This study aimed to conduct a coordinate-based meta-analysis (CBMA) to investigate white matter (WM) abnormalities in healthy individuals with overweight or obesity. d mapping (SDM) software, employing stringent thresholds for significance. Sensitivity analyses and meta-regression analysis were also performed to examine the robustness of the results and explore potential associations with age and body mass index (BMI).  A systematic literature search using Web of Science and PubMed datasets was performed. Original investigations that used diffusion tensor imaging (DTI) to explore fractional anisotropy (FA) differences between healthy overweight/obese individuals and normal weight controls were collected. The meta-analysis was conducted using the seed-based  The analysis included five studies comprising 232 overweight/obese individuals and 219 healthy normal weight controls. The findings showed that overweight/obese individuals exhibited reduced fractional anisotropy (FA) in specific regions, namely, the right superior longitudinal fasciculus (SLF), the splenium of the corpus callosum (CC), and the right median network, cingulum. Meta-regression analysis further revealed that these FA reductions were associated with age.  These findings provided insights into the potential impact of overweight/obesity on cognition, emotion, and neural functions and highlighted the significance of early prevention and intervention for overweight on the basis of neuroimaging. Overweight as well as obesity is closely associated with 21 diseases, including cardiovascular, metabolic, digestive, respiratory, neurological, musculoskeletal, and infectious diseases , 4, suggOne recent meta-analysis of structural MRI in obesity exhibited abnormalities in gray matter volume (GMV) in regional brain regions such as the frontal lobe, temporal lobe, precentral gyrus, and occipital lobe . The stuMeta-analysis is a valuable technique that allows researchers to consolidate and analyze data from multiple studies, providing a more robust and applicable estimate of the effect size. By combining data from various sources, meta-analysis increases the sample size and statistical power, making it easier to detect even small effects and reducing the risk of erroneous findings, such as false positives or false negatives . CoordinThe aforementioned meta-analysis considered obese cohorts with comorbidities such as type 2 diabetes (T2DM), but there is a lack of research specifically examining WM characteristics in healthy individuals who are overweight or obese. Herein, we intended to conduct a CBMA solely on healthy overweight or obese individuals compared with healthy individuals with a normal weight. Building on previous findings from published articles, our hypothesis was that the overweight/obese group would exhibit alterations in WM microstructures, particularly in central nerve tracts such as the SLF and the CC.https://www.crd.york.ac.uk/PROSPERO) under registration number CRD42022303123 and adhered to PRISMA guidelines [We registered our CBMA protocol with PROSPERO  or Talairach coordinates and using a threshold for significance. We excluded case reports, reviews, meta-analyses, and tractography-based only studies, as well as studies with no direct between-group comparison or from which peak coordinates or parametric maps could not be obtained.Z-statistics, t-statistics, and P value).Following the guidelines for neuroimaging meta-analyses , two authttps://www.sdmproject.com) [P < 0.001, a peak height threshold of Z = 1.00, and a cluster size threshold of 10 voxels.The SDM software (ect.com) , 19 was ect.com) . We appln times (where n corresponds to the number of datasets included) and systematically excluding one study at a time. We considered a brain region highly reliable if it remained significant after performing jackknife sensitivity in all or most of the combinations of studies [To examine the robustness of our findings, we performed a jackknife sensitivity analysis. This approach entailed repeating the primary analysis for a total of  studies .P < 0.0005 was employed. This threshold was consistent with previous meta-analyses and the recommendations of the SDM creators [To minimize the detection of potential correlations between demographics and neuroimaging, a more stringent threshold of creators . We explA total of 366 articles were initially identified. Based on the inclusion and exclusion criteria, a total of 5 articles were finally included –25. The Overweight/obese individuals exhibited FA reductions in the right superior longitudinal fasciculus (SLF), the splenium of the corpus callosum (CC), and the right median network, cingulum . There wP < 0.0005 , and radial diffusivity (RD) would offer valuable insights into characterizing microstructural WM alterations in healthy overweight individuals. Regrettably, we encountered limitations in conducting meta-analyses involving these DTI metrics due to the inadequacy of available datasets. Lastly, we only utilized peak coordinates and effect sizes from published studies, rather than the original statistical brain maps, which might result in partial loss of original information.In conclusion, our study found that healthy overweight/obese individuals exhibited age-related decreased FA in the right SLF, the splenium of the CC, and the right median network, cingulum. These findings provide valuable insights into the potential impact of overweight/obesity on cognition, emotion, and neural system functions. The study also highlights the importance of developing prevention and intervention strategies for brain structural changes associated with overweight/obesity and suggests that these changes may serve as early warning signs for cognitive disorders in this population.


Some reports demonstrate that asthma benefits from milk and dairy products, however, the findings are controversial. We used meta-analysis as a tool to summarize published data on the association between dairy products consumption and asthma.A systematic literature search was conducted to identify studies of dairy products and asthma in children in PubMed, ISI (Web of Science), and EMBASE until 21 July 2022. Random-effect meta-analyses with summarized data were performed for total (high/low) milk and dairy intake. Subgroup analysis was used to identify sources of variation in responses. Publication bias and sensitivity analysis were done to examine the stability of results.There was no correlation between consumption of dairy products and reduced risk of asthma . Our results revealed that elevated consumption of milk and dairy has significant correlation with reduced risk of asthma in Non-Asian population  and high quality studies . No individual study influence and publication bias was seen in the sensitivity analysis and publication bias assessment.There was no correlation between consumption of dairy products and reduced risk of asthma. However, we observed that elevated consumption of milk and dairy has significant correlation with reduced risk of asthma in Non-Asian population and high quality studies. More high-quality and population-specific studies should be conducted to determine the risk link between milk consumption and asthma in children.The online version contains supplementary material available at 10.1186/s13690-023-01162-8. The dramatic increase in noncommunicable diseases (NCD) prevalence can be explained by the emergence of risk factors or the loss of protective factors, or both in the past decades . As the There is growing evidences that diet plays a big role in the development and treatment of asthma . Diet, aOur study was conducted by using systematic literature search in PubMed/Medline, EMBASE and ISI web of Science, prior to 21 July 2022 based on the PRISMA  statement. The detail search strategy is shown in the Supplemental Table In the present meta-analysis, two investigators were asked to independently select articles based on three certain criteria as follows: (1) all observational studies  performed on children who were younger than 18 years old; (2) studies used explicit method for assessing milk and dairy consumption and asthma diagnosis; (3) articles reported odds ratios (ORs), hazard risks (HRs), or relative risks (RRs) accompanied by 95% confidence intervals for asthma or data which can be calculated for confidence intervals, (4) the language is limited to English. Discrepancies were resolved by discussion with a third investigator.Meta-analyses, reviews, letters, and comments were excluded. When multiple publications were available for the same study, only the most comprehensive publication was included in the present meta-analysis.Information was independently extracted by two investigators for all the included articles as follows: publication time, study design, first author, country, number of cases, sample size, age range, gender, exposure variable, assessment of exposure, outcome variable, assessment of outcome, relevant effect sizes that are aORs, aRRs, or aHRs with their confidence intervals (95%), and adjusted covariates.The Newcastle–Ottawa Scale (NOS) was used to assess the qualities of cohort and case-control studies included. The NOS assigns up to 9 points per study: 2 points for comparability, 4 points for selection, and another 3 points for assessment of exposures and outcomes. For the analysis in this study, we calculated the sum of each item score, with scores of seven and above representing high quality and scores below seven representing low quality.I2 index measure and Cochran’s Q test were conducted to evaluate heterogeneity. P < 0.05 was identified being statistically significant for the Q statistic; for the I2 statistic, I2 values of approximately 75, 50, and 25% refer to high, moderate, and low heterogeneity, respectively. We used subgroup analysis to explore possible sources of heterogeneity in the study, and sensitivity analysis to assess the level to which inferences have the possibility to depend on one particular study. Egger’s regression asymmetry test and visual inspection of Begg’s funnel plots were used to examine publication bias in this study. The software, STATA version 14.2  was used as a tool for statistical analyses, and P-value qualities < 0.05 were considered as statistically significant.The term ‘‘OR’’ was used as a generic term for ORs and HRs in the study. Based on the OR of asthma for the lowest vs. the highest intake of dairy products reported in one publication , we compThere were 11 articles –19 , with a high substantial heterogeneity (P = 0.0864) and Begg’ funnel plot which were showed in Supplementary Figure S2.To identify the potential sources of heterogeneity and examine the robustness of the result, subgroup analysis was conducted according to study design, quality of study, sample size, location, and adjustment for gender and age Table . The corThis meta-analysis including 13 studies aimed to clarify the association between dairy products consumption and risk of asthma. The result of our study supported that greater dairy products consumption was not linked to reduced risk of asthma, however, inverse association was observed in Non-Asian population and high quality included studies.The inconsistent association among studies might be related to inverse effect of raw milk (protective factor) and heat-treated milk (risk factor) . There wOur study suggested the negative association between dairy products consumption and risk of childhood asthma in Non-Asian population but not found in Asian population. A reasonable explanation could be the limited dairy products consumption in Asian population compared to Non-Asian population. According to the findings reported by the International Study of Asthma and Allergies in Childhood (ISAAC) in 1998, the prevalence of asthma-related symptoms declined in Western Europe, but increased in Asia Pacific . The powSome specific biological mechanisms could illustrate the relationship between dairy products consumption and childhood asthma. Milk and dairy products are rich in proteins, oligoelements and macroelements, as well as lipophilic and hydrophilic vitamin . The proThis systematic review and meta-analysis used a combination of evidence from all studies published to assess if milk and dairy consumption has association with the risk of childhood asthma, which increased the statistical power to identify a negative association of dairy products intake and risk of asthma. In addition, the potential publication bias in the present meta-analysis was minimized though the application of a broad literature search as mentioned above. Since the development of asthma symptoms could be linked to substantial factors , 24, theConsidering articles included for the final analysis were limited, we did not perform linear and non-linear dose–response meta-analysis (DRMA) on the theme in this study. Future studies examining multiple aspects of milk and dairy consumption are needed to explore their association.There was no correlation between consumption of dairy products and reduced risk of asthma. However, we observed that elevated consumption of milk and dairy has significant correlation with reduced risk of asthma in Non-Asian population and high quality studies. More high-quality and population-specific studies should be conducted to determine the risk link between milk consumption and asthma in children.Below is the link to the electronic supplementary material.Supplementary Material 1


