Background/Purpose: To prevent falling, a common incident with debilitating health consequences among stroke survivors, it is important to identify significant fall risk factors (FRFs) towards developing and implementing predictive and preventive strategies and guidelines. This review provides a systematic approach for identifying the relevant FRFs and shedding light on future directions of research.Methods: A systematic search was conducted in 5 popular research databases. Studies investigating the FRFs in the stroke community were evaluated to identify the commonality and trend of FRFs in the relevant literature.Results: twenty-seven relevant articles were reviewed and analyzed spanning the years 1995–2020. The results confirmed that the most common FRFs were age , gender (21/27), motion-related measures (19/27), motor function/impairment (17/27), balance-related measures (16/27), and cognitive impairment (11/27). Among these factors, motion-related measures had the highest rate of significance . Due to the high commonality of balance/motion-related measures, we further analyzed these factors. We identified a trend reflecting that subjective tools are increasingly being replaced by simple objective measures , and most recently by quantitative measures based on detailed motion analysis.Conclusion: There remains a gap for a standardized systematic approach for selecting relevant FRFs in stroke fall risk literature. This study provides an evidence-based methodology to identify the relevant risk factors, as well as their commonalities and trends. Three significant areas for future research on post stroke fall risk assessment have been identified: 1) further exploration the efficacy of quantitative detailed motion analysis; 2) implementation of inertial measurement units as a cost-effective and accessible tool in clinics and beyond; and 3) investigation of the capability of cognitive-motor dual-task paradigms and their association with FRFs. Stroke is currently considered as the second leading cause of mortality for individuals above the age of 60 years, and the fifth leading cause of death in individuals aged 15–59 years old, worldwide . AccordiIn the last two decades, several studies have targeted fall risk assessment among stroke survivors . More spTo the best of our knowledge, only three review papers on fall risk assessment within the stroke community were published prior to this study. To bridge the aforementioned knowledge gap in literature, researchers need to establish a standard reference point for identifying the appropriate FRFs to generate an initial pool of risk factors. To this end, this review will provide a commonality analysis on the FRFs and their significance ratio among the articles considering each factor. Furthermore, the articles will be explored to categorize their considered FRFs into subjective and objective classes. Finally, the articles will be reviewed to identify the trend of implementing motion analysis to identify the risk of fall in stroke community. Briefly, the results of this study will help: 1) to provide evidence-based data by which researchers can determine which FRFs to include in the initial pool of factors; 2) to explore changes over time regarding the most salient FRFs as described by researchers; and 3) to identify the potential opportunities such as conducting detailed motion analysis employing IMU sensors while performing cognitive-motor dual-task to improve the quality of fall risk assessment among stroke survivors. The outcome of this study may facilitate the development of a more efficient and accurate approach/model to conduct future fall risk assessment studies.In order to conduct the review, the guidelines for Preferred Reporting Items for Systematic review and Meta-analyses (PRISMA) were implemented . A systeStudies addressing the prediction of fall risk and/or those identifying significant risk factors among stroke survivors were recorded. Since the focus of this review was to evaluate the factors involved in the FRFs among stroke patients, any prospective study describing a follow-up period of more than one day was included. Two authors independently searched the literature and merged their results, and then the final selected studies were carefully reviewed to ensure that all the articles met the inclusion criteria for the review. The inclusion criteria consisted of: 1) a prospective study on stroke survivors; 2) assessing the risk of fall; 3) published in English. Studies were excluded if participants had other neurological diseases, such as Alzheimer, Parkinson’s disease, multiple sclerosis, and spinal cord injury.The results of the comprehensive database search were screened for relevance, and the selected papers were analyzed. The data from each study were extracted using a format developed by the authors. The form included the following information from each article: Authors, Publication date (year), Location of the study, Sample size, Setting, Number of Parameters, Labeling of the Participants, Significant Factors, Non-Significant Factors, Univariate/Bivariate analysis: Output Type, Multivariate Analysis (Model): Method, Age of the participants, and Notes.Most fall risk assessment studies could be categorized as cohort studies which fall under the umbrella of observational studies. Considering the various available tools to assess the risk of bias in observational studies , the CocAs noted earlier, it was not feasible to conduct a thorough meta-analysis on the various FRFs due to the limited number of studies for each FRF required for such an analysis. This impediment stems from discrepancies in the heterogeneity of factors, as well as discrepancies in the format of outcomes—principally involving a variety of preferred statistical measures. To address these issues, we have developed a list of significant risk factors towards affording researchers better insight into the commonality and significance of the factors. Using this risk factor-specific approach, we have reported the number of studies considering each factor, as well as the number of studies in which that particular factor was determined to be significant. In order to simplify the process of comparing factors, a scale was created for each factor to calculate the ratio of the number of studies which identified a given FRF to be a significant to the number of the studies considering that factor.Note that if at least one of the items in a particular category had a significant impact on the fall risk, the category was classified as a significant factor. As an example, Mansfield et al. conducted a balance test requiring participants to stand as still as possible on a force plate. They subsequently calculated the mediolateral root mean square (RMS) of the center of pressure (COP), identifying it as a significant risk factor for falls, in contrast, to the anteroposterior RMS of COP which was determined to be non-significant. Therefore, since there was a factor from the category of balance-related measures among the significant FRFs, we considered that category  as significant in that study.This study also analyzed changes over time in the methods assessing the balance and mobility of stroke patients and how that information factored into the fall risk assessment process. Accordingly, any articles considering these factors were further analyzed to determine all implemented approaches. Initially, the identified balance and mobility-related factors from literature were categorized as either subjective or objective. We have also classified objective balance and mobility-related factors according to the equipment used for assessment, which provides researchers with a more accurate depiction of the level of motion analysis achieved in the various studies. For example, TUG testing typically measures the time for accomplishing a specific physical task, notably standing from/sitting on a chair, walking, and turning. Since the only equipment measuring the output of this test  is a timer, we can conclude that it does not pay sufficient attention to more detailed motion analysis parameters such as gait characteristics. However, a similarly designed study might utilize a force plate or inertial measurement unit (IMU) sensors which can deliver more detailed gait-analysis data, potentially improving the accuracy of identifying the risk for falls among stroke victims.A total of 10,746 articles were initially identified through the process of searching the databases and relevant repositories as described above. Due to duplication and not meeting the inclusion criteria, a portion of these articles were removed, resulting in a total of 27 articles considered relevant .The characteristics of interest included publication year, location, sample size, setting, and details of the patient labeling, as shown in Assessment of the risk of bias indicated that all the articles in the review had at least acceptable quality based on formula described earlier. The detailed results of this analysis are shown in The frequency for the 14 most common FRFs assessed in the articles is shown in To the best of our knowledge, up to date, there is no comprehensive literature review on fall risk assessment among stroke survivors. The most recent review presented a relevant meta-analysis on the various FRFs impacting stroke population , but onlAccording to the commonality table , the mosAmong the less common FRFs, such as history of falls, depression, visual impairment, and fall efficacy scale (FES), FES presented the highest significance ratio. Representing the level of fear of falling among stroke survivor, FES had a significance ratio of 75%, which is the third largest after motion- and balance-related measures with significance ratios of 84% and 81%, respectively. It is noteworthy that visual impairment with a 43% significance ratio was among the important FRFs, which also confirms the importance of factors associated with balance control. In fact, vison, along with proprioception and balance-control mechanisms in the inner ear, are the primary systems for maintaining human balance. Consequently, since visual impairment could affect balance, a stroke victim’s vision represents a potentially important factor in fall risk assessment. Moreover, an inclusive assessment of balance measures should represent the combined effects of vision, as well as other sensory systems and proprioception in fall risk. Hence, it is highly recommended that both balance and FES should be considered in the initial pool of FRFs in future studies. Finally, the FRFs with the least significance ratios were urinary incontinence/medications, use of sedative/psychotropic medications, duration of stroke, and stroke type. It is worthy to note, that among the eight articles which considered stroke type, none identified it as a significant fall risk factor .As mentioned, the most common significant factors among the pool of reviewed articles were balance and motion-related measures, thus confirming the critical importance of these measures in determining the risk for falls