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Oxidative balance scores and gallstone disease: mediating effects of oxidative stress

Nutrition Journal volume 24, Article number: 4 (2025) Cite this article

Abstract

Background

Gallstone disease (GSD) is a prevalent gastrointestinal disorder, few studies have examined the combined effects of dietary and lifestyle factors on GSD. This study aims to investigate the relationship between oxidative balance score (OBS) and GSD, and explores the potential mediating role of oxidative stress.

Methods

Cross-sectional data from 6,196 participants in the NHANES 2017–2020 were analyzed. OBS, encompassing 16 dietary and 4 lifestyle factors, was assessed alongside GSD prevalence. Weighted multivariate logistic regression, restricted cubic spline (RCS) analysis were used to explore the relationship between OBS and GSD and mediation analysis was used to test the indirect effect of oxidative stress indicators. Subgroup analysis and sensitivity analysis were used to determine the stability of results.

Results

A higher OBS was significantly associated with a reduced risk of GSD (OR: 0.701, 95% CI: 0.492–0.999, P < 0.05). RCS analysis revealed a linear association between OBS and GSD risk. Mediation analysis indicated significant mediating effects of albumin and uric acid, with a combined mediation proportion of 19.540% (P < 0.05). Subgroup analysis revealed differences and interrelationships based on education level, providing additional insights into the relationship between OBS and GSD and sensitivity analysis confirmed the stability of these associations.

Conclusions

A higher OBS is associated with a reduced risk of GSD, especially among higher education levels groups, and albumin, uric acid may act as mediators of this association. These findings underscore the potential role of oxidative stress in GSD and the significance of maintaining a healthy diet and lifestyle to decrease GSD risk.

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Introduction

Gallstone disease (GSD) is a prevalent gastrointestinal disorder characterized by the formation of stones in the gallbladder and bile ducts [1]. Its etiology primarily involves cholesterol supersaturation, the nucleation of cholesterol crystals within bile, and impaired gallbladder motility [2]. In Western nations, cholesterol constitutes approximately 75% of gallstone composition [3]. Epidemiological evidence indicates that the prevalence of gallstones in adults in the United States ranges from 5 to 25%. This condition accounts for up to 1.5 million annual medical consultations, thereby imposing a substantial economic burden on families and society [4,5,6]. GSD is a multifactorial condition influenced by various recognized risk factors, including gender, age, race, genetic predisposition, and lifestyle [7,8,9]. The available evidence indicates evidence underscores an association between GSD and heightened levels of oxidative stress coupled with diminished antioxidant capacity [10, 11]. Oxidative stress, characterized by the accumulation of free radicals like reactive oxygen species (ROS), remains unmitigated by the antioxidant defense system, thereby precipitating DNA and protein damage, escalated metabolite levels, and lipid peroxidation [12, 13].

Previous studies have demonstrated a potential association between several antioxidants and GSD [14, 15], Specifically, vitamin E, vitamin C, and carotenoids possess antioxidant properties that may mitigate oxidative stress. Nevertheless, the efficacy of single antioxidants is constrained by their limitations. Furthermore, various lifestyle factors, including alcohol consumption, smoking, physical activity, and obesity, also contribute to oxidative stress [16,17,18,19]. A thorough evaluation of combinations of pro-oxidants and antioxidants may better elucidate their correlation with GSD.

The Oxidative Balance Score (OBS), as a comprehensive indicator for assessing individual oxidative balance, has been proven to be inversely correlated with various diseases, including cancer [20], metabolic syndrome [21], chronic diseases [22] and cardiovascular diseases [23]. However, no research has investigated the relationship between OBS and GSD. Furthermore, a study in Korea found an inverse correlation between OBS and serum γ-glutamyltransferase(GGT) which is used as a biomarker of oxidative stress [12]. Based on these research findings, we utilized cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) 2017–2020 to explore the relationship between OBS and GSD. Given the significant correlation between OBS and oxidative stress biomarkers, and further investigated the mediating role of oxidative stress in this relationship.