The same result was obtained with the weighted median and the MR-egger (p > 0.05). Conclusion: Our study did not find a genetic causal relationship between susceptibility to these autoimmune diseases and GC, which suggests that unmeasured confounders  or shared genetic architecture may be responsible for the reported epidemiologic associations. Further studies of ancestral diversity are warranted to validate such causal associations.Background: Whether the positive associations of gastric cancer (GC) with autoimmune diseases are causal has always been controversial. This study aims to estimate the causal relationship between GC and 12 autoimmune diseases by means of Mendelian randomization (MR) analysis. Methods: After rigorous evaluation, potential candidate single nucleotide polymorphisms (SNPs) for GC and 12 autoimmune diseases were extracted from genome-wide association study (GWAS) datasets. We performed the MR analyses using the inverse variance weighted (IVW) method as the primary approach to the analysis. Three sensitivity analysis methods were added to assess the robustness of the results. In addition, heterogeneity was measured using Cochran’s Q-value, and horizontal pleiotropy was assessed using MR-Egger regression and leave-one-out analysis. Results: The IVW result, which is the main method of analysis, shows no evidence of a causal association between GC and any autoimmune disease. The results of IVW analysis show the relationship between rheumatoid arthritis ( Helicobacter pylori, a high intake of salt, and a diet low in fruits and vegetables [Gastric cancer (GC) is the fifth most common type of cancer and the third leading cause of cancer death in the world . Althouggetables ,6. The 5getables ,8. Due tgetables . South Kgetables . Increasgetables .Autoimmune diseases, which occur in multiple organs or systems throughout the body, are characterized by the loss of self-tolerance, which results in the immune-mediated destruction of the body’s own tissues . Immune Mendelian randomization (MR) analysis, an emerging statistical method, estimates the causal relationship between exposure and outcome by using genetic variants such as single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) . To relihttps://www.finngen.fi/en/access_results (accessed on 10 June 2023) [https://gwas.mrcieu.ac.uk/ (accessed on 10 June 2023)). Autoimmune disorders in this study include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), ulcerative colitis (UC), Crohn‘s disease (CD), celiac disease (CeD), asthma, eczema, type 1 diabetes (T1D), primary sclerosing cholangitis (PSC), and psoriasis (PsO). In these studies, all of the cohorts of cases and controls were of European ancestry, and there is also no significant overlap between the populations of the GWAS. The initial studies provide detailed information on enrollment procedures and diagnostic criteria. More detailed information for the cohorts of cases and controls can be found in We performed a systematic analysis with GWAS summary-level data obtained from different large-scale cohorts to infer causal relationships between GC and autoimmune diseases . GWAS sune 2023) . The sump < 5 × 10−8) for each instrument and used a clustering procedure with R2 < 0.001 and cluster distance = 10,000 kb to avoid linkage disequilibrium (LD) [A/G versus A/C) or ambiguous strand . To detect the underlying weak instrumental variable bias, we also calculated the proportion of variance explained (R2) and the F statistic for all SNPs. A mean F-statistic  >  10 indicates suitable instrumental variables [We used the R package TwoSampleMR to select genetic instruments from each of the 12 autoimmune disease GWASs . A rigorium (LD) . Then, wariables ,28.https://sb452.shinyapps.io/power/ (accessed on 10 June 2023)) was applied to calculate the statistical power of each IV. The odd ratios (ORs) are described as an increase in the level of the risk factor per standard deviation (SD) [In this study, we estimated the causal associations between 12 autoimmune diseases and GC separately using different MR methods by combining summary statistics (β coefficients and standard errors) . We applion (SD) . p value < 0.05 was considered significant heterogeneity [To detect potential horizontal pleiotropic effects and to examine the consistency of the associations, several sensitivity analysis methods were performed, including weighted median, MR-Egger, and MR pleiotropy residual sum and outlier (MR-PRESSO) analyses . It is wogeneity ,36. Multogeneity .R tool (version 4.3.0) was used for all statistical analyses in this study. The MR analyses were carried out using the R packages TwosampleMR (version 0.5.6), MR-PRESSO (version 1.0), and qvalue.p > 0.05). The results of IVW analysis show the relationship between RA , SLE , CD , MS , PSC , PBC , T1D , UC , eczema , asthma , CeD , and PsO  and GC susceptibility. F-statistics for PBC and PsO could not be calculated due to missing data from some GWASs. In addition, F-statistic > 62 for all of the instruments, which is above the standard cut-off (>10) and indicates that the instrument has sufficient power.The causal relationship from MR analysis between GC and autoimmune diseases is graphically summarized in For each IV, a sensitivity analysis is performed to detect the presence of horizontal pleiotropy. IVs for PBC were found to be significantly heterogeneous (IVW: Cochran’s Q = 0.027). SNPs with heterogeneity were found using MR-PRESSO analysis with R. Then, four SNPs  with heterogeneity were extracted using MR-PRESSO analysis, the SNPs were removed for outliers, and the MR analysis was performed again. The MR-Egger regression intercept was insignificant . SensitiTo the best of our knowledge, this is the first study that has used MR analysis and large-scale GWAS data sets to demonstrate a causal relationship between GC and autoimmune diseases. Our results suggest that there is no apparent genetic causal relationship between autoimmune diseases and the chance of GC, which means that there is a lack of genetic association with correlating traits. This finding is consistent across multiple GWAS data sources and has been confirmed in sensitivity analyses.Helicobacter pylori eradication strategies have greatly reduced the incidence of gastric cancer compared to the previous period. Perhaps rational immune management will be a new direction for the reduction of the incidence of gastric cancer or the improvement of the survival rate of gastric cancer.Recent studies have shown that several autoimmune diseases can cause a slight increase in the risk of developing multiple cancers ,39. In aIn contrast to our findings, a study that included 30 different immune system diseases  found thSLE, RA, and MS are characterized by chronic, systemic, and exaggerated immune activation and inflammation affecting nearly every tissue in the body. Chronic inflammation caused by autoimmune diseases has long been implicated in carcinogenesis, but no genetic causality between these disorders and GC was found in this study. In a large retrospective study, Zhou Z et al. found that RA generally increased the incidence of solid tumors, with no significant association with GC. Most of the tumors developed nine years after the diagnosis of RA, suggesting that the potential carcinogenic effect of long-term use of antirheumatic drugs or NSAIDs deserves attention. Patients with SLE and MS also have a significantly increased risk of cancer, especially cancer of the female reproductive organs and solid cancers, with no significant association with GC .ATG16L1 T300A variant, a major CD susceptibility allele, has been shown to be associated with the development of gastric cancer susceptibility [EGFR and PPAR pathways in gastric cancer [Inflammatory bowel disease plays a significant role in the development and progression of gastrointestinal tumors, and the association between the risk of colorectal cancer and inflammatory bowel disease is well established . Howevertibility , and is c cancer .Patients with PSC have been reported to have a higher incidence of cancer than the general population, but the reason for the increased cancer risk is unclear and may be related to chronic liver and intestinal inflammation . In a map = 0.021) [We found that genetically predicted eczema and asthma were not causally related to GC risk. However, the link between asthma and cancer has been mixed in previous studies. Two independent longitudinal cohort studies involving 480,637 participants suggest that the development of asthma increases the risk of secondary cancer overall, and this association remained after a stratified study based on age and sex status . There i= 0.021) . The rea= 0.021) ,55. Alle= 0.021) ,57. In a= 0.021) . FurtherOur research has several major strengths, the most important of which is the MR design, which allows causal inference free from confounding and reverse causality . SecondlNevertheless, we still have a number of limitations, and therefore the results should be treated cautiously. Firstly, the participants in the study were of European descent, so further research is needed to determine whether the findings apply to other populations. Second, the results may be biased because there is an additional complicating factor in using Finnish genetic data for the results: The Finnish population is one of the most diverse from the European population. Furthermore, there are also limitations to using summary GWAS statistics. It is well-known that selecting IV SNPs from the exposure GWAS results in the winner’s curse. Although sensitivity and multiplicity analyses have been performed to assess the validity of Mendelian randomization studies, this does not completely eliminate the bias it may introduce. Finally, although we have taken steps to eliminate the possibility of confounding, we cannot completely rule out the possible influence of horizontal pleiotropy on our results.Our MR results suggest that there is no genetic causal relationship between gastric cancer and 12 autoimmune diseases, which means that there is a lack of genetic association with correlating traits. However, this does not exclude the possibility that they are related to unmeasured confounders  other than genetic. To further dissect the complex relationship between GC and autoimmune disease, more population-based and experimental studies are warranted.