among stroke victims. The list of measures in the various reviewed articles revealed that numerous subjective and objective scales were used to evaluate balance and motion in stroke survivors . For exaIt is expected that reviewing the utilization of different factors reported in earlier studies could lead to beneficial information in the fall risk assessment and hence inspire more effective management strategies of stroke survivors. For example, exploring the evolution of balance and motion-based tools confirmed that earlier studies focused more on the implementation of subjective versus objective tools. Specifically, articles dating from 1997 to 2014 (12 out 19 articles) used subjective tools to assess the balance and motion of stroke survivors . Moreovevia the implementation of a thorough motion analysis protocol of stroke survivors.Overall, among the reviewed articles, there were only four studies involving detailed motion analysis designed to identify the effect of motion in fall risk assessment . These sConsidering the gaps in the existing literature may shed some light on the future directions for this important area of study. The initial pool of FRFs in future studies could be identified according to To augment the numerous available tests for assessing balance and motion in stroke survivors, the effect of the data type  of a given system for capturing balance/motion data needs to be explored. Another area within the scope of improvement of fall risk assessment studies involves the type of tasks during which motion data is collected. Importantly, although the significance ratio for cognitive impairment as an FRF was found to be 36%, cognitive factors may have larger impact on fall risk assessment when physical task performance is also factored in. For instance, dual-task paradigms are often utilized in fall risk assessment of the elderly population and patients suffering from multiple sclerosis . LikewisSeveral methods could be implemented to execute cognitive-motor dual-task paradigm. To this end, there will be a physical task such as walking, TUG test, and balance test tied with a second task which is mainly to put a cognitive load on the stroke survivors. The physical task could be selected according to the objective of the studies. However, to put the cognitive load on the individuals, there are limited number of methods to be utilized. Generally, there are five categories of activities to be considered in dual-task paradigms. The first approach is the n-back tasks in which the subject is presented with a sequence of stimuli, and the task consists of indicating when the current stimulus matches the one from n steps earlier in the sequence . The loaThere are several limitations in this review and the relevant literature which need to be improved in the future studies. The main drawback in the literature is that the studies did not provide the effect size for their analyses on the FRFs. Due to this gap in the literature, Xu et al., could not perform any analyses on the FRF with more than four articles which is a very few sample size to make a reliable decision based on it . To addrThere is a significant benefit in providing a review on the statistical methods implemented to analyze the FRFs in the literature. So far, the reviews on the FRFs have been focused on the outcome of the statistical analyses. However, a review of the implemented statistical methods in the studies could help the researchers to compare and select the adequate statistical methods for their analyses. Furthermore, this type of study could investigate the effects of using various statistical approaches/models on the outcome of the fall risk assessment. Such a review study on the methods could be considered as a potential next phase for this systematic review. To this end, a preliminary review was conducted on the articles involved in this review and the statistical methods were summarized in According to the results of this review, motion analysis demonstrates a high capability for identifying those at risk for falling. However, obtaining accurate and timely patient information  is a critical issue which needs to be addressed in future studies. Recent advancements in wearable tools and smartphone technologies, as well as in computational platforms, big data mining and artificial intelligence, have certainly improved options for monitoring and evaluating patients, where several literature reports describe the successful implementation of smartphone motion data to categorize physical status attributes, such as balance or fatigue level . SimilarThis study presented a systematic review of 27 published papers on fall risk factors and fall risk assessment post stroke, with findings indicating that balance and motion-related measures constitute the most common and significant factors for this at-risk population. Further analysis of these studies demonstrated a clear paradigm shift from using traditional subjective tools to more quantitative objective approaches for assessing balance and motion deficits. Due to the relevance of these two factors in fall risk identification, it is recommended that further studies are needed to investigate an optimal combination of balance/motion assessment tools and protocols for investigating the fall risk for stroke survivors. Considering the accessibility and low cost of high performance IMU sensors, IMU-based analysis, along with other smart sensors, is suggested for capturing motion and balance dynamics. Furthermore, cognitive-motor dual-task studies are highly recommended for future implementation on fall risk assessment of stroke patients for more realistic outcomes. Given the multiple challenges that stroke sufferers face and the critical importance of avoiding additional physical and emotional harm resulting from falls, research targeting the development of advanced fall risk assessment models should be prioritized.


Single nucleotide polymorphisms (SNPs) interfere with the function of certain genes and thus may influence the probability of skin cancer. The correlation between SNPs and skin cancer (SC) lacks statistical power, however. Therefore, the purpose of this study was to identify the gene polymorphisms involved in skin cancer susceptibility using network meta-analysis and to determine the relationship between SNPs and SC risk.CIs) were determined to estimate heterogeneity within and between studies. Meta-analysis and network meta-analysis were carried out to identify the SNPs associated with SC. The P-score of each SNP was compared to obtain the rank of probability. Subgroup analyses were performed by cancer type.PubMed, Embase, and Web of Science were searched for articles including “SNP” and different types of SC as keywords between January 2005 and May 2022. The Newcastle-Ottawa Scale was used to assess bias judgments. The odds ratio (ORs) and their 95% confidence intervals  and rs13181 (ERCC2) were the first-ranking SNPs in both subgroups one and two of the allele model, respectively. The homozygous dominant genotype and heterozygous genotype of rs475007 in subgroup one and the homozygous recessive genotype of rs238406 in subgroup two were most likely to be associated with skin cancer based on the dominant model.According to the allele model, SNPs FokI rs2228570 and ERCC2 rs13181 and, according to the dominant model, SNPs MMP1 rs475007 and ERCC2 rs238406 are closely linked to SC risk. They arSingle nucleotide polymorphisms (SNPs) are genetic variations caused by point mutations. The allelic distribution of SNPs may interfere with the function of genes and then influence the probability of certain diseases , 9, whicNetwork meta-analysis (NMA), and in particular, Bayesian network meta-analysis, analyzes the direct and indirect evidence from multiple comparisons of tests within and between studies , making Therefore, the aim of our study was to identify and compare the single nucleotide polymorphisms predominantly involved in skin cancer susceptibility by conducting a network meta-analysis.22.1We searched the PubMed, Embase, and Web of Science electronic databases from their starting dates to May 2022 to identify relevant studies. The search strategy is shown in detail in 2.2Two researchers (LZ and YS) independently screened the titles and abstracts of the search results and extracted the following information from the included articles: authors’ names, year of publication, population of country and ethnicity, genotyping method, case and control numbers, control’s source, case–control match, cancer type, gene, SNP, and allele frequency.Subsequently, we applied the Newcastle-Ottawa Scale (NOS) score for case-control studies to evaluate the quality and risk of bias of the included studies Figure 22.3Alleles are represented differently in different genomes. Therefore, for clarity, all reference alleles were represented by “A” in this study, and the corresponding alternative alleles were represented by “B.” Hence, for genotype, “AA” meant the homozygous dominant genotype, “AB” meant the heterozygote genotype, and “BB” meant the homozygous recessive genotype. The allele model (A vs. B) was employed to explore dominance. Furthermore, the dominant model (AA + AB vs. BB) and the recessive model (AA vs. AB + BB) were used for investigating the association between different genotypes and phenotypes .ORs) and their 95% confidence intervals (CIs) were used for estimating heterogeneity within and between studies. Then, pooled sensitivity (Se), specificity (Sp), positive likelihood ratio (LR), negative likelihood ratio (LR), diagnostic OR (DOR), and area under the summary receiver operating characteristic curve (AUROC) were calculated for each genotyping. The pooled AUROC was used as an indicator for testing to examine the diagnostic accuracy of each genotyping. The statistical heterogeneity between each study was assessed using the inconsistency index I-square. Additionally, meta-regression analysis was performed based on cancer type to assess heterogeneity. Cancer types included: CM, NMSC, and SC (including both CM and NMSC).A bivariate random effect model was performed for the meta-analysis of the comparative studies. Odds ratios  was used to clarify the relationships between the SNPs and skin cancer according to the allele model (A vs. B) and the dominant model (AA + AB vs. BB). The fixed-effects model that had four chains, 1,000 burn-ins, 200,000 iterations, and a thinning interval of 10 was selected for the MCMC simulation . The GelP <0.05 was statistically significant. RStudio software and StataSE 16.0 software were used for calculations and plotting. The software packages used in the study are listed in 33.1The literature search initially identified 3,575 studies from PubMed, Embase, and Web of Science. The search ended on 2 May 2022. As 3.23.3A direct meta-analysis was performed to determine the correlation between 275 SNPs and SC risk  among CM, NMSC, and SC (including both CM and NMSC)  Table 3.3.73.7.1The network plot depicts the rough comparison of each pair of SNPs Figure 3P-values of the