Materials and methods

Study population

NHANES is a cross-sectional study designed to collect comprehensive demographic, socioeconomic, and health-related data through interviews, laboratory tests, and physical examinations, with the objective of assessing the health and nutritional status of the American population. All participants have provided written informed consent.

This study utilized publicly available data from NHANES 2017–2020. Initially, 8965 participants were included. We excluded 421 participants who lacked information on GSD and 1764 participants missing OBS-related data. Additionally, participants with missing covariate information were excluded. Consequently, the final study sample comprised 6196 participants (Figure 1).

Fig. 1
figure 1

Flow chart of sample selection from the NHANES 2017–2020

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Definition of gallstones

Information on GSD was collected through a questionnaire. Participants were classified as having GSD if they responded affirmatively to the question, “Has a doctor ever told you that you have gallstones?”

Oxidative balance scores

In accordance with the methodology delineated in the pertinent literature, we calculated OBS levels [13]. OBS integrates 16 dietary components and 4 lifestyle factors. We gathered dietary data through 24-hour dietary recalls, and the lifestyle factors included physical activity, alcohol consumption, body mass index (BMI), and serum cotinine levels. We evaluated physical activity using metabolic equivalent (MET) scores based on NHANES guidelines, dividing them into 3 groups: 0 score (< 400 MET minutes/week), 1 score (400-1,000 MET minutes/week), and 2 score (> 1,000 MET minutes/week). Alcohol consumption was categorized into 3 groups: 2 score (≥ 15 g/day for female, ≥ 30 g/day for male), 1 score (0–15 g/day for female, 0–30 g/day for male), and non-drinkers. The body mass index (BMI) classified into 3 groups: 2 score (< 25 kg/m2), 1 score (25–30 kg/m2), and 0 score (≥ 30 kg/m2). Serum cotinine levels were utilized to evaluate active smoking status. The remaining components were grouped by sex and then divided into tertiles. Antioxidants were scored 0–2 in tertiles 1–3, while pro-oxidants were inversely scored from 2 to 0 in the same tertiles. The overall OBS was calculated by aggregating the scores of all individual components. Table 1 lists the categorization and assigned scores for each OBS component.

Table 1 Oxidative balance score assignment scheme
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Oxidative stress indicators

In order to explore the possible influencing factors of oxidative stress, we selected albumin, GGT, bilirubin and uric acid as evaluation indicators. The activity of GGT was quantitatively evaluated by enzyme kinetic technology, and the content of albumin was determined by two-color dye termination method. Total bilirubin levels were quantified using a timed approach to the end point, while uric acid was measured using a quantitative technique for the time end point. Detailed descriptions of the various laboratory processes used by NHANES are displayed on the website.

Potential confounding variables

Variable factors covered age, sex, race (including Hispanics and other ethnic groups such as non-Hispanic white and non-Hispanic black), education (divided into less than high school education and more than high school education), marital status (single, married and divorced), and the proportion of household income and poverty (less than 1.3, 1.3–3.5, and > 3). Involves long-term health problems reported by the individual, such as diabetes and hypertension.

Statistical analysis

According to the guidelines of the Centers for Disease Control and Prevention (CDC), all data were subjected to weighted analysis. Continuous variables representing the the basic attributes of participants were presented as means and standard deviations (SD), categorical variables were expressed as unweighted numbers and weighted proportions. The Wilcoxon rank sum test was used to analyze the continuous data, while the Rau-Scott chi-square test was used to compare the categorical data, aiming to reveal the significant differences between different categories. Multivariate weighted logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for the association between overall OBS and GSD. Three models were adjusted: Model 1 = unadjusted; Model 2 = adjusted for age, sex, race, PIR, marital status, and education level, and Model 3 further adjusted for hypertension and diabetes in addition to the covariates included in Model 2. To further explore the link between diet and lifestyle and GSD, we developed restricted cubic spline (RCS) curves to determine the dose-response relationship between OBS and GSD. Subgroup analysis were performed using stratified multivariate regression analyses to assess the interaction between OBS and specific covariates. Additionally, sensitivity analyses were conducted by systematically removing each component of OBS to evaluate the stability of the results. To explore the potential mediating role of oxidative stress markers on the association between OBS and GSD, we performed mediation analyses of four oxidative stress indicators and included variables with significant mediating effects in the same multivariate model to analyse their overall mediating effects. All statistical analyses were conducted using R version 4.3.0, and p-values < 0.05 were considered statistically significant.

