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Journal of Cachexia, Sarcopenia and... Jun 2024Proliferating cancer cells shift their metabolism towards glycolysis, even in the presence of oxygen, to especially generate glycolytic intermediates as substrates for...
BACKGROUND
Proliferating cancer cells shift their metabolism towards glycolysis, even in the presence of oxygen, to especially generate glycolytic intermediates as substrates for anabolic reactions. We hypothesize that a similar metabolic remodelling occurs during skeletal muscle hypertrophy.
METHODS
We used mass spectrometry in hypertrophying C2C12 myotubes in vitro and plantaris mouse muscle in vivo and assessed metabolomic changes and the incorporation of the [U-C]glucose tracer. We performed enzyme inhibition of the key serine synthesis pathway enzyme phosphoglycerate dehydrogenase (Phgdh) for further mechanistic analysis and conducted a systematic review to align any changes in metabolomics during muscle growth with published findings. Finally, the UK Biobank was used to link the findings to population level.
RESULTS
The metabolomics analysis in myotubes revealed insulin-like growth factor-1 (IGF-1)-induced altered metabolite concentrations in anabolic pathways such as pentose phosphate (ribose-5-phosphate/ribulose-5-phosphate: +40%; P = 0.01) and serine synthesis pathway (serine: -36.8%; P = 0.009). Like the hypertrophy stimulation with IGF-1 in myotubes in vitro, the concentration of the dipeptide l-carnosine was decreased by 26.6% (P = 0.001) during skeletal muscle growth in vivo. However, phosphorylated sugar (glucose-6-phosphate, fructose-6-phosphate or glucose-1-phosphate) decreased by 32.2% (P = 0.004) in the overloaded muscle in vivo while increasing in the IGF-1-stimulated myotubes in vitro. The systematic review revealed that 10 metabolites linked to muscle hypertrophy were directly associated with glycolysis and its interconnected anabolic pathways. We demonstrated that labelled carbon from [U-C]glucose is increasingly incorporated by ~13% (P = 0.001) into the non-essential amino acids in hypertrophying myotubes, which is accompanied by an increased depletion of media serine (P = 0.006). The inhibition of Phgdh suppressed muscle protein synthesis in growing myotubes by 58.1% (P < 0.001), highlighting the importance of the serine synthesis pathway for maintaining muscle size. Utilizing data from the UK Biobank (n = 450 243), we then discerned genetic variations linked to the serine synthesis pathway (PHGDH and PSPH) and to its downstream enzyme (SHMT1), revealing their association with appendicular lean mass in humans (P < 5.0e-8).
CONCLUSIONS
Understanding the mechanisms that regulate skeletal muscle mass will help in developing effective treatments for muscle weakness. Our results provide evidence for the metabolic rewiring of glycolytic intermediates into anabolic pathways during muscle growth, such as in serine synthesis.
Topics: Glucose; Muscle, Skeletal; Animals; Mice; Humans; Hypertrophy; Muscle Fibers, Skeletal; Insulin-Like Growth Factor I; Metabolomics
PubMed: 38742477
DOI: 10.1002/jcsm.13468 -
PloS One 2024Multiple sclerosis (MS) is a chronic progressive autoimmune disorder of the central nervous system (CNS) that can cause inflammation, demyelination, and axon... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND OBJECTIVE
Multiple sclerosis (MS) is a chronic progressive autoimmune disorder of the central nervous system (CNS) that can cause inflammation, demyelination, and axon degeneration. Insulin-like growth factor-1 (IGF-1) is a single-chain polypeptide mainly synthesized in the liver and brain. IGF-1 causes neuronal and non-neuronal cell proliferation, survival, and differentiation. Therefore, it can be used in treating neuro-demyelinating diseases such as MS. The current systematic review and meta-analysis aims to compare the levels of IGF-1 in MS patients and healthy controls and also investigates IGF binding proteins (IGF-BP) and growth hormone (GH) levels between MS patients and healthy controls.
