Whether smoking is related to a decreased risk of meningioma in women is still controversial. We conducted a systematic review and meta-analysis examining the association between smoking and risk of meningiomas in women.Two authors independently performed a systematic literature review in the PubMed, Cochrane Library, and EMBASE databases. We identified case-control and cohort studies quantifying associations between smoking and risk of meningioma in women. A meta-analysis by pooling studies was performed according to the multivariate-adjusted risk estimates and 95% confidence intervals (CIs) preferentially. We further conducted additional subgroup and sensitivity analyses to explore possible explanations of the results.A total of seven observational studies were included, with a total of 2132 female patients diagnosed with meningiomas. Ever smoking was associated with a significantly reduced risk of meningioma in women, with pooled odds ratio (OR) of 0.83 (95% CI 0.70–0.98). Similar findings were noted for current  and past  smokers. However, considering the areas, the OR of ever smoking was 0.77 (95% CI 0.68–0.87) in three American studies, but 0.99 (95% CI 0.73–1.35) in four studies conducted in other countries.Based on limited epidemiological evidence, a decreased risk of meningioma in women smokers was only observed in American studies rather than studies conducted in other countries. Meningiomas are suggested to be among the most common primitive tumors of the central nervous system and account for about a third of all intracranial tumors –3. AlthoIt is now well established from a variety of studies, that smoking is associated with a wide range of tumors, including lung cancer, liver cancer, ovarian cancer, prostate cancer, and others –12. To dIt is interesting to note that women smokers in American studies tended to had a significantly decreased risk of meningioma [13 17], whereas women smokers in studies conducted in other countries showed no significantly decreased risk of meningioma [14 15 21]. Therefore, whether the association between smoking and risk of meningioma in women differs across countries is still poorly understood. To the best of our knowledge, no formal systematic review and meta-analysis based on the existing epidemiological data is available regarding the association between smoking and meningioma in women in different countries. To address this research gap, based on the updated epidemiological data, we performed a formal systematic review and meta-analysis of smoking in relation to risk of meningioma in women, with a special focus on the difference of relationship in different countries.The meta-analysis was carried out following the guidelines from the Meta-analysis of Observational Studies in Epidemiology Group . In DeceTwo literature reviewers (PZ and TC) evaluated studies independently for possible inclusion and resolved any discrepancies by discussion. The following inclusion criteria were applied: (1) used a cohort or case-control study design; (2) availability of a quantitative estimate of the associations between smoking and risk of meningiomas; (3) provided the relative risk (RR) or odds ratio (OR) with confidence intervals (CIs); (4) availability of at least one of the following smoking exposure variables: never versus ever, past, current, or passive smoking; (5) could get raw data of female population; (6) when multiple reports were based on the same target population, the most informative one was included in this meta-analysis.Titles and/or abstracts of reviews were screened independently by two reviewers to identify publications that potentially meet the inclusion criteria outlined above. No study will be excluded a priori for the weakness of design or data quality. The full texts of all the retained original articles were retrieved. A standardized form was used to extract data from each identified publication. Relevant information included: study name; authors; country; period of publication; gender; sample sizes ; study design; variables of adjustment; availability of data on smoking; risk estimates (RRs or ORs) and their corresponding 95% CIs.X2-based Q statistical test and the I2 test. Heterogeneity was considered significant when I2 > 50% and P < 0.1. When no heterogeneity was presented, the results from single comparisons were combined using a fixed-effect model with the Mantel-Haenszel method. Otherwise, the random-effect model with the DerSimonian-Laird method was applied for pooling.All statistical analyses were used by STATA 12 . The multivariate-adjusted risk estimates and 95% CIs were used to estimate the pooled risk of smoking in meningioma development. For case-control studies, the OR was used as estimates of the RR because meningioma is sufficiently rare. When cohort studies reported only crude data and no information on person-years, we treated it as a control study using noncases as controls. The potential heterogeneity between publications was assessed by P < 0.05 was considered indicative of significant publication bias. All P values were two-sided.For the reason that the characteristics of target populations, study location, study designs, assessments of smoking, and adjustments for confounding factors were not consistent among studies, we further conducted additional subgroup and sensitivity analyses to explore possible explanations of heterogeneity and to assess the potential impact modification of these variables on outcomes. We also analyzed the effect of a single study on the overall risk estimate by omitting one study in each turn. Due to rather small numbers of studies for other outcomes, the sensitivity analysis was performed only for “ever versus never smoking”. The presence of publication bias will be assessed by applying the tests proposed by Begg’s and Egger’s tests. n=768), EMBASE (n=1710), and Cochrane Library databases (n=0). Most of these articles were not focused on the topic, and were no longer considered, whereas 34 unique publications were selected for full-text review. A total of 21 articles were excluded because of not present raw data for OR/RR (n=4), article type with review or case report (n=2), not availability of smoking exposure (n=2), and no quantitative estimating of association between smoking and risk of meningioma (n=13). Then, 13 publications were retained for the review. One article [Figure  article  was exclEMBASE n=10, and C article , 24–26.  article –17, 21.Table P for heterogeneity, 0.362). Among four studies conducted in other countries, the pooled OR was 0.99 . Overall, the OR was 0.83 .Figure P for heterogeneity, 0.229) for total studies  for total studies .Table Sensitivity analyses showed that the exclusion of five single studies could materially alter the overall combined risk estimate, with a narrow range from 0.83 (95% CI: 0.66–1.04) to 0.86 (95% CI: 0.73–1.02). However, exclusion of a single study  conducteP=0.565) and Begg’s (P= 0.368) tests confirmed no evidence of publication bias.Figure In the present meta-analysis, we reviewed and summarized the extensive but controversial evidence on the association between smoking and meningioma in women. We found that ever smoking was associated with a significantly reduced risk of meningioma in women. Similar findings were noted for current and past smokers. Importantly, a decreased risk of meningioma in women smokers was only observed in American studies rather than studies conducted in other countries according to the results of subgroup analyses. However, these findings were based on limited epidemiological evidence, including seven studies with 2132 female meningioma cases that provided risk estimates for smoking.The possible role of smoking in the development of meningioma in women is still unclear. It is widely recognized that meningioma is a hormone-sensitive tumor at a population level, with approximately 30% of meningioma expressing estrogen receptors and approximately 70% expressing progesterone receptors . An assoOur results are in accord with a previous meta-analysis which indicated that a statistically significant negative association between ever smoking and meningioma in women is found . HoweverDespite the intriguing findings of our study, several important limitations should be considered. Firstly, the major limitation of this study is the small number of studies: only seven studies were included in our meta-analysis of meningioma risk associated with ever versus never smoking. Meanwhile, only three studies were included to analyze the association between past or current smoking and risk of meningioma in women. Secondly, meningiomas are rare and most patients are asymptomatic, making it difficult to get high-quality information in epidemiological research. In our study, only one prospective cohort study was included, and most of the information on this topic came from case-control studies, which may be affected by various sources of bias. Furthermore, as the current studies use different assessment instruments (interview or mailed questionnaires) to assess the participants’ smoking status, the possibility of mis-reporting of cigarette smoking by study participants may exist. With different methods, the study participants may have different attitudes, which could affect the accuracy of the data collection. However, subgroup analyses based on the different study design and the different assessment instruments got consistent results. Thirdly, considering the multivariate adjusted OR values reported in the literature are the most precise risk estimates, these values were used in our meta-analysis preferably. However, not all included studies in this meta-analysis reported the multivariate adjusted OR. In fact, the variables of adjustment in current studies are inconsistent. Unfortunately, when the data were restricted to studies that reported adjusted OR, it resulted in a null association between the two. Therefore, evidence for an apparent protective effect of ever smoking on risk for meningioma in women is still weak.In conclusion, based on limited epidemiological evidence, ever smoking (including past or current smoking) is related to a decreased risk of meningioma in women. Importantly, a decreased risk of meningioma in women smokers was only observed in American studies rather than studies conducted in other countries according to the results of subgroup analyses. Thus, we infer that smoking behaviors differ across socioeconomic development levels and race may be the explanations of the inconsistent results in different studies. However, the evidence for this protective effect of smoking on risk for meningioma in women is still weak, particularly when the data are restricted to studies reported adjusted OR, which resulted in a null association between the two. Therefore, there remains a need for further prospective cohort studies including adequate numbers of cases that can more clearly evaluate the temporal relationship between smoking and risk of meningioma in women.


Introduction: The neuropeptide-Y (NPY) is involved in the development of alcoholism through NPY receptors. A T>C mutation causes substitution of leucine to proline at codon 7  in the signal peptide of neuropeptide Y is known to cause a 42% increase in plasma NPY levels. Studies that analyzed the association between NPY rs16139 and alcoholism risk did not demonstrate conclusive evidence for this relationship. The present study aims to evaluate the association between NPY gene rs16139 variant and alcohol dependence.Method: An electronic search of databases including PubMed and Google Scholar was performed to retrieve studies investigating the association between NPY rs16139 and alcoholism. The pooled odds ratio (OR) with 95% confidence interval (CI) was calculated in allelic and dominant genetic models. Sensitivity analyses and publication bias were assessed in our meta-analysis. The meta-analysis was conducted using the MetaGenyo web tool.Result: Significant heterogeneity was observed across studies (p < 0.001). Our results have shown that there is no significant association between NPY rs16139 variant and the risk of alcoholism in allelic  and dominant models . Begg's funnel plot and Egger's test have not shown publication bias (p = 0.332).Conclusion: To the best of our knowledge, this is the first meta-analysis that evaluates the relationship between the NPY rs16139 polymorphism and the risk of alcoholism. Our large-scale meta-analysis suggests that NPY rs16139 polymorphism is not associated with alcoholism. However, further studies are needed to increase our understanding of the relationship between NPY variants in alcoholism. ADH1B, ALDH2, CHRM2, DRD2, GABRA2, OPRM1, NPY, and SLC10A2 are associated with alcoholism  , 9. The NPY gene variant and alcoholism has been demonstrated in large cohorts of alcohol users and veterans  Studies having rs16139 genotypes for estimating the odds ratio. Studies with no specific control group and no detailed genotyping data for calculating odds ratios and 95% confidence intervals have been excluded. From each paper, first author, year of publication, country, genotypes from both alcoholism and control groups were extracted and tabulated  and 95% confidence intervals (CI) limits. As the homozygous mutant allele is rare and not present in all studies, only the allelic and dominant effects were analyzed. Overall Pooled effects and 95% confidence intervals were estimated and presented as a forest plot. To know each study's influence on the overall effect size, sensitivity analysis was conducted using a “leave-one-out” meta-analysis. It estimated the ORs for the remaining studies. A Begg's funnel plot and an Egger's regression test were used to assessing potential publication bias. For conducting the meta-analysis and constructing all plots, MetaGenyo web tool software was used .heterogeneity = 0.003, I2 = 63%; dominant model: PHeterogeneity = 0.003, I2 = 62.5%). Hence, a random-effects model was used for the pooled analysis.The search criteria and study selection process is depicted in NPY rs16139 variant and the risk of alcoholism, 11 studies were included in the pooled analysis. Our results have shown that there is no significant association between the risk of alcoholism and NPY rs16139 variant in allelic  and dominant models  (In order to find the association between = 0.919) .NPY rs16139 variant, the shape of Begg's funnel plot did not reveal any evidence of publication bias (p = 0.332).Sensitivity analysis was conducted to identify the effect of each study on pooled estimates. Sensitivity analysis did not reveal any qualitative changes in pooled ORs, indicating that the results of this meta-analysis are robust . For NPYion bias . In addiThe present study found no significant relation between NPY rs16139 variant and alcoholism in either allelic or dominant models. Although there is significant heterogeneity across studies, sensitivity analysis showed that the results of this meta-analysis are robust. Furthermore, there is no evidence of publication bias.NPY Pro7 variant in regulating human alcohol consumption has been found in Eastern Finland, where individuals with the Pro7 variant showed >34% mean alcohol intake compared to the controls  , 42. LatDespite considering some limitations, Accumulating evidence of the NPY system may offer an attractive target for developing novel therapies for alcohol dependence. However, the present meta-analysis suggests that NPY rs16139 polymorphism is not associated with alcoholism. To the best of our knowledge, this is the first meta-analysis to examine the link between the NPY rs16139 and the risk of alcoholism. For the precise results, further studies with large-scale animal and human models are needed to increase our understanding of the relationship between NPY variants in alcoholism.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.BC, MY, WY, and LB contributed to conception and design of manuscript. MY and MM searched, screened the articles and extracted data. MY and LS performed the data-analyses. BC, HV, and LB provided additional suggestions and assisted in the interpretation of data. BC and MY drafted the manuscript. WY and LB critically revised the manuscript. All authors contributed to the article and approved the submitted version.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.