Pneumonitis is one of the most common adverse events induced by the use of immune checkpoint inhibitors (ICI), accounting for a 20% of all ICI-associated deaths. Despite numerous efforts to identify risk factors and develop predictive models, there is no clinically deployed risk prediction model for patient risk stratification or for guiding subsequent monitoring. We believe this is due to systemic suboptimal approaches in study designs and methodologies in the literature. The nature and prevalence of different methodological approaches has not been thoroughly examined in prior systematic reviews.The PubMed, medRxiv and bioRxiv databases were used to identify studies that aimed at risk factor discovery and/or risk prediction model development for ICI-induced pneumonitis (ICI pneumonitis). Studies were then analysed to identify common methodological pitfalls and their contribution to the risk of bias, assessed using the QUIPS and PROBAST tools.There were 51 manuscripts eligible for the review, with Japan-based studies over-represented, being nearly half (24/51) of all papers considered. Only 2/51 studies had a low risk of bias overall. Common bias-inducing practices included unclear diagnostic method or potential misdiagnosis, lack of multiple testing correction, the use of univariate analysis for selecting features for multivariable analysis, discretization of continuous variables, and inappropriate handling of missing values. Results from the risk model development studies were also likely to have been overoptimistic due to lack of holdout sets.Studies with low risk of bias in their methodology are lacking in the existing literature. High-quality risk factor identification and risk model development studies are urgently required by the community to give the best chance of them progressing into a clinically deployable risk prediction model. Recommendations and alternative approaches for reducing the risk of bias were also discussed to guide future studies. Success has been seen in melanoma, lung and kidney cancer, although their use is rapidly expanding to other cancer types . In addiOne of the more common irAEs that lead to drug discontinuation is pneumonitis, also known as interstitial lung disease (ILD), an inflammation of the lung tissue. It accounts for 20% of all ICI-associated deaths . PatientICI pneumonitis can be challenging to distinguish from other pathologies such as pulmonary embolus, infection, heart failure or underlying cancer progression . StrategSince the introduction of ICIs, many studies have been conducted to discover risk factors and to build risk prediction models. Both systematic and non-systematic reviews have been written to identify possible mechanisms for ICI pneumonitis , to summDespite these efforts, none of the risk factors and risk prediction models have yet translated through to clinical deployment of risk prediction tools. Due to the lack of large-scale high-quality validation studies for the commonly investigated risk factors, the community does not have good evidence to rely on to form a consensual set of risk factors for risk modelling. Findings on individual risk factors are also inconsistent between studies. This inconsistency may be a result of suboptimal methodology, examples include 1) bias in the study populations; 2) difficulty in ICI pneumonitis diagnosis; 3) increased risk of chance findings in small datasets; 4) bias in statistical analysis.Risk of bias analysis has been reported only in one previous review , which, 22.1Published works and preprints were identified using a Python interface for arXiv (arxiv=1.4.2) and R interfaces for PubMed (RISmed=2.3.0), medRxiv (medrxivr=0.0.5) and bioRxiv . The databases were searched from 1 January 2000 to 30 September 2022. An initial high-level search was performed for risk factor and risk prediction studies on anti-cancer drug-related pneumonitis. The subsequent search had a narrower scope, focusing on risk factor and risk prediction studies for ICI-related pneumonitis and specifically included individual ICIs in the search terms. The only preprint was removed after confirming that it did not investigate ICI pneumonitis.A two-stage process was then adopted to identify papers that reported risk factors or risk models for ICI pneumonitis; first, the title and abstract were screened followed by a second screen of the full article text.2.1.1Three reviewers  determined the relevance of the studies based on titles and abstracts. Each paper was assessed by two reviewers independently. Conflicts were resolved by consensus between the three reviewers.The inclusion criteria were: 1. Indication of risk factors, biomarkers and/or predictive models for ICI pneumonitis, including comparison of ICI pneumonitis incidence between different patient subgroups. 2. Reporting of imaging characteristics for ICI pneumonitis2.1.2Four reviewers  determined the relevance of the studies based on the full text. Each paper was assessed by two reviewers independently, conflicts were resolved by consensus between the four reviewers.In this review, we included any original study that reported: risk factors, predictive biomarkers and/or models for ICI pneumonitis (including a comparison of ICI pneumonitis incidence between different patient subgroups). The analysis must use statistical tests or predictive modelling for inclusion in our review.2.2The QUIPS tool  was adop2.3The following information was extracted from the papers , imaging data  or specialized laboratory tests such as genetics (2/50) and antibody abundance (2/50). 2/50 studies additionally developed a risk prediction model after risk factor identification from clinical data , 11. The3.1.1Most (47/50) studies used private data collected from their authors’ affiliated institutions. The remaining 3/51 studies used public databases , which have limited availability for clinical variables and diagnostic method. Study sample size ranged between 17 and 40826  (median=Close to 50% (24/50) of the studies used data from Japan, followed by USA (10/50), China (10/50), Australia (1/50), South Korea (1/50), Mexico (1/50) and Spain (1/50). 3/51 studies were analysed data from the FAERS database (2/3) and the VigiBase database (1/3) (74% (20/27) of imaging-based risk factor studies used computerized tomography (CT) as the sole imaging technique. The remaining 7 did not specify the imaging modality. All the studies relied on manual interpretation to determine radiographic features. 11/27 studies had 2-3 radiologists or pulmonologists reviewing the CT scans, 2/27 studies used a central review committee, 14/27 did not report the number of investigators involved in extracting the imaging findings. Acquisition parameters for the images were described in only 7/27 studies.A majority of risk factor studies (39/50) conducted analyses on lung cancer, of which 33/38 recruited only NSCLC patients  used dat19/50 studies summarized follow-up duration. The median time to onset is shorter than the median follow-up duration in all studies that reported both follow-up time and time to onset.3.1.2A total of 3 studies attempted to develop risk prediction models –12. All Imaging features were investigated in 2/3 studies. The modality of imaging was described in one study  that useIn terms of cancer type, all models were built on data from lung cancer patients  tool  was adopFor studies that aim to develop a risk prediction model, the Risk Of Bias Assessment Tool (PROBAST) was used . The fou3.2.13.2.1.13/50 studies were determined to have high risk of bias Table 2.3.2.1.237/50 studies were considered to have low risk of bias for prognostic factor measurement, with clear information on data source and data handling Table 2.3.2.1.3All studies explicitly stated ICI pneumonitis as the outcome of interest, alternative terms used in the studies include: pneumonitis (as a type of immune-related adverse event), immune-related pneumonitis/ILD and exacerbation of interstitial pneumonia after ICI administration. 16/50 studies had sufficient description on ICI pneumonitis diagnosis  or excluded other possible cause of lung inflammation by design, so were considered to have low risk for bias for outcome measurement Table 2.3.2.1.48/50 studies were considered to have low risk of bias Table 2.3.2.23.2.2.1According to PROBAST, all three studies reporting risk prediction models had low risk of bias in terms of participant or study sample selection. They retrospectively included data from cancer patients who were given ICI treatments in hospitals, no bias was identified from the inclusion/exclusion criteria.3.2.2.2All three studies reporting risk prediction models had low risk of bias introduced by predictors or their assessment. Candidate predictors were all extracted pre-treatment or at baseline without knowledge of outcome data. All the predictors were available in training, internal validation, and the external validation sets when used.3.2.2.3All three studies had unclear risk of bias for outcome determination due to lack of description on how ICI pneumonitis were distinguished from other alternative diagnoses such as infection and tumour progression.3.2.2.4All three studies had high risk of bias for data analysis due to low sample size:feature ratio (24 cases and 24 controls for deep learning in Tan 2022) , discret3.33.3.13.3.1.1Missing values were reported in 22/50 studies, the maximum proportion of missing values in a single-variable ranges between 0.2% and 64.7% across the studies . 4/22 of the studies included the missing values as a separate level in regression analysis , 41, 46,3.3.1.22/3 studies reported missing values and also investigated risk factors. One had a maximum of 17% of values missing in a single variable and excluded samples with missing values from analysis ; the oth3.3.23.3.2.1Univariate analysis was performed in 47/50 studies, most of them 26/47) used logistic regression in combination with other tests or by itself: 6/26 studies used contingency and/or two-sample tests to determine variables that should be further assessed by univariate logistic regression /47 used , 47, 58.Survival analysis was the second most popular method for univariate analysis, and was performed in 8/47 studies that conducted univariate analysis: 5/8 studies used survival analysis alone to identify risk factors  , 61, 63.Amongst the remaining studies that conducted univariate analysis, 12 used nothing but contingency and/or two-sample tests, one applied significance test on area under the receiver operating characteristics curve (ROC) , and one46/47 studies that performed univariate analysis used p=0.05 as significance threshold, one implied a threshold of p=0.001 . None, eMultivariable analysis was performed in 31/51 studies, most of them (23/31) used only logistic regression, another 6/31 used only survival modelling  , 61, 63.A total of 21/31 studies performing multivariable analysis relied solely (14/21) or partially (7/21) on univariate analysis for feature preselection, so only variables that were below a small p-value  or had sufficiently large effect size were passed to the multivariable analysis. 6/31 studies did not conduct any data-driven pre-selection at all , 56, 61.3.3.2.2Each of the three studies used different tests for univariate analysis. Chao et al. used logistic regression to select predictors for model building ; Jia et The risk prediction models were all multivariable. 