correlations between the SNPs in subgroup one were above 0.05 (The SNPs rs731236 vs. rs2228570 had the strongest negative correlation with SC risk in subgroup one (standardized mean differences (SMD) of OR = −0.08, 95% CI )  ranked first in subgroup one in the allele model, and the SNP rs13181 had the highest P-score in subgroup two (P-score = 0.94).To select the SNPs with the highest chance of a significant association with skin cancer, the 3.7.2In There was no inconsistency between the direct and indirect evidence in Group 1. The strongest positive correlations in this subgroup were the comparison of rs475007 vs. rs1729376 and the comparison of rs475007 vs. rs2071231 . These were followed by the rs475007 vs rs491152 comparison, which SNPs were negatively correlated with SC risk . The comparison of rs494379 and rs514921 showed the strongest indirect correlation   of rs2228570 (FokI) and (C) of rs13181 (ERCC2) were the highest-ranking SNPs in both subgroups one and two of the allele model. On the other hand, using the dominant model, the homozygous dominant genotype and heterozygote genotype (AA + AT) of rs475007 in subgroup one and the homozygous dominant genotype (AA) of rs238406 in subgroup two were most likely to be associated with skin cancer.Based on direct comparisons from pairwise meta-analysis and added indirect comparisons, our study employed network meta-analysis to compare the associations between single-nucleotide polymorphisms and skin cancer using the allele model and the dominant model. Our network meta-analysis identified two subgroups in each genetic model, respectively. We ranked SNPs based on their The single-nucleotide polymorphism rs2228570 (FokI) is in the vitamin D receptor (VDR) gene. It is one of the common human VDR SNPs along with rs1544410 (BsmI), rs7975232 (ApaI), and rs731236 (TaqI). Vitamin D is metabolized to vitamin D: 1,25(OH)2D3.1 in response to ultraviolet B (UVB) radiation. This metabolite is the ligand of the VDR, which in turn initiates a series of biological responses in bone metabolism, immunity, cell proliferation, and differentiation by binding to vitamin D response elements in DNA , atopic SNPs rs13181 and rs238406 ranked first and second in subgroups two in both the allele and dominant models. Both SNPs are in the ERCC2  gene. The ERCC2 polymorphisms have ATP-dependent DNA helicase activity, which may impact DNA repair functions. Deficiency of ERCC2 has been reported to lead to xeroderma pigmentosum (XP), trichothiodystrophy (TTD), and Cockayne’s syndrome (CS) . This obMatrix metalloproteinases (MMPs) are a family of proteolytic enzymes that are involved in cell mobility, proliferation, differentiation, and apoptosis by degrading extracellular proteins . MMP1, a5Due to technical differences and differences in sensitivity, our analysis only included studies that used the PCR genotypic detection method and excluded microarray detection or genome-wide association studies (GWAS). However, GWAS allows for much larger sample sizes than PCR studies. Additionally, due to the limitations of the RStudio and StataSE software and the complexity of multi-arm studies, SNPs only reported in one single article were not included in the final network meta-analysis.6Our article indicated that people with mutations in the genes FokI (rs2228570), ERCC2 (rs13181), MMP1 (rs475007), and ERCC2 (rs238406) were more likely to have skin cancer. Dysplastic nevi  are precursors and risk factors for malignant melanoma . HoweverIn addition, we obtained direct and indirect evidence between the SNP pairs through network analysis, which proposed the possibility of hitherto unexplored relationships between certain gene mutations. For example, ERCC2 gene mutations have been shown to indirectly increase the risk of SC , 107, anFinally, as an added scientific value, we applied an innovative research design by performing a network analysis of case–control studies, thus providing a fresh perspective on the NMA method. Our analysis implies that all studies involving genetically-related diseases, whether cohort or case–control studies, can be used to build a network in the meta-analysis, which may then provide valuable information for the diseases’ early detection, diagnosis, staging, treatment, and prognosis.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Conceptualization: LZ, HL, and IK. Methodology: LZ and HL. Data curation: LZ, YS, HA, and JZ. Statistical analysis: LZ and HL. Writing : LZ and IK. Review and editing: ÉP, JM, YS, HA, JZ, HL, and IK. Visualization: ZL. Supervision: HL and IK. Project administration: LZ and IK. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


The association of dietary fat and colorectal cancer (CRC) was frequently reported. However, few studies assessed the effects of different types of dietary fats on CRC. This study aimed to investigate the association between intakes of different types of dietary fatty acids with colorectal cancer risk.This case-control study was conducted on 480 participants including 160 CRC cases and 320 healthy controls in Firoozgar Hospital, Tehran, Iran. The intake of dietary fatty acids of the participants was assessed using a semi quantitative food frequency questionnaire (FFQ).P = 0.001), polyunsaturated fatty acids (PUFA) , and calorie  was higher and the mean intake of oleic acid (5.59 ± 3.17 vs. 8.21 ± 5.46) and linoleic acid  was lower in the case group compared to the control group. An inverse association was found between colorectal cancer (CRC) and dietary intake of oleic acid , linoleic acid , and α-linolenic acid . The association remained significant after adjusting for age and sex, sleep, smoking, and alcohol consumption, and BMI.The mean intake of cholesterol (273.07 ± 53.63 vs. 254.17 ± 61.12, The results of this study support a protective effect of oleic acid, linoleic acid, and α-linolenic acid against CRC. Further longitudinal studies are warranted to confirm these results. Colorectal cancer is the second leading cause of cancer death and the third most common cancer in the world. Keum and Giovannucci  Over thevia increasing TNFα, interleukin (IL) 1B, IL6, and interferon γ (IFNγ) and decreasing IL10, IL17, and IL22 (The effect of dietary intake on chronic diseases was frequently reported –15. Alsoand IL22  and can and IL22 . In addiand IL22 . Recent and IL22 . It was and IL22 . An incrand IL22 . On the and IL22 . A prospand IL22 . A Case-and IL22 . Furtherand IL22 . Howeverand IL22 –40. For and IL22 . A systeand IL22 . Howeverhttp://www.openepi.com/) and the odds ratios obtained in previous studies  . Data coInformation on the level of physical activity was collected by the International Physical Activity Questionnaire (IPAQ), which has already been validated in Iran . Using tt-test were used to compare qualitative and quantitative variables between the case and control groups, respectively. The logistic regression analysis method was used to investigate the relationship between CRC and dietary fatty acids. A stepwise (forward) selection procedure was used for modeling and variables were selected based on significance and background knowledge as crude regression model (Model 1), adjusted for age and sex (Model 2), further adjustment for physical activity, smoking, and alcohol consumption (Model 3), and additionally adjustment for BMI (Model 4). Statistical analyses were performed using SPSS software version 20  and P-value < 0.05 was considered as significant in all analyses.Chi-square and independent P < 0.001), lower body mass index (BMI) , and higher smoking . The amount of dietary fat intake of the participants is presented in P = 0.001), PUFA , and calorie  in the case group was significantly higher than the control group. The mean intake of oleic acid (5.59 ± 3.17 vs. 8.21 ± 5.46 g/d), linoleic acid , and α-linolenic acid  in the case group was significantly lower than the control group.Distribution of the characteristics of the cases and controls is presented in P = 0.001), oleic acid , and α-linolenic acid . The association remained significant after adjusting for age and sex (Model 2) and further adjustments for physical activity, smoking, and alcohol consumption (Model3). The association between CRC and oleic acid was disappeared after additional adjustment for BMI (Model 4).The association between dietary intake of fatty acid and the risk of colorectal cancer is presented in The results of the present study indicated that there was an inverse association between colorectal cancer and dietary intake of oleic acid, linoleic acid and, α-linolenic acid. Epidemiological and experimental studies reported contradictory results on the association of dietary fatty acids and colorectal cancer. Butler et al. performed a nested case-control study of 350 colorectal cancer cases and an equal number of individually matched control subjects within the Singapore Chinese Health cohort Study to evaluate the associations between plasma fatty acid composition and colorectal cancer risk and reported a statistically significant inverse associations with colon cancer risk for higher levels of the essential PUFAs , oleic acid, and also found that the oleic: stearic acid ratio was positively associated with reduced frequency of colon cancer. The protective effects of alpha-linolenic acid may be due to its role as a precursor to the biosynthesis of EPA and DHA and their effects on increasing apoptosis and reducing the proliferation of cancer cells , 47.Regarding the association of CRC with oleic acid, the consumption of an olive oil rich diet has been linked to a reduction in the incidence of cardiovascular disease and cancer , which wThe results of the present study indicated an inverse association between CRC and omega-6 fatty acids. A cohort study in the United States observed no association between intake of omega-6 and omega-3 fatty acids and colorectal cancer . AnotherWe found an inverse association between CRC and the intake of omega-3 fatty acids. Omega-3 may be a protective factor against CRC by reducing the level of pro-inflammatory cytokines produced by the cyclooxygenase pathway. The inefficient metabolic conversion of ALA to very long-chain omega-3 fatty acids including EPA and DHA  can be lHowever, some other studies reported contradictory results. One study on Chinese women found no association between omega-3 intake and colorectal cancer . In addiThe strengths of this study were the adequate sample size, focus on diet prior to diagnosis, and highlighting the differences between different types of dietary fatty acids. However, this study had some limitations. One limitation of assessing dietary intake in case-control studies is the using of self-report FFQ which has potentially a recall bias. In addition, there are several other factors that may affect the results. However, the effects of some confounders such as age, sex, smoking, tobacco, and BMI were adjusted, but the effects of other factors, such as genetics and stress were not assessed.In the present study, the patients with CRC had higher intake of cholesterol and lower intake of oleic acid, linoleic acid, and α-linolenic acid than the control group. Higher intake of oleic acid, linoleic acid, and α-linolenic acid was associated with a reduced frequency of CRC. Dietary modification in terms of receiving rich sources of unsaturated fatty acids may be effective in reducing the risk of colorectal cancer. Further longitudinal studies are warranted to examine the effects of different types of fatty acids on colorectal cancer and to discover the underlying mechanisms.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by (Code: IR.SBMU.CRC.REC.1398.028). The patients/participants provided their written informed consent to participate in this study.SS, SF, ST, NH, ZR, and MG designed the study and carried out the data collection. MA, MEA, FB, SK, HS, MS, SN, AA, and SD were involved in the design of the study, analysis of the data, and critically reviewed the manuscript. All authors contributed to the article and approved the submitted version.Funding for this study was provided by Cancer Research Center (CRC), Shahid Beheshti University of Medical Sciences, Tehran, Iran (Code:15784).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


