This systematic review and dose–response meta‐analysis examined the risk of chronic obstructive pulmonary disease (COPD) following dietary fiber intake. Relevant articles were retrieved from a variety of databases, including Scopus, Embase, and Medline, until March 2023. Spirometry was the most frequently used method for determining the presence of COPD. Based on the search, there were a total of 213,912 participants across five separate studies. Random effects model was used to combine the data and a dose–response analysis was further conducted. Five distinct cohort studies were identified. Based on highest versus lowest analysis, there was an inverse correlation between the intake of total fiber , cereal fiber , and fruit fiber . Although this result was not significant for vegetable fiber . Dose–response analysis revealed that daily increase of 10 g of total dietary fiber, cereal fiber, or fruit fiber reduced the risk of COPD by 26%, 21%, and 37%, respectively. The ROBINS‐E tool classified all cohort studies as having a moderate risk of bias. Total fiber, cereal fiber, and fruit fiber intake were found to have low credibility using the NutriGrade tool. Additionally, there is a lack of scientific evidence supporting the use of vegetable fiber. Larger, more comprehensive studies are required to confirm these findings. This systematic review and dose‐response meta‐analysis examined the risk of chronic obstructive pulmonary disease (COPD) following dietary fiber intake. Dose‐response analysis revealed that daily increase of 10 g of total dietary fiber, cereal fiber, or fruit fiber reduced the risk of COPD by 26%, 21%, and 37%, respectively. Consuming a high fiber diet was associated with a decreased risk of COPD. Larger, more comprehensive studies are required to confirm these findings. Exclusion criteria included the following: (1) animal studies or other study designs such as reviews, case reports, or letters; (2) reporting duplicate data from other included studies; (3) failing to examine the primary outcome measure (risk of COPD); and (4) containing insufficient or unextractable data.2.3Two authors extracted the relevant data (NV and SMG). Any discrepancies in data were discussed with a third author (HM). Additionally, demographic characteristics such as age and gender were considered during the extraction process, as well as the methods and doses used to assess dietary fiber intake (method of COPD diagnosis assessment). For analyses using multiple adjustment models, results from the model using the largest number of covariates were included.2.4Two reviewers (NV and SMG) assessed the risk of bias and the quality of data using the ROBINS‐E tool, evaluating multiple domains Table : bias du2.5The effect size was calculated using the RR and 95% CIs from cohort studies. When cohort study results were compared, the reported hazard ratios were consistent with the risk ratios. The reported HRs in cohort studies were equal to RRs , RRs and ORs were calculated using a random effects model. If effect sizes were reported for exposure increments of one serving per day, we included them in the meta‐analysis. For studies that reported the effect size per specific increase in amount of exposure, we exponentiated the log effect size times the study specific intake of exposure to obtain the effect size for one additional serving of exposure.According to Harrell, a non‐linear dose–response analysis was conducted using restricted cubic splines with knots at the 10%, 50%, and 90% percentiles of the distribution , lack of significant outcomes (n = 6), and lack of relevant experimental designs (n = 2). Finally, five cohort studies were eligible for inclusion into the meta‐analysis.Out of 11,948 titles and abstracts, we identified 2084 duplicate studies, leaving only 9864 unique studies for the initial screening. Based on the inclusion criteria, the full texts of 23 studies were screened  with a total of 6142 cases. Using the highest and lowest levels of cereal fiber intake, it was discovered that the risk of COPD was greater in the highest category  and Begg's (p = .73) tests revealed no evidence of publication bias.The analysis of cereal fiber intake included over 203,874 individuals from four prospective cohort studies , respectively), it was determined that there was no evidence of publication bias.In four prospective cohort studies involving 203,877 participants, 6142 people were identified as having COPD   Figure .3.6I2 = 0%, p = .85). According to a sensitivity analysis, the RR remained unchanged when each study was excluded individually. No evidence of publication bias was discovered using Egger's (p = .03) or Begg's (p = .29) tests.There were 4371 cases of COPD among the 191,977 participants across three prospective cohort studies . According to findings, dietary fiber consumption was shown to significantly reduce the risk of developing COPD in cohort studies. COPD risk was reduced by 26%, 21%, and 37% for every additional daily 10 g of total dietary fiber, cereal fiber, and fruit fiber, respectively. There was no correlation between a high vegetable fiber intake and a decreased risk of COPD. The reviewed studies revealed no evidence of significant heterogeneity.Patients with COPD are impacted by its progression across multiple organs, often resulting in a myriad of complications. COPD is characterized by breathing difficulties, persistent coughs, and recurrent lower respiratory tract infections. It is recommended to combine non‐pharmacological and pharmaceutical treatments in order to manage the severity and prevent exacerbations of COPD, as well as to improve overall quality of life Ostroff, . PreviouThe Dietary Approaches to Stop Hypertension (DASH) eating plan is a low‐glycemic index, low‐energy dense diet that has been suggested for lowering blood pressure. The DASH diet focuses on vegetables, fruits, and whole grains. It includes fat‐free or low‐fat dairy products, fish, poultry, beans, and nuts  made this a thorough analysis. Consumption of dietary fiber was associated with an increased risk of COPD in a nonlinear dose–response analysis using the most advanced statistical method.This review has several distinct strengths. Despite the small number of articles included in the review, the total number of combined participants , there may have been differences in the classification of dietary fiber intake between studies. Given these limitations, studies may have been more open to discovering a inverse correlation between dietary fiber intake and risk of COPD than a positive correlation.5According to this meta‐analysis of five cohort studies, the risk of developing COPD was shown to be reduced with the daily consumption of 10 grams of total dietary fiber, cereal fiber, and fruit fiber. Consumption of vegetable fiber had no discernible effect on the incidence of COPD. Given that the evidence supporting a protective effect of dietary fiber on the risk of COPD was of low quality, larger and longer follow‐up prospective cohort studies are necessary to corroborate our findings.Neda Valisoltani: Investigation ; methodology ; writing – original draft . Seyed Mojtaba Ghoreishy: Formal analysis . Hossein Imani: Project administration . Asma Rajabi Harsini: Investigation . Mohammadreza Jowshan: Writing – review and editing . Nikolaj Travica: Writing – review and editing . Hamed Mohammadi: Project administration .This study was financially supported by a grant from School of Nutrition Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran.The authors declared no conflicts of interest.The participants were all adults, and the data provided to the researchers contained no personal information about them.Tables S1–S4.Click here for additional data file.


MTHFR) gene polymorphisms, specifically C677T and A1298C, and the susceptibility to myocardial infarction (MI).This meta-analysis aimed to provide a comprehensive assessment of the association between Methylenetetrahydrofolate reductase (MTHFR gene polymorphisms (C677T and A1298C) and the risk of MI.A systematic literature search was conducted in MEDLINE, Web of Science, and Scopus until April 2023 to identify studies investigating the relationship between P = 0.008), recessive , allelic , TT vs. CC , and CT vs. CC . Furthermore, an overall analysis indicated a marginally significant association between the A1298C polymorphism and MI risk in the recessive model , allelic model , and CC vs. AA model . Meta-regression analysis revealed that none of the potential factors contributed to the observed heterogeneity.The analysis included 66 studies involving 16,860 cases and 20,403 controls for the C677T polymorphism and 18 studies comprising 3162 cases and 3632 controls for the A1298C polymorphism. Significant associations were observed between the C677T polymorphism and MI risk in various genetic models: dominant (OR = 1.16, 95 % CI = 1.06–1.28, MTHFR gene C677T and A1298C polymorphisms and the risk of MI.This meta-analysis revealed an association between  These SNPs influence MTHFR enzyme activity and have been associated with the risk of CVD Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme involved in the folate metabolic pathway, which plays a vital role in methyl group transportation MTHFR gene C677T and A1298C SNPs and the risk of MI MTHFR gene C677T and A1298C polymorphisms and the risk of MI, a comprehensive meta-analysis was conducted, incorporating all eligible case-control studies that had been published.Several studies have examined the association between the 2This study was designed and conducted based on the PRISMA statement 2.1The search procedure involved a thorough and systematic exploration of pertinent literature across multiple databases, including PubMed, Web of Science, and Scopus to retrieve all potential literatures evaluating C677T and/or A1298C polymorphisms and susceptibility to MI. Key words and Medical Subject Headings (Mesh) terms were as: (“Methylenetetrahydrofolate Reductase” OR “MTHFR” OR “C667T” OR “A1298C”) AND (“SNP” OR “single nucleotide polymorphism” OR “polymorphisms” OR “variation” OR “mutation”) AND  . The pri2.2MTHFR gene C677T and/or A1298C polymorphisms and susceptibility to MI; 3) Any publications that provide the necessary information to derive or compute risk estimates alongside their corresponding 95 % confidence intervals are included. The studies were excluded if were: books, letters, case reports, duplicate publications, review, study on animal, and studies with insufficient data. Upon initial search, to ensure the highest level of quality and relevance, we systematically assessed each study's title, abstract, and keywords. Irrelevant and duplicative studies were promptly excluded at this stage. Following this initial screening, the remaining studies underwent a thorough full-text review, during which our rigorous inclusion and exclusion criteria were meticulously applied to ascertain that only studies of the utmost relevance and scientific merit were incorporated. The application of these criteria yelled 66 publications for C677T SNP and 18 publications for A1298C SNP.To qualify for consideration, it is necessary to fulfill the following set of criteria: 1) publications with case-control design; 2) All publications evaluated the association between 2.3The data