2/3 were based on logistic regression , 11, the44.1In this analysis, we found that almost all of papers on ICI pneumonitis prediction focused on statistical significance and effect sizes of risk factors rather than risk model development. While statistical significance and the effect sizes (e.g. odds ratio and hazard ratio) may inform clinicians about the relative risk of ICI pneumonitis development for a patient, a clinical decision made without an estimate of the absolute risk can be suboptimal: a 2-fold increase in relative risk could represent a change of absolute risk from 40% to 80%, or from 5% to 10%. We suggest that future studies should particularly focus on validation of existing risk factors and the development of risk prediction models. Both types of study require a much larger sample size than the existing studies (median = 169) for the findings to be considered reliable enough for clinical application. For example, the Liverpool Lung Project (LLP) lung cancer risk prediction model was developed on 1736 subjects and validated on two large cohorts with sample sizes of 2922 and 7652, respectively , 68. Fur4.2In terms of the datasets considered, 47% of studies 24/51, Figure 2In studies that investigated imaging-based risk factors, all but one study used imaging features that were derived from manually identified abnormal radiological patterns in the lungs. Although the studies sought agreement between multiple radiologists or pulmonologists, subjective bias may still exist and lead to inaccuracy in the labels due to varying levels of experience and training. Automated tools should be developed to identify the radiological patterns to limit such bias.4.3One of the main observations from the risk of bias analysis is the between-study inconsistency in the definition of the ICI pneumonitis population and a lack of description on how ICI pneumonitis was distinguished from other diagnoses. This reflects the lack of gold-standard diagnostic criteria for ICI pneumonitis.Regardless of the cause, patients experiencing pneumonitis will undergo the same or similar clinical management and differentiating the cause of pneumonitis may not necessarily add value to clinical decision-making during its direct management. However, for cancer patients, accurate identification of the cause of pneumonitis in similar subjects is crucial, as if severe ICI induced pneumonitis is suspected this may lead to discontinuation of an effective treatment.Further studies should endeavour to accurately establish the cause and type of pneumonitis, and document the associated risk factors, so that the community can build a better understanding of managing this clinical situation4.4The risk of bias analysis also revealed some suboptimal techniques in the statistical analysis of the reviewed studies. One prevalent method was the use of univariate analysis to select variables to include in the multivariable analysis, this was observed in 21/31 studies reporting risk factors from multivariable analysis and 1/3 studies reporting risk model development. With this approach, variables that are only informative after controlling for other variables will be dropped out from the final model . This phThe widespread lack of multiple testing correction  was another common source of bias when many potential risk factors were simultaneously tested. The bias was exaggerated when the same factors were tested multiple times with different discretization thresholds. For instance, under the assumption of independence between the risk factors, a study should expect at least one false discovery when more than 20 factors are tested at a significance threshold of p = 0.05. This can lead to optimistic and non-reproducible results. To reduce the Type I error, i.e. when a null hypothesis is rejected when it is actually true, methods such as Benjamini-Hochberg correction and Bonferroni correction could be employed .In studies that report risk model development, the most concerning source of optimism came from ill-defined cross-validation where univariate feature selection and data-driven feature transformation  was conducted on the entire population rather than the training set in each round of cross-validation. Similarly, reporting only the cross-validation performance after it has been used in hyperparameter optimisation can also lead to an overestimated model performance. To obtain the least biased estimate on model performance, investigators should ideally use internal and (whenever possible) external holdout sets that have not been exposed to any part of model optimisation.Many (13/22) of the reviewed studies that contained missing values simply discarded the observations from corresponding analyses. This approach assumes that the missing values are randomly distributed and are not related to the outcome or other potential risk factors; this assumption was not verified in any of the studies. As a result, the studies that had sizable numbers of missing values were likely to contain biased results due to failure to account for informative missing values. Statistical power can also be jeopardized due to the reduction in sample size. Future studies should explain and check assumptions on the distribution of missing values, reasons for missingness, and use appropriate imputation methods before considering excluding observations . One wayWe noted the overwhelming popularity of logistic regression in the risk factor analysis studies  and in risk model development studies (75%). The results from these studies could be interpreted as identifying the odds ratios for (or predicting the risk of) developing ICI pneumonitis before the last follow-up or death regardless of the timing of the events. This limits clinical utility, as the user would not know whether the intervention should be urgent. Recorded follow-up time ranges from days to months, making survival analysis a better and clinically-actionable alternative.5Overall, our work highlighted several common methodological pitfalls in ICI pneumonitis risk factor identification and risk model development studies, covering areas from diagnosis of ICI pneumonitis to statistical analysis and risk modelling. The majority of the studies considered here are likely to have reported biased results due to those pitfalls. We also provided recommendations and alternative approaches for reducing the risk of bias. Studies with low risk of bias in all domains are lacking in the existing literature , paper searching (YC), title/abstract/full-text screen (YC/SW/MR/JJ), data extraction and review of bias (YC/AP), draft manuscript (YC/JR/JJ/MR). All authors contributed to the article and approved the submitted version.


Aspirin has been observed to reduce the risk of developing hepatocellular carcinoma (HCC). This review pooled together the results of all available published studies and found that aspirin reduces the risk of HCC by around 30%. In patients with cirrhosis, this effect was not seen and, overall, patients treated with aspirin were at a higher risk of bleeding, as expected. Our findings provide compelling observational evidence for the use of aspirin as a potential preventative treatment for patients at risk of HCC, but highlight the need for further study into the optimal patient group that would benefit, and the need to balance against the risk of bleeding.p = 0.13), which involved a total of 1961 HCC cases. In a subgroup meta-analysis of patients with cirrhosis, the relationship between aspirin use and incident HCC diminished to non-significance . Aspirin use was associated with a statistically significant increase in bleeding events when all relevant studies were pooled together . Prospectively collected data should be sought, to define the optimal patient group in which aspirin is safe and effective for the chemoprophylaxis of HCC.An increasing number of observational studies have described an association between aspirin use and a reduced risk of incident hepatocellular carcinoma. We performed this meta-analysis to provide a comprehensive and updated aggregate assessment of the effect of aspirin on HCC incidence. Two independent authors performed a systematic search of the literature, utilising the Medline, Embase, Scopus, and PubMed databases. A total of 16 studies  were selected for inclusion, with a large number of studies excluded, due to an overlapping study population. The pooled analysis of cohort studies involving a total population of approximately 2.5 million subjects, 822,680 aspirin users, and 20,626 HCC cases demonstrated a 30% reduced risk of HCC associated with aspirin use . There was a similar but non-significant association observed across the case-control studies (adjusted OR 0.60, 95%CI 0.32–1.15,  Hepatocellular carcinoma (HCC) is a major and rapidly increasing cause of global premature morbidity and death, projected to account for 60% of all deaths due to chronic liver disease by 2030 . IncreasAspirin is an inexpensive, widely available drug that targets the cyclo-oxygenase group of enzymes. It is thought, based on animal studies, to interfere with HCC carcinogenesis, through both its anti-platelet ,12 and aThe systematic review and meta-analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines ,32. The The criteria for inclusion in the systematic review and meta-analysis were: (1) the full manuscript was available in English; (2) it reported a quantitative statistic describing the association between incident HCC or liver cancer and either aspirin alone, or non-steroidal anti-inflammatory or antiplatelet drugs, with aspirin as a subpopulation; (3) it reported on a unique study population, with no included persons across more than one study.Two authors then, after excluding duplicates, independently reviewed the titles and abstracts of each result, to determine its eligibility for inclusion. The full text of relevant studies was then independently reviewed, to confirm that it met the eligibility criteria. In cases of multiple studies drawing from the same population registry, the years of data extraction and the exclusion criteria were noted. Studies were carefully chosen, with preference given to the highest-quality study, as assessed by the modified Newcastle–Ottawa Quality Assessment Scale (mNOS)  and, if The following data were collected from the included studies: the first author, the year of publication, the country of study, the type of population, the exclusion criteria where relevant, the specific definition of aspirin use, the specific criteria used for the HCC diagnosis, the crude risk estimate statistic, the adjusted risk estimate statistic if available, the variables used for the adjustment of the model, and the quality of each study using the mNOS. Additionally, further data collected for the cohort studies were: the total number of participants, the number of aspirin users, the number of controls, and the number of HCC cases in the aspirin users and controls. For case-control studies, the number of cases and controls was tabulated together with the rates of aspirin use in each group. Subgroup analyses, dose/duration analyses, and bleeding risk estimates were recorded, where available.I2 statistic, which represents the percentage of the total variability between studies, where we considered 0–25% to be low, 25–75% to be moderate, and >75% to be high. The homogeneity between studies was tested using the chi-square test. The main effect for each analysis was tested using the z-test. The primary analysis incorporated adjusted effect sizes where available. A sensitivity analysis was conducted by performing a meta-analysis on only the unadjusted effect sizes. A two-sided p < 0.05 was considered to be statistically significant. All analyses were performed using Stata/IC 16.1 .The pooled hazard ratios (HR) and odds ratios (OR), and 95% confidence intervals (CI) were calculated, using a random-effects meta-analysis to account for between-study variability. We quantified the degree of heterogeneity between studies using the The initial screening identified a total of 4132 studies. Of these, 4083 were excluded after the screening of titles and abstracts, as they failed to meet the inclusion criteria. After a review of the full texts of the remaining 49 studies, a further 13 studies were found to fail to meet the inclusion criteria, and were excluded. A large number of cohort studies involved the same population, in part due to the availability of large national databases, such as the Taiwan National Health Insurance Research Database, the South Korea National Health Insurance Service Database, and the Hong Kong Hospital Authority Clinical Data repository, and also due to the duplication of efforts in the same longitudinal US cohorts and European population registries. A total of 20 studies were excluded due to overlapping study populations , and the details of these are outlined in A summary of the selected studies and their characteristics, including bias assessment, is presented in p < 0.01), with a high degree of statistical heterogeneity    . The sen < 0.01) .I2 = 87.01%, p < 0.01), with a trend towards risk reduction that was non-significant, with a wide confidence interval  (p = 0.31)  . There w = 0.31) .p = 0.52), without significant statistical heterogeneity  (p = 0.19) . Two studies ,39 (n =  = 0.05) . The sen = 0.19) .A total of four cohort studies ,41,42,43p = 0.02), without significant statistical heterogeneity   . The oveGlobally, hepatocellular carcinoma remains a major and increasing cause of cancer-related death , with thAspirin is widely used in the primary and secondary prevention of cardiovascular disease; however, its anti-cancer effects (primarily through its anti-cyclooxygenase activity) have been widely described, including in liver cancer mouse models ,14. It iMultiple meta-analyses ,28,29,30Similar to previous reports, our updated systematic review and careful meta-analysis affirms the presence of a negative relationship between aspirin use and incident HCC. However, unlike previous reports, our meta-analysis is the first to report a diminished risk-reduction effect