Results

Baseline characteristics

A total of 6,196 participants were enrolled in the study, with a median age of 48 years, and 51.69% of the participants were female. OBS scores were classified into quartiles: Q1, Q2, Q3, and Q4. Compared to Q1, Q4 participants were more likely to be female, non-Hispanic white, higher educational attainment, higher income levels, and a lower prevalence of hypertension and diabetes. Notably, single individuals exhibited lower OBS scores. No statistically significant differences were observed in gender or age among the groups (Table 2).

Table 2 Baseline characteristics of participants according to the oxidative balance score’s quartile
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Association between OBS and GSD

As demonstrated in Table 3, we conducted a study to investigate the relationship between OBS and GSD risk using three weighted logistic regression models. When OBS was treated as a continuous variable, a higher total OBS was found to be significantly and negatively associated with the incidence of GSD (OR: 0.981; 95% CI: 0.966–0.995; P < 0.05). In the fully adjusted model 3, the risk of developing GSD was reduced by 29.9% in the fourth OBS quartile compared to the reference category in the first OBS quartile. This was indicated by an OR (95% CI) of 0.701 (0.492–0.999), with a statistically significant test for trend (P for trend < 0.05).

Table 3 The relationship between OBS and Gallstone disease
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Restricted cubic splines

The relationship between OBS and GSD was investigated using RCS curves. After adjusting for all covariates, a linear trend was found in the correlation between total OBS, lifestyle OBS, dietary OBS, and the risk of GSD(P for non-linearity = 0.962; P for non-linearity = 0.758; P for non-linearity = 0.585. A consistent trend was observed whereby the OR for GSD decreased with increasing lifestyle OBS. However, with increasing dietary OBS, the risk of GSD initially decreased and then increased, with all OR remaining below 1 (Figure 2).

Fig. 2
figure 2

RCS curves of the relationships between three distinct OBS types and risk of GSD. (A) Total OBS; (B) Lifestyle OBS; (C) Dietary OBS

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Subgroup and interaction analysis

Figure 3 presents subgroup analysis of potential confounding factors. These analyses were conducted to assess whether this relationship is consistent across the general population. Our findings indicated a significant interaction between OBS and education level among participants diagnosed with GSD (P for interaction = 0.044). A comparison of the risk of developing GSD between groups with low and high levels of education revealed that individuals with higher levels of education were relatively less likely to experience the disease (OR: 0.55, 95% CI: 0.40–0.75, P < 0.05). However, OBS was not statistically significant in the other subgroups.

Fig. 3
figure 3

Subgroup analysis of the association between OBS and GSD

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Mediating role of oxidative stress

Table 4 revealed the regulatory effect of oxidative stress in the association of OBS with GSD. The mediation effect analysis revealed that albumin (β: -0.0002, 95% CI: -0.0003, -0.0001) and uric acid (β: -0.0002, 95% CI: -0.0003, -0.0001) were significant mediators, with mediation ratios of 9.161% and 10.559% (both P < 0.05). Considering multiple testing, we analyzed four biomarkers and therefore applied Bonferroni correction for multiple comparisons. Consequently, we divided the significance level P = 0.05 by 4, resulting in a Bonferroni-corrected significance level of P = 0.0125. Albumin and uric acid remained significant mediating factors. Including both albumin and uric acid in the multivariate model resulted in a significant overall mediating effect, with a mediation proportion of 19.540% (P < 0.05). This study did not identify any mediating effects of bilirubin and GGT(Figure 4).