Sarcomas are a rare and heterogeneous group of tumors originating from mesenchymal or connective tissue. They represent less than 1% of all adult cancers. The etiology and epidemiology of sarcomas remain understudied and poorly understood. The main objective of our study was to systematically assess the association between various occupational exposures and risk of sarcomas.We performed a systematic literature search using the PubMed, Scopus, EMBASE and Cochrane databases to identify relevant cohort and case–control studies. A meta-analysis method was applied on the incidence and mortality outcomes where the estimate with 95% confidence interval (CI) was obtained.We included a total of 50 publications in our systematic review and 35 in meta-analysis. For exposures to phenoxy herbicides and chlorophenols, the pooled odds ratio (OR) for sarcoma was 1.85 , based on 16 studies with 2254 participants, while the pooled standardized mortality ratio was 40.93 , based on 4 cohort studies with 59,289 participants. For exposure to vinyl chloride monomers the pooled risk ratios for angiosarcoma of the liver and other STS were 19.23  and 2.23  respectively based on 3 cohort studies with 12,816 participants. Exposure to dioxins was associated with an increased STS mortality; the pooled standardized mortality ratio was 2.56  based on 4 cohort studies with 30,797 participants. Finally, woodworking occupation was associated with an increased risk of STS with the pooled OR of 2.16 .Our findings suggest a positive association between higher exposure to dioxins and increased mortality from STS, between cumulative exposure to vinyl chloride monomers and increased mortality from angiosarcoma of the liver and STS, and between woodworking occupation and STS incidence. These findings were all statistically significant.The online version contains supplementary material available at 10.1186/s13643-021-01769-4. Sarcomas constitute a rare and heterogeneous group of tumors with over 70 different subtypes, originating from connective and mesenchymal tissue. They represent less than 1% of all adult cancers .Exposures to pesticides are amongst one of the most extensively studied exposures in epidemiological studies. Considerable attention has been focused on potential health effects of agricultural and non-agricultural exposures to phenoxy herbicides and chlorophenols as excess incidence and mortality for some specific cancers, including soft tissue sarcomas (STS), has been observed in exposed workers. The association between these compounds and STS was first reported in the Swedish observational study by Hardell et al. in 1977 . The assSince 1969, some of the herbicides including 2,4,5-trichlorophenoxyacetic acid  were banned in Europe and the United States (US) due to contamination by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [STS is one of the few specific tumors linked to dioxins. TCDD, which is considered as the most potent dioxin, is classified as a group 1 carcinogen by the IARC. This is based on sufficient evidence in experimental animals and limited evidence in humans . While tVinyl chloride monomer (VCM) is another compound studied in relation to angiosarcoma of the liver (ASL) and other soft-tissue sarcomas. The first reports on cases of ASL among workers occupationally exposed to VCM appeared in 1974 –16. The Various occupational exposures have been studied to examine sarcoma incidence and mortality with inconsistent results. We aimed to include new epidemiological evidence in our systematic review and meta-analysis. The objective of this study is to explore the incidence and mortality of sarcomas in adult population with various occupational exposures.We conducted a systematic literature search using the PubMed, Scopus, Embase, and Cochrane databases, as well as using backward citation tracking, to search for all reports of cohort or case–control studies that provided data on the risk of sarcoma in relation to occupational factors published up to May 2021. The literature review and meta-analysis was carried out and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) recommendations  Supplem. The sysThe literature search was developed by two medical research librarians (GA and DG). In order to identify relevant studies, we used terms that combined various occupational exposure types with outcomes of interest—incidence and mortality of sarcomas. The full search strategy is available in supplementary table After removal of duplicates, two authors (DE and AV) independently identified studies eligible for inclusion based on an initial screen of reference titles and abstracts. The inclusion and exclusion criteria for this review are provided in Table Two authors (DE and AV) independently extracted data using a standardized form. The publications that met the inclusion criteria were abstracted onto tables, separately for cohort and case–control studies. The data included author, year of publication, country, time period covered, exposure duration, exposure type, description of study and reference groups, outcome of interest, and risk estimates for relevant outcomes. The effect estimates that were abstracted were odds ratio (OR), risk ratio (RR), standardized incidence ratio (SIR) or standardized mortality ratio (SMR) estimates, and their 95% confidence intervals. Studies that did not report the later were excluded, and no crude numbers were abstracted to compute effect estimates. For cohort studies, risk estimates took the form of standardized mortality or risk ratios. For case–control studies, risk estimates were presented as odds ratios. The quality of case–control and cohort studies was assessed using the Newcastle–Ottawa Scale . CofoundQ statistic) and I2 statistic, which represents the amount of variability in the meta-analysis attributed to study heterogeneity [I2 of < 25% was considered as low-level heterogeneity and 25 to 50% as moderate level. P ≤ 0.10 and/or I2 > 50% indicated significant heterogeneity [We used Microsoft Excel for data abstraction. The primary meta-analyses were conducted to assess the association between various occupational exposures and sarcoma incidence and mortality. Pooled effect estimates of ORs, RRs, SIRs or SMRs, and 95% CI were calculated using a random-effects model. Forest plots were generated, displaying the individual study effects and the pooled estimate effect. Heterogeneity between individual studies was assessed by the chi-square test  confirmed the earlier findings of an increase of the same magnitude in the risk for STS after exposure to phenoxy herbicides and chlorophenols. The third Swedish study [The earlier study conducted in 1979 by Hardell et al. in Northern Sweden demonstrated a six-fold increased risk of STS with exposure to phenoxy herbicides . A southsh study  also conStudies from New Zealand  and AustIn contrast, the results of the largest US population-based study  that included 295 male STS cases from eight population-based cancer registries supported the hypothesis of an association of sarcoma with exposure of chlorophenols in cutting oils and wood preservation . The finAs for Agent Orange, in a hospital-based study, Kang et al. concluded that there was no significant association of STS and previous military service in Vietnam . Howevern = 331), Wiklund et al. reported no increased risk of STS [In a cohort study of workers in manufacture