extraction process involved two independent investigators (DI and BR) who acquired full-text of eligible publications. Cohen’s kappa coefficient was applied to examine the differences between the two authors in the selection of studies and in the evaluation of the quality of evidence for the studies. In case of no agreement on selection of a publication, we achieved consensus through comprehensive discussions in the presence of third researcher, thereby establishing a unified approach to study selection. This collaborative effort ensures the methodological rigor and reliability of our meta-analysis, strengthening the validity of the results presented in this study. The data that was taken out includes: author’s last name, the country study, sample size, year of publication, ethnicity of subjects, age, method of genotyping, and genotype and allele distribution in both the case as well as control group. The methodological quality of included studies was assessed using the Newcastle-Ottawa Scale (NOS) 2.4Trial sequential analysis (TSA) is a statistical approach that combines the calculation of information size  in order to reduce both type I  and type II (beta) errors in meta-analysis, while maintaining a threshold for statistical significance. The required information size (RIS) was determined with a 5 % level of type I error, 80 % statistical power, a relative risk reduction (RRR) of 20 %, and a two-sided boundary type. If the cumulative Z‐curve crosses the TSA monitoring boundary or exceeds the RIS, which indicates sufficient evidence, further studies are not needed. The reverse condition necessitates continuous trials.2.5P < 0.05 was considered significant). The five models of MTHFR gene C677T and A1298C polymorphisms included dominant, allelic, recessive, heterozygote, and homozygote models. The extent of association between models of each MTHFR gene polymorphisms and MI risk was evaluated through pooled odds ratio (ORs) and their 95 % confidence intervals (CIs). Cochrane's Q test and the I2 test were conducted to find between study heterogeneity. The fixed-effected model (FEM) was applied if PQ-statistic > 0.10 or I2 was < 50 %; any other way, the random-effected model (REM) was used In the control group, Pearson's chi square test was applied to assess the deviation from Hardy–Weinberg equilibrium (HWE) for genotype frequency , 1831 manuscripts were screened based on the titles and abstracts, from which 1688 were excluded. The remaining 143 manuscripts were screened and assessed based on the full text for eligibility. Eventually, 66 studies for C677T and 18 studies for A1298C qualified for quantitative analysis 3.2MTHFR gene C677T polymorphism and the risk of MI. The quantitative analysis encompassed a sample size of 16,860 cases and 20,403 controls. Out of the publications analyzed, 24 were performed in European countries, 23 were in Asian countries, 10 publications in Africans, and 9 studies in countries with mixed ethnicity . The results of combined OR for overall population indicated a statistically significant association between MTHFR gene C677T SNP and MI risk across all five genotype models, including dominant model , recessive model , allelic model , TT vs. CC model  and the CT vs. TT model  . Alongside with these findings, the results of subgroup stratification based on ethnicity revealed that C677T SNP was significantly associated with MI risk in Asians, according to dominant model , recessive model , allelic model , TT vs. CC model ], and the CT vs. TT model  in Africans by dominant model , recessive model , allelic model , and TT vs. CC model   . Alongsi01, FEM) . The cum01, FEM) . However01, FEM) .Fig. 2A.3.3MTHFR gene A1298C polymorphism and the risk of MI. Among the included studies, four publications were conducted in European countries, ten publications were in Asian countries, three publications in Africans, and only one study in a country with mixed ethnicity (Mexico).In total, the final analysis included 18 studies comprising 3,162 cases and 3,632 controls to examine the potential association between the P = 0.008, FEM), allelic model , and CC vs. AA model . The results of TSA revealed that the cumulative Z-curve did not intersect any of trial sequential monitoring boundary and the RIS, suggesting more trials are required to reach a robust conclusion  and CC vs. AA model  had significant associations with MI risk in Asians. Due to the limited availability of data from only one study involving individuals with mixed ethnicity, we excluded it from the subgroup analysis.Our findings indicated significant association between A1298C SNP and the risk of MI under recessive model .Meta-regression analysis was conducted for 3.5The study employed Begg's funnel plot visualization and Egger's weighted regression test to assess publication bias. No significant publication bias was observed based on the findings, as illustrated in 4rs1801133 and A1298C/rs1801131, have been associated with hyperhomocysteinemia and an increased risk of developing cardiovascular disease (CVD) MTHFR gene polymorphisms are particularly important in the context of MI susceptibility due to their involvement in the one-carbon metabolism pathway, which has significant mechanistic implications. These genetic variations can lead to reduced MTHFR enzymatic activity, resulting in lower levels of active folate and impaired homocysteine metabolism. Elevated homocysteine levels, which are a consequence of specific MTHFR polymorphisms, have been linked to endothelial dysfunction, oxidative stress, inflammation, and an increased propensity for blood clot formation. These factors collectively contribute to the development of atherosclerosis, a precursor to MI MTHFR gene polymorphisms may have an increased risk of MI due to these interconnected factors The metabolism of homocysteine involves an enzyme called MTHFR, which plays a key role in converting 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. This enzymatic reaction is critical for the production of methionine from homocysteine MTHFR gene polymorphisms and susceptibility to MI is of great importance due to its numerous advantages. This approach aims to consolidate findings from multiple individual studies, effectively pooling evidence to provide a comprehensive and accurate assessment of this genetic association. By gathering data from various sources, meta-analysis enhances statistical power, enabling the detection of subtle associations that may not be apparent in individual investigations. Additionally, it facilitates a thorough exploration of sources of heterogeneity, shedding light on the reasons for variations in findings among studies. By resolving conflicts and distinguishing genuine associations from spurious ones, meta-analysis produces robust effect size estimates and contributes to well-informed clinical practices. It also addresses publication bias by assessing selective publication of significant results. By illuminating these aspects, meta-analysis not only advances scientific knowledge but also has the potential to influence clinical strategies, risk assessment, and personalized treatment approaches for individuals with specific MTHFR gene polymorphisms and those at risk of MI. Therefore, we conducted an up-to-date meta-analysis of available data on MTHFR gene C667T and A1298C SNPs in relation to predisposition to MI. Our analysis revealed a significant association between C677T and A1298C SNPs and the risk of MI in the pooled analysis.Performing a meta-analysis study on the relationship between MTHFR gene SNPs and the risk of myocardial infarction (MI) was conducted by Xuan et al. in 2011 MTHFR gene C677T SNP by including 30 studies, which encompassed a total of 10,522 controls and 8,140 MI cases. The study findings suggested that the TT vs. CT model (OR = 1.18) of the MTHFR gene C677T SNP was associated with an increased risk of MI. Subsequently, in 2016, Alizadeh et al. MTHFR gene C677T SNP and 7 studies  for the A1298C SNP in relation to MI. Their pooled analysis indicated that none of the five genetic models for both C677T and A1298C polymorphisms showed significant associations with MI risk. In our analysis, we incorporated 66 studies  for the MTHFR gene C677T polymorphism and 18 studies  for the A1298C polymorphism concerning the risk of MI. Our analysis revealed significant associations between four models of the MTHFR gene C677T polymorphism and an increased risk of MI. These models include the dominant model (OR = 1.16), recessive model (OR = 1.20), allelic model (OR = 1.13), TT vs. CC model (OR = 1.19), and CT vs. CC model (OR = 1.11). Additionally, our analysis demonstrated a significant association between the A1298C SNP and the risk of MI under the recessive model (OR = 1.27), allelic model (OR = 1.18), and TT vs. CC genotypic model (OR = 1.22) in the overall analysis.The initial meta-analysis investigating the association between vs. CT model of the MTHFR gene C677T SNP increased the risk of MI in Caucasians (OR = 1.13) and young/middle-aged Caucasians (<50 years) (OR = 1.27). Additionally, Alizadeh et al. The subgroup analysis conducted in the study by Xuan et al. MTHFR gene C677T SNP and MI. The results of the TSA analysis demonstrated that the existing body of data was substantial and robust enough to establish a valid and conclusive association between the MTHFR gene C677T SNP and susceptibility to MI. This indicates that the available evidence was not only consistent but also sufficient to support a strong and reliable relationship between the C677T SNP and the risk of MI. Conversely, when examining the MTHFR gene A1298C SNP, the TSA analysis revealed a different perspective. The analysis indicated that the studies available at the time were insufficient to establish a conclusive association between the A1298C SNP and MI. In other words, the existing data did not reach a level of adequacy to provide a definitive and reliable association between this specific SNP and the risk of MI. These findings highlight the necessity for further research and studies dedicated to the investigation of the MTHFR gene A1298C SNP to obtain a more comprehensive and conclusive understanding of its relationship with MI. It is evident that additional investigations are essential to gather enough data and evidence to support a valid association between the A1298C SNP and the risk of MI.The TSA conducted in this study provided valuable insights into the available data regarding the association between the MTHFR gene polymorphisms and MI susceptibility, but it is important to acknowledge several limitations that warrant consideration and suggest future research directions. Firstly, it is worth noting that six out of the 68 studies included in this analysis had control groups with deviations from HWE. This discrepancy in control group genotypes could potentially introduce bias into the original studies and may contribute to heterogeneity in the overall analysis. Although our analysis did not identify significant heterogeneity, addressing the issue of HWE deviations in control groups is crucial to enhance the robustness of future studies in this field. Secondly, MI is recognized as a polygenic disease, meaning that multiple genes and their interactions contribute to MI susceptibility. Exploring gene-to-gene