in cirrhosis, and is also the first to observe, in this setting, a statistically significant increase in bleeding events associated with aspirin. Our review involves 16 studies across 8 countries, with just under 2.5 million participants, and more than 22,000 unique cases of HCC, whilst acknowledging and excluding a further 20 otherwise-eligible studies, due to overlapping study populations.We found that the evidence of risk reduction in HCC incidence with aspirin was similar, regardless of the type of study evaluated. The overall reduction in the HCC risk was 30% among cohort studies, and 40% across case-control studies, although the confidence in the risk estimate from the case-control studies was poor, due to a wide confidence interval, driven by significant heterogeneity and a relatively small number of studies. Furthermore, the sensitivity analyses utilising unadjusted data demonstrated similar results, increasing the confidence in the strength and direction of relationship observed.Of the five studies that examined differences between the varying duration of aspirin use, four of them provided supportive evidence of a duration-dependent effect ,41,42,43Interestingly, the subgroup analysis of over 120,000 patients with cirrhosis demonstrated a comparatively diminished effect of aspirin use on incident HCC, with a statistically insignificant trend towards risk reduction in both the primary and sensitivity analyses. Given that the postulated mechanism of aspirin’s chemoprophylactic role in hepatocarcinogenesis operates primarily through a reduction in the hepatic accumulation of inflammatory cells, and a reduction in the hepatocellular injury that drives oncogenic mutations ,39 direcThe expected increase in bleeding risk associated with aspirin therapy is a major consideration to balance against the reduction of HCC risk, particularly in patients with underlying liver disease, who are at higher risk of both variceal and non-variceal gastrointestinal bleeding. Previous reports from the general population have suggested that aspirin leads to a modest increase in the risk of major bleeding (RR estimates between 1.40 and 1.43) ,80,81. AGiven that our data are solely observational, reverse causality should be considered as a possible contributor to the observed results. Patients with more advanced liver disease, where the risk of HCC is higher, may be less likely to be treated with aspirin therapy, due to concern about the bleeding risk. Additionally, it is important to consider the possibility of competing risks  biasing the aspirin-user group to an artificially lower rate of observed incident HCC, and magnifying the apparent risk reduction. It should also be noted that aspirin use might be a surrogate marker for engagement with healthcare, and be positively associated with other factors known to reduce HCC risk, such as the moderation of alcohol intake, metabolic risk factor modification, and adherence with antiviral treatments for hepatitis B and C infection. Furthermore, patients taking aspirin therapy are more likely to be on statin or metformin therapy, and these medications have also been shown to be associated with HCC risk reduction ,83.The significant degree of heterogeneity we observed in this meta-analysis may be due to bias, stemming from one of several reasons. Firstly, and most importantly, the majority of studies failed to consider and/or adjust for key related variables in their risk estimate analysis. Three of the twelve cohort studies ,38,45, aThis updated systematic review and careful meta-analysis suggests that aspirin use is associated with a strong duration-dependent effect in reducing the risk of incident HCC, and that this relationship appears to be somewhat diminished in cirrhosis. Aspirin use, as expected, is associated with a small increase in bleeding risk. There is therefore an urgent need to perform randomised placebo-controlled trials in well-phenotyped populations, such as those with non-cirrhotic chronic hepatitis B infection, to establish the clinical efficacy and safety of aspirin use for HCC chemoprophylaxis.


FADS genes encoding enzymes that catalyze the rate-limiting steps of PUFA biosynthesis appear to be associated with n-3 and n-6 PUFA contents. Therefore, we conducted the first systematic review and meta-analysis to explore the association of the A-allele carriers of the FADS1 rs174556 with PUFA status. The PRISMA guidelines were followed. The literature search was conducted up to November 2022 in PubMed, Web of Science, Embase, Cochrane Library, Airiti Library, and CINAHL. The Joanna Briggs Institute checklists were used to assess the methodological quality. The correlation with 95% CIs was determined by a random-effect meta-analysis. Eleven studies that met the inclusion criteria and acceptable quality were included in this systematic review. The data on PUFA contents were collected when they were mainly analyzed using blood samples and breast milk. Results of the meta-analysis on eight studies  showed that the A-allele carriers of rs174556 were significantly negatively correlated with the concentrations of AA (P = 0.001), EPA (P = 0.004), and DHA (P = 0.025). However, ALA and LA were not associated with the A-allele carriers. To clarify the discrepancy, we further divided the studies into blood samples and breast milk subgroups. The subgroup analysis revealed that the A-allele carriers of rs174556 were significantly positively correlated with LA (P = 0.031) and negatively correlated with AA (P = 0.001), EPA (P = 0.036), and DHA (P < 0.001) in the blood sample group, but not in the breast milk group. The current meta-analysis proved that the A-allele carriers of the FADS1 rs174556 appeared to be highly associated with lower concentrations of AA, EPA, and DHA but higher LA in the blood samples. The study has been registered on the International Prospective Register of Systematic Reviews (PROSPERO:CRD42022363978). Adv Nutr 2023;x:xx–xx.PUFA status is highly implicated in cognitive development and metabolic disorder-related diseases. Genetic variants of  FADS1 rs174556 polymorphisms and PUFA status. The results indicate that A-allele carriers of the FADS1 rs174556 are negatively associated with AA, EPA, and DHA but positively associated with linoleic acid in the blood samples.This study is the first systematic review and meta-analysis of the association between the FAPUFAs are a group of important nutrients that are highly implicated in cognitive development and pathogenesis, including cardiovascular disease and metabolic syndrome . PUFAs cFADS1 and FADS2 catalyze the rate-limiting steps of the PUFA biosynthetic pathway that generates AA, EPA, and DHA . The metFADS1 FADS2 gene cluster located on chromosome 11 (11q12.2-13.1) and arranged head-to-head .FADS1 rs174556 SNP on PUFA composition in human tissues. Our results revealed that the population with the rs174556 A-allele exhibited significantly lower n-6 and n-3 LCPUFA products, AA, EPA, and DHA, and higher 18-carbon FA substrate, LA in the blood, which is highly implicated in impairing cognitive function or increased the risk of cardiovascular and metabolic syndrome [The current study was the first meta-analysis research to investigate the effect of syndrome .FADS1 rs174556 SNP with pathological manifestations has been addressed where rs174556 SNP was reported to be associated with asthma [FADS1-rs174556, a higher percentage of LA is metabolized to AA which can act as a substrate of inflammatory eicosanoids [FADS1-rs174 556’s mothers had 2-d shorter pregnancies (P = 0.035), and their children were 140 g lighter (P = 0.006) than those of the GG genotype’s mothers [The significance of the h asthma ,35, pregh asthma , and bloh asthma ,16. Dailosanoids . The AA FADS1 gene, <100 base pairs 3’ to exon 2, and within a region of H3K4Me1 and H3K27Ac marks indicating that this locus may play a critical role in alternative splicing, splicing frequency, and epigenetic modulation of transcription activity. Besides, rs174556 is a locus for several gene transcripts in multiple tissues, including both FADS1 and FADS2 [FADS1 rs174556 genotype significantly affected desaturase activity in some studies [FADS1 rs174556 had lower FADS desaturase activity. However, one cannot exclude the possibility that the decrease in enzyme activity may be directly due to the reduced amount of enzyme.Functional intron polymorphisms may occur and affect the transcriptional activity when mutations in crucial elements within introns are implicated in RNA splicing . The rs1 studies ,25. When studies , Women wP = 0.001) appeared much higher than that of DHA  and EPA . This phenomenon may be explained by the fact that the human tissues contained relatively higher AA content to EPA and DHA  [FADS1-rs174556 becomes relatively limited [Results of the meta-analysis indicated that the impact of genetic variation on AA  ,25. Whenctively) ,25; ther limited ,25,27.FADS1 rs174556 SNP. The results showed that the FAs in the blood sample group (plasma or red blood cells) were more significantly affected by the rs174556 variation. The A-allele of rs174556 showed a significant positive correlation with ALA and LA concentrations and a significant negative correlation with AA, EPA, and DHA in blood. However, no significant association was found between the PUFA content of the breast milk and A-allele carriers of the FADS1-rs174556. Because only two publications in breast milk-related studies were incorporated into the analysis, the results may be less representative. However, it is worth noting that both diet and genotype and their interaction contribute to the FA composition of breast milk [FADS genotype  significantly affected the proportion of DHA in erythrocyte, plasma phospholipids and breast milk of postpartum women [FADS SNP. Nonetheless, more studies on the effects of the FADS1 rs174556 SNP and its combination with diet on the FA composition of breast milk would clarify the picture.Also, we carried out the subgroup analysis to evaluate the tissues that were affected by the ast milk ,12. It hum women . The amoFADS1-rs174556 has an ethnic discrepancy. Most of the studies included in the current meta-analysis had Europeans as the main subjects, and the major/minor alleles of the FADS1-rs174556 were G/A. In contrast, American Mexicans [FADS1-rs174556, respectively. This is in agreement with the information in the SNP database of the NCBI [FADS gene. Although the major allele of rs1535 SNP differs between Caucasians (A) and Southern Han Chinese (G) [The allele frequency of the Mexicans  and Asiathe NCBI  that thenese (G) , carrierFADS1 rs174556 SNP to PUFA contents that might inspire future investigations in detailed subgroup analysis, such as long-term RCTs or cohort studies on various tissues, in different populations to overcome the limitations.This systematic review and meta-analysis had some limitations. First, there may be a publication bias in this analysis because only studies with favorable results were easily searched, whereas literature with poor results or interruptions in follow-up might not have been identified. Furthermore, the number of articles recruited in this meta-analysis was relatively small, which may limit the meta-analysis, sensitivity analysis, and subgroup analysis results. Third, the literature included in the analysis was relatively old such that most of the literature was from >5 y ago. Fourth, we did not investigate the interaction between genes and diet because the studies included in this meta-analysis did not have enough raw data, including dietary information. Nonetheless, the current analysis provided indisputable evidence connecting the significance of the FADS1 rs174556 may exhibit altered PUFA metabolism with lower concentrations of AA, EPA, and DHA but higher LA in the blood, in particular.In conclusion, the current meta-analysis indicated that the A-allele carrier of the Ministry of Science and Technology, Taiwan, grant number MOST 111-2320-B-039-020-MY3, and China Medical University, Taiwan, grant number CMU107-S-22 and CMU109-MF-53.This research was funded by the The authors report no conflicts of interest.The authors’ responsibilities were as follows: W-CW and C-YH conceptualized the study. W-CW, P-YW, C-YC, M-FL, and C-YH performed the literature search, data extraction, and verification. W-CW and P-YW contributed to the statistical analysis and data interpretation. W-CW, P-YW, C-YC, M-FL, and C-YH participated in writing and original draft preparation. W-CW, M-FL, and C-YH assisted in writing, reviewing, and editing. All authors have read and agreed to the published version of the manuscript.The data that support the findings of this study are available from the corresponding author upon request.