of phenoxy herbicides in Denmark, findings of Lynge et al. supported the earlier Swedish observations of an excess risk of STS following exposure to herbicides . In contk of STS . The fink of STS  and Swedk of STS , presentk of STS . Similark of STS .Increased mortality from STS was on the border of statistical significance among workers at a plant in Alabama manufacturing agricultural and other chemicals, based on small numbers (n = 3) . SimilarIn a large international cohort of chemical workers from ten courtiers in manufacturing agricultural and other chemicals, set up by the IARC, Saracci et al. found a six-fold excess of STS in the cohort as a whole and a nine-fold excess among sprayers 10–19 years from first exposure .We included 4 cohort studies that provided data on occupational exposures to dioxins –54. The The largest study was a historical cohort of 21,863 male and female workers from 12 countries coordinated by the IARC and followed for 70 years . In thisWe included 5 cohort studies –59 obserThe European multicenter study   was an eMundt et al. aimed to evaluate exposure–response relationships for mortality from ASL and hepatocellular carcinoma (HCC) in the North American cohort mortality data for men engaged in the manufacture of VC or PVC resin at any of 35 factories in the US . The assCollins et al. reported 15 cases of ASL in the most recent update of the Dow chemical company diseases registry for ASL . ThirteeWe included 6 cohort studies –71 and 1Zahm et al. demonstrated an association between woodworking occupations and increasing risk of STS in a population-based case–control study in Kansas. Hoar etIn a large historical cohort of Danish paper mill workers, Rix et al. found an increased risk of STS female workers with a high risk among paper sorters employed in manual sorting and packing . AnotherIn a large case–control study from six Canadian provinces, Hossain et al. found an increased risk for STS associated with an exposure to radium, longest-held job as a machinist, short-term job as chicken farm worker, pulp and paper industry worker, and apartment complex worker .A large population-based study from the US reported by Hoppin et al. demonstrated excess risk of different sarcoma subtypes from various occupational exposures . In thisIn a case–control study from Sweden, Wingren et al. demonstrated that gardeners, railroad workers, unspecified chemical workers, workers in contact with wood, and construction workers with exposure to asbestos and pressure impregnating agents had an increased risk of STS . In a caP = 0.008, indicating significant positive association between exposure to phenoxy herbicides and chlorophenols and incidence of sarcoma. There was significant heterogeneity across the individual studies I2 = 79.0%, P ≤ 0.001.We conducted a meta-analysis of 16 case–control studies, involving 2254 sarcoma cases and 24,148 con1trols , d et al. and Wiklud et al. , that shP = 0.010, indicating no association between exposure to phenoxy herbicides sarcoma incidence , P ≤ 0.001, indicating a statistically significant positive association between exposure to dioxins and STS mortality. There was no evidence of heterogeneity across the included studies, I2 0.0%.A meta-analysis of 4 cohort studies involving 30,797 participants evaluated the association between exposure to dioxins and STS mortality Fig. . There wP = 0.010), indicating a statistically significant positive association between exposure to VCM and ASL mortality (Fig. I2 = 94.4%, P ≤ 0.001.We conducted a meta-analysis of 3 cohort studies, including 12,816 participants. There were 110 deaths from STS in these studies. The RR of ASL was increased in all studies included in meta-analysis. The pooled RR was 19.23 (95% CI 2.03, 182.46, ity Fig. . There wP < 0.001, indicating statistically significant positive association between VCM exposure and STS. The study results were adequately similar, as I2 = 0.0%.Excess death due to connective and soft tissue cancer was observed and was strongest amongst highly exposed workers in tree cohort studies including 12,816 participants (Fig. With regard to other occupational exposures, population-based studies reported increased sarcoma incidence with exposure to insecticides used on animals, benzene, radium, cutting oil, and wood dust, in female paper sorters, gardeners, railroad workers, farmers, farm managers, long-term jobs as a machinist, short-term jobs as chicken farm workers, temporary jobs at apartment complexes, pulp and paper industry workers, meatpacking and woodworking occupations, and sulfite mill and nuclear facility workers.P < 0.001, indicating a statistically significant positive association. There was no significant heterogeneity across the studies, I2 = 0.0%.Meta-analysis of 4 case–control studies with 8593 participants assessed the association between STS incidence and occupational exposure to woodworking and wood dust (Fig. Our systematic review and meta-analysis included a comprehensive review of the PubMed, Scopus, EMBASE, and Cochrane databases, allowing for a considerable amount of data collection. This is the largest study to date that evaluates the association between various occupational exposures and sarcoma incidence and mortality. Our study has multiple strengths. We have included studies from various geographical areas from several countries that add to the generalizability of our results. A broad mix of studies was analyzed, including different populations and a wide variety of occupational exposures. The total amount of participants was large and different study designs were included. Many studies confirmed their sarcoma diagnosis with review of histology, and long time for follow-up was preferred. The majority of included studies were rated between moderate and high quality of evidence (supplementary table However, there were several limitations noted both in case–control and cohort studies that contributed to the inconsistency of outcomes across the studies. We believe this inconsistency is most likely due to limitations faced with study design based on questionnaires that are prone to recall bias, among other biases including measurement bias from lack of accurate exposure levels among the different studies. These limitations were specifically noted in regard to exposures to phenoxy herbicides and chlorophenols. A number of studies have been limited by inadequate exposure information and difficulties in determining type, duration, and level of exposure in different jobs and different countries. The studies, in general, also lacked information on specific individual exposure level, on the proportion of exposed workers, or extent of exposure , 40, 43.Other possible reasons for a lack of consistency between the results may be differences between the study populations with respect to other uncontrolled confounding factors such as environmental conditions, lifestyle, and inherited factors. Main confounding factors considered in these studies were age and sex. Many studies excluded female workers due to small numbers and rarity of involvement in highly exposed occupations. Therefore, subgroup analysis based on gender was not performed due to population selection bias.A number of cohort studies reported a limited statistical power and wide confidence interval, owing to the small number of sarcoma cases and low response rate , 54. In