METHODS
In this study, we systematically searched electronic databases of PubMed, Scopus, Web of Science (WOS), and Google Scholar, up to December 2022. Studies that measured IGF-1, GH, IGFBP-1, IGFBP-2, or IGFBP-3 in MS patients and healthy controls in either blood or cerebral spinal fluid (CSF) were identified. We calculated Standardized mean differences (SMD) to compare levels of IGF-1, GH, IGFBP-1, IGFBP-2, or IGFBP-3 in MS patients and controls.
RESULTS
Finally, we included 11 eligible studies from 1998 to 2018. The sample size of included studies varied from 20 to 200 resulting in a total sample size of 1067 individuals, 531 MS patients, and 536 healthy controls. The mean age of the patient and control groups were 38.96 and 39.38, respectively. The average EDSS among patients was 4.56. We found that blood levels of IGF-1 (SMD = 0.20, 95% CI = -0.20 to 0.59, I2 = 82.4%, K = 8, n = 692), CSF level of IGF-1 (SMD = 0.25, 95% CI = -0.06 to 0.56, I2 = 0.0%, K = 3 n = 164) and blood levels of GH were not significantly higher in MS patients than controls (SMD = 0.08, 95% CI = -0.33 to 0.49, I2 = 77.0% K = 3, n = 421). Moreover, the blood levels of IGFBP-1 (SMD = 0.70, 95% CI = 0.01 to 1.40, I2 = 77%, K = 4, n = 255) were significantly higher in MS cases than in controls. However, the blood levels of IGFBP-2 (SMD = 0.43, 95% CI = -0.34 to 1.21, I2 = 64.2%, K = 3, n = 78) and blood levels of IGFBP-3 (SMD = 1.04, 95% CI = -0.09 to 2.17, I2 = 95.6%, K = 6, n = 443) were not significantly higher in patients than controls.
CONCLUSION
Our meta-analysis revealed no significant difference in serum levels of IGF-1, GH, IGFBP-2, and IGFBP-3 between the MS group and healthy controls, except for IGFBP1. However, our systematic review showed that the studies were controversial for IGFBP-3 serum levels. Some studies found an increase in serum level of IGFBP-3 in MS patients compared to the healthy group, while others showed a decrease.
Topics: Humans; Insulin-Like Growth Factor I; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 2; Multiple Sclerosis; Insulin-Like Peptides; Insulin-Like Growth Factor Binding Proteins
PubMed: 38630771
DOI: 10.1371/journal.pone.0297091 -
International Journal of Molecular... Apr 2024This study examines the impact of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2) on various aspects of children's health-from the realms... (Review)
Review
This study examines the impact of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2) on various aspects of children's health-from the realms of growth and puberty to the nuanced characteristics of metabolic syndrome, diabetes, liver pathology, carcinogenic potential, and cardiovascular disorders. A comprehensive literature review was conducted using PubMed, with a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method employing specific keywords related to child health, obesity, and insulin-like growth factors. This study reveals associations between insulin-like growth factor 1 and birth weight, early growth, and adiposity. Moreover, insulin-like growth factors play a pivotal role in regulating bone development and height during childhood, with potential implications for puberty onset. This research uncovers insulin-like growth factor 1 and insulin-like growth factor 2 as potential biomarkers and therapeutic targets for metabolic dysfunction-associated liver disease and hepatocellular carcinoma, and it also highlights the association between insulin-like growth factors (IGFs) and cancer. Additionally, this research explores the impact of insulin-like growth factors on cardiovascular health, noting their role in cardiomyocyte hypertrophy. Insulin-like growth factors play vital roles in human physiology, influencing growth and development from fetal stages to adulthood. The impact of maternal obesity on children's IGF levels is complex, influencing growth and carrying potential metabolic consequences. Imbalances in IGF levels are linked to a range of health conditions (e.g., insulin resistance, glucose intolerance, metabolic syndrome, and diabetes), prompting researchers to seek novel therapies and preventive strategies, offering challenges and opportunities in healthcare.
Topics: Pregnancy; Child; Female; Humans; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Metabolic Syndrome; Obesity; Insulin-Like Peptides; Diabetes Mellitus
PubMed: 38612776
DOI: 10.3390/ijms25073966 -
Experimental Gerontology Jun 2024The effects of tamoxifen on the serum levels of hormones and acute phase reactants have been studied previously, but study results have been inconsistent, especially in... (Meta-Analysis)
Meta-Analysis Review
The effect of tamoxifen on estradiol, SHBG, IGF-1, and CRP in women with breast cancer or at risk of developing breast cancer: a meta-analysis of randomized controlled trials.