interactions, haplotype associations, and gene-environment interactions can provide a more comprehensive understanding of MI predisposition. Unfortunately, due to the limited availability of well-structured data in the included studies, we were unable to conduct such analyses in this meta-analysis. Future investigations should aim to explore these complex genetic interactions to unravel the full spectrum of genetic contributors to MI risk. Lastly, it is important to highlight that there was a limited number of studies specifically related to the MTHFR gene A1298C polymorphism, resulting in a relatively small data pool for this specific polymorphism. To overcome this limitation and obtain a more comprehensive understanding of the involvement of this functional SNP in MI risk, further research is strongly recommended. These future studies should encompass diverse ethnic populations to ensure broader applicability of the findings and better representation of the genetic diversity in different communities. Taken together, while this meta-analysis advances our knowledge of the role of the MTHFR gene in MI susceptibility, it is important to address these limitations in future research endeavors. This will help refine our understanding of the genetic associations with MI and provide more personalized insights into risk assessment and clinical strategies for individuals with specific MTHFR gene polymorphisms.This meta-analysis provides valuable insights into the association between 5MTHFR gene SNPs and susceptibility to MI. The analysis encompassed various genetic models for MTHFR gene C677T polymorphism, including the dominant, allelic, recessive, CT vs. CC, and TT vs. CC models, all of which exhibited a substantial link with an increased risk of MI. Furthermore, our analysis revealed a noteworthy association between the A1298C SNP and MI risk under three different genotype models when considering the entire dataset. Interestingly, when we delved into specific ethnic populations, we observed variations in these genetic associations. For the C677T SNP, it was significantly linked to MI risk in both Asian and African populations. On the other hand, the A1298C SNP demonstrated a propensity to elevate MI risk in the Asian population. These findings highlight the importance of considering genetic diversity and ethnicity when exploring the relationship between MTHFR gene polymorphisms and MI susceptibility. However, despite the valuable insights gained from this meta-analysis, there is still a need for further research, particularly regarding the MTHFR gene A1298C SNP. To obtain a thorough and unequivocal understanding of the MTHFR gene involvement in association with MI, additional studies are warranted. These future investigations should encompass diverse populations and ethnicities to provide a more comprehensive and universally applicable insight into the intricate genetic factors contributing to MI risk.In conclusion, this comprehensive and up-to-date meta-analysis has shed light on the significant association between The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Although higher consumption of ultra-processed food (UPF) has been linked to a higher risk of metabolic syndrome (MetS), the results remain controversial. Herein, we performed a systematic review and meta-analysis of observational studies to clarify the relationship between UPF consumption defined by the NOVA framework and risk of MetS.2). Publication bias was investigated using the visual inspection of asymmetry in funnel plots and Begg's and Egger's tests.An extensive literature search on PubMed, ISI Web of Science, EBSCO and China National Knowledge Infrastructure (CNKI) databases was conducted to search for the relevant articles published priori to January 2023, and newly published articles between January 2023 and March 2023 were re-searched. Random-effects or fixed-effects models were adopted to calculate the pooled relative risks (RRs) and 95% confidence intervals (CIs). The between-study heterogeneity was explored using the Cochran's Q test and I-square (IP < 0.0001). Subgroup analyses revealed a positive association between consumption of UPF and MetS risk in cross-sectional studies , and no significant association in cohort studies , respectively. In addition, a more significant association between UPF consumption and increased risk of MetS was found in the subgroups of study quality <7  than study quality ≥7 . Similarly, when we performed analyses separately by sample size, there was a significant association between UPF consumption and MetS risk in sample size ≥5,000 , and in sample size <5,000 , respectively.Nine studies  totaling 23,500 participants with 6,192 MetS cases were included in the final analysis. The pooled effect size for the highest vs. lowest categories of UPF consumption indicated a positive association with the risk of MetS (RR: 1.25, 95%CI: 1.09–1.42, Our findings suggest that higher consumption of UPF is significantly associated with an increased risk of MetS. Further longitudinal studies are needed to confirm the effect of UPF consumption on MetS. Metabolic syndrome (MetS) is a pathophysiological state and cluster of ≥3 different cardiovascular risk factors, including abdominal obesity, insulin resistance, elevated blood pressure and dyslipidemia . Parallen = 4). Since then, several new epidemiological studies have also been published evaluating the association of UPF consumption with the risk of MetS  did not use the NOVA food classification system ; (4) studies not reported as HRs, RRs or ORs with 95%CIs; (5) unrelated articles.Two authors (C.-J. S and L.S.) independently screened and crosschecked each article from the literature search, and a third author (Q.Z.) was consulted to settle any discrepancies. After comprehensive screening all the titles and abstracts, the full-text versions of the articles were reviewed according to the inclusion and exclusion criteria of this meta-analysis. Studies were included in our analyses when they met all the following eligibility criteria: (1) were observational studies ; (2) were carried out in humans of any age; (3) UPF was considered as the main exposure of interest (according to the NOVA food classification system); (4) evaluated the association with MetS risk; (5) reported adjusted estimates of the RRs [e.g. hazard ratios (HRs) or odds ratios (ORs)] and 95%CIs for the link between UPF consumption and MetS risk. Where the original studies didn't provide sufficient data, the corresponding author of the study was contacted by email for additional information. Studies were excluded if they met one of the following criteria: (1) non-observational studies, e.g. reviews, editorials, case reports and conference letters; (2) animal, cell culture, and Data were extracted by two independent authors (X.-Y. Z and J.-Y. Z) from the identified eligible studies, including first author's last name, year of publication, study design, study area, sample size, number of MetS cases, mean age or age range of participants, duration of follow-up for cohort studies, method of UPF assessment, adjustments for confounding factors, and effect sizes  for the relationship between UPF consumption and risk of MetS.In the NOVA food classification system, UPF is characterized by high intake of foods made up entirely or mostly from unhealthy components, including food products having high energy density, added sugar, salt, saturated and trans fats, and low amounts of dietary fiber, vitamins and minerals, e.g. pizza, instant noodles, hamburger and smoking meats .The authors (L.S. and X.-Y. Z) independently assessed each included study's quality using the Newcastle-Ottawa Scale (NOS), which was designed for case-control and cohort studies . In the 2) statistics. P-values of Cochran's Q test <0.10 and I2>50% were considered to show substantial heterogeneity among the included studies, and subsequently the random-effects models (DerSimonnian and Laird method) were used to summary the pooled RRs. Otherwise, the fixed-effects models were adopted , moderate (25%~75%) and high (I2 ≥ 75%), respectively. In the case of significant between-study heterogeneity (I2 > 50%), the potential sources of heterogeneity across studies were explored using subgroup and sensitivity analyses. In our analyses, subgroup analyses were performed based on the study design , exposure assessment , study quality (≥7 or <7), mean age (≥55 or <55), study area (developed countries or developing countries) and sample size . Sensitivity analysis was performed, excluding one study removed at one time to confirm whether the results were robust or sensitive to the influence of individual study. Publication bias was assessed through examining the funnel plots, and statistical assessment of funnel plot asymmetry was quantified by Begg's or Egger's tests , the outcome of interest was components of metabolic syndrome (n = 2), the main exposure was processed meats (n = 2), conference abstract (n = 2), reported data as β coefficient (n = 1) and reported the same participants (n = 1). Finally, nine articles met the inclusion criteria and were included in our main analyses.The main characteristics of all included studies are outlined in P < 0.0001). The high heterogeneity was observed among the included studies , thus random-effects model was used to calculate the pooled RRs.Nine studies  including 6192 cases and 23500 participants were included in this meta-analysis that investigated the association between UPF consumption and MetS. 2 = 85.0%, P < 0.0001), we performed subgroup analyses to find the potential sources of heterogeneity. The results of subgroup analyses were presented in P = 0.002). However, there was evidence of heterogeneity between studies . Meanwhile, there was no significant association between UPF intake and MetS risk in cohort studies , with more evidence of heterogeneity . For exposure assessment, there was a significant association between UPF intake and risk of MetS  in 24-h dietary recall, with less evidence of heterogeneity . In addition, we also found significant association between UPF intake and MetS risk in FFQ , and there was more heterogeneity . For mean age, the positive association between UPF intake and risk of MetS was observed in the subgroups of age <50 , and there was evidence of significant heterogeneity . Moreover, we also observed the significant positive association between UPF intake and MetS risk in the subgroups of age ≥50 , and there was evidence of heterogeneity . For study area, there was a significant association between UPF intake and risk of MetS in developed countries  and the between-studies heterogeneity decreased from 85.0% to 74.3%. However, the statistical association was also observed between UPF intake and risk of MetS in developing countries . For sample size, we found a positive association between UPF intake and risk of MetS in sample size <5,000 . However, the heterogeneity was apparent . In contrast, we also found a significant association between UPF intake and MetS risk in sample size ≥5,000 , and there was no heterogeneity . For study quality, significant positive association was found between UPF intake and MetS risk in the subgroups of study quality ≥7 , and there was more heterogeneity . In addition, there was less evidence