Table 4 Mediation analyses with separate and multiple mediators between OBS and Gallstone disease
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Fig. 4
figure 4

Estimated proportion of the association between OBS and GSD mediated by oxidative stress markers. (a) Albumin; (b) Uric acid; (c) Albumin and Uric acid

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Sensitivity analysis

To validate the stability of the association between OBS and GSD, we conducted sensitivity analysis by removing each component of OBS individually and re-analyzing its effect on the observed association. The results demonstrated that none of the individual components significantly influenced the association between OBS and GSD (Table 5).

Table 5 Sensitivity analyses to assess the effects of individual OBS components on the gallstone disease
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Discussion

In order to clarify the association, a cross-sectional analysis was performed using data from 6,196 participants in NHANES 2017–2020. A negative association between OBS and GSD was observed. Additionally, after adjusting for potential confounders, Q4 showed a significantly lower risk of GSD compared to Q1. RCS analysis revealed a negative linear association between total OBS, lifestyle OBS, dietary OBS, and the risk of GSD. It is noteworthy that while the risk of GSD did not decrease continuously with increasing dietary OBS, it exhibited an upward trend; however, all OR values were less than 1. Subgroup analysis revealed that education level may influence the association between OBS and GSD risk. Sensitivity analysis confirmed a robust association between OBS and GSD.Furthermore, mediation analysis revealed a negative correlation between OBS and two markers of oxidative stress (albumin and uric acid), suggesting that albumin and uric acid may mediate the impact of OBS on GSD. Our findings confirm the value of diet and lifestyle in reducing GSD and highlight the significance of maintaining a healthy diet and lifestyle.

Previous studies have demonstrated that oxidative stress plays a role in the pathophysiological processes of GSD and may underlie the association between OBS and GSD [24,25,26]. Under normal conditions, the generation of ROS is regulated by mitochondria and mitigated from oxidative damage through enzymatic and non-enzymatic mechanisms. However, when the antioxidant defense system is compromised, excessive ROS accumulation can result in DNA damage, elevated levels of protein damage metabolites, and lipid peroxidation [27]. Mitochondrial DNA can induce abnormal cholesterol transport by activating the AMPK signaling pathway, thus increasing the risk of GSD [28].

Our findings align with previous research, which has shown a correlation between dietary factors, lifestyle, and the risk of GSD. Epidemiological evidence has highlighted the significant role of diet and lifestyle in GSD. A low intake of dietary fiber increases the risk of GSD, whereas the intake of total fat, unsaturated fatty acids, saturated fatty acids, and cholesterol also raises the risk [29, 30]. Additionally, the intake of nutrients such as folate, vitamin C, niacin, calcium, and magnesium has been associated with GSD [31]. Regarding lifestyle, moderate physical activity has been found to lower cholesterol levels, prevent cholesterol precipitation in the bile, and thus reduce the incidence of GSD [32]. Finally, obesity has been shown to elevate the risk of GSD [8]. Smoking may influence gallstone formation by inhibiting the synthesis of prostaglandins and mucus production in the gallbladder [33]. Additionally, excessive alcohol consumption increases the risk of chronic liver damage and cirrhosis, which in turn raises the risk of GSD [34, 35].

The study results indicate a significant negative correlation between OBS and GSD. The OR of GSD demonstrated a downward trend prior to an upward surge in correlation with the increase in dietary OBS. This may be attributed to several factors. Firstly, excessive intake of certain antioxidants has been shown to have pro-oxidative effects. Copper ions, a powerful antioxidant, effectively counteract oxidative damage in vitro and in cell cultures. However, excessive copper ions may also promote oxidative damage [36]. Vitamin C, vitamin E, and carotene can exhibit pro-oxidant effects under certain conditions [37,38,39,40,41]. Additionally, excessive alcohol consumption has been linked to an increased risk of GSD. Nevertheless, a prospective study documented a protective effect of low-dose alcohol on GSD [42]. Alcohol has been shown to have a beneficial effect on GSD by inhibiting the cholesteryl ester transfer protein (CETP)-mediated conversion of high-density lipoprotein (HDL) to low-density lipoprotein (LDL) cholesterol [43], this process may reduce bile cholesterol saturation [44, 45].