However, the statistical difference in leptin level was changed after eliminating the confounding influence of leptin sources and assay approaches. Furthermore, a positive association (r = 0.28) between leptin level and body mass index (BMI) as well as a negative association (r = −0.33) between adiponectin level and BMD was found. Moreover, adiponectin had the highest probability of predicting PMOP (84%). Current evidence suggests that leptin positively affects BMI and adiponectin negatively affects BMD, and adiponectin is the most relevant adipokine negatively associated with PMOP.The clinical relevance of blood levels of adipokines in individuals with postmenopausal osteoporosis (PMOP) has not been previously clarified. We performed this meta‐analysis to clarify the association between three common adipokines levels and the occurrence of PMOP. PubMed, Embase, Cochrane library, and China National Knowledgement Infrastructure (CNKI) were searched for collecting articles published before 31 October 2021, without language and status restrictions. Fourteen studies met the selection criteria. Meta‐analysis revealed that blood leptin level was remarkably lower (mean difference [MD], −1.94; 95% confidence interval [CI], −3.83 to −0.06; I Issued data revealed that OP has become a prevalent public health problem worldwide, and its prevalence is estimated to rise from approximately 10 million to more than 14 million by 2020 in the United States.Actually, studies have revealed several factors contributing to the occurrence and progression of OP. Of which, menopause has been especially emphasized because it causes a predominance of bone resorption and therefore, increases the incidence of OP and the risk of bone fractures.So far, studies revealed multiple mechanisms that construct the specific association between bone metabolism and changes in fat. Traditionally, fat mass was considered to play an important role in mechanical load or oestrogen secretion as an endocrine organ. However, except oestrogen synthesis in postmenopausal women, adipocytes are also responsible for producing adipokines, such as leptin, adiponectin, and resistinA previous meta‐analysis investigated the influence of blood levels of adipokines on BMD, osteoporotic status, and fracture risk in healthy men and women,2We conducted this meta‐analysis following the Preferred Reporting Items for Systematic Reviews and Meta‐analysis (PRISMA) for Network Meta‐analysis (PRISMA‐NMA)2.1In 2020, a meta‐analysis investigated the association between adipocytokines and postmenopausal osteoporosis (PMOP), which was published in the Chinese language and identified eligible studies published before February 2020.2.2Two independent authors evaluated and selected relevant studies according to the following criteria: (1) postmenopausal individuals were confirmed as PMOP with recognized criteria in the case group and healthy postmenopausal individuals with normal BMD in the control group; (2) observational studies were considered to be eligible if data of three common adipokines between both groups were available; and (3) studies were published in full‐texts. We also developed the following exclusion criteria: abstracts, studies without data of interest and ineligible design, animal experiments, or the methodological quality were recognized as weak . Any disagreements were resolved by consultation with a third senior author.2.3From the included articles, two independently authors extracted the following information: (1) name of the first author and publication year; (2) country; (3) basic characteristics of individuals including sample size, mean age, mean BMI, and mean time since menopause; (4) details of biochemical examination including sources of indicators and assay approaches; and (5) details of methodology. Moreover, we also extracted correlation coefficients2.4We used the NOS to assess the methodological quality of the included studies, which was developed based on a star‐based system.2.5In this meta‐analysis, we defined the difference in leptin, adiponectin, and resistin concentrations between individuals with PMOP and normal individuals as the primary outcomes, and the relationship between the concentrations of adipokines and BMI and BMD as the secondary outcomes.2.62 statistic.Z values based on a generic inverse‐variance model. Finally, summary r values were converted from the summary of Fisher's Z values using recognized formulas. We also tested the robustness of all pooled results using the leave‐one‐out method. It is noted that we calculated standardized levels of adipokines using Z‐scores methods for the purpose of further evaluating the strength of relationships in the different comparisons by introducing the surface under the cumulative ranking curve (SUCRA),p‐value of <0.05 was considered statistically significant.All statistical analyses were conducted using RevMan 5.4 software . The levels of adipokines were continuous variables, and thus we used the mean difference (MD) with a 95% confidence interval (CI) to express the pooled results because all indicators were calculated using comparable data units. Statistical heterogeneity across studies in individual outcomes was evaluated using Cochrane Q examination2.7We used the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework to rate the certainty of evidence. In the GRADE system, the certainty of evidence will be classified as “very low,” “low,” “moderate,” and “high.”33.1n = 13), Embase (n = 24), the Cochrane library (n = 2), and CNKI (n = 4). We removed 9 duplicate records through running software, then 33 ineligible studies were excluded after carefully screening the titles and abstracts. A total of 14 studies were identified from a previous meta‐analysis which was published in the Chinese language, and thus, a total of 15 studies were retained for further eligibility assessment. After screening full texts, 14 studiesWe identified 43 records after performing the updated search in the initial retrieval, including Pubmed n = 3, Embase3.2A total of 14 studies were included in this meta‐analysis finally, which enrolled 615 individuals with PMOP and 499 healthy patients with normal BMD. Of these studies, 8 studies3.3The NOS was used to assess the methodological quality of the included articles. Three studies scored 5, four studies scored 6, five studies scored 7, and the remaining two studies scored 8. In general, the overall methodological quality of included studies was at a moderate level.3.4p = 0.04; Figure 2 = 96%, p < 0.001), we therefore conducted a series of subgroup analyses based on leptin sources and assay approaches to explore potential influencing factors. Pooled results were reversely changed to have no statistical significance although statistical heterogeneity was not obviously decreased, as shown in Figure Among 14 studies included, 10 reported leptin levels in 374 individuals with PMOP and 340 controls. The pooled result suggested that individuals with PMOP had significantly lower leptin levels compared to controls . Although substantial statistical heterogeneity was detected , no subgroup analysis was conducted because serum adiponectin levels were measured using the ELISA method in these studies. It is noted that the results of sensitivity analysis confirmed the robustness of the pooled result because it was not significantly changed after omitting one study at one time . No subgroup analysis was conducted because serum adiponectin levels were measured using the ELISA method in these studies. We detected substantial statistical heterogeneity for this indicator , however, we did not conduct a subgroup analysis because serum resistin levels were measured using the ELISA method in these studies. Unfortunately, the pooled result should be cautiously interpreted because there was statistical changes after omitting one study at one time , −0.34 , and 0.14  for leptin, adiponectin, and resistin, respectively. Therefore, a summary r value was 0.26, −0.33, and 0.14 for leptin, adiponectin, and resistin, respectively. This meta‐analysis of correlation coefficients revealed a significantly negative relationship between adiponectin levels and BMD. However, sensitivity analysis did not confirm the robustness of the pooled results  and 0.22  for leptin and adiponectin, respectively. Therefore, a summary r value was 0.52 and 0.22 for leptin and adiponectin, respectively. This meta‐analysis of correlation coefficients revealed a significantly positive relationship between leptin levels and BMI, which was further confirmed by the results of sensitivity analysis , and has been speculated to have an association with BMD due to its polymorphisms.2 > 90%), and most importantly is that subgroup analysis changed the estimates in terms of the difference in blood leptin levels between postmenopausal individuals with OP and healthy individuals with normal BMD, suggesting that the estimates for leptin should be cautiously interpreted. Meanwhile, heterogeneity of each subgroup remained high after subgroup analyses for available factors, suggesting that several unknown factors contributed to the observed study heterogeneity, such as mean BMI and mean time since menopause.It is noted that our meta‐analysis encountered substantial overall statistical heterogeneity for the individual outcome ; formal analysis ; writing – original draft . Linyuan Shu: Conceptualization ; data curation ; formal analysis ; writing – original draft . Hui Sun: Conceptualization ; data curation ; formal analysis ; writing – review and editing .The authors confirm that there are no conflicts of interest.Figure S1Click here for additional data file.Figure S2Click here for additional data file.Table S1Click here for additional data file.Table S2Click here for additional data file.Table S3Click here for additional data file.Table S4Click here for additional data file.