Another challenge across many studies was reliable and complete ascertainment of the cancers of main interest. Survival rates for sarcoma could be relatively high , meaningWith regard to VCM exposure, the included studies differed in design, size, length of follow-up, and covered time periods. Almost all studies concluded that the risk of malignant liver neoplasms, particularly ASL, was increased by exposure to VCM. However, the actual mechanisms of action of inducing ASL by VCM are unclear. The studies reported the highest incidence of ASL in workers of VCM production and polymerization. Some of the later observations report a dramatic decline in ASL cases from the late 1970s as a result of much stricter regulations implemented in North America and Western European countries to reduce VCM exposure. Most studies were unable to provide direct measurement of exposure to VCM and quantitative VCM exposure measure or analysis of liver cancer subtypes. The European multicenter study was the only study that provided a quantitative estimate of VCM exposure based on calendar-period-specific exposure, job, and plant. Some studies also noted difficulties in assessment of VCM as a cause of ASL or other STS because of lack of histological or other definitive clinical information to discriminate HCC from ASL. In most studies, the cause of death was obtained from death certificates that often incorrectly stated specific cause from liver cancer death and could have underestimated the number of cases of ASL and thus enabling misclassification bias. Only some studies provided SMR or SIR for ASL due to the rarity of the disease in the general population.The results of our meta-analysis indicate that higher exposure to dioxins was associated with STS. However, the results were based on small number of STS due to rarity of sarcomas. Overall, included studies were good quality, with a large number of participants, long follow-up, and no significant heterogeneity across the included studies, which strengthen the validity of our findings.Various other agricultural or non-agricultural exposures have been found to be associated with an increased risk of bone or soft-tissue sarcomas. However, due to limited number of studies, we were unable to conduct quantitative analysis for these occupations or exposures.Overall, our findings from the meta-analysis suggest a statistically significant positive association between higher exposure to dioxins and increased mortality from STS, between cumulative exposure to VCM and increased mortality from ASL and other sarcomas in organs other than the liver, and between woodworking occupation and exposure to wood dust and sarcoma incidence. Notwithstanding the high heterogeneity of the studies, workers exposed to phenoxy herbicides and chlorophenols may experience an increased incidence of sarcoma based on meta-analysis of case–control studies. Meta-analysis of cohort studies for exposure to chlorophenols and phenoxy herbicides, however, produced conflicting results.Conducting new large case–control studies using better characterizations of exposure and extending follow-up of previously assembled cohort studies would be effective ways at reducing uncertainties and could provide more evidence on other risk factors reported in our study.Additional file 1. Supplementary tables.


The mean age of the patients and the follow-up period were 64.15 ± 16.09 years and 8.9 years, respectively. Included studies were of moderate to high quality. The pooled estimate revealed a significantly higher risk of dementia in AKI patients with an overall relative risk/risk ratio (RR) of 1.92 (95% CI: 1.52–2.43), p ≤ 0.00001. Dementia risk increases by 10% with one year increase in age with an RR of 1.10 (95% CI: 1.09–1.11), p < 0.00001. Subgroup analysis based on stroke as a co-morbid condition also revealed significantly higher dementia risk in AKI patients (RR 2.30 (95% CI: 1.62–3.28), p = 0.009). All-cause mortality risk was also significantly higher in AKI patients with dementia with a pooled RR of 2.11 (95% CI: 1.20–3.70), p = 0.009. The strength of the evidence was of very low certainty as per the GRADE assessment. Patients with AKI have a higher risk of dementia. Further large epidemiological studies are needed to confirm the mechanistic association.Acute kidney injury (AKI) is associated with several adverse outcomes, including new or progressive chronic kidney disease, end-stage kidney disease, and mortality. Epidemiological studies have reported an association between AKI and dementia as a long-term adverse outcome. This meta-analysis was aimed to understand the association between AKI and dementia risk. A literature search was performed in MEDLINE and Embase databases, from inception to July 2021, to identify epidemiological studies reporting the association between AKI and dementia risk. Title and abstract followed by the full-text of retrieved articles were screened, data were extracted, and quality was assessed, using the Newcastle–Ottawa scale by two investigators independently. The primary outcome was to compute the pooled risk of dementia in AKI patients. Subgroup analysis was also performed based on age and co-morbidities. Certainty of evidence was assessed using the GRADE approach. Statistical analysis was performed using Review Manager 5.4 software. Four studies (cohort ( Acute kidney injury (AKI) is a complex disorder characterized by an abrupt decline in kidney function over a short period of time . AKI is Studies have reported that chronic kidney conditions such as CKD and ESKD are associated with accelerated cardiovascular events and share common risk factors with dementia ,17,18,19Although the long-term neurological effects of AKI are unclear, these factors may predispose patients with AKI to an increased risk of developing dementia, as observed in a few recent studies ,25. AlthThe preliminary search of existing systematic reviews or meta-analysis was performed on July 2021 in Epistemonikos, PROSPERO, Open Science Framework, Cochrane Library, and JBI Evidence Synthesis, and no reviews evaluating the association of acute kidney injury with the risk of dementia were identified. Hence, we conducted a meta-analysis of existing evidence from primary epidemiological studies that compared the risk of dementia in patients with AKI versus individuals without AKI.The present meta-analysis followed the preferred reporting items for systematic review and meta-analysis (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines ,27. RefeA three-step search strategy was utilized to locate both published and unpublished studies. An initial, limited search was undertaken in MEDLINE (Ovid) using keywords and index terms related to AKI and dementia. An analysis of the text words in the title and abstract as well as the index terms used to describe the articles were followed. A second search using all identified keywords and index terms was conducted in MEDLINE (Ovid) and Embase (Ovid) databases (the search period was from inception to 14 July 2021). Thirdly, the reference lists of all studies that met the inclusion criteria were checked manually for additional records. Lastly, abstract booklets of major international nephrology and neurology congress—World Congress of Nephrology, American Society of Nephrology, European Renal Association–European Dialysis and Transplant Association (ERA-EDTA), Asian