Persistent infection by oncogenic human papillomavirus (HPV) is necessary although not sufficient for development of cervical cancer. Behavioural, environmental, or comorbid exposures may promote or protect against malignant transformation. Randomised evidence is limited and the validity of observational studies describing these associations remains unclear.In this umbrella review, we searched electronic databases to identify meta-analyses of observational studies that evaluated risk or protective factors and the incidence of HPV infection, cervical intra-epithelial neoplasia (CIN), cervical cancer incidence and mortality. Following re-analysis, evidence was classified and graded based on a pre-defined set of statistical criteria. Quality was assessed with AMSTAR-2. For all associations graded as weak evidence or above, with available genetic instruments, we also performed Mendelian randomisation to examine the potential causal effect of modifiable exposures with risk of cervical cancer. The protocol for this study was registered on PROSPERO (CRD42020189995).We included 171 meta-analyses of different exposure contrasts from 50 studies. Systemic immunosuppression including HIV infection (RR = 2.20 (95% CI = 1.89–2.54)) and immunosuppressive medications for inflammatory bowel disease (RR = 1.33 (95% CI = 1.27–1.39)), as well as an altered vaginal microbiome (RR = 1.59 (95% CI = 1.40–1.81)), were supported by strong and highly suggestive evidence for an association with HPV persistence, CIN or cervical cancer. Smoking, number of sexual partners and young age at first pregnancy were supported by highly suggestive evidence and confirmed by Mendelian randomisation.Our main analysis supported the association of systemic  and local immunosuppression  with increased risk for worse HPV and cervical disease outcomes. Mendelian randomisation confirmed the link for genetically predicted lifetime smoking index, and young age at first pregnancy with cervical cancer, highlighting also that observational evidence can hide different inherent biases. This evidence strengthens the need for more frequent HPV screening in people with immunosuppression, further investigation of the vaginal microbiome and access to sexual health services.The online version contains supplementary material available at 10.1186/s12916-023-02965-w. Although persistent infection with high-risk human papillomavirus (hrHPV) is causally associated with cervical cancer, only a fraction of women that get infected with HPV develop persistence, high-grade CIN and if not detected and treated cervical cancer. Cancer promotion in some individuals is likely to be explained by a complex interplay between the host system, the HPV virus and behavioural, environmental, or comorbid factors. Genetic variation and predisposition to cervical cancer only explain a small amount of the difference in underlying risk between individuals . HrHPV iOver the last three decades, many epidemiological studies have investigated the risk factors associated with hrHPV persistence and development of cervical cancer including immunosuppression –6, concoWe performed an umbrella review of systematic reviews and meta-analyses exploring the association between modifiable risk factors and environmental exposures and hrHPV infection, cervical intraepithelial neoplasia (CIN) and cervical cancer incidence and mortality. We further conducted a MR analysis, to assess the strength and validity and potential causal effect of previously reported estimates.We searched PubMed, Ovid MEDLINE and Embase Classic, and the Cochrane database for systematic reviews to investigate the association between non-genetic behavioural, environmental, or comorbid risk factors and incidence or prevalence of hrHPV, CIN or cervical cancer, cervical cancer mortality, and regression or progression of disease. All articles were screened at least in duplicate  using pre-defined search terms  [p < 0.05) in the published literature is different from the expected number of studies [For each exposure and outcome pair, we calculated the summary effect and the 95% CI using fixed and random effects methods . The hettatistic  with 95%tatistic . To furttatistic , 27 for  ≤ 0.10)  and whet studies . Finally studies . We grad studies , 17 and We used the AMSTAR-2 criteria  to assesThe main analysis was restricted to cohort studies only. We conducted a sensitivity analysis which included all eligible observational studies, i.e. meta-analyses including both cohort and case–control studies. These were then graded using the same criteria as for the main analyses.In the event of multiple meta-analyses reporting on the same exposure-outcome associations, we selected the one with the largest number of studies to prevent duplication of the original studies. The concordance between the included and duplicate meta-analyses was explored in a sensitivity analysis  MR as the main analysis to estimate the causal effect on risk for cervical cancer . For expThe funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.The literature search was performed in November 2020 and identified 4722 systematic reviews or meta-analytical papers. Following sequential title, abstract and full-text screening, 56 meta-analysis papers met the inclusion criteria. After exclusion of duplicate meta-analyses, 50 papers remained , 39–83, A total of 11 outcomes were identified, which related to either HPV infection, CIN and/or cervical cancer: cervical disease regression , disease incidence and prevalence , disease persistence , disease progression (CIN progression) and cancer mortality.Chlamydia trachomatis, Trichomonas, U. urealyticum, Mycoplasmas, Candida albicans, vaginal Lactobacillus spp., herpes simplex virus (HSV) infection); anthropometric measures (body mass index (BMI), height); lifestyle and/or behavioural factors ; medical co-morbidities and/or medication use (retinoid use); gynaecological and obstetric factors , gestational diabetes mellitus (GDM), vaginal douching); hormonal medication use , intrauterine devices (IUD), injectable contraception); dietary, vitamin or antioxidant intake .Fifty exposures were identified, which belonged to eight broad categories: immunocompromise  on medication, rheumatoid arthritis (RA), systemic lupus erythematous (SLE), transplant recipients); co-infection and vaginal microbiome (VMB), (Epstein-Barr virus (EBV) infection, Twelve per cent of all the included papers were graded as high quality   or moderOf the 171 meta-analyses, 87 included two or more cohort studies and were included in the main analysis and assessed a total of 39 exposures across the eight categories Table .Table 1Sp < 0.05 as a threshold for the level of significance, the summary fixed effects estimates were significant in 62% of cohort studies (54/87) and the summary random effects in 60% (52/87) of the meta-analyses  and 39% (34/87) of the studies presented significant summary fixed and random effects estimates, respectively. Where a cut-off of p < 10−6 was applied, 32% (28/87) and 19% (16/87) of the meta-analyses produced significant summary results in the fixed and random effects model, respectively. Out of the 16 meta-analyses with a random p < 10−6, 14 exposures were associated with an increased risk of either hrHPV incidence or persistence, or the increased risk of progression to LSIL or HSIL, CIN or cervical cancer , while two exposures were associated with a decreased risk for hrHPV clearance .Applying studies 5/87 and tp ≤ 0.10 in 27 of 87 meta-analyses (31%). Twenty-five studies (29%) presented a high heterogeneity (I2 = 50–75%) and nine (10%) very high (I2 > 75%), which included 5 different exposures . When calculating the 95% prediction intervals, the null hypothesis was excluded for nine associations  : Chlamydia trachomatis infection – hrHPV incidence, HIV + – CIN1 + treatment failure, and gestational diabetes mellitus – cervical cancer incidence  of varying exposures including bacterial vaginosis, N = 2323, RR 2.20, 95% CI 1.89–2.54, p = 3.01 × 10−26, I2 = 22 and highly suggestive evidence, N = 1151, RR 3.1, 95% CI = 2.17–4.4, random p = 3.75 × 10−10, I2 = 82, respectively), while a decreased risk of hrHPV clearance was also associated with HIV positivity . An increased risk for progression from normal to LSIL or HSIL was related to vaginal dysbiosis  and an increased risk for cervical cancer incidence was associated with people with IBD using immunosuppressive medications , p = 7.78 × 10−37, I2 = 0) and with HIV positivity   with a credibility ceiling of 5%. With ceilings of 10%, 15% and 20%, twenty-two (25%), fourteen (16%) and four (5%) studies remained significant respectively  retained nominal statistical significance , while increased risk of CIN was related to multiple sexual partners CIN . An increased risk of cervical cancer incidence was associated with not only Chlamydia trachomatis infection , but also with Trichomonas Vaginalis infection  and oral contraception use . Meanwhile, co-infection of hrHPV with Chlamydia Trachomatis seems to increase the risk of cervical cancer by more than four times , while in a subgroup analysis Chlamydia trachomatis infection