In this study, we further explore the potential pathway from OBS to GSD. Mediation analysis results indicated that albumin and uric acid mediate the relationship between OBS and GSD risk. The overall mediation effect was significant, with a mediation proportion of 19.540% (P < 0.05). The findings validate the role of oxidative stress indicators, indicating that lower OBS may increase the risk of GSD by inducing oxidative stress. Several studies have indicated a correlation between OBS and oxidative stress indicators. A research observed a significant inverse correlation between OBS and both albumin and uric acid [46]. Albumin is a reliable indicator of oxidative stress due to its redox state at cysteine-34 (Cys-34) and may help prevent excessive oxidative stress [47]. Previous studies have demonstrated that uric acid, an endogenous antioxidant, can prevent oxidative stress [48]. The results of our study support the hypothesis that albumin and uric acid exert a protective effect on GSD.

Currently, we have not found GGT to have a mediating role in the association between OBS and the risk of GSD. We analyze the reasons as follows. Firstly, the key difference between our study and the Korean study lies in the study populations. Our study was conducted using NHANES data from a diverse U.S. population, which includes a wide range of ethnicities, age groups, and socio-economic backgrounds. In contrast, the Korean study focused on a more homogenous population, which may have different baseline levels of oxidative stress markers and their association with OBS. Genetic, environmental, and lifestyle factors can vary significantly between populations, influencing the way GGT functions as a biomarker of oxidative stress.

Furthermore, GGT is an enzyme involved in the metabolism of glutathione, a major antioxidant. Its levels are influenced by a variety of factors such as alcohol consumption, liver function, and obesity. The role of GGT as a biomarker for oxidative stress may be more prominent in populations with higher rates of liver disease or alcohol use, conditions that are more common in certain populations than others. In the current study, the lack of a significant mediating effect of GGT could suggest that the population under study may not have had the same level of liver dysfunction or oxidative stress linked to GGT as the Korean cohort did. Besides, there could also be methodological differences between the two studies. The Korean study may have employed different methodologies or analytical techniques for measuring oxidative stress biomarkers.

The study results indicate that individuals with a higher OBS are more likely to have a higher level of education. Education level is a factor in translating nutritional knowledge into better dietary habits [49]. A cross-sectional study from Denmark showed that individuals with higher education levels consumed more fruits and vegetables and less red meat daily than those with lower education levels [50]. A study on diet in the United States revealed that participants with higher education levels tended to consume more fruits, vegetables, and whole grains while controlling for cholesterol, alcohol, and added sugar [51].

However, we acknowledge that the observed interactions may be influenced by confounding factors related to education, such as socioeconomic status, accessibility of healthcare services, or lifestyle factors, which are typically associated with educational attainment. For instance, lower education levels may be associated with poorer dietary quality, reduced accessibility to healthcare services, and higher risk factors for gallstones, which could explain the stronger association with gallstone risk in this group. Additionally, the protective effect of higher education levels may reflect better health awareness and accessibility to preventive measures.

Notably, in our study, the “High School and below” category had a smaller sample size compared to the “Above High School” category. This sample imbalance could lead to unstable effect estimates in the “High School and below” group, resulting in wider confidence intervals and significant overlap with the “Above High School” group. The influence of education level on the relationship between OBS and GSD risk might not be initially interpreted. The effect could be gradual, meaning that education level affects OBS and GSD risk interaction in a more nuanced way, rather than showing a clear-cut difference between “High School and below” and “Above High School” categories. Future studies could consider more refined subgroup analyses are needed to further examine the progressive effect of education level on the relationship between OBS and GSD.

In our study, we observed that singles had lower OBS. This finding may reflect several lifestyle and psychosocial factors associated with being single. the category of “singles” included individuals who were never married, divorced, or widowed that may lack family responsibilities or social support, which can lead to irregular eating habits and lower levels of physical activity. Additionally, they might be more inclined to engage in behaviors such as smoking or drinking, both of which can negatively impact the OBS score. Psychosocial factors also play a critical role; single individuals may experience higher levels of psychological stress or depression, potentially resulting in reduced physical activity or a tendency toward unhealthy eating patterns. Additionally, economic status is an important consideration; unmarried or separated individuals may face economic disadvantages that limit their access to healthy foods, such as antioxidant-rich fruits and vegetables. These changes can adversely affect oxidative balance, increasing the risk of GSD.