BACKGROUND AND AIM
The effects of tamoxifen on the serum levels of hormones and acute phase reactants have been studied previously, but study results have been inconsistent, especially in women with breast cancer. Hence, we conducted this meta-analysis of randomized controlled trials (RCTs) to try to clarify the effects of tamoxifen on estradiol, insulin-like growth factor 1 (IGF-1), sex hormone binding globulin (SHBG), and C-reactive protein (CRP) serum levels in women with breast cancer or at risk of developing breast cancer.
METHODS
Databases were systematically searched up to December 2023. The meta-analysis was generated through a random-effects model and is presented as the weighted mean difference (WMD) and 95 % confidence intervals (CI).
RESULTS
Nine publications were included in the present meta-analysis. The comprehensive findings from the random-effects model revealed an elevation in estradiol (WMD: 13.04 pg/mL, 95 % CI: 0.79, 25.30, p = 0.037) and SHBG levels (WMD: 21.26 nmol/l, 95 % CI: 14.85, 27.68, p = 0.000), as well as a reduction in IGF-1 (WMD: -14.41 μg/L, 95 % CI: -24.23, -4.60, p = 0.004) and CRP concentrations (WMD: -1.17 mg/dL, 95 % CI: -2.29, -0.05, p = 0.039) following treatment with tamoxifen in women with breast cancer or at risk of developing breast cancer, with no impact on IGFBP-3 levels (WMD: 0.11 μg/mL, 95 % CI: -0.07, 0.30, p = 0.240).
CONCLUSION
Tamoxifen administration seems to increase estradiol and SHBG levels and reduce CRP and IGF-1 levels in women with breast cancer or at risk of developing breast cancer. Further studies are needed to determine whether these changes have any clinical relevance.
Topics: Humans; Tamoxifen; Breast Neoplasms; Insulin-Like Growth Factor I; Female; Sex Hormone-Binding Globulin; C-Reactive Protein; Estradiol; Randomized Controlled Trials as Topic; Antineoplastic Agents, Hormonal
PubMed: 38608792
DOI: 10.1016/j.exger.2024.112431 -
Phytomedicine : International Journal... Jul 2024Over years, there has been a widespread quest for effective dietary patterns and natural extracts to mitigate prostate cancer risk. However, despite numerous... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Over years, there has been a widespread quest for effective dietary patterns and natural extracts to mitigate prostate cancer risk. However, despite numerous experimental studies conducted on various natural extracts, the evidence substantiating their efficacy remains largely insufficient. This dearth of compelling evidence presents a significant challenge in advocating for their widespread use as preventive measures against prostate cancer.
OBJECTIVE
Our study endeavors to undertake a network meta-analysis to evaluate the influence of natural extracts on prostate cancer.
METHODS
Researchers systematically searched through Embase, PubMed, Cochrane Library, and Web of Science databases until December 2023. The main focus was on assessing primary outcomes comprising prostate-specific antigen (PSA), insulin-like growth factor-binding protein-3 (IGFBP-3), insulin-like growth factor-1 (IGF-1). We conducted data analysis utilizing StataMP 15.0 software. Therapeutic effects were ranked based on the probability values derived from Surface Under the Cumulative Ranking curve (SUCRA). Additionally, cluster analysis was employed to assess the impacts of natural extracts on three distinct outcomes.
RESULTS
Following screening procedures, the 28 eligible studies were incorporated, the selected studies encompassed 1,566 prostate cancer patients and evaluated 16 different natural extract treatments. Specifically, 24 trials included PSA indicators, 10 included IGF-1 indicators, and 8 included IGFBP-3 indicators. The findings revealed that, based on the SUCRA values, the combined therapy of silybin with selenium (74%) appears to be the most effective approach for reducing serum PSA levels. Simultaneously, silybin alone (84.6%) stands out as the most promising option for decreasing serum IGF-1 levels. Lastly, concerning IGFBP-3, silybin alone (67.7%) emerges as the optimal choice. Twelve studies provided comprehensive information on adverse drug reactions/events (ADR/ADE), whereas five articles did not report any significant ADR/ADE.