RASSF1A) gene in cell-free DNA on the outcomes of patients with different types of cancer have been reported, the results are inconsistent.  Although the effects of methylation of the Ras association domain-containing protein 1 isoform A , which suggested there was a significant association between RASSF1A methylation and overall survival, and patients with an RASSF1A methylation status had a significantly increased risk of total death. Moreover, the Egger test result suggested there was no significant publication bias among the included studies.  Nine relevant publications involving a combined total of 1254 patients with different types of cancer were included in this study. The combined results of the random effects models yielded a hazard ratio of 1.73 (95% confidence interval: 1.31, 2.29; RASSF1A in cell-free DNA in cancer patients was observably associated with an increased risk of poor overall survival. The methylation of  DNA methylation, a form of epigenetic modification, plays an important role in many physiological and pathophysiological processes, including carcinogenesis –3. EpigeRASSF1A) gene, which encodes a member of the Ras association domain family, belongs to a class of genes that are often silenced by methylation rather than by mutation events. The RASSF1A protein is associated with the cell cycle, microtubule stabilization, and apoptosis [RASSF1A is usually expressed in most normal tissues, but it is downregulated or lost in some tumor cell lines and tissues [RASSF1A is associated with various types of tumors, including lung cancer and esophageal squamous carcinoma [RASSF1A methylation on the prognosis of patients with different types of cancer, the results are inconsistent across different studies [RASSF1A methylation in cfDNA and the prognosis of cancer patients.The Ras association domain-containing protein 1 isoform A  the study was of cohort type; and (4) the study reported hazard ratios (HRs) with 95% confidence intervals (95% CIs) of overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), or relapse-free survival (RFS), adjusted by univariate or multivariable analysis.After the literature search, the retrieved articles were further screened according to certain inclusion and exclusion criteria. The inclusion criteria were as follows: (1) the study participants were adult patients with a histologically or pathologically confirmed cancer; (2) the study investigated the relationship between The exclusion criteria were as follows: (1) reviews, conference abstracts, commentaries, and other nonliterary research articles; (2) studies in which HRs (95% CIs) were not reported or could not be calculated according to the information in the article; and (3) repeated publications or multiple articles with the same data (only the one with the most complete research information was included).The data extraction according to the inclusion and exclusion criteria described above was performed by two reviewers. The following data were extracted: the first author name, year of publication, country in which the research was conducted, research type, basic characteristics of the object of study (sample size), patient gender, patient age, cancer type, sampling time, follow-up time, confounding factors, and research outcomes. After completing the data extraction, the two reviewers would exchange their extraction tables and discuss and resolve any inconsistencies.The methodological quality of the studies, which was evaluated on the basis of the selection, comparability, and exposure of the included subjects, was scored according to the Newcastle-Ottawa Scale  . StudiesRASSF1A methylation status and the prognosis of cancer patients, HRs and 95% CIs were used as effect size indicators for evaluating whether the difference in risk of death between the methylated and unmethylated groups was statistically significant. Cochran's Q test and the I2 test were used to test for heterogeneity [Q statistic of P < 0.05 or I2 > 50% indicates that there is significant heterogeneity between studies, and the random effects model should be used for the meta-analysis. Values of P ≥ 0.05 and I2 ≤ 50% suggest that heterogeneity is not significant, and the fixed effects model is used instead. In addition to the inclusion of all cancer patients for the meta-analysis, the effect of RASSF1A methylation on patient prognosis was also evaluated according to specific cancer types. Egger's test was used to assess whether there was significant publication bias in the included studies [To explore the association between the ogeneity . A Q sta studies . Additio studies .RASSF1A methylation status in cfDNA. Only three studies reported an HR (95% CI) with multifactor adjustment, whereas the remaining studies conducted single-factor analyses.As indicated in The results of the methodological quality evaluations are shown in RASSF1A methylation and OS for all the cancer patients, where it can be seen that there was significant statistical heterogeneity among the included studies. The combined results of the random effect models suggested a significant relationship between RASSF1A methylation and OS (P < 0.001). Therefore, cancer patients with RASSF1A methylated may have a significantly increased risk of a poor survival prognosis.Since only one article reported RFS, DFS, and PFS results, this meta-analysis only incorporated effect values on OS. RASSF1A methylation and OS in patients with GC, CRC, and BC specifically are illustrated in Figures P = 0.004) between RASSF1A methylation and GC prognosis (P < 0.001) between RASSF1A methylation and CRC prognosis , and the combined results were stable and not affected by any single study. Similarly, the sensitivity analysis of the CRC patients also suggested stable combined outcomes. However, the meta-analysis results for the GC patients were not stable because they became insignificant (P = 0.238) after the Karamitrousis [As shown in itrousis  study haP values of greater than 0.05 for the total, GC, and CRC studies, indicating the absence of any publication bias  rendered them unsuitable for sensitivity analysis or Egger's test.Egger's test, which was used to evaluate whether there was observable publication bias between the studies, yielded ion bias . The limRASSF1A, a well-known tumor suppressor gene, affects cancer development and progression. Its inactivation through mutation, loss of heterozygosity, or promoter methylation occurs in various cancer types. The effect of RASSF1A methylation on the prognosis of patients with specific types of cancer has been well reported, whereas there are no published studies on the association between RASSF1A methylation in cfDNA and prognosis for all cancer patients. Therefore, we conducted this meta-analysis and found significant correlations between RASSF1A methylation in cfDNA and cancer prognosis in general, especially in GC, CRC, and BC.RASSF1A methylation is considered to be one of the first cellular changes to occur during tumor progression, and the frequency of this epigenetic modification varies widely among solid tumors [RASSF1A has also been investigated. Hassan et al. found that methylation of RASSF1A was associated with poor prognosis in patients with neuroblastoma [RASSF1A methylation in lung cancer tissues was significantly associated with a lower OS [RASSF1A is often caused by hypermethylation of the promoter region, which allows the abnormal methylation of RASSF1A being more easily detected in a variety of cancers, including BC, lung cancer, and gastrointestinal cancer [RASSF1A promoter hypermethylation had poor prognoses [RASSF1A promoter methylation had significant lower PSF and OS [RASSF1A remains expressed in cancer, concentrations of RASSF1A protein above or below its optimal expression threshold can disrupt signal transduction and lead to malignant transformation [RASSF1A was also found to be significantly correlated with tumor size and histological grade of BC [RASSF1A promoter disrupts normal body signal transduction, leading to tumor recurrence, and metastasis and poorer clinical outcomes.d tumors , 28. Theblastoma . Sensitilower OS . These fl cancer . The sturognoses . CompareF and OS . Althougormation . Promotede of BC . TherefoRASSF1A in cfDNA, that can easily be detected in liquid biopsy samples or blood samples from cancer patients to predict their prognostic risks and clinical outcomes.Clinically, liquid biopsy or collection and analysis of easily accessible patient samples, such as blood, can contribute to the diagnosis of early tumors, as a less invasive diagnostic approach , 35. CfDTo illustrate the strengths of this meta-analysis, we not only included patients with various types of cancer for the combination of effect values but also grouped specific cancers for analysis, with the combination results showing good consistency. Furthermore, the evaluation of the methodological quality of the included studies showed that selection bias, measurement bias, and lost track bias were reasonably controlled , which suggested the studies were of medium and high quality. More importantly, no significant publication bias was found in this meta-analysis, and the combined results were highly reliable.RASSF1A methylation and disease progression and recurrence for comparison with the OS association.There were several limitations to our meta-analysis. First, although the statistical heterogeneity of the nine studies was relatively small, the clinical and methodological heterogeneity among them  should not be ignored. Second, the number of studies included in the meta-analysis was small, with less than five articles for each specific cancer type. Additionally, the incomplete literature information made it difficult for us to explore the influences of age, cancer stage, treatment methods, and other factors on the combined results through subgroup analysis. Third, because the meta-analysis results for GC and BC were unstable, more large-sample studies are needed to verify the findings. Finally, it is recommended that follow-up studies focus on the relationships between RASSF1A methylation in cfDNA was observably associated with an increased risk of total deaths for patients with GC, CRC, and BC. Therefore, more high-quality, large-sample, and prospective cohort studies are recommended to verify the stability of the results.In conclusion, this meta-analysis revealed that


