were compared between patients with an increase in albumin and without an increase in albumin after 7 days using Pearson’s χ
PMC10564620
Results
PMC10564620
Patient population
From the 2088 participants of the initial trial, we had complete data on 763 patients regarding baseline and day 7 albumin concentration and all clinical outcomes (Fig.
PMC10564620
Survival of patients according to increase or decrease in albumin levels over 7 days.
Kaplan–Meier estimate for 180-days mortality for increase and decrease in serum albumin from baseline to day 7.
PMC10564620
Effect of nutritional intervention in association with kinetics of serum albumin levels
Last, we evaluated whether the effectiveness of nutritional support concerning 30-day mortality in the intervention group and control group would differ according to changes in albumin concentrations. The mortality benefit of nutritional support was independent of changes in albumin concentrations in the overall popula...
PMC10564620
Forest plot for 30-days mortality, Effect of nutritional intervention depending on kinetics of serum albumin concentrations.
OR Odds ratio, 95% CI Confidence interval.
PMC10564620
Discussion
ACUTE DISEASE, SECONDARY, DISEASE
In this secondary post-hoc analysis of a randomized clinical trial, we investigated first whether nutritional support affects short-term changes in serum albumin concentrations among medical inpatients at nutritional risk, and second, whether an increase in albumin concentrations has prognostic implications regarding c...
PMC10564620
Conclusion
inflammation
INFLAMMATION, SECONDARY
Results from this secondary analysis including medical inpatients at nutritional risk indicate that nutritional support did not increase concentrations of albumin within 7 days, and changes in serum albumin concentrations did not correlate with treatment response to nutritional interventions. However, an increase in al...
PMC10564620
Supplementary information
The online version contains supplementary material available at 10.1038/s41430-023-01303-w.
PMC10564620
Acknowledgements
We thank all patients and hospital staff for their support of our trial.
PMC10564620
Author contributions
SECONDARY
FB and PS were responsible for the data analysis and interpretation of the present secondary analysis. FB, DNL, and PS drafted the final manuscript and all authors contributed to the critical revision of the manuscript. PS was responsible for obtaining funding. PS, ZS, and BM were involved in obtaining funding, draftin...
PMC10564620
Funding
The initial trial was supported by grants from the Swiss National Science Foundation to PS and the Research Council of Kantonsspital Aarau, Switzerland. Unrelated to this trial, Nestlé Health Science and Abbott Nutrition previously provided unrestricted grant money to the institution of PS; The institution of ZS receiv...
PMC10564620
Data availability
SECONDARY
We intend to make data collected for the study, including anonymized individual participant data and a data dictionary defining each field in the set, available to others. Related documents will be available, including the trial protocol and the statistical analysis plan. These data will be available with the publicati...
PMC10564620
Competing interests
The authors declare no competing interests.
PMC10564620
References
PMC10564620