CONCLUSION
The NMA suggests that, compared to placebo, utilizing silybin either alone or in combination with selenium has been shown to enhance therapeutic effects, offering potential benefits to patients with prostate cancer. This study can offer valuable insights for prostate patients considering natural extract treatments. Further evidence is required to confirm the safety profile of these treatments.
Topics: Male; Prostatic Neoplasms; Humans; Insulin-Like Growth Factor I; Insulin-Like Growth Factor Binding Protein 3; Network Meta-Analysis; Prostate-Specific Antigen; Plant Extracts; Biological Products
PubMed: 38608596
DOI: 10.1016/j.phymed.2024.155598 -
Clinical Endocrinology Jun 2024Pseudoacromegaly encompasses conditions with features of acromegaly/gigantism, but no growth hormone (GH) or insulin-like growth factor-1 (IGF-1) excess. We aimed to...
OBJECTIVE
Pseudoacromegaly encompasses conditions with features of acromegaly/gigantism, but no growth hormone (GH) or insulin-like growth factor-1 (IGF-1) excess. We aimed to review published pseudoacromegaly cases evaluated due to clinical suspicion of acromegaly.
DESIGN/PATIENTS
PubMed/Medline search was conducted to identify reported pseudoacromegaly cases, which were systematically reviewed to ensure they met eligibility criteria: (1) presentation suggestive of acromegaly; (2) acromegaly excluded based on normal GH, IGF-1 and/or GH suppression on oral glucose tolerance test (OGTT-GH); (3) diagnosis of the pseudoacromegaly condition was established. Data were retrieved from each case and analysed collectively.
RESULTS
Of 76 cases, 47 were males, mean ages at presentation and at first acromegaloid symptoms were 28 ± 16 and 17 ± 10 years, respectively. Most common conditions were pachydermoperiostosis (47%) and insulin-mediated pseudoacromegaly (IMP) (24%). Acromegaloid facies (75%) and acral enlargement (80%) were the most common features. Measurement of random GH was reported in 65%, IGF-1 in 79%, OGTT-GH in 51%. GH excess was more frequently excluded based on two tests (53%). Magnetic resonance imaging (MRI) was performed in 30 patients, with pituitary adenoma or hyperplasia being reported in eight and three patients, respectively. Investigations differed between cases managed by endocrine and non-endocrine specialists, the former requesting more often IGF-1, OGTT-GH and pituitary MRI.
CONCLUSIONS
Pseudoacromegaly is a challenging entity that may be encountered by endocrinologists. Pachydermoperiostosis and IMP are the conditions most often mimicking acromegaly. Adequate assessment of GH/IGF-1 is crucial to exclude acromegaly, which may be better performed by endocrinologists. Pituitary incidentalomas are common and require careful judgement to prevent unnecessary pituitary surgery.
Topics: Humans; Acromegaly; Male; Insulin-Like Growth Factor I; Female; Adult; Human Growth Hormone; Gigantism; Glucose Tolerance Test; Adolescent; Young Adult
PubMed: 38549284
DOI: 10.1111/cen.15053 -
Growth Hormone & IGF Research :... Apr 2024Hormonal substitution with growth hormone in aged patients remains a debated research topic and is rarely initiated in clinical practice. This reluctance may originate... (Review)
Review
OBJECTIVE
Hormonal substitution with growth hormone in aged patients remains a debated research topic and is rarely initiated in clinical practice. This reluctance may originate from concerns about adverse effects and the uncritical use as an anti-aging agent. Nevertheless, beneficial effects for selected patients suffering from certain acute and chronic illnesses could justify its use at an advanced age. This systematic review analyzes randomized controlled studies of GH interventions in older patients with different comorbidities to assess both, beneficial and harmful effects.
DESIGN
A systematic search strategy was implemented to identify relevant studies from PubMed, MEDLINE, and The Cochrane Library.
INCLUSION CRITERIA
participants aged over 65 years, randomized controlled trials involving human growth hormone (GH) and presence of at least one additional comorbidity independent of a flawed somatotropic axis.