appears to increase the risk of squamous cell cervical cancer incidence  (evidence for adenocarcinoma was weak only).When also including case–control studies, 11/171 meta-analyses met the criteria for strong evidence, including eight additional exposure-outcome pairs  and number of sexual partners   and immunosuppressive medications in women with IBD were all supported by strong evidence, while smoking, Chlamydia infection and bacterial vaginosis were supported by highly suggestive or suggestive evidence. Sensitivity analyses also identified strong or highly suggestive evidence for an association between Trichomonas infection, increased number of sexual partners, medium- to long-term COCP usage, high parity, earlier age at first pregnancy, low vegetable intake, increased vitamin C or selenium intake, and HPV, CIN, or ICC.We present an umbrella review of 87 meta-analyses of observational studies on life course exposures including co-morbidities, environmental and behavioural exposures and risk of HPV infection, CIN and invasive cervical cancer (ICC). HIV, vaginal dysbiosis  increases CIN regression rates. The included studies were graded as low and critically low in the AMSTAR assessment while there were no genetic instruments to perform an MR analysis. Our findings support that of a recent study published jointly by the WHO and the International Agency for Research on Cancer (IARC), which reported that women living with HIV have a six-fold higher risk of developing cervical cancer . ImmunosThe evidence for women with other forms of chronic immunosuppression and cervical cancer was more limited. We found strong evidence in the main analysis that women with IBD on immunosuppression are at increased risk for high-grade CIN and cervical cancer compared to the general population. The quality of the study scored moderate on AMSTAR while MR analysis didn’t show any significant association. It is unclear, though, whether IBD alone is associated with cervical cancer regardless of medication.We found weak evidence for an increased risk of cervical cancer for other autoimmune diseases, including a meta-analysis on SLE and CIN. Multiple studies have suggested that SLE alone is associated with hrHPV acquisition , CIN 9191–96 andLactobacillus spp. deplete VMB, as well as cervicovaginal infection (including Chlamydia trachomatis and Trichomonas spp.) increase the risk of hrHPV acquisition, CIN incidence and cancer incidence, including progression from normal cytology to HSIL. Evidence was particularly strong for progression to LSIL or HSIL [N = 460,746). The evidence of the association between chlamydia and hrHPV incidence [Lactobacillus spp. maintain a low pH and the acidic environment is essential for the function of the cervical epithelial barrier [We found strong and suggestive evidence that a  or HSIL  due to tncidence  was down barrier –102 and  barrier –105. Stu barrier , while l barrier . There wp-values and the presence of small study effects. All the studies investigating smoking scored critically low in AMSTAR, mainly due to study design, risk of bias assessment, heterogeneity and small study bias. Cigarette smoking is widely accepted as a strong carcinogen which hampers cellular immunity at the cervix [Although smoking is widely considered to be a strong risk factor for cervical cancer, the evidence was graded as suggestive between smoking and increased HPV incidence and as only weak between active smoking and ICC. The meta-analyses of ICC were considered to present only weak evidence of association due to the small number of cases, relatively large e cervix  and thisThere were no meta-analyses based on cohort studies for the evaluation of the sexual and reproductive history on cervical cancer. The association of multiple sexual partners , 70 withWhile BMI was linked to increased cervical cancer mortality possibly due to other obesity-related complications, there was no link to any other HPV or cervical cancer outcome, which was confirmed on MR. Our study provided only weak evidence that the use of COCP increases the risk of invasive cervical cancer, although the evidence became strong for medium to long-term COCP use when case–control studies were included as well .We used a well-established methodology for this analysis , 21, 111Possible limitations should be considered in the interpretation of our findings. This review relies on the previously published meta-analyses and literatures searches performed by the authors of those studies. Some literature may have been missed; however, the assessment of duplicate analyses did not highlight any discordant results which minimises this risk. Additionally, we studied exposures against several outcomes linked to the development of cervical cancer, these results were also consistent across meta-analyses. Although the overall number of studies included was large, for some associations, the number of studies and participants was small, limiting our ability to assess for the presence of small study effects and excess significance due to low power. It is likely that this would result in a more conservative estimate and the true association may be more severe. Additionally, most studies in the umbrella were graded as low or critically low according to the AMSTAR2 criteria, suggesting a high risk of bias within this evidence. Although we assessed for risk of bias, the statistical tests are unable to explain the definitive presence or the likely source of bias. Furthermore, MR analyses were underpowered for some exposures (such as for IBD), and sample overlap in some of the associations was relatively large  .Lactobacillus spp. depletion and immunosuppressive medications for women with IBD are also strongly associated, with a suggestion that other forms of immunosuppression increase risk of cervical cancer. Our results suggest that the presence of Chlamydia trachomatis and Trichomonas infections influence the development of cervical cancer in the presence of hrHPV and prompt treatment should be prioritised. In conservatively managed HPV infections and CIN, additional screening and treatment for concomitant bacterial infection and bacterial vaginosis should be considered [There is consistently strong and highly suggestive evidence that HIV positivity reduces HPV clearance rates and increases the risk of HPV infection and cervical cancer development. Vaginal nsidered , 114. ThThis evidence highlights the importance of preventative strategies including the provision of sexual health and family planning services, with early initiation of ART in HIV-positive women, alongside cervical screening. The strong interaction between HIV and cervical cancer necessitates the prioritisation of HPV vaccination in populations where HIV prevalence is high in initiatives to increase global access.Additional file 1: Supplementary Methods. Additional details including electronic search terms and data analysis pipeline of Umbrella review.Additional file 2: Supplementary Table 1. Statistical criteria for grading of the evidence.Additional file 3: Supplementary Table 2. Summary quality assessment for all included systematic reviews using the ASMTAR 2 tool (A Measurement Tool to Assess Systematic Reviews 2).Additional file 4: Supplementary Table 3. Description of 87 meta-analyses investigating risk factors associated with HPV, cervical pre cancer and cancer outcomes - only cohort studies included.Additional file 5: Supplementary Table 4. Evaluation of heterogeneity, small study effects and excess significance bias in the 87 meta-analyses investigating the risk factors associated with HPV, cervical pre cancer and cancer outcomes - only cohort studies included.Additional file 6: Supplementary Table 5. Details of evidence grading for meta-analysis of risk factors for HPV, cervical precancer and cancer outcomes – _only cohort studies included*.Additional file 7: Supplementary Table 6. Sensitivity analysis using credibility ceilings when the association is non-significant of the 87 studies investigating the risk factors associated with HPV, cervical pre cancer and cancer outcomes - only cohort studies included.Additional file 8: Supplementary Table 7. Details of evidence grading for meta-analyses of risk factors for HPV, pre-invasive and invasive cervical cancer incidence, progression, regression, or mortality - all study types included .Additional file 9: Supplementary Table 8. Excluded duplicate studies and studies selected in their place to be included in the analysis.Additional file 10: Supplementary Table 9. Mendelian randomisation (MR) analysis; exposure-outcome pairs included in the main analysis, cohorts only.Additional file 11: Supplementary Table 10. Main GWAS study characteristics.Additional file 12: Supplementary Table 11. Two-sample inverse variance weighted mendelian randomization full results of the analyses of risk factors on cervical cancer.Additional file 13: Supplementary Table 12. Results from Mendelian randomisation sensitivity analyses of risk factors on cervical cancer. Supplementary Table 13. Results from multivariable (MV) Mendelian randomisation (MR) sensitivity analyses of risk factors on cervical cancer.