Toll like receptor 4(TLR4) gene Asp299Gly polymorphism and diabetic microvascular complications (DMI) is unclear. Therefore, the aim of this meta analysis was to explore the relationship between TLR4 Asp299Gly polymorphism and DMI.The relationship between TLR4 gene Asp299Gly polymorphism and DMI published before June 2020 was collected.System search PubMed, Web of science, Springer, Cochrane library, ELSEVIER, Wanfang database, VIP, CNKI, a case–control study of the correlation between TLR4 gene Asp299Gly polymorphism increased the risk of microvascular complications in T2DM . Subgroup analysis by race and different type of microvascular complications, we found that TLR4 gene Asp299Gly polymorphism was associated with increased risk of microvascular complications in the Caucasian population  and increased the risk of retinopathy in patients with T2DM.We included 6 articles, a total of 11 studies involving patients with type 2 diabetes mellitus (T2DM) complicated by microvascular complications 1834 cases, without corresponding microvascular complications 4069 cases. TLR4 gene Asp299Gly polymorphism was associated with increased risk of microvascular complications in patients with T2DM, especially diabetic retinopathy (DR). Diabetic microvascular complications (DMI) are the most common chronic complications of diabetes, which are the main causes of disability and death in diabetic patients , includiTLR4 gene, encodes TLR4 protein, located on chromosome 9Q32-33 and its variations can alter TLR4's recognition and interaction functions [TLR4Asp299Gly gene may affect ligand binding, folding efficiency, cell surface expression and protein stability, while the polymorphism of Thr399Ile gene has little effect [unctions , 11. Thee effect .TLR4 gene polymorphism and type 2 diabetes mellitus (T2DM) and its complications have attracted extensive attention. Yin et al. indicated that TLR4 gene Asp299Gly and Thr399Ile polymorphisms are not associated with increased T2DM risk through a meta-analysis [TLR4 gene polymorphism is associated with the occurrence of DMI, among which the research on TLR4Asp299Gly is the hotspot [TLR4Asp299Gly allele increased the risk of DR. That is to say, a significant increase of G allele frequency was observed in DR compared to those without it in T2DM , p = 0.0002). Yet Balistreri et al. [TLR4 gene polymorphism can be considered as a risk factor or diagnostic marker for DMI.Recently, studies on the relationship between analysis , whereasanalysis . Several hotspot –24. Khag hotspot  showed t hotspot  concludei et al.  revealedThe electronic databases PubMed, Web of science, Springer link, Cochrane library, ELSEVIER, Wanfang database, VIP, CNKI were searched using the following terms: “(TLR4 or toll-like receptor-4) and  and (diabetic or diabetes) and (nephropathy or retinopathy or neuropathy)”. All literature is limited to Chinese or English published before June 20 2020 ranging from 2000 to 2020 (last research was updated on May 2020). At the same time, the literature was traced, and the literature related to this study was searched according to the abstract and the full text was obtained.TLR4Asp299Gly gene polymorphism and diabetic microvascular complications; (2) case–control study; (3) population studies; (4) the original text provides the frequency of the genotype or allele or can be extrapolated; (5) the control group was type 2 diabetes patients without corresponding microvascular complications; (6) sufficient data are available to estimate OR values and 95 percent confidence intervals; (7) the control group met the law of genetic balance. Exclusion criteria: (1) critical literature, case reports, conference abstracts, letters etc.; (2) non-case–control studies; (3) the original text does not provide raw data or data is insufficient.Inclusion criteria: (1) study of the relationship between All the data are extracted independently by the two authors according to the set retrieval strategy and the inclusion criteria, the dissenting literature was judged by the third author and finally reached an agreement. The data extracted in the literature included the first author, year of publication, country, race, type of diabetic microvascular complications, sample size of case group and control group, distribution of genotypes and alleles. In addition, whether the control group included in the study complied with Hardy–Weinberg balance (HWE) was also mentioned in this paper.The literature quality assessment scale of case–control studies, namely Newcastle-Ottawascale (NOS), was used for evaluation, including the selection of study subjects, comparability between groups and measurement of exposure factors. The scores ranged from 0 to 9, and the higher the score, the better the quality of the literature.TLR4Asp299Gly loci in case group and control group. That is, the relationship between TLR4Asp299Gly gene polymorphism and diabetic microvascular complications was estimated by ORs and its 95% confidence interval under different genetic models: dominant model(G/G + A/G vs A/A), allelic model(G vs A), recessive model(G/G vs A/G + A/A), additive model(G/G vs A/A). Judging the heterogeneity by I2 and P, if the heterogeneity is slight , the fixed effect model was used. When there is obvious heterogeneity , the possible source of heterogeneity is subgroup analysis or sensitivity analysis, and heterogeneity is eliminated as far as possible. If the reason of heterogeneity is not found, random effect model is used for combined statistical analysis. The final result was statistically significant with P < 0.05.Genetic balance test was carried out for each genotype distribution in the control group. The HWE P < 0.05 was considered significant. Review Manager 5.3 statistical software was used to analyze different models of TLR4Asp299Gly polymorphism. Ethnic groups among these studies were as follows: 2 were Asians involving 478 population and 4 were Caucasians with 5425 population.The study selection process is detailed in Fig. NOS score results showed that the overall quality of the literature included in the study was high. The distribution of genotypes and alleles in the case group and the control group and the results of genetic balance were shown in Table 2 = 58%; P = 0.003, I2 = 63% respectively), but not in the recessive model and additive model . So we chose the random effects model while we analyze the dominant model and the allele model and used fixed-effects model to analyze the data of recessive model and additive model, as shown in Fig. Heterogeneity is significant among included studies in the dominant model and allelic model , p = 0.01) and allelic model , p = 0.04). However, there was no significant correlation between this gene polymorphism and DMI either using a recessive model , p = 0.16) or additive model , p = 0.14).As shown in Fig. TLR4Asp299Gly gene polymorphism increased the risk of microvascular complications in Caucasian patients with T2DM , P = 0.002; allelic model OR = 1.56, 95% CI (1.10–2.21), P = 0.01). However, we found no correlation in the Asian population , P = 0.52; allelic model OR = 0.89, 95% CI (0.56–1.39), P = 0.60), as shown in Fig. TLR4Asp299Gly gene polymorphism.Subgroup analysis was performed by different ethnic groups, we can draw the conclusion that I 1.22–2.5, P = 0.TLR4Asp299Gly genetic polymorphism increased the risk of retinopathy in T2DM under dominant model and allelic model , P = 0.03; OR = 1.77, 95% CI (1.05–2.98), P = 0.03 respectively). But no significant association was found between DN or diabetic neuropathy and this gene polymorphism , P = 0.38; allelic model OR = 0.91, 95% CI (0.50–1.64), P = 0.75; diabetic neuropathy: dominant model OR = 1.42, 95% CI (0.76–2.67), P = 0.27; allelic model OR = 1.40, 95% CI (0.80–2.44), P = 0.24), as shown in Fig. TLR4Asp299Gly polymorphism with DMI risk was shown in Table With regard to the specific type of DMI, we also conducted the subgroup analysis stratified by DR or DN or diabetic neuropathy. The results showed that  CI 1.04–.14, P = 2 = 0. We found significant changes in OR value and 95%CI, and the heterogeneity disappeared, suggesting that the heterogeneity may be caused by the excluded studies.The method of one-by-one exclusion was used to conduct sensitivity analysis, and the results showed that the combined OR value and 95% CI were not significantly affected in the whole population under the dominant model, indicating that the meta results were stable and reliable under the analysis of this model. And under the allelic model analysis one by one to eliminate are included in each of the study results show that OR value and 95% CI had essential changes after the merger, so we have to cut out the significant change in merger results in 5 cases of study , the merge OR = 0.95, 95% CI , P = 0.70, heterogeneity, P = 0.81, IFunnel plots was used to evaluate publication bias among included studies. The included studies in the funnel plots are basically symmetrical around the center line, suggesting that there was no significant publication bias among included studies, as shown in Figs. TLR4 gene polymorphism [TLR4 can alter TLR4’s recognition and interaction functions, and then, change the immune response [TLR4, Asp299Gly gene polymorphism is known to alter the extracellular domain of the receptor, resulting in hyporesponsiveness to LPS, attenuating the TLR4 signaling pathway and reducing the inflammatory response to Gram-negative pathogens [TLR4, as one of the key members of the earliest and most clearly studied Toll-like Receptors (TLRs) family, consists of extracellular domain, transmembrane domain and intracellular domain. The extracellular domain of 22 leucine-rich repeats mediates Lipopolysaccharide (LPS) recognition and receptor dimerization, while the intracellular domain is structurally similar to interleukin 1(TIR1) and plays an important role in downstream signal transduction . TLR4 ismorphism . Geneticresponse . It has response . As one athogens , 37. In athogens .TLR4 gene polymorphism is closely related to the occurrence and development of DMI [TLR4 gene polymorphisms such as rs4986791, rs1927911, rs1927914, rs10759931, are associated with DMI. What’s more, the relationship between TLR4Asp299Gly gene polymorphism and DMI is a hot topic [TLR4Asp299Gly/Thr399Ile will change the structure of TLR4 itself, leading to problems in ligand binding. This structural/functional irregularity seems ultimately to lead to a blunt immune response, such as the reduction of IgA production against microbial targets and the decrease of functional TLR4 levels [TLR4Asp299Gly gene polymorphism increased the risk of DMI under dominant model and allele model , p = 0.01; OR = 1.42, 95% CI (1.02–1.96), p = 0.04 respectively). However, we found that there was no correlation between them under the recessive model and additive model , p = 0.16; OR = 1.94, 95% CI (0.81–4.61), p = 0.14 respectively). The conclusion of Carmela, CS Aioanei and Gottfried were contradictory to our results, which may be attributed to the ethnic difference of the included population and the difference of DMI types [Several studies have shown that t of DMI –24. Multot topic –21, 23. 