of heterogeneity in the subgroups of study quality <7 , where significant positive association with risk of MetS was observed .Given the significant heterogeneity of this meta-analysis (IP = 0.001). However, in our analyses, Begg's test for publication bias was not statistically significant (highest vs. lowest level of UPF consumption: Begg's test: P = 0.917). When trim and fill was applied filling added no study to the funnel plot, indicating a low degree of asymmetry and no change in the overall effect.As shown in P < 0.0001). In addition, the heterogeneity of included studies decreased from 85.0 to 59.2%.Based on the findings of sensitivity analysis , a cohorThe quality of included studies using NOS criteria is shown in In the present study, the pooled results illustrated that high consumption of UPF was significantly associated with an increased risk of MetS. Nonetheless, the results of this meta-analysis must be interpreted with caution due to the high heterogeneity among the included studies. Moreover, subgroup analyses showed the positive association between high consumption of UPF and risk of MetS was more robust in cross-sectional studies and the subgroups of study quality <7. Likewise, the results of sensitivity analysis indicated that Magalhãesas et al.' study might be the source of heterogeneity. To the authors' knowledge, this is the first comprehensive systematic review and meta-analysis to assess the relationship between consumption of UPF and MetS risk. Our findings confirm the positive association results of previous studies and add to the growing evidence for the role of UPF consumption in diet-related chronic diseases, including MetS.2 = 85.0%; P < 0.001). This is in agreement with findings from some previous studies reporting that high UPF consumption is associated with an increased risk of MetS . Although between-study heterogeneity is common in meta-analysis (In our analyses, it is important to point out that there was evidence for high between-study heterogeneity among all included studies (Ianalysis , exploriThis study has several strengths and limitations. First, to our knowledge, this is the first comprehensive systematic review and meta-analysis to evaluate the relationship between consumption of UPF and the risk of MetS. Our findings add to the growing evidence for the impact of UPF consumption on MetS and help inform public policy for the prevention and management of MetS. Second, a rigorous selection of articles was conducted based on the predetermined inclusion criteria, with the inclusion only of studies in which the classification of UPFs faithfully followed the characteristics proposed by the NOVA system. Third, MetS cases were ascertained through medical records, reducing the risk of misclassification. Fourth, the quality of the included studies was moderate to high, and the reported RRs were multivariate and adjusted for some known confounders, such as sex, age, physical activity and total energy intake. Meanwhile, we also performed subgroup and sensitivity analyses to explore the potential sources of heterogeneity. Fifth, no signs of publication bias were evident in the funnel plot, and the Begg's test for publication bias was non-significant. Despite the above-mentioned strengths, this study also has some limitations that should be acknowledged. First, although our findings show a positive relationship between UPF consumption and MetS risk, the majority of included studies are cross-sectional in design, which are limited by the potential for reverse causality. Second, five of the included studies used the FFQs that were not specifically designed to assess the NOVA classification groups, which might have led to an under- or over-estimation of the size of the observed associations. Likewise, information bias, as a consequence of self-reported data on dietary intake, might have occurred. Third, even though all of included studies in this meta-analysis have adjusted for a wide range of important confounders, residual confounding from unmeasured factors cannot be completely ruled out. Also, there was also an inconsistent adjustment for potential confounders in the all included studies. Consequently, the data included in this meta-analysis might suffer from differing degrees of completeness and accuracy. Fourth, high heterogeneity was found in this meta-analysis, which might have distorted the reliability of our results. Although we performed subgroup and sensitivity analyses to explore the potential sources of heterogeneity, we were unable to adequately ascertain and explain the sources of inter-study heterogeneity. Finally, given the limited number of included studies and the fact that most of them were performed in developing countries, caution is advised in the interpretation and extrapolation of our findings.In summary, findings from this study suggest that higher consumption of UPF is significantly related to an increased risk of developing MetS. Our findings add valuable evidence to the existing literature showing a positive relationship between UPF consumption and risk of MetS, and highlight the importance of limiting UPF consumption in decreasing the modifiable burden of MetS. Thus, active discouragement of UPF consumption should be considered as part of MetS prevention strategies. Considering the high level of evidence provided in the included studies, more well-designed prospective studies, particularly in different geographic regions and settings, are warranted to further confirm these findings.The original contributions presented in the study are included in the article/CS conceived and designed the systematic review, meta-analysis, and interpreted the results. XZ and JZ acquired the data. LS and QZ performed the statistical analysis and obtained the funding. LS conceived the idea and drafted this manuscript. All authors critically revised the manuscript for important intellectual content. All authors contributed to the article and approved the submitted version.


Acute leukemia commonly occurs in young children with peak incidence at the age of 2–5 years. However, the etiology is still unclear and many preventable risk factors still deserve to be reviewed. The focus of this systematic review and meta-analysis is to summarize the evidence concerning early life nourishment , neonatal vitamin K administration and the risk of acute leukemia. All epidemiological studies published up to June 2023 and assessing diet-related risk factors for childhood acute leukemia were identified in two electronic databases (PubMed and Web of Science), with no limits on publication year or language. A total of 38 studies  were included. The published risk estimates were combined into a meta-analysis using the Generic Inverse Variance method. The current evidence shows that breastfeeding (yes vs. no) has a protective effect against acute lymphoblastic leukemia . Evidence related to the role of other studied factors (foods and supplements) is inconclusive. Further research into the potential role of diet in early life and the risk of acute leukemia is needed to develop prevention strategies at population level. Review Registration: PROSPERO registration no. CRD42019128937. Childhood cancer is a notable cause of morbidity and mortality, with incidence rising from 124 to 140 per million person years between the eighties and 2000s in populations covered by cancer registration . The metAlmost 80% of AL cases are lymphoblastic lineage (ALL) and 15% are myeloid lineage (AML) in children from 0 to 14 years old , althougTherefore, in this systematic review, we focused on the likely role of breastfeeding, early child’s diet, and neonatal administration of vitamin K on the risk of AL in children. The combined evidence could be used to assess the development of preventive strategies on a population level to reduce the incidence and mortality of leukemia.For the systematic review, the incidence of AL in children aged 0–14 years and adolescents aged 15–19 years was the main outcome. Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) were included as subtypes of leukemia ,10,11.The considered risk factors were breastfeeding , early child’s diet circa first 3 years of life , and the neonatal administration of vitamin K.PROSPERO was used to record the protocol details of this systematic review on registration number CRD42019128937.To identify early life nutritional factors that have been studied in relation to leukemia risk, we conducted a comprehensive multi-level literature search using Medline (via PubMed) and Web of Science. The first level of analysis for this systematic review consisted of an exploratory search for studies on leukemia in infants, children and adolescents and early life exposures (pregnancy to early life—first three years). This first search was conducted in December 2017, without being limited by language or publication date. A total of 66 studies were identified in this search; at this stage, exposures during pregnancy and early life were included. Based on these results, and after sub-grouping the exposures, we were able to further restrict the keywords and carry out a more targeted search, updated in June 2023, which focused on the nutritional exposures identified in early life, described in Studies were included if they provided estimates of effect (relative risk (RR), odds ratio (OR) or hazard ratio (HR) and 95% confidence intervals (CI)), or if they provided sufficient data to calculate estimates for different exposure levels.Quality control of the selected articles was then carried out using the checklist established by Fowkes et al. to ensure the inclusion of high-quality studies . This chA meta-analysis was performed to estimate which factors had an impact on AL, ALL or AML. For each factor included, the choice to perform an additional quantitative analysis was based on the number (at least two studies) and homogeneity of the included studies , and data from overlapping studies were also excluded. We used the reported adjusted odds ratio (OR) in case–control studies and the relative risk (RR) in cohort studies to calculate the overall effect. Analyses were performed using the generic inverse variance method, in which the weight of each study is equivalent to the inverse of the variance of the effect estimate . A randoThe results of the search strategy and the process of selecting studies for review are illustrated in The quality assessment  of the iTwenty-five case–control studies studied the link between breastfeeding and risk of AL in children ,36,37,38From eleven case–control studies ,33,35,37Eighteen case control studies evaluated the association of breastfeeding with ALL ,36,37,38Nine case control studies ,35,36,37I2 = 47%) (I2 = 0%)  versus children not breastfed was performed . The age of participants ranged between less than 14 years old and less than 16 years old ,34,36,372 = 47%) , and forSix case control studies explored the association between children’s early diet and the risk of AL ,40,41,42Three case control studies ,40,41 inAmong the three case control studies that investigated the association between food consumption and ALL ,39,42, oOur meta-analysis, performed on two studies ,39, evalEight case–control studies ,48,49,51The study with the pooled analysis  includedIn a case–control study