RESULTS
The eight eligible studies encompassed various comorbidities including osteoporosis, frailty, chronic heart failure, hip fracture, amyotrophic lateral sclerosis and hemodialysis. Outcomes varied, including changes in body composition, physical performance, strength, bone mineral density, cardiovascular parameters, quality of life and housing situation. Study protocols differed greatly in GH application frequency (daily, 2nd day or 3×/week), doses (0.41 mg-2.6 mg; mean 1.3 mg per 60 kg patient) and duration (1-12 months; mean 7 months). Mild dose-related side effects were reported, alongside noticeable positive impacts particularly on body composition, functionality, and quality of life.
CONCLUSION
Despite limited evidence, GH treatment might offer diverse benefits with few adverse effects. Further research with IGF-I dependent indication and clear outcomes, incorporating IGF-I dependent GH titration in older adults is warranted.
Topics: Aged; Humans; Comorbidity; Growth Hormone; Human Growth Hormone; Insulin-Like Growth Factor I; Quality of Life; Randomized Controlled Trials as Topic; Aging
PubMed: 38489867
DOI: 10.1016/j.ghir.2024.101584 -
Endocrinology, Diabetes & Metabolism Mar 2024Insulin-like growth factor-2 (IGF-2)-mediated hypoglycemia is a rare yet clinically significant entity with considerable morbidity and mortality. Existing literature is... (Review)
Review
INTRODUCTION
Insulin-like growth factor-2 (IGF-2)-mediated hypoglycemia is a rare yet clinically significant entity with considerable morbidity and mortality. Existing literature is limited and fails to offer a comprehensive understanding of its clinical trajectory, management and prognostication.
METHODS
Systematic review of English-language articles reporting primary patient data on IMH was searched using electronic databases (PubMed, Scopus and Embase) from any date up to 21 December 2022. Data were analysed in STATA-16.
RESULTS
The systematic review contains 172 studies, including 1 Randomised controlled trial, 1 prospective observational study, 5 retrospective observational studies, 150 case reports, 11 case series and 4 conference abstracts. A total of 233 patients were analysed, averaging 60.6 ± 17.1 years in age, with comparable proportions of males and females. The commonest tumours associated with Insulin-like Growth Factor-2-mediated hypoglycaemia were fibrous tumours (N = 124, 53.2%), followed by non-fibrous tumours originating from the liver (N = 21, 9%), hemangiopericytomas (N = 20, 8.5%) and mesotheliomas (N = 11, 4.7%). Hypoglycaemia was the presenting feature of NICT in 42% of cases. Predominant clinical features included loss of consciousness (26.7%) and confusion (21%). The mean IGF-2 and IGF-1 levels were 882.3 ± 630.6 ng/dL and 41.8 ± 47.8, respectively, with no significant correlation between these levels and patient outcomes. Surgical removal was the most employed treatment modality (47.2%), followed by medication therapy. The recovery rate was 77%, with chronic liver disease (CLD) significantly associated with a poor outcome (OR: 7.23, P: 0.03). Tumours originating from fibrous tissues were significantly associated with recovery (p < .001). In the logistic regression model, CLD remained a significant predictor of poor outcomes.
CONCLUSION
This systematic review highlights that most non-islet-cell tumour-hypoglycaemia (NICTH) is due to fibrous tumours. NICTs demonstrate a variable prognosis, which is fair if originating from fibrous tissue. Management such as octreotide, corticosteroids, diazoxide, embolization, radiotherapy and surgical resection have disparate success rates.
Topics: Male; Female; Humans; Insulin-Like Growth Factor II; Insulin-Like Peptides; Retrospective Studies; Hypoglycemia; Observational Studies as Topic
PubMed: 38411039
DOI: 10.1002/edm2.471 -
The Laryngoscope Jul 2024To assess whether adenotonsillectomy improves levels of inflammatory and cardiometabolic markers in children with polysomnographically diagnosed obstructive sleep apnea... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To assess whether adenotonsillectomy improves levels of inflammatory and cardiometabolic markers in children with polysomnographically diagnosed obstructive sleep apnea (OSA).