4 levels . The resMI types , 21, 23.TLR4Asp299Gly gene polymorphism and DN and diabetic neuropathy subgroup (p > 0.05). The studies of Buraczynska et al. [TLR4Asp299Gly gene polymorphism was significantly associated with increased risk of DR. Therefore, we can infer that although DR, DN and diabetic neuropathy were included in microvascular complications, there still exists some differences in the pathogenesis.So it is necessary to perform subgroup analysis, we found that the significant association was observed in DR subgroup under dominant model and allele model , P = 0.03; OR = 1.77, 95% CI (1.05–2.98), P = 0.03 respectively) from subgroup analysis of the difference of DMI types. Nevertheless, no significant association was observed between a et al. , Buraczya et al. , and Zaha et al.  were conTLR4Asp299Gly gene polymorphism and DMI. The results showed that TLR4Asp299Gly gene polymorphism increased the risk of retinopathy in patients with T2DM, P = 0.03; allelic model OR = 1.77, 95% CI (1.05–2.98), P = 0.03), but there was no correlation between this gene polymorphism and DN or diabetic neuropathy, P = 0.38; allelic model OR = 0.91, 95% CI (0.50–1.64), P = 0.75; diabetic neuropathy: dominant model OR = 1.42, 95% CI (0.76–2.67), P = 0.27; allelic model OR = 1.40, 95% CI (0.80–2.44), P = 0.24). Hence, we speculated that the expression of TLR4 or its ligands in retinal vessels, glomerular microvessels and neural tissues may exist tissue specificity, and TLR4/MyD88/NF-κB inflammatory response regulated by signal channels may have the greatest effect on retinal vessels. From this we can put forward a hypothesis: TLR4Asp299Gly gene polymorphism may be a susceptibility indicator of DR and the detection of this susceptibility gene can be used as a clinical diagnostic index, which may be a new target for drug therapy of DR in the future.To our knowledge, this is the first meta-analysis to investigate the relationship between TLR4Asp299Gly site is population specificity. African populations have the highest Asp299Gly mutation rates, and then Caucasians, and the probability of mutation in Asian population, especially in Chinese Han population, is very low [TLR4Asp299Gly gene polymorphism varies widely among races, we performed a subgroup analysis of different ethnic groups in terms of Caucasian and Asian populations. The results showed that TLR4Asp299Gly gene polymorphism was associated with increased risk of DMI in Caucasian patients with T2DM under dominant model and allele model , P = 0.002; allelic model OR = 1.56, 95% CI (1.10–2.21), P = 0.01). This gene polymorphism may be a risk factor for DMI in the Caucasian population. Therefore, it may be used as a target for early prevention and treatment. But in the Asian population we found no correlation , P = 0.52; allelic model OR = 0.89, 95% CI (0.56–1.39), P = 0.60). This further confirmed that there are racial differences in TLR4Asp299Gly gene polymorphism. It's worth noting that the absence of GG genotype of TLR4Asp299Gly in some studies [A number of studies have found that distribution of very low –41. The very low  found novery low . Because studies , 17, 20,2 = 0) were significantly altered under the allelic model and the heterogeneity disappeared, suggesting that the heterogeneity among the meta-included studies may be attributed to these studies which are excluded by us. At the same time, we can conclude that there was no correlation between TLR4Asp299Gly gene polymorphism and DMI in the allelic model after sensitivity analysis.Furthermore, we performed sensitivity analysis. The results showed that the corresponding OR value did not change significantly after the combination under the dominant model, which suggested that the overall results were statistically robust under this genetic model. However, the merge OR value and 95% CI , P = 0.70; heterogeneity: P = 0.81, ITLR4 gene or other susceptible genes polymorphisms and environmental factors. Secondly, some studies have shown that glycated albumin(GA) can be used as a predictor of diabetes, its microvascular complications and cardiovascular prognosis compared with fasting glucose(FPG) and glycated hemoglobin(HbA1c), and it would be more convincing if GA was detected in our meta-included studies[In order to explain the results obtained better, some limitations of this meta-analysis should not be ignored. Firstly, DMI are a complex metabolic disease with multiple genetic and environmental factors. This meta analysis does not take into account the effects of other loci of d studies, 44. ThiTLR4Asp299Gly gene polymorphism was associated with increased risk of DMI under dominant model, while no significant correlation was observed under allelic model, recessive model and additive model. TLR4Asp299Gly gene polymorphism may be considered as one of the risk factors for DMI. More importantly, our study have shown that this gene polymorphism increased the risk of DR in patients with T2DM, but not DN or diabetic neuropathy. Therefore, the detection of TLR4Asp299Gly can be used as a clinical diagnostic index and may be a new target for drug therapy of DR in the future.In conclusion, this meta analysis showed that


The potential modifiable role of diet in common psychological disorders, including depression and anxiety, has attracted growing interest. Diet may influence the occurrence of mental disorders through its inflammatory characteristics. The purpose of this meta-analysis was to explore whether dietary inflammatory potential is associated with the risk of depression and anxiety. A systematic literature search was conducted in PubMed, Web of Science, and Embase databases up to February 2021. Articles related to dietary inflammatory potential and risk of depression or anxiety were included. After the elimination of repetitive and irrelevant literature, we conducted quality assessment, publication bias, and sensitivity analysis. In total, 17 studies with a total of 157,409 participants were included in the final analysis. Compared with the lowest inflammatory diet group, the highest group was significantly associated with the incidence of depression and anxiety, with the following pooled odds ratios (ORs) and 95% confidence intervals (95% CIs): 1.45 (1.30 ~ 1.62) for depression and 1.66 (1.41 ~ 1.96) for anxiety. A subgroup analysis by gender showed that this association was more prominent in women. For depression, the increased risk was 49% in women  and 27% in men . As for anxiety, the increased risk was 80% in women  and 47% in men . As a result, long-term anti-inflammatory eating patterns may prevent depression and anxiety, whereas pro-inflammatory eating patterns may promote these conditions. People should add more fish, fish oil, fresh fruit, walnuts, and brown rice to their diet.The online version contains supplementary material available at 10.1186/s41043-022-00303-z. Mental health disorders represent a major public health concern. More than 300 million people suffer from depression worldwide, and more than 70% of people experience anxiety in their lifetimes. Psychiatric disorders impose great societal burden on developed countries . Accordiβ, IL-6, IL-10, and TNF-α, by regulating the immune system, intestinal flora, and macrophages. A diet that can raise the level of inflammation in the body is called pro-inflammatory diet, and a diet that has an opposite effect is called an anti-inflammatory diet. To understand the inflammatory potential of diet, experts have developed the Dietary Inflammation Index (DII) to assess the inflammatory capacity of diet according to the pro-inflammatory and anti-inflammatory efficacy of different dietary components [Among the modifiable factors, diet is one of the main lifestyle-related factors for mental disorders that individuals are exposed to daily. It is worth noting that experts from the International Society for Nutritional Psychiatry Research state that “diet and nutrition are the central determinants of mental health” . Recentlmponents , 8.The inconsistent findings of previous research and the lack of overview of other major mental health outcomes, such as anxiety, make it difficult to draw a reliable and universal conclusion. Therefore, the purpose of the present meta-analysis was to summarize the evidence on the association between the inflammatory potential of diet and depression or anxiety.This meta-analysis was conducted in accordance with the guidelines indicated in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocols . The PRIDepressive disorder, a mood disorder caused by multiple causes, has a variety of unique symptom combinations. This disorder is characterized by persistent low mood, loss of interest, difficulty in concentrating, sleep disturbance, and fatigue, and its severe form is characterized by functional impairment and suicidal tendency . The maiAnxiety is an unpleasant emotional experience of inner tension, fear, or anticipation of an adverse situation, and coping with it is difficult. Anxiety disorder can increase the risk of depression. The HADS is a common diagnostic tool in clinics.A systematic literature search was performed in PubMed, Web of Science, and Embase from inception to February 2021 for the identification of relevant studies. The following search terms were used:  and . Searches were limited to articles written in English. We also searched the references of related articles to obtain other potential studies. Two researchers (XLL and ZCY) searched independently with the same retrieval strategy. According to the inclusion and exclusion criteria, the included studies were screened out by eliminating duplicate studies, reading the titles and abstracts of articles, and reading full texts. Disagreements were resolved by an experienced third researcher (ZNL).The following inclusion criteria were used: (1) population: adults; (2) intervention/comparison: dietary inflammatory index or blood inflammatory markers; (3) outcomes: clinical depression or anxiety assessed by the study staff or medical records; depressive symptoms or anxiety assessed by validated scales or questionnaires, and defined according to the validated cutoffs of these scales; the use of anti-depressive drugs considered only when it was combined to clinical depression or depressive symptoms assessment; (4) Study design: observational studies . Exclusion criteria included: (1) population: non-adults; (2) intervention/comparison: not measured the inflammatory potential of the diet; (3) outcomes: any other outcome outside of the inclusion criteria; (4) study design: non-observational studies; (5) review articles, studies not published as a full article , and studies lacking sufficient data.Data and characteristics extracted from each study included: first author’s surname, year of publication, geographical location, study design, sample size, percentage of females, mean age, length of study follow-up (if applicable), diagnosis of depression or anxiety, assessment tool of dietary inflammatory potential, risk estimates, the 95% CIs from the most fully adjusted models for the association between a pro-inflammatory diet and the incidence of depression or anxiety, and adjustment factors. Since the majority of articles reported gender-specific effects, we extracted separate effect sizes for males and females.Subjects were grouped differently in the included studies according to dietary inflammatory potential. Where studies had stratified subjects into groups , the pro-inflammatory diet was defined as the highest grouping and the anti-inflammatory diet was defined as the lowest grouping. The likelihood of depression or anxiety was obtained from a combination of hazard ratio (HR), odds ratio (OR), and relative risk (RR) effects.Quality of cohort and case–control studies was assessed using the Newcastle–Ottawa Quality Assessment Scale (NOS) , and quaThe total NOS score was nine points. Studies identified as having the NOS ≥ 7 are considered high quality, whereas studies with a total NOS score < 7 are considered low quality. AHRQ includes 11 items. An item would be scored “0” if it was answered “NO” or “UNCLEAR”; if it was answered “YES,” then the item scored “1.” Article quality was assessed as follows: low quality = 0–3; moderate quality = 4–7; high quality = 8–11.In the meta-analysis, the combined OR value and 95%CI were used to evaluate the relationship between dietary inflammation and the risk of depression and anxiety . The associated effects include the OR, RR, and HR. Considering that depression with a low incidence rate, the OR, HR, and RR can be directly combined with the effect sizes and expressed as OR. The most fully adjusted HRs and RRs with their 95% CIs from individual