Pacific Congress of Nephrology, Neuroscience, Alzheimer’s Association International Conference (AAIC), and American Academy of Neurology—from the last two years were also searched. Citation tracking was also performed for all the articles qualified for inclusion. The search strategy used in this study is available in Studies that are eligible for inclusion into the meta-analysis must be observational analytical studies  that assessed the risk of dementia in the AKI population compared to the risk of dementia in the population without AKI. Primary studies including individuals with AKI with dementia at the entry of the cohort were excluded from the analysis. Eligible studies must report relative risk/risk ratio (RR), hazard ratio (HR), or odds ratio (OR) with 95% confidence intervals (CI) or must provide enough raw data to calculate those ratios. In the case of insufficient information, primary study authors were contacted.www.covidence.org, accessed on 20 September 2021) by two investigators (S.H. and A.S.) independently, firstly by title/abstract screening and secondly by full-text screening. Studies excluded from full-text screening are available in The studies retrieved from the database search were evaluated against eligibility for inclusion using the Covidence software , ensuring the accuracy of the data extracted. The extracted data for all studies were then cross-checked by the third investigator (M.K.) for any data discrepancies which were resolved by referring to the primary source.We used Newcastle–Ottawa (NOS) quality assessment scale to evaluate the quality of the included studies. Two reviewers assessed the quality of eligible studies independently. The NOS is a standard quality assessment tool used to evaluate the quality of the observational study on the basis of three domains: (1) the recruitment of the cases and controls, (2) the comparability between cases and controls, and (3) the ascertainment of the key outcomes of interest . Based oThe Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool was used to assess the certainty or quality of the evidence . The GRAWe used Cochrane’s  Review Manager 5.4 data analysis software to perform the meta-analysis. The dementia events in AKI patients are considered as rare; therefore, odds ratio, RR, and hazard ratio were used interchangeably. For simplicity, RR was used for all these measures . We usedConsidering the high probability of between-study variance due to distinction in populations and techniques used to diagnose AKI and dementia, the random-effect model was picked over the fixed-effect model. We used the Cochran’s Q test, complemented with the I2 statistic, to evaluate the between-study statistical heterogeneity . The I2 Of 976 citations retrieved, four articles ,25,36,37n = 2), China (n = 1), and the USA (n = 1) and published between 2017 and 2020. There were two studies from Taiwan [—an organization that covers patients from the Utah and Idaho region. AKI was ascertained based on the International Classification of Diseases (ICD) 9th edition codes, procedure codes, and definitions outlined in KDIGO guidelines, while dementia was confirmed using ICD-9 codes and clinical modification codes in all the included studies . However, the inherent bias of observational studies design should be considered while interpreting the result. Refer to The evidence on the association between AKI and risk of dementia was of very low certainty as per the GRADE rating system. Certainty assessment ratings and the summary of findings are presented in p ≤ 0.00001 ,  0.00001 .p < 0.00001 . Dementia risk increases 10% with one year increase in age with an RR of 1.10 (95% CI: 1.09–1.11),  0.00001 .p ≤ 0.00001).Subgroup analysis based on stroke as a co-morbidity revealed significantly higher dementia risk  in AKI pp = 0.009. Only one study analyzed and reported a higher dementia risk with a hazard ratio of 2.01 (95% CI: 1.19–3.39), p = 0.01 in AKI patients who survived at least 90 days after recovery from acute dialysis.All-cause mortality risk was also significantly higher  in AKI pThere was no evidence of change in significance level of effect size as confirmed through sensitivity analysis by omitting each study one by one (leave-one-out) from the pooled analysis. Refer to This is the first meta-analysis to investigate the association of AKI with dementia risk. A significantly higher dementia risk was observed in patients with AKI as compared to patients without AKI in an adjusted analysis . Sensitivity analysis also revealed a consistently higher risk of dementia in AKI patients. All-cause mortality risk was higher in AKI patients who developed dementia.CKD is a common risk factor for the development of dementia, and CKD following AKI might be responsible for the development of dementia. AKI increases the risk of developing new or progressive CKD (HR: 2.67) and ESKD (HR: 4.67) . The stuCognitive impairment is a well-recognized complication of CKD . EvidencAge is also a potential risk factor for the development of dementia, as we have observed in our meta-analysis that the risk of dementia increases 10% with one year increase in age. Kao et al. , in the The strength of the current study includes a literature search in major databases, an extensive search of major nephrology and neurology conference proceedings, and citation tracking of all the included articles. The majority of the included studies were of high-quality with a large sample size and use of the GRADE approach to rate the certainty of evidence. Pooled analysis was based on data adjusted for several possible confounding factors, which strengthen the conclusion. Furthermore, subgroup and sensitivity analysis also confirm the higher dementia risk.This meta-analysis has few limitations, such as a diagnosis of AKI based on ICD-9 codes in the majority of the included studies, and dementia was also identified based on ICD-9 codes. Classification of disease based on ICD-9 codes may lead to misdiagnosis as the included studies collected data retrospectively. Preexisting cognitive impairment was not ruled out at the baseline of the study in two of the included studies and might have imparted influence on the overall results; however, a higher risk of developing dementia risk was consistent in the sensitivity analysis. We noticed significantly high heterogeneity among the included studies. In order to explore the heterogeneity, a random effect model was chosen, and findings from subgroup analysis were reported separately. Lastly, retrospective studies are typically a source of inherent bias, which decreased the certainty of the evidence.Overall, this meta-analysis showed a higher dementia risk in AKI patients. Future studies should look to establish the mechanistic association of AKI with dementia and stratification of dementia risk as per AKI stages. Furthermore, future, large prospective studies should adjust the findings for potential clinical  and other associated covariates.In conclusion, this meta-analysis demonstrated a significantly higher risk of dementia among patients with AKI compared with individuals without AKI. The strength of evidence was of very low certainty as per the GRADE assessment. Further large epidemiological studies are needed to confirm the mechanistic association. We recommend close monitoring of patients for dementia after AKI to curtail morbidity.