DATA SOURCES
Two authors independently searched PubMed, Embase, and Cochrane databases up to August 16, 2022, for studies relating to pre- and post-operative levels of serum markers in pediatric patients undergoing adenotonsillectomy.
REVIEW METHODS
Data were extracted from included articles into a structured proforma. Meta-analyses of the standardized mean difference (SMD) were conducted in random-effects models. We calculated the probability of benefit (POB) and number needed to treat (NNT) for outcomes that demonstrated a statistically significant effect after adenotonsillectomy. The primary outcomes were changes in serum markers including C-reactive protein (CRP), high-sensitivity CRP (hs-CRP), Insulin-like growth factor 1 (IGF-1), interleukin-10 (IL-10), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), Brain natriuretic peptide (BNP), insulin, glucose, total cholesterol, triglyceride, low-density lipoprotein (LDL), high-density lipoprotein (HDL).
RESULTS
We screened 1616 studies and included 26 studies with 1331 participants. Meta-analysis was performed on 20 of the included studies. Adenotonsillectomy was associated with a significant decrease in insulin levels (SMD = -0.322, 95% Confidence Interval (CI) = -0.583 to -0.061), CRP (SMD = -0.946, 95% CI = -1.578 to -0.314), and BNP (SMD = -1.416, 95% CI = -2.355 to -0.477) and significant increase in levels of IGF-1 (SMD = 0.691, 95% CI = 0.207 to 1.176). There were no significant changes in levels of triglyceride, total cholesterol, TNF-α, LDL, HDL, glucose, IL-10, and IL-6.
CONCLUSION
In children with polysomnographically diagnosed OSA, adenotonsillectomy was associated with improvements in serum biomarkers, comprising lower CRP, insulin, and BNP, and higher IGF-1. Laryngoscope, 134:3030-3037, 2024.
Topics: Humans; Sleep Apnea, Obstructive; Tonsillectomy; Adenoidectomy; Biomarkers; Child; C-Reactive Protein; Interleukin-10; Interleukin-6; Insulin-Like Growth Factor I; Tumor Necrosis Factor-alpha; Natriuretic Peptide, Brain; Child, Preschool
PubMed: 38380991
DOI: 10.1002/lary.31249 -
Journal of Psychiatric Research Jan 2024Leptin and insulin-like growth factor-1 (IGF-1) may play a role in clinical identification of post-stroke depression (PSD). Here, eight databases (including CNKI,... (Meta-Analysis)
Meta-Analysis Review
Leptin and insulin-like growth factor-1 (IGF-1) may play a role in clinical identification of post-stroke depression (PSD). Here, eight databases (including CNKI, Wanfang, SinoMed, VIP, PubMed, the Cochrane Library, Embase, and the Web of Science) were employed to search for studies on serum leptin and insulin-like growth factor-1 expression levels in patients with PSD. In total, 13 articles were included, of which 6 studies investigated the expression level of serum leptin in patients with PSD, 7 studies explored the serum IGF-1 in PSD patients. Then, the RevMan 5.4 software was used for meta-analysis. The results showed that serum leptin levels were significantly higher in PSD patients than in patients without PSD (SMD = 1.54, 95% CI: 0.84, 2.23; P = 0.006). The result of subgroup analysis showed that the serum leptin levels in PSD patients were significantly higher than those without PSD in acute phase (SMD = 1.38, 95% CI: 0.04, 2.71; P = 0.04), subacute phase (SMD = 2.31, 95% CI: 0.88, 3.73; P = 0.001), and chronic phase (SMD = 1.02, 95% CI: 0.43, 1.60; P = 0.0007); There was no significant difference in serum IGF-1 level between PSD patients and patients without PSD (SMD = 0.49, 95% CI: -0.55, 1.52; P = 0.36). Moreover, the subgroup analysis also showed that there was no statistical difference in acute stage (SMD = 0.36, 95% CI: 0.89, 1.60; P = 0.57). Our study provides evidence to prove that serum leptin level has potential clinical application value as biomarkers for identifying PSD.
Topics: Humans; Biomarkers; Depression; Insulin-Like Growth Factor I; Insulin-Like Peptides; Leptin; Stroke
PubMed: 38091723
DOI: 10.1016/j.jpsychires.2023.12.006