assessing intramuscular and oral administration of vitamin K, no association with the risk of ALL or AL was found in children aged one year or older . Non-sigOur meta-analysis, performed on two studies ,50, evalWith this systematic review and meta-analysis, we aimed to integrate the available scientific research on nutritional factors in early life (birth to age 3) and the impact of vitamin K administration that could be linked to the development of childhood acute leukemia.Our systematic review and meta-analyses indicate a protective effect of breastfeeding against the risk of ALL (the minimum duration of breastfeeding in the included studies was less than 1 month or less than 3 months). All case–control studies that have investigated the impact of breastfeeding have found a decreased risk for breastfed children. In line with our findings, a meta-analysis of 33 studies published in 2021 compared systematic breastfeeding with ever-breastfed versus non- or occasional breastfeeding  and longer breastfeeding with shorter breastfeeding versus shortest and longest duration , showing a protective effect . SimilarIn our meta-analyses, breastfeeding of any duration had a protective effect against ALL  and for AML . This protective effect of breastfeeding on both ALL and AML risk can be explained by the complex composition of the human milk. Breastfeeding provides nutrients , maternal antibodies and immunological components  and many other components that contribute to the advancement of the immune system and microbiota of the infant . BreastfRegarding children’s early diet, only a few studies evaluated the potential role of the food and supplements in leukemogenesis. The results from our meta-analysis, and those from a previous one, were not conclusive . As mentSupplementing neonates with vitamin K is a common practice that was introduced to prevent the hemorrhagic disease of the newborn (HDN). This supplementation may be administrated as oral or intramuscular to all the newborns, or only to those at higher risk of HDN. During the nineties, many studies consider the potential association between the intramuscular administration of vitamin K and the risk of AL ,48,49,51While studies of breastfeeding could partly rely on registered data (more reliable), all dietary information were collected through interviews and their integrity could not be evaluated. Therefore, the protective effect of breastfeeding is more convincing than the identified effects of diet.We would like to highlight the need for studies that explore early life dietary factors and the risk of developing childhood AL in a comprehensive way (standardized questionnaires), including general information on the main food groups and supplements, but also other approaches that might be considered . Micronutrient supplementation, including neonatal administration of vitamin K, needs to be evaluated in a more comprehensive way, including dose, dilutants, etc., to provide the best evidence on their potential role in developing leukemia. It should be noted that AL is a rare disease, therefore most of the results come from retrospective case–control studies often with a restricted number of cases. This is an important consideration when interpreting results. It is also important to mention the proposed mechanism for leukemogenesis, which involves early pre-leukemic genetic changes in utero, followed by triggers  in early life that induce secondary genetic changes and an immune response .After reviewing the available evidence that evaluates early life nutritional factors and the risk of childhood acute leukemia, the most abundant and conclusive evidence points to the protective role of breastfeeding. However, the reviewed studies did not provide sufficient evidence on the role of early diet in the development of childhood acute leukemia. Although further research is needed to develop and test cost-effective, evidence-based prevention strategies to combat acute leukemia in children, breastfeeding can be recommended as a factor contributing to prevention of childhood leukemia.


Caffeine exposure modifies the turnover of monoamine neurotransmitters, which play a role in several neuropsychiatric disorders. We conducted a Mendelian randomization study to investigate whether higher plasma caffeine levels are causally associated with the risk of anorexia nervosa, bipolar disorder, major depressive disorder (MDD), and schizophrenia.n = 72,517 to 807,553) and meta-analyzed with the corresponding data from the FinnGen study . Summary-level data on plasma caffeine were extracted from a GWAS meta-analysis of 9876 European ancestry individuals. The Mendelian randomization analyses estimated the Wald ratio for each genetic variant and meta-analyzed the variant-specific estimates using multiplicative random effects meta-analysis.Summary-level data on the neuropsychiatric disorders were obtained from large-scale genome-wide association studies (GWASs) of European ancestry participants (pFDR = 0.039) and a lower odds of bipolar disorder  and MDD . Instrumented plasma caffeine levels were not associated with schizophrenia .After correcting for multiple testing, genetically predicted higher plasma caffeine levels were associated with higher odds of anorexia nervosa (odds ratio [OR] = 1.124; 95% confidence interval [CI] = 1.024–1.238, These Mendelian randomization findings indicate that long-term higher plasma caffeine levels may lower the risk of bipolar disorder and MDD but increase the risk of anorexia nervosa. These results warrant further research to explore whether caffeine consumption, supplementation, or abstinence could render clinically relevant therapeutic or preventative psychiatric effects.The online version contains supplementary material available at 10.1186/s12916-023-03008-0. The effects of caffeine are mainly mediated through the blockade of adenosine Arenaline , depressrenaline , and schrenaline . Furtherrenaline , 7, wherrenaline . HoweverCYP1A2 gene are associated with a lower paraxanthine to caffeine ratio (which reflects slower caffeine metabolism), higher plasma caffeine levels, and lower habitual caffeine consumption [The metabolism of caffeine is highly variable among individuals and depends in part on genetic variations in the activity of the enzyme cytochrome P450 1A2 (CYP1A2), which is responsible for over 90% of caffeine metabolism. For example, genetic variants in the To investigate whether long-term higher caffeine exposure causally associates with the risk of neuropsychiatric disorders, we conducted a Mendelian randomization (MR) study of the association between genetically predicted plasma caffeine levels and the risk of anorexia nervosa, bipolar disorder, major depressive disorder (MDD), and schizophrenia. Using genetic variants to instrument an exposure of interest  through MR reduces the biases that often limit observational studies, including reverse causation, as genetic variants cannot be modified by the outcome (such as neuropsychiatric disorders).This study applied a two-sample MR design with publicly available summary-level data taken from meta-analyses of genome-wide association studies (GWASs) as well as the FinnGen study, which was not included in any of the GWAS meta-analyses Fig. . OutcomeCornelis et al. performed a meta-analysis of summary statistics from six plasma caffeine  GWASs comprising 9876 participants of mainly European ancestry, with mean ages between 47 and 71 years . ParticiWatson et al.’s GWAS was a meta-analysis from the Psychiatric Genetic Consortium (PGC) Eating Disorders Working Group, which contained 16,992 cases of anorexia nervosa and 55,525 controls from 33 studies—mostly of European ancestry individuals , 16. StuThis study is a meta-analysis of 41,917 cases of bipolar disorder and 371,549 controls from the PGC and five population-based cohort studies including the UK Biobank (UKB) , 17. SamHoward et al. meta-analyzed GWAS summary statistics of 170,756 MDD cases and 329,443 controls from the PGC and the UK Biobank . All stuTrubetskoy et al. meta-analyzed genetic data from 90 cohorts within the PGC , 16. Then = 356,077 in round 8) population biobank, based in Finland, described in detail elsewhere [The FinnGen study is a large  with plasma caffeine levels and located within 100 kb of the CYP1A2 and aryl hydrocarbon receptor (AHR) gene regions as instrumental variables . These genes were selected owing to their role in caffeine metabolism [p < 5 × 10−5 was selected to ensure that the used SNPs would be strong instruments for plasma caffeine, while accounting for gene region-wide . SNPs were clumped with a r2 of 0.3 and 10,000 kb windows using the TwoSampleMR R package [We selected single-nucleotide polymorphisms (SNPs) that were strongly associated  adjusted p-value < 0.05 was regarded as statistically significant. Odds ratios (OR) presented here represent the multiplicative increase in the odds for each standard deviation (SD) increase in plasma caffeine levels.We firstly meta-analyzed the SNP-outcome associations from each GWAS meta-analysis with the equivalent outcome data in the FinnGen study using an inverse variance weighted meta-analysis. Secondly, we conducted the MR analysis. The primary estimator was the Wald ratio, which was defined as the ratio of the SNP-outcome association to the SNP-exposure association. Wald ratios were combined using a multiplicative inverse variance-weighted (IVW) random effects model, using SNPs’ LD matrix estimated from the European subsample of the 1000 Genomes Project to account for correlations between variants . This wacis settings with correlated variants, we first explore the robustness of outlier SNPs using leave-one-out analyses and then explore heterogeneity between the AHR and CYP1A2 genes. We additionally explore the heterogeneity in the MR estimates between data sources and replicate our analysis using only the lead SNP from each gene region (rs4410790 for AHR and rs2472297 for CYP1A2). To the best of our knowledge, there is no sample overlap between the exposure and outcome GWASs.Heterogeneity tests have been proposed as sensitivity analyses for pleiotropy in MR studies . BecauseF statistic of 44 and 25, respectively. This is consistent with approximately 2–4% bias in the MR estimates due to the use of weak instruments.After clumping and harmonization, we included 7 SNPs as instrumental variables for plasma caffeine in all analyses except for MDD, where 8 SNPs were included  fold higher odds of anorexia nervosa  and MDD . There was no evidence of an association with schizophrenia .Our MR analysis indicated that each SD increase in genetically predicted plasma caffeine was associated with a 1.124 , bipolar disorder (I2 = 0%), MDD (I2 = 41%), or schizophrenia (I2 = 0%). We also did not find evidence of heterogeneity between the two data sources for anorexia nervosa, bipolar disorder, or MDD , although an additive random effects meta-analysis of the MR estimates from the PGC and FinnGen still did not find evidence of an effect (95% CI: 0.72 to 1.14).We did not find strong evidence of heterogeneity between AHR and CYP1A2 estimates for anorexia nervosa (MDD I2 = 1%, or scThis two-sample MR study found that genetically predicted long-term higher plasma caffeine levels were associated with a higher risk of anorexia