The CXC chemokines belong to a unique family of cytokines that participates in the progression and development of many malignant tumors. Evidence for the relationship between chemokine (C-X-C motif) receptor 2 (CXCR2) C1208T polymorphism and susceptibility to cancer remains inconsistent.  Odds ratios (ORs), 95% confidence intervals (CIs), and combined analysis were used to investigate the effect of CXCR2 variation on cancer risk. Gene Set Enrichment Analysis (GSEA) and enzyme-linked immunosorbent assay (ELISA) were also used to evaluate the expression of CXCR2 in prostate cancer (PCA). P = 0.025). Individuals carrying the TT genotype had a 39% higher risk of urinary cancer than those carrying CC genotype . Individuals with a TT genotype showed a 56% augmented breast cancer risk, compared to those with a CC genotype . It was found that CXCR2 expression was downregulated in PCA. Compared with PCA subjects carrying the CC genotype, the expression of CXCR2 was decreased in patients with the TT genotype.  Across 11 case-control studies, 4,909 cases and 5,884 controls were involved in the current analysis. Individuals with a TT genotype were associated with increased risk of digestive cancer, compared to those with a TC+CC genotype (OR = 1.16, 95%CI = 1.02-1.31,  The CXCR2 C1208T variation was associated with elevated risk of urinary, breast, and digestive cancer. However, the C1208T polymorphism was correlated with attenuated risk of lung cancer. Cancer continues to be a major public health problem all over the world . The incChemokines are a large class of structurally related small protein molecules that play an important role in cell recruitment and migration , 8. PrevPrevious studies have shown that genetic variants of CXCR2 may affect the development of cancer by regulating tumor angiogenesis and the antitumor immune response pathway , 25. An We conducted an online database search based on Embase, The National Library of Medicine (NLM), Chinese Wanfang, and Google Scholar. The keywords were (‘+1235C/T' OR ‘C1208T' OR ‘CXCR2' OR ‘Chemokine C-X-C motif receptor 2') AND (‘cancer' OR ‘carcinoma') AND (‘polymorphism' OR ‘variant' OR ‘mutant'). The last search update was on May 31, 2021. To increase the number of selected publications, we also retrieved studies by examining the references in published articles.A suitable study was included in our analysis when it met all of the following criteria: (a) case-control studies focused on the relationship between the CXCR2 C1208T polymorphism and susceptibility to cancer, (b) studies containing essential genotype information for calculating ORs, (c) control group must be consistent with Hardy-Weinberg equilibrium (HWE) balance, and (d) manuscripts written in English or Chinese. The exclusion criteria were as follows: (a) data for the control group was not available, (b) not enough data to measure the odds ratios (ORs), and/or (c) no relevance to the CXCR2 C1208T polymorphism and risk of cancer.Study characteristics were as follows: name of the author, publication year, origin, cancer type, race of population, control source, genetic distribution of CXCR2 variant, sample size of case and control, HWE, and age range of the case and control groups. In the subgroup analysis, PCA and bladder cancer (BLCA) were classified as the urinary cancer group. The digestive system cancer included gastric, esophageal, colon, and rectal cancers. One study focused on Kaposi's sarcoma, and it was classified as “other cancer.”Q statistic test was used to calculate the heterogeneity among the included studies. A P value of heterogeneity (Pheterogeneity) of less than 0.05 indicated heterogeneity among studies. In this case, the random effects method was selected (DerSimonian and Laird). If Pheterogeneity > 0.05, the fixed effects method was chosen (Mantel–Haenszel) [P value of HWE (PHWE). Studies that were not in accordance with the HWE balance were removed. Studies with a sample size greater than 1000 were classified as large-sample groups. Stratification analysis included cancer type, control source, race, sample size, and quality of studies. Sensitivity analysis for the CXCR2 C1208T mutation was carried out by removing every single study in turn. Publication bias was evaluated by Begg's funnel plot and Egger's test. P > 0.05 indicated no evidence of publication bias. All statistical analyses were conducted using STATA software .We applied ORs and 95% confidence intervals (CIs) to investigate the strength of association between the CXCR2 C1208T variant and susceptibility to cancer. Five genetic models were adopted to evaluate the overall ORs. For the CXCR2 C1208T polymorphism, the five models were allelic contrast , heterozygous comparison (TC vs. CC), homozygous model (TT vs. CC), dominant (TT+TC vs. CC), and recessive (TT vs. TC+CC) model , 38. A Qaenszel) , 40. We https://www.ncbi.nlm.nih.gov/snp). The gene expression profile of CXCR2 in various cancers was assessed using Gene Expression Profiling Interactive Analysis  and The Human Protein Atlas  database. The immune cell infiltration survival curve of PCA, BLCA, and kidney renal clear cell carcinoma (KIRC) patients was evaluated by the Tumor Immune Estimation Resource (TIMER) database (https://cistrome.shinyapps.io/timer). The expression of CXCR2 in PCA was assessed by the Tumor, Normal and Metastatic plot database . The STRING online server was adopted to demonstrate the protein-protein correlation of the CXCR2 protein in Homo sapiens (https://string-db.org/cgi/input.pl). GSEA of the transcriptomes in PCA samples was conducted via GSEA software , a joint project produced by UC San Diego and the Broad Institute. We used GSEA to evaluate the difference of gene expression between the CXCR2 high-expression and low-expression groups in MSigDB library (c2.cp.KEGG.v7.4.symbol.gmt) enrichment. For this analysis, gene set alignment was performed 1000 times. Phenotypic tags were represented by high or low CXCR2 expression values, and all other parameters were default values [Minor allele frequencies (MAFs) in global populations were investigated using the HapMap database of the National Center for Biotechnology Information (NCBI) repository , East Asian , and West Asian groups  and digestive cancer . Similar results were evident in a recessive genetic model . For lung cancer, individuals with the TT genotype had a 30% decreased risk compared to those with CC genotype . Similar findings were observed in the allelic contrast, heterozygous comparison, and dominant models. In the subgroup analysis by sample size, the results were different between the large- and small-sample studies. In small-sample size studies, individuals with the TT+TC genotype had a 15% decreased risk compared to those with the CC genotype . In large-sample size studies, individuals carrying the TC genotype had a 26% increased risk, compared to those with the CC .We used ORs and 95% CIs to evaluate the relationship between the CXCR2 C1208T variation and the risk of cancer. Stratified analysis by race did not reveal a significant association of this variant in the European . Furthermore, we used IHS analysis to verify the results of bioinformatical findings. As shown in P < 0.05). The expression of CXCR2 was decreased in PCA participants, relative to that in normal counterparts . Signaling pathways, including mitogen-activated protein kinase (MAPK) signaling (P = 0.006). The survival time of KIRC patients with a high expression of CXCR2 was significantly longer than that in the low CXCR2 group  and Egger's tests  also revealed no evidence of publication bias among the studies on the CXCR2 variants.We performed a sensitivity analysis to evaluate the effect of each single study on overall ORs. Publication