The effects of isoflavones on postmenopausal female’s blood lipid profile have yielded conflicting results in previous studies. Further investigation is necessary to determine the potential benefits of isoflavone therapy in managing cardiovascular health in this population.This meta-analysis aimed to assess the effects of isoflavones on blood lipid concentrations in postmenopausal females. A comprehensive search was conducted in major databases for randomized controlled trials published between 2000 and 2023. Eighteen studies were included in the analysis, which examined the impact of isoflavone intake on blood lipids in postmenopausal females. Isoflavone consumption resulted in a significant reduction in triacylglycerol (TG) concentrations  and a modest increase in high-density lipoprotein cholesterol (HDL cholesterol) concentrations . Subgroup analysis showed that isoflavones significantly decreased TG  and increased HDL cholesterol  in postmenopausal females under 65 y old. No significant effects were observed in females over 65 y old. Both low (≤80 mg/d) and high (>80 mg/d) doses of isoflavones exhibited TG-lowering effects, whereas only the high dose increased HDL cholesterol. Longer treatment duration (≥24 wk) was associated with a significant reduction in TG, whereas HDL cholesterol improvement occurred during the early period (<24 wk) of supplementation. The consumption of isoflavones resulted in a significant reduction in TG concentrations and an increase in HDL cholesterol concentrations among postmenopausal females under 65 y of age. This meta-analysis is the most comprehensive evaluation to date, highlighting the differential impacts of isoflavone consumption on blood lipids in postmenopausal females based on age and dosage. Our findings emphasize that the consumption of isoflavones resulted in a significant reduction in TG concentrations and an increase in HDL cholesterol concentrations, especially in postmenopausal females below 65 y.The incidence of cardiovascular disease is significantly lower in pre-menopausal females compared to males of the same age. However, after menopause, the incidence in females rapidly increases and approaches that of men. This temporal change suggests that female sex hormones may play a crucial role in protecting against atherosclerosis. Estrogen has been shown to reduce LDL cholesterol, increase HDL cholesterol, improve vascular function, and contribute to longer life expectancy in females ,2. NeverThe ideal hormone replacement therapy (HRT) should replicate the beneficial effects of estrogen without inducing the aforementioned adverse reactions. This concept has led to the development of selective estrogen receptor modulators (SERMs), which exhibit mixed functional activity as agonists or antagonists of the estrogen receptor depending on the target tissue . HoweverIsoflavones, the primary active compounds in soy foods, structurally resemble endogenous estrogen, bind to the estrogen receptor, and function as natural SERMs. Research has suggested that isoflavones may reduce risk of certain cancers, including lung, prostate, colon , and breast cancers, without any reported associations with thrombosis or stroke ,11. ThusIn this meta-analysis, we aimed to combine the findings from multiple studies, varying in sample sizes, to gain a deeper understanding of the effects of isoflavones on the changes in blood lipid concentrations in postmenopausal females.1) the study population consisted exclusively of postmenopausal females; 2) the study was an RCT with either a parallel or a crossover design; and 3) the study provided information on the age of participants, as well as the dose and duration of isoflavone treatments. To ensure the credibility of the analysis, studies were excluded if they met any of the following criteria: 1) the study was not in English; 2) the research utilized unpurified isoflavones for treatment; 3) the study lacked the required information or employed an inappropriate control group; and 4) the study lacked follow-up data.Medline, Embase, and the Cochrane Central Register of Controlled Trials were thoroughly searched for English-language reports of randomized controlled trials (RCTs) published between 2000 and 2023, examining the effects of isoflavones on blood lipid profile. Search strategies were developed focusing on postmenopausal females, isoflavones, blood lipids, and RCTs . The incData were extracted independently by 2 authors (SY and QZ). Any discrepancies were resolved through discussion or by consulting a senior researcher (ZL). The extracted data included various study characteristics, such as the first author’s name, year of publication, study design, age and number of participants, dose and duration of isoflavones treatment, health characteristics of the study population, and location of the study. Additionally, information on the final concentrations of plasma/serum TC, LDL cholesterol, HDL cholesterol, and TG in the treatment and control group were also collected. The quality of the studies was assessed using risk of bias tool outlined in the Cochrane Handbook, which evaluated various aspects such as blinding and outcome reporting We conducted the meta-analysis using REVMAN version 5.2 (Cochrane Collaboration). The effect size employed in this study was the difference in means between the treatment and control groups. We utilized plasma/serum lipid concentrations obtained at the end of each intervention. If multiple time points for follow-up were reported, we included the value corresponding to the time point with the longest duration of follow-up. Typically, serum cholesterol concentrations are ∼3% higher than corresponding plasma concentrations . However2 test and the I2 statistics. If the test for heterogeneity yielded a significant result (I2 >30%), we presented the results from the random-effect models. Otherwise, the estimate of the difference was calculated using the fixed-effect model. To examine potential publication bias, we employed a funnel plot and conducted Egger’s regression asymmetry test. A 2-sided P value <0.05 was considered statistically significant.For studies reporting results in mmol/L, we converted them to mg/dL using standard conversion factors . Mean differences and their 95% confidence intervals (CIs) were calculated using random-effect or fixed-effect models. Heterogeneity was assessed using the χOut of the initial 562 potentially relevant studies identified through database searches, a total of 18 articles comprising 20 comparisons met our inclusion criteria . A flowcThe characteristics of the 18 studies that met the selection criteria are presented in Intake of isoflavones resulted in a significant reduction in blood TG concentration, with a mean difference of –12.50 mg/dL , as shown in In the sub-studies involving only postmenopausal females under 65 y old, there was a significant reduction in TG concentrations, with a mean difference of –15.79 mg/dL  and an increase in HDL cholesterol concentrations, with a mean difference of 2.49 mg/dL . However, changes in TC concentrations, with a mean difference of 0.33 mg/dL , and LDL cholesterol concentrations, with a mean difference of –4.96 mg/dL , remained non-significant. In the sub-studies that included postmenopausal females over 65 y old, none of the results for TG, TC, LDL cholesterol, and HDL cholesterol were significant . The pooWhen the limit of isoflavones ingestion was set at ≤80 mg/d and >80 mg/d, significant reductions in TG were observed in the isoflavones groups compared to the corresponding control groups for both the ≤80 mg/d and >80 mg/d subjects. Additionally, when ingesting isoflavones exceeded 80 mg/d, there was a significant increase in HDL cholesterol .In terms of the duration of isoflavone intake, no significant changes in TG were found in the isoflavone group compared to the corresponding control group for subjects with a duration of <24 wk. However, when the duration exceeded 24 wk, there was a significant decrease in TG. On the contrary, HDL cholesterol concentrations increased significantly in studies with a duration of <24 wk of isoflavone intake .2 values ranged from 71% to 96% in the overall analysis. In the subgroup analyses based on age, dose, and intervention time of isoflavones, the I2 values ranged from 64% to 91%, 65% to 91%, and 72% to 95%, respectively.As for heterogeneity, the IThe funnel plots depicting the effects on lipid profile in the comparison groups are presented in Although numerous clinical trials have investigated the effects of isoflavones on blood lipid concentrations in postmenopausal females, the results have been inconsistent. The present study quantitatively analyzed RCTs conducted in the past 23 y that specifically focused on the effects of isoflavones on lipid profiles in postmenopausal females.Our analysis demonstrates that the intake of isoflavones is associated with favorable effects on blood lipids in postmenopausal females. Specifically, we observed a significant reduction in TG and an increase in HDL cholesterol among postmenopausal females under 65 y old. However, no significant effects were observed in older participants. These findings suggest that isoflavone supplementation may significantly benefit the lipid profile by decreasing TG and increasing HDL cholesterol, specifically in postmenopausal females under 65 y old. Subgroup analysis further revealed that remarkable reductions in TG were observed in the isoflavones groups across different doses (≤80 mg/d and >80 mg/d) and intervention durations (≥24 wk). Moreover, HDL cholesterol significantly increased in studies where isoflavone intake exceeded 80 mg/d or had a duration of <24 wk.Numerous studies have provided evidence supporting the significant role of blood lipids in developing cardiovascular disease. Research has shown that LDL cholesterol is the primary risk factor for atherosclerosis . Small dThe mechanisms underlying the effects of isoflavones on lipid metabolism are still being investigated. One possible explanation is their weak estrogenic effects. Previous research has indicated that isoflavones can enhance the activity of steroidogenic enzymes such as cytochrome P450 aromatase, 3β-Hydroxysteroid dehydrogenase, and 17β-hydroxysteroid dehydrogenase, leading to increased estrogen secretion ,40. Isofn = 11 for females under 65 y old, n = 9 for females over 65 y old). To further explore whether the effects of isoflavones are truly associated with the age of postmenopausal females, a subgroup meta-analysis was conducted. The results indicated that the effects of isoflavones on lipid metabolism were only significant when the participants were under 65 y old. This suggests that initiating isoflavone supplementation early may be more effective in counteracting the unfavorable changes in blood lipids that occur after menopause. The specific processes underlying the age-related impact of isoflavones on blood lipids remain unknown. Estrogen therapy has been found to have favorable effects on cardiovascular disease risk factors when initiated near the time of menopause [Studies have shown that the impact of estrogen on lipid variations depends on age ,45. A reenopause ,45, suggA study conducted by Ho et al.  found thOne limitation of this analysis is that it was based on data from studies investigating the effects of isoflavones, whereas it is likely to be more relevant to real-life situations where soy foods are included as part of the diet. Another limitation to consider is the exclusive inclusion of only English-language studies, which may have omitted relevant research from non-English sources. Additionally, considerable heterogeneity was noted in the treatment effects of the included studies. A major contributor to this heterogeneity appears to be the diverse geographical origins of the subjects, including China, Japan, Korea, Canada, America, Brazil, Chile, and Germany. Moreover, the action mechanisms by which isoflavones modify the lipid profile have not been fully established in the discussions. It is also noteworthy that the effect of isoflavones seems to be predominantly observed in the population under 65 y of age, though the reasons for this remain unclear. Furthermore, although most of the included RCTs recruited healthy postmenopausal females, some studies also included females with conditions such as hyperlipidemia ,34, diabIn conclusion, this meta-analysis demonstrates a strong association between the consumption of isoflavones and notable reductions in blood TG concentrations, as well as increased concentrations of HDL cholesterol in postmenopausal females under 65 y of age, and when aiming to regulate lipid concentrations, it is advisable to consider the appropriate dosage and duration of isoflavone intake. Given the substantial demand for safe and effective HRT to enhance quality of life and life expectancy, numerous studies have focused on natural SERMs. Based on the findings of this meta-analysis, isoflavone therapy appears to be a valuable alternative to estrogen for postmenopausal females below 65 y old. However, additional research is necessary to validate the reported results, and a thorough exploration of the underlying mechanism is warranted.The authors’ responsibilities were as follows– SY: designed the study; SY and QZ: contributed to the interpretation and analysis of the data; SY, QZ, and ZL: wrote the initial draft; HH and XH contributed to the revision of the manuscript, and all authors: read and approved the final manuscript.The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hongpu Hu reports financial support was provided by National Social Science Fund of China.National Social Science Fund of China (22&ZD141 and 22AZD089). The funding bodies were not involved in any aspect of the study, from its conception and design to the collection, handling, analysis, or interpretation of the data, nor in the drafting, reviewing, or approving the manuscript.This research was funded by the Data described in the manuscript, code book, and analytic code will be made publicly and freely available without restriction. Original data generated and analyzed during this study are included in this published article or the data repositories listed in References.