studies were extracted and transformed into their logarithms for the stabilization of variances and normalization of distributions.2 metric to quantify the heterogeneity between studies. I2 > 50% indicated high heterogeneity, I2 = 25–50% indicated moderate heterogeneity, and I2 < 25% indicated low heterogeneity [I2 statistic > 50%, or a fixed-effects model was used otherwise. As a result of the heterogeneity of the results, the following factors were considered for subgroup analysis based on professional knowledge and previous reports in the historical studies: sex, study design, effect measure, average age at baseline, follow-up period, sample size, and diagnostic method.We used the Iogeneity . A randoP values were considered significant at a level of < 0.05.We conducted a sensitivity analysis in which the meta-analysis was repeatedly carried out after omitting each study in turn to observe the stability of the comprehensive results . The potAccording to the search strategy, 1579 studies were collected, including 695 PubMed, 729 Embase, and 155 Web of Science. After initial assessment, the remaining 736 papers were included. After reading the title and abstract, 43 articles were retained. Twenty-six publications were excluded after full-text screening for different reasons . Seventeen studies reported the effect of dietary inflammatory potential on depression disorders in 26 populations . The results of random-effects model showed that the risk of depression in pro-inflammatory diet group individuals were elevated when compared to those in anti-inflammatory diets  , as opposed to males , and studies reporting mixed sex effects were significant .We used a random-effects model to estimate the aggregate OR and 95% CI of all studies. The meta-analysis showed a positive correlation between the pro-inflammatory diet and the risk of depression and anxiety  with high heterogeneity , sample size, average age at baseline, and diagnostic methods Table . SubgrouP = 0.113) and Begg’s test (P = 0.142) were nonsignificant. The absence of publication bias was determined through funnel plot inspection , as shown in Fig. P = 0.0003), as opposed to males .The results of random-effects model showed that the risk of anxiety disorders in pro-inflammatory diet group individuals was elevated when compared to those in anti-inflammatory diets  and Begg’s test (P = 0.602) did not identify any potential publication bia. Funnel plot indicated no publication bias  can prevent mental disorders , 37. In The mechanisms by which dietary inflammatory potential correlates with the incidence of depression and anxiety are not fully clarified. Nevertheless, some studies showed that mental disorders are associated with circulating inflammation markers , 40. ProThe DII, a novel tool for dietary inflammation potential assessment exploited recently, was employed for the included studies . In 2013Despite the strengths of the current analysis, there are certain limitations that should be noted. Firstly, different measurement methods and inclusion criteria adopted in the included studies may generate heterogeneity. For example, different scales and thresholds were used for the diagnosis of depression and anxiety. Despite this, we utilized random-effects models and subgroup analyses to limit and detect such sources of variability. Further, there are only four studies on anxiety; thus, more observational studies are needed to confirm this conclusion.In addition, it shall seem plausible that dietary consumption preferences are influenced by an individual’s mental health status. Papier et al. investigated the effect of stress and selection for foods. Their results suggested that mild-to-moderate degree of stress could drive students toward three times higher consumption of processed food rather than choosing fruit and vegetables as found in unstressed students . The rolIn summary, the positive association between pro-inflammatory dietary style patterns with depression and anxiety found in this analysis can be useful in exploring strategies for the prevention and treatment of depression and anxiety. A scientific and healthy diet that includes a variety of anti-inflammatory food, such as fruit, vegetables, fish, whole grains, and olive oil, should be promoted, and pro-inflammatory food, such as red meat, processed food, and animal oils, should be avoided. Further well-designed prospective trials are needed to strengthen the evidence of the associations between the dietary inflammatory potential and mental health.Additional file1: PRISMA checklist.Additional file 2: References of studies excluded in the meta-analysis.Additional file 3: Methodological quality of the included studies.


SERPINE1 (rs1799889) is closely linked to coronary artery disease (CAD). This study aims to clarify the effects of the rs1799889 variant on lipid levels and to insight into the mechanisms underlying the rs1799889 variant and CAD.Recent studies have shown that the 4G/5G insertion/deletion variant of P = 0.01], total cholesterol (TC) , and low-density lipoprotein cholesterol (LDL-C)  levels. Intriguingly, the significant effects of the rs1799889 variant on LDL-C  and TC  levels were primarily observed in the Asian population. However, the significant effect of the rs1799889 variant on high-density lipoprotein cholesterol (HDL-C)  levels was detected only in female subjects.By searching PubMed and the Cochrane databases for studies published before 31 October 2021, 40 studies conducted on a total of 13,117 subjects were included for the analysis. The consistent findings for the effects of the 5G allele of rs1799889 variant on lipid metabolism were the significantly decreased triglycerides (TG) [standardized mean difference (SMD) = –0.12, 95% CI = –0.21 to 0.03, SERPINE1 is a protective genetic factor against CAD, the Asian population with the 5G allele of the rs1799889 variant may have a reduced CAD risk.The rs1799889 variant of  PAI-1), also known as SERPINE1, is a member of the serine protease inhibitor superfamily and plays a major role in regulating fibrinolysis by inhibiting plasminogen activity.The plasminogen activator inhibitor-1 (SERPINE1 gene is located on the long arm of human chromosome 7 (7q21.3-22). The most-studied rs1799889 variant, also known as 4G/5G insertion/deletion sequence, is located in the SERPINE1 promoter region and formed by the 5th guanine (G base) insertion or deletion in the 4G sequence at position-675th base. The 5G allele has lower transcriptional activity than the 4G allele (The some 7 7q1.3-22. TSERPINE1 knockout (SERPINE1–/–) inhibits the expression of adipogenic genes (SERPINE1–/– mice into obese mice reduces plasma triglycerides (TG) and total cholesterol (TC) levels (SERPINE1 expression decreases proprotein convertase subtilisin/kexin type 9 (PCSK9) and increases low-density lipoprotein receptor (LDLR) levels  levels . Moreove) levels . Taken t) levels .Currently, a series of meta-analyses –10 showeThe study design followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) .The literature search was carried out by using PubMed, Medline, Embase, Cochrane Library, Web of Science, Google Scholar, Foreign Medical Journal Service, and Excerpta Medica for manuscripts published before 31 October 2021, by entering the following keywords: , , , and .The inclusion criteria of this meta-analysis were as follows. (1) The studies investigated the effects of the rs1799889 variant on lipid levels. (2) The studies at least provided one of the four lipid parameters . (3) The studies provided the genotype frequencies of the rs1799889 variant. (4) The rs1799889 variant offered the mean lipid levels with standard deviation (SD) or standard error (SE) by genotypes. (5) The interventional studies provided pre-intervention data. (6) The language of eligible studies was restricted to English or Chinese. The exclusion criteria of this meta-analysis include (1) studies that were not related to the rs1799889 variant, (2) studies that were not related to lipid levels, (3) studies not presenting genotype or allele counts, (4) studies having invalid data, (5) studies having incomplete data, (6) pedigree studies (7), overlapping studies, and (8) abstract, review, case report, meta-analysis, and animal studies.Subgroup analysis was carried out by ethnicity, gender, and health status. The ethnicity was divided into Caucasian, Asian, Turkish, and other ethnics. The healthy status was divided into patients with CAD, patients with type 2 diabetes mellitus (T2DM), and healthy subjects.Refer to the previous publication  for moreBy searching the PubMed and Cochrane database, 2,598 studies were screened; after excluding duplicates, 2,386 studies were removed by their title and abstract. Then, 46 full-text studies were included for assessing eligibility, in which two studies , 14 provSERPINE1 rs1799889 variant were presented in The characteristics of the eligible studies were summarized in P = 0.01], TC , and TG  levels (The consistent findings for the effects of the rs1799889 variant on lipid metabolism were the significantly decreased LDL-C  levels –4. After] levels .P < 0.01) and TC  levels were only observed in the Asian population. Meanwhile, the significant effect of the rs1799889 variant on TG  level was only observed in the Turkish population. Moreover, a marginally significant effect of the rs1799889 variant on TG  and HDL-C [SMD = 0.14, 95% CI = –0.02 to 0.31, P = 0.09; Subgroup analysis by ethnicity showed that the significant effects of the rs1799889 variant on LDL-C  By repressing peroxisome proliferator-activated receptor γ (PPARγ) expression: PPARγ, a known adipogenic gene , plays aThis analysis indicated the 5G allele of the rs1799889 variant significantly decreased TG, TC, and LDL-C levels , 2, whenSERPINE1 potentially be the target for CAD therapy. Moreover, subgroup analysis by ethnicity showed that the significant effects of the rs1799889 variant on LDL-C and TC levels were primarily in Asians (According to the 2018 ACC/AHA , the 201n Asians , 2, indin Asians .SERPINE1 4G/5G insertion/deletion sequence on circulating lipid levels. Several strengths of the meta-analysis should be noted. For instance, all data were recalculated after excluding the studies with heterogeneity, which no doubt advances the preciseness of conclusions drawn in this manuscript. In addition, the analysis results benefit insight into the mechanism underlying the rs1799889 variant and CAD. More importantly, our data indicate that the 4G/5G insertion/deletion sequence of the SERPINE1 gene potentially be the target for CAD therapy. However, this meta-analysis did not investigate the interaction between the rs1799889 variant and environmental factors on lipid levels due to the lack of available data from the included studies.To the best of our knowledge, this is the first meta-analysis to investigate the effects of the SERPINE1 is a protective genetic factor against CAD, and the Asian population with the 5G allele of the rs1799889 variant may have a reduced CAD risk.The rs1799889 variant of The original contributions presented in this study are included in the article/ZL, BW, JW, and YL conceived and designed this study as well as drafted the manuscript and performed the statistical analyses. HL, YZ, YP, XL, and YF carried out the searches and collected the data. All authors reviewed and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.