nervosa, but a lower risk of bipolar disorder and MDD. We found no significant associations of genetically predicted plasma caffeine levels with the risk of schizophrenia.The link between dietary caffeine intake and depressive symptoms has been reported in several observational, mainly cross-sectional studies, which were by nature of their design unable to investigate the direction of the association. A recent meta-analysis of observational studies reported that high versus low caffeine intake was associated with an overall 14% lower risk of future depressive symptoms in two cohort studies and an amalgamated 13% lower odds of depressive symptoms across 10 cross-sectional studies . Our invCaffeine may through adenosine antagonism play a role in anorexia nervosa as altered serotonergic and dopaminergic function is commonly observed in those suffering from this disorder . AlthougAlthough a positive association between caffeine intake and prevalent schizophrenia has been reported , we did Summary data MR estimates should be interpreted as the average lifetime effect of greater exposure to caffeine . HoweverOur study has several strengths. The MR design reduces the risk of reverse causation bias and confounding by environmental factors. We further strengthen the validity of our findings by biologically plausible genetic instruments from genes known to affect caffeine metabolism and plasma caffeine levels. A priori gene selection additionally reduces the risk of confounding by pleiotropy. Finally, the use of large-scale GWAS data within a two-sample MR framework increased the statistical power of our analyses.cis design should provide greater robustness through establishing the biological mechanism linking SNPs to the exposure [Nevertheless, despite the use of the largest publicly available GWAS data for the outcomes, we cannot exclude the possibility that we might have overlooked weak associations between plasma caffeine and the studied disorders. Furthermore, the possibility of genetic confounding by metabolites other than caffeine that are metabolized by the CYP1A2 enzyme cannot be ruled out. Although the use of a exposure , a limitexposure , the outexposure , 34. In This MR investigation provides evidence of possible causal relationships of long-term higher plasma caffeine levels with a higher risk of anorexia nervosa and a reduced risk of bipolar disorder and MDD. These results warrant further research to explore whether caffeine consumption, supplementation, or abstinence could render clinically relevant therapeutic or preventative psychiatric effects.Additional file 1:Table S1. Exposure related genome-wide association study summary data taken from Cornelis et al. Table S2. Summary-level data from FinnGen. Table S3. Genome-wide association study summary statistics taken from other data sources. Table S4. Meta-analyzed variant-outcome associations and Mendelian randomization Wald ratios. Fig. S1. X-Y scatter graphs of Mendelian randomization results. Fig. S2. Leave-one-out analyses.


To evaluate the quality of evidence, potential biases, and validity of all available studies on dietary sugar consumption and health outcomes.Umbrella review of existing meta-analyses.PubMed, Embase, Web of Science, Cochrane Database of Systematic Reviews, and hand searching of reference lists.Systematic reviews and meta-analyses of randomised controlled trials, cohort studies, case-control studies, or cross sectional studies that evaluated the effect of dietary sugar consumption on any health outcomes in humans free from acute or chronic diseases.The search identified 73 meta-analyses and 83 health outcomes from 8601 unique articles, including 74 unique outcomes in meta-analyses of observational studies and nine unique outcomes in meta-analyses of randomised controlled trials. Significant harmful associations between dietary sugar consumption and 18 endocrine/metabolic outcomes, 10 cardiovascular outcomes, seven cancer outcomes, and 10 other outcomes  were detected. Moderate quality evidence suggested that the highest versus lowest dietary sugar consumption was associated with increased body weight (sugar sweetened beverages) (class IV evidence) and ectopic fatty accumulation (added sugars) (class IV evidence). Low quality evidence indicated that each serving/week increment of sugar sweetened beverage consumption was associated with a 4% higher risk of gout (class III evidence) and each 250 mL/day increment of sugar sweetened beverage consumption was associated with a 17% and 4% higher risk of coronary heart disease (class II evidence) and all cause mortality (class III evidence), respectively. In addition, low quality evidence suggested that every 25 g/day increment of fructose consumption was associated with a 22% higher risk of pancreatic cancer (class III evidence).High dietary sugar consumption is generally more harmful than beneficial for health, especially in cardiometabolic disease. Reducing the consumption of free sugars or added sugars to below 25 g/day (approximately 6 teaspoons/day) and limiting the consumption of sugar sweetened beverages to less than one serving/week (approximately 200-355 mL/week) are recommended to reduce the adverse effect of sugars on health.PROSPERO CRD42022300982. As an important component of the human diet, sugars have been shown to be harmfully associated with a variety of risk factors for decades, mainly including obesity,In recent years, many studies have focused on the adverse effects of sugar sweetened beverages on human health, given the substantial contribution of these drinks to total added sugar or free sugar intake and the rapidly increasing rate of their consumption.Although many meta-analyses of observational studies and randomised controlled trials focused on the associations between sugar consumption and a range of health outcomes have been published in recent decades, deficiencies in the study design, varying measurements of dietary sugar consumption, inconsistent findings, and different definitions of exposure make drawing definitive conclusions difficult. Therefore, before developing detailed policies for sugar restriction, the quality of existing evidence on the associations of dietary sugar consumption with all health outcomes needs to be comprehensively evaluated. To evaluate the quality of evidence, potential biases, and validity of all studies available on dietary sugar intake and any health outcomes, we did an umbrella review of meta-analyses on this topic.https://www.crd.york.ac.uk/PROSPERO/).We systematically searched, extracted, and analysed large amounts of data from published systematic reviews and meta-analyses that research the associations between various health outcomes and dietary sugar consumption.We searched PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews from inception through January 2022 (last update) for systematic reviews and meta-analyses of randomised controlled trials and observational studies. We searched the databases through a combination of Medical Subject Headings terms, keywords, and variations of text words associated with sugars following the Scottish Intercollegiate Guidelines Network’s guidance for literature searching: (sugars OR sugar) AND .We identified dietary sugar consumption as the intake of total sugars and the consumption of a component of total sugars , which are expressed in absolute amounts or as a percentage of total energy, or the intake of sugar sweetened beverages or foods .3 We incThe exclusion criteria for these umbrella reviews included meta-analyses of the association between carbohydrates, non-nutritive sweeteners, and artificially sweetened beverages and health outcomes; meta-analyses evaluating the therapeutic or metabolic effects of short term sugar supplementation; meta-analyses that evaluated the effects of dietary sugar consumption on health outcomes in certain disease populations; randomised controlled trials that aimed to achieve isoenergetic replacement of sugars with other forms of carbohydrate; studies with insufficient data to evaluate sugar consumption from sugar containing foods ; and non-English studies and animal and cell culture studies.2 statistic and Cochran’s Q test P value), and publication bias assessment . If dose-response analysis and subgroup analysis were conducted, we also extracted the non-linearity tests’ P value and results of subgroup analysis in meta-analyses. If a meta-analysis was conducted on both cohort and case-control/cross sectional studies and stratification analysis was conducted through study design, we selected the cohort design subanalysis results for data extraction or reanalysed. Any disagreement was determined by a third author (LRL).Two reviewers (YH and ZYC) independently extracted the following information from each eligible study: first author’s name, publication year, type of dietary sugar consumption , measurement of dietary sugar consumption, health outcome, number of included studies, number of cases and total participants, study design , comparison  versus none), and estimated summary effect . Furthermore, we extracted the model of effect (random and fixed), heterogeneity (ITwo reviewers (YH and ZYC) evaluated the methodological quality of the included articles by using AMSTAR (a measurement tool to assess systematic reviews), a valid and dependable measurement tool in assessing the quality of systematic reviews and meta-analyses.2 statistic, P value of Cochran’s Q test for heterogeneity, and P value of Egger’s regression test (at least 10 studies were included) for small study effects in each included meta-analysis that reported the metric, number of cases, and participants of the included original studies.We reanalysed the risk ratio, odds ratio, weighted mean difference, or standardised mean difference with 95% confidence intervals through random or fixed effects models and calculated the IPatients and the public were not involved in the planning, design, and implementation of the study, as this study used secondary data. No patients were asked to advise on interpretation or writing up of the manuscript.Most of the included meta-analyses focused on the associations between dietary sugar consumption and endocrine/metabolic diseases (n=28), followed by cancer (n=25), cardiovascular diseases (n=17), neuropsychiatric diseases (n=3), dental diseases (n=2), and other diseases (n=8) . DietaryA meta-analysis of six randomised controlled trials found that sugar sweetened beverage consumption was significantly associated with increased body weight for highest versus lowest consumption  ).Dose-response analysis based on seven cohort studies showed that a one serving/day increment of sugar sweetened beverages was associated with a 0.22 kg weight gain in one year .The most recent meta-analysis found a 1.46 mg/dL  decrement of high density lipoprotein cholesterol for the highest versus lowest sugar sweetened beverage consumption.The risk of metabolic syndrome was increased by 14%  for a 355 mL/day increment of sugar sweetened beverages, with no evidence for departure from linearity.We found no significant association between sugar sweetened beverage consumption and changes in body mass index in adults,In a single article,Except for a beneficial association between sucrose intake and cardiovascular