We considered gender differences when constructing the OBS score because the gender-specific OBS score enables a more precise and nuanced understanding of how dietary patterns contribute to gallstone disease risk, accounting for the unique metabolic and hormonal differences between men and women. In public health and clinical practice, this approach could lead to more targeted interventions, better risk assessment, and improved prevention strategies that ultimately enhance patient outcomes and reduce the burden of gallstone disease.

Strengths and limitations

This study has several strengths. Firstly, the data used in this study were derived from the nationally representative NHANES database, enhancing the reliability of the results. Secondly, combined dietary and lifestyle-based OBS were employed to assess individual oxidative balance. Finally, mediation analysis was used to elucidate the underlying mechanism between OBS and GSD. However, this study has some limitations. Firstly, because NHANES employed a cross-sectional design and the blood samples were collected cross-sectionally, there are potential concerns regarding the temporal relationship between OBS and GSD incidence. In our study, we acknowledge that the temporal association may not be fully captured, and the observed association could be influenced by reverse causality or unmeasured confounding factors. Therefore, future research should adopt a longitudinal design to better understand the temporal relationship between exposure and outcome and to explore potential mediating factors in the relationship between exposure and outcome. Additionally, dietary data were collected via a 24-hour recall, which may be subject to recall bias. Finally, residual confounding by unknown or unmeasured factors may remain. Despite these limitations, this study has important clinical implications, as it analyzed the relationship between OBS and GSD risk and explored the role of oxidative stress. Maintaining a healthy diet and lifestyle is of paramount importance.

Conclusions

Our study indicates that higher OBS is inversely associated with GSD risk, especially among higher education levels subgroups, and albumin, uric acid could be the driving mediators of the association. These findings underscore the potential role of oxidative stress in GSD and the importance of maintaining a healthy diet and lifestyle to decrease GSD risk. Further longitudinal studies are warranted to explore the causal association and underlying pathological mechanisms linking OBS and GSD.

Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

The data used in this study were from the NHANES. We thank the participants in the NHANES for their contribution.

Funding

This work was supported by grants from the Key Medical Science and Technology Project of Zhejiang Province (No. WKJ-ZJ-2201), and the Key Projects of Zhejiang Provincial Science and Technology (No. 2022C03099). Zhejiang Provincial Science and Technology Program of Traditional Chinese Medicine (No. GZY-ZJ-KJ-24056, No. 2023ZL252) and the Zhejiang Provincial Medical and Health Technology Program (No. 2023KY517).

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Authors and Affiliations

  1. The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China

    HaoPeng Zhu, Lei Jin, Zhe Zhang & WeiWei Jin

  2. General Surgery, Gastroenterology & Pancreatic Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China

    HaoPeng Zhu, Lei Jin, Zhe Zhang, Chao Lu, QiTao Jiang, YiPing Mou & WeiWei Jin

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Contributions

H.P Z. participated in the design of research schemes, extracted and analyzed the data, and wrote the main manuscript text; L. J. collected the data and participated in the design of research schemes; Z. Z. participated in the design of research schemes; C.L. and Q.T. J. analyzed and interpreted the data; Y.P. M. and W.W. J. reviewed and edited the manuscript. All the authors have read and agreed on the final version of the manuscript.

Corresponding authors

Correspondence to YiPing Mou or WeiWei Jin.

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Ethics approval and consent to participate

Data of this research was taken from the NHANES. The NHANES was approved by the National Center for Health Statistics Research Ethics Review Board. All participants were informed and provided their consent prior to their participation, and signed the related documents. The study was conducted in accordance with the Declaration of Helsinki.

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Zhu, H., Jin, L., Zhang, Z. et al. Oxidative balance scores and gallstone disease: mediating effects of oxidative stress. Nutr J 24, 4 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12937-025-01073-0

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Nutrition Journal

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