disease mortality, all categories of dietary sugar exposure were adversely associated with various cardiovascular outcomes. A recent dose-response meta-analysis showed that each 250 mL/day increment of sugar sweetened beverage consumption was positively associated with a 7%  higher risk of stroke.We observed no significant association between sugar sweetened beverage consumption and changes in diastolic blood pressure (children and adolescents)A dose-response meta-analysis showed that the risk of hepatocellular carcinoma increased by 100%  for the highest sugar sweetened beverage consumption compared with the lowest .A recent meta-analysis of six observational studies showed a higher risk of breast cancer for highest versus lowest sugar sweetened beverage consumption .We observed no significant association between sugar sweetened beverage consumption and the risk of biliary track cancer,A recent meta-analysis of 11 cohort studies suggested that an increment in sugar sweetened beverage consumption of 250 mL/day was associated with a 4%  higher risk of all cause mortality .The highest versus lowest sugar sweetened beverage consumption might increase the risk of asthma in children by 26% .Sugar sweetened beverage consumption was not associated with the risk of chronic kidney disease.2>50% or P value of Cochran’s Q test <0.1). The heterogeneity of most outcomes could be explained by some potential factors, including setting, region, ethnicity, sex, age, study quality, study design, sample size, duration of follow-up, and adjustment for confounding factors. Of the 26 outcomes that we could not reanalyse, approximately 54% had significant heterogeneity and 4% did not report the results of the heterogeneity evaluation.We reanalysed the heterogeneity in 69% of all health outcomes by a random or fixed effects model. Reanalysis found that approximately 46% of the health outcomes that we reanalysed had significant heterogeneity  (P=0.016), overall cancer risk (P=0.005), and hypertension in adults (sugar sweetened beverages) (P=0.02). For outcomes that we could not reanalyse, publication bias was detected for cardiovascular disease mortality (sugar sweetened beverages), non-alcoholic fatty liver disease, obesity in adults, and change in body weight (one year) by statistical test or funnel plot. The remaining outcomes did not show significant publication bias or did not report an evaluation for publication bias.The median AMSTAR score of all health outcomes was 8  (supplementary table E). Supplementary table F provides the detailed AMSTAR scores for each outcome. All evidence from meta-analyses of cohorts, population based case-control studies, and cross sectional studies is graded as “low” or “very low” quality owing to the observational study design and factors for quality downgrade . Among the nine meta-analyses of randomised controlled trials, four , and change in body weight (sugar sweetened beverages)) were downgraded as “moderate” quality given the imprecision, and the remaining ) were downgraded as “low” or “very low” owing to the risk of bias, inconsistency, indirectness, or imprecision (supplementary table E). Supplementary Table G shows the detailed GRADE classification for each outcome. In terms of evidence classification, type 2 diabetes mellitus (sugar sweetened beverages), hyperuricaemia (fructose), obesity in children (sugar sweetened beverages), coronary heart disease, hypertension in adults (sugar sweetened beverages), dental caries, depression, and non-alcoholic fatty liver disease were graded as class II. For the remaining 75 outcomes, 15 (18.1%) were graded as class III, 26 (31.3%) were graded as class IV, and 34 (41.0%) were identified as non-significant (supplementary table E). Sensitivity analyses of each outcome graded as class II did not alter the direction or significance of the association.Dietary sugar consumption is harmfully associated with multiple health outcomes across various measurements of exposure, including high versus low, never/low versus moderate/high, any versus none, or an extra increment of sugars per day (or week) versus none. We identified 73 meta-analyses and 83 health outcomes from 8601 unique articles, including 74 unique outcomes in meta-analyses of observational studies and nine unique outcomes in meta-analyses of randomised controlled trials.Dietary sugar consumption had harmful associations with endocrine and metabolic outcomes, including changes in body mass index in children,In general, no reliable evidence shows beneficial associations between dietary sugar consumption and any health outcomes, apart from glioma (sugar sweetened beverages),Our umbrella review showed harmful associations between dietary sugar consumption and a range of cardiometabolic diseases, especially weight gain, ectopic fat accumulation, obesity, and cardiovascular disease, which can largely be attributed to excessive consumption of fructose containing sugars. In response to the intake of large carbohydrates, fructose could enhance hepatic lipogenic capacity by inducing hepatic master transcription factors.Another important mechanism to explain the associations between dietary sugar consumption and cardiometabolic diseases involves uric acid synthesis. Many studies have confirmed that excessive fructose consumption can promote uric acid synthesis by inducing degradation ATP to AMP, a substrate for uric acid production.Until now, the evidence for the association between dietary sugar consumption and the risk of cancer has remained limited and controversial.The effect of dietary sugars on obesity might partly explain their association with the risk of cancer.On the other hand, dietary sugar consumption has also been shown to be negatively associated with some neuropsychiatric diseases, such as depression and attention deficit/hyperactivity disorder.In addition, the adverse association between sugar consumption and bone mineral density might be attributed to the increased loss of urinary calcium and imbalance in calcium homoeostasis induced by high sugar intake.Of the subgroup analyses conducted in this umbrella review, the most noteworthy is the stratification according to region, as several health outcomes showed a regional discrepancy, including overall cancer mortality, high density lipoprotein cholesterol, low density lipoprotein cholesterol, and total cholesterol. Potential reasons for these discrepancies may include regional differences in sugar consumption and culture. According to the report conducted in 2010 for the quantification of global, regional, and national consumption of sugar sweetened beverages in 187 countries, consumption among Asian countries was lower than that among European and American countries.This umbrella review first reported a comprehensive summary of the current evidence from previous meta-analyses of observational studies and randomised controlled trials for the association between dietary sugar consumption and all health outcomes. Given the high levels of dietary sugar consumption worldwide, this study has clinical and social significance for developing preventive strategies against excessive sugar consumption, especially for children and adolescents. This study was carried out on the basis of systematic methods in which independent literature searching, study selection, and data extraction by two authors were involved. If the data were sufficient, we reanalysed the risk ratio, odds ratio, weighted mean difference, or standardised mean difference with 95% confidence intervals through random or fixed effects models and evaluated the heterogeneity and publication bias for each included meta-analysis. Furthermore, we used three standard approaches, AMSTAR, GRADE, and evidence classification criteria, to assess the methodological quality (AMSTAR), strength (GRADE) and classification (evidence classification criteria) of evidence for each health outcome and to evaluate our confidence in the estimates. Interestingly, in our umbrella review, the GRADE rating of several health outcomes was not completely consistent with the results of evidence classification. As we know, evidence classification criteria are a completely objective classification standard, whereas the GRADE rating has a certain degree of subjectivity.Original studies included in meta-analyses used different methods of food intake investigation, including food records, 24 hour dietary recall, food frequency questionnaires, and dietary history. All of these are associated with an unavoidable measurement bias even if validated methods are used.We reviewed details of competing interest and funding disclosures from meta-analyses included in this umbrella review. Only two meta-analyses were funded by companies that produce sugar sweetened beverages.The harmful association between dietary sugar consumption and multiple health outcomes observed in our umbrella review is supported by several large scale prospective cohort studies published in recent years. The first was a large prospective cohort study conducted using the results of the French NutriNet-Santé cohort 2009-17), which included 101 257 participants with an average age of 42.2.09-17, whThe positive associations between sugar sweetened beverage consumption and the risk of mortality detected in this umbrella review were supported by a prospective cohort study of 118 363 people followed for 34 years in the US, during which time 36 436 deaths were documented.This umbrella review shows that high dietary sugar consumption, especially intake of sugars that contain fructose, is harmfully associated with large numbers of health outcomes. Evidence for the harmful associations between dietary sugar consumption and changes in body weight (sugar sweetened beverages), ectopic fat accumulation (added sugars), obesity in children (sugar sweetened beverages), coronary heart disease (sugar sweetened beverages), and depression (sugar sweetened beverages) seems to be more reliable than that for other outcomes. Evidence of the association between dietary sugar consumption and cancer remains limited but warrants further research. In combination with the WHO and WCRF/AICR recommendations and our findings, we recommend reducing the consumption of free sugars or added sugars to below 25 g/day (approximately six teaspoons a day) and limiting the consumption of sugar sweetened beverages to less than one serving a week (approximately 200-355 mL/week).Sugar consumption could have negative effects on health, especially obesity, diabetes, cardiovascular disease, hyperuricaemia, gout, ectopic fatty accumulation, dental caries, and some cancersDeficiencies in study design, varying measurements, inconsistent findings, and different definitions of exposure make drawing final conclusions on associations difficultComprehensive evaluation of the quality of existing evidence on the associations of sugar consumption with all health outcomes is neededHigh dietary sugar consumption is generally more harmful than beneficial for health, especially in cardiometabolic diseaseEvidence of the association between dietary sugar consumption and cancer remains limited but warrants further researchExisting evidence is mostly observational and of low quality, and further randomised controlled trials are needed


Conclusions: A significant protective effect of BRS against the development of CRC is implied. In the present analysis, the incidence rate of colorectal cancer was approximately halved amongst the obese individuals that were operated on.Background: Obesity is a known risk factor for developing colorectal cancer (CRC) and is associated with the formation of precancerous colonic adenomas. Bariatric surgery (BRS) is considered to reduce the cancer risk in morbidly obese patients. However, the currently available literature yields contradicting results regarding the impact of bariatric surgery on the incidence of CRC. Methods: A systematic literature search of the Medline, Embase, CENTRAL, CINAHL, Web of Science, and clinicaltrials.gov databases was undertaken following the PRISMA guidelines. A random effects model was selected. Results: Twelve retrospective cohort studies, incorporating a total of 6,279,722 patients, were eligible for inclusion in the final quantitative analysis. Eight studies originated from North America, while four reported on European patients. Patients in the Bariatric Surgery group exhibited a significantly reduced risk for developing colorectal cancer (RR 0.56, 95% CI 0.4–0.8,  Obesity is a serious worldwide concern with significant implications for Global Public Health. In a 2016 report, the World Health Organization estimated that more than 1.9 billion adults (18 years old and older) worldwide were overweight, with 650 million of them being obese. Overall, about 13% of the world’s adult population (11% of men and 15% of women) is obese, with the prevalence having nearly tripled between the years 1975 and 2016 [It is a well-established fact that the risk of developing several types of cancers is increased in the morbidly obese population. The International Agency for Research on Cancer (IARC) has designated 14 types of cancer as obesity-related ones, including colorectal cancer (CRC) ,6,7. ObeThis meta-analysis aims to elucidate the effect of bariatric surgery on CRC by investigating the incidence rates of colorectal neoplasias in obese patients that have undergone a bariatric operation versus those who have not and to evaluate the impact of each bariatric procedure on the incidence of CRC.A systematic literature search of the Medline, Embase, CENTRAL, CINAHL, Web of Science, and clinicaltrials.gov databases was undertaken using the search terms “colorectal cancer”, “colorectal neoplasms”, colorectal adenoma”, “colorectal polyp”, “obesity”, “overweight”, and “bariatric”, combined with the Boolean operators AND/OR as appropriate for each database. The search for Medline was phrased as follows: colorectal cancer AND (obese OR obesity OR overweight) AND (bariatric). After the removal of duplicate studies, the generated abstract list was independently screened by two authors (AP and MM), for studies reporting the comparative incidences of colorectal cancer in patients with a history of bariatric surgery (BRS group) and those without (control group). The reference lists of potentially relevant studies were screened for further eligible studies.All of the studies, irrespective of language, deemed to be relevant by the screening process were evaluated in full independently by two authors (AP and MM), with a third one (DP) acting as a referee in cases of disagreement. The predetermined set of exclusion criteria were: (1) case reports and non-clinical studies, (2) studies reporting neoplasms other than those of colorectal origin, (3) studies without a comparator control group, (4) studies exhibiting population overlap or originating from the same database (the study with the largest sample size was selected), (5) studies not reporting colorectal cancer incidence rates, and (6) studies focusing on specific population subsets .The present systematic review and meta-analysis was conducted according to PRISMA guidelines  and was Data extraction was performed by two authors (AC and GB) to ensure data accuracy and completeness. The primary variables of interest were the incidence rates of colorectal cancer and colorectal adenomas or polyps and the type of bariatric surgery that had previously been performed. The secondary outcomes of interest were the patient demographics, the interval of data collection, the country of origin, and the type of database reported. The extracted data were entered into standardized Excel spreadsheets  for further tabulation.The risk of bias was evaluated independently by two authors (DD and CN) using the ROBINS-I tool, which assesses studies across seven domains: bias due to confounding variables, bias due to the selection of participants, bias in the classification of interventions, bias due to deviations of the intended interventions, bias due to missing data, bias in the measurement of outcomes, and bias in the selection of the reported results. For each domain, the risk of bias can be low, moderate, or serious.2 statistic; values below 30% represent low heterogeneity, values between 30 and 60% represent moderate heterogeneity, and values above 60% represent substantial heterogeneity. A further subgroup analysis was performed by stratifying the studies by type and continent of origin, and a leave-one-out sensitivity analysis was performed by iteratively removing one study at a time to identify potential outliers influencing the obtained pooled results.Statistical analyses were performed using Stata v. 17 . Risk Ratios (RR) and corresponding 95% confidence intervals (CI) were calculated using a random effects model (DerSimonian-Laird), anticipating high clinical heterogeneity in terms of the patient baseline parameters. Statistical heterogeneity was quantified with the Higgin’s Ip-value below 0.05 was considered to be statistically significant.Risk of publication bias was assessed by the visual symmetry of associated funnel plots and using Egger’s and Begg’s tests for every outcome incorporating at least ten studies. For all of the statistical analyses in the present study, a After screening two hundred and ten unique studies and applying the exclusion criteria, thirteen studies, incorporating a total of 6,279,722 patients , were deemed eligible for inclusion in the final quantitative analysis . All of p < 0.001, 2 = 95.2%).Based on reports from eleven studies ,18,19,20p < 0.001, p = 0.05 and 0.27, respectively, When different types of bariatric procedures were considered, sleeve gastrectomy was found to be significantly associated with fewer cases of colorectal cancer .The risk of the development of colorectal adenomas was assessed in four studies ,20,21,22p = 0.25).When the studies were stratified according to origin, the North American studies were found to report a more protective effect of bariatric surgery than the European studies did . Moreovep = 0.95 and 0.75, respectively), indicating the absence of publication bias.Visual assessment of funnel plots did not reveal any gross asymmetries. Egger’s and Begg’s tests were utilized to quantitatively assess the risk of publication bias in the colorectal cancer incidence outcome (The data in all of the included studies are derived from databases, of which ten are large cross-sectional databases and three are institutional databases. The average follow-up after bariatric surgery was reported in nine studies. In most cases, the follow-up averaged 60 or more months after bariatric surgery, with a single study reporting a shorter follow-up of 36 months. In the latter case, the reported RR was entirely balanced between the BRS and control group, with a value of one .2 and a moderate one was encountered in six other cases that either lacked information on how the patients were selected or used BMI cut-offs in the range from 30 to 40 kg/m2. Finally, a single study was found to be at a moderate risk for missing data bias since the reported average follow-up of 36.4 months might have been inadequate to detect all of the emerging cases of colorectal neoplasias.Overall, the risk of bias of the included studies was low in three cases, moderate in nine cases, and serious in one study . When thIn the present systematic review and meta-analysis, bariatric surgery was found to reduce the risk for colorectal cancer by 44%. A trend towards reduced adenoma formation was also observed, albeit to a non-significant degree. Both of these findings suggest a strong protective effect of BRS, which is in line with previously published reports ,24. In fA rational assumption is that the risk of CRC would decrease with bariatric surgery because of the improved metabolic effect after the surgery. Yet, the evidence is, to date, controversial. For example, early bariatric surgery studies did not investigate the CRC risk specifically and showed no change in the CRC risk after bariatric surgery. Recent US and French cohorts that followed the patients for up to 10 years after surgery indicate that bariatric surgery decreases the risk of CRC in female patients ,26. NeveIn the present analysis we also explored, within the constraints of the available literature, the role of different bariatric procedures on reducing the risk of CRC. Amongst the evaluated studies, sleeve gastrectomy presented a stronger association with a reduced CRC incidence, followed by gastric bypass and gastric banding . HoweverA significant decrease in the incidence rates of colorectal adenomas could not be presently demonstrated, although a trend towards less risk was appreciated. Previous reports indicate that obesity is not only associated with increased risk for adenoma formation , but it In the complementary subgroup analysis presented herein, geography seemingly plays a central role in the risk colorectal cancer development within the evaluated patient population. North American studies were associated with more protection following BRS . A diffeWhile the pooled results obtained from the present analysis indicate a strongly significant protective effect of BRS on CRC development, some important caveats should be acknowledged in addition to those previously discussed. First and foremost, despite the CRC incidence rates amongst the patients in the BRS group being almost halved, an explicit causal relationship between BRS and the observed reduced incidence rates cannot be documented based on the findings of this study. Although the evidence indirectly suggests that weight loss leads to reduction of the risk of CRC ,34, the In conclusion, accumulating evidence points at a significant protective effect of BRS on the development of CRC. In the present analysis, the incidence rate of colorectal cancer was approximately halved the amongst obese individuals that had been operated on. Moreover, sleeve gastrectomy was found to perform better in terms of CRC prevention than gastric bypass does, indicating that malabsorptive procedures have a more modest effect, plausibly due to detrimental changes exerted in the microenvironment of the colon and rectum. Important limitations exist in the present analysis, which could potentially be overcome with a randomized trial. Nevertheless, randomizing obese individuals in surgical and non-surgical cohorts would be especially problematic from an ethical perspective. Ultimately, future case–control studies with long-term follow-up will help to further delineate the exact effect of BRS on the incidence of colorectal neoplasias.