bias was investigated using Begg's funnel plots and Egger's tests. As shown in Supplemental Figure P = 0.003, OR = 1.29). Peng et al. [Carcinoma remains a significant health issue worldwide, even though a large number of previous studies have explored the susceptibility and high-risk factors of malignant tumors. However, specific markers for several cancers have not been identified up to now , 45. It g et al.  assessedg et al.  performeg et al.  conducteg et al. . HoweverIn the stratified analysis by cancer type, we observed that the C1208T variant was correlated with increased risk of urinary, breast, and digestive cancers. For lung cancer, individuals with the TT genotype had a 30% decreased risk compared to those with the CC genotype, consistent with the reports in previous studies by Peng et al. . In the We further used GSEA to explore the signaling pathways potentially correlated with CXCR2 expression. Signaling pathways, such as MAPK signaling and calcium signaling system, were associated with high CXCR2 expression. Moreover, we used the TIMER database to evaluate the prognostic relevance of immune cell infiltration in PCA, BLCA, and KIRC samples. The survival time of BLCA patients with high CD8+ T cells was significantly shorter than that of BLCA patients with low infiltration. The survival time of KIRC patients with high expression of CXCR2 was significantly longer than that of the low CXCR2 group. There are, however, several limitations to the current analysis. First, there is only one case-control study on participants of African descent based on the inclusion criteria. Future studies with large-sample sizes focused on African populations are warranted. Second, the sample size of the included studies on the CXCR2 C1208T polymorphism remains insufficient. The number of studies on tumors including KIRC, PCA, and BLCA is quite limited. Third, we revealed that the CXCR2 C1208T polymorphism may be associated with increased risk of PCA. Further research is warranted to confirm whether the CXCR2 C1208T mutation has an impact on CXCR2 expression in PCA. As a single variation cannot have a huge impact on the development of cancer, it is necessary to investigate the gene-gene or gene-environment interactions in future research.In conclusion, the present study summarizes all eligible genetic data for correlation between the CXCR2 C1208T variant and risk of cancer. Our study revealed that the CXCR2 C1208T polymorphism is associated with increased risk of urinary, breast, and digestive cancers. CXCR2 C1208T may also be associated with risk of PCA. Finally, CXCR2 expression was negatively correlated with the degree of PCA malignancy.


Based on a large volume of observational scientific studies and many summary papers, a high consumption of meat and processed meat products has been suggested to have a harmful effect on human health. These results have led guideline panels worldwide to recommend to the general population a reduced consumption of processed meat and meat products, with the overarching aim of lowering disease risk, especially of cancer. We revisited and updated the evidence base, evaluating the methodological quality and the certainty of estimates in the published systematic reviews and meta-analyses that examined the association between processed meat consumption and the risk of cancer at different sites across the body, as well as the overall risk of cancer mortality. We further explored if discrepancies in study designs and risks of bias could explain the heterogeneity observed in meta-analyses. In summary, there are severe methodological limitations to the majority of the previously published systematic reviews and meta-analyses that examined the consumption of processed meat and the risk of cancer. Many lacked the proper assessment of the methodological quality of the primary studies they included, or the literature searches did not fulfill the methodological standards needed in order to be systematic and transparent. The primary studies included in the reviews had a potential risk for the misclassification of exposure, a serious risk of bias due to confounding, a moderate to serious risk of bias due to missing data, and/or a moderate to serious risk of selection of the reported results. All these factors may have potentially led to the overestimation of the risk related to processed meat intake across all cancer outcomes. Thus, with the aim of lowering the risk of cancer, the recommendation to reduce the consumption of processed meat and meat products in the general population seems to be based on evidence that is not methodologically strong. Both the production and consumption of red meat and preserved or processed meat products  have been rapidly increasing over recent decades, most significantly in emerging economies . In addiUnder the auspices of the World Health Organization , the IntTo date, few reviews report only relative effects of red and processed meat on cancer outcomes, and few reviews—if any—report absolute effects. While relative effects for red and processed meat may be positive and statistically significant, absolute effects are small (less than 1%) . FurtherUntil now, there have been few randomized trials that have investigated the consumption of red meat and the risk of colon cancer, as recently reviewed by Johnston and colleagues . SimilarIn a recent overview published in 2019 . AMSTAR We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach  to assesStudies had to comply with the following two main quality requirements (two of the items in AMSTAR) to be included in our review : (1) theThe main identified methodological shortcomings were (1) a lack of a reference to a predetermined/a priori published research objective, that is, a protocol or an ethics approval, which, according to AMSTAR, indicates a high risk of selectively reported results; (2) incomprehensive literature searches, which indicates a high risk of overlooking relevant literature; (3) not considering the scientific quality of the evidence in formulating the conclusions, which indicates a high risk of emphasizing results from weak study designs; (4) not reporting the conflicts of interest of the authors of the reviews as well as those of the original included primary studies.Our results indicate that all the reviews and meta-results that were based on case-control studies , which, n = 4104, controls: n = 501,730).For other cancers, often only case-control studies were available. For instance, the risk of cancer of the oral cavity and oropharynx was 91% higher among the cases that reported having had a higher consumption of processed meat compared to controls . The resFor head and neck cancer , the risk was 46% higher among cases with a processed meat intake below 30 g/week compared to those who reported never eating processed meat . These mOnly a modestly higher risk among high compared to low consumers of processed meat was seen in relation to non-Hodgkin lymphoma (17%), renal cell carcinoma (13%), and overall cancer mortality (13%). For non-Hodgkin lymphoma and renal cell carcinoma, the results were based on a mixture of case-control and cohort studies, while overall cancer mortality was based solely on cohort studies. Processed meat consumption did not seem to be associated with cancer in the liver, brain (glioma), ovaries, or lung ,35,36,37In 2020 , we perfUsing the GRADE approach, we concluded that the overall certainty for the body of evidence examining the association between processed meat and cancer was very low across all individual cancer outcomes, meaning that the true effect could be markedly different from the estimated effect ,38. Our The rationale for the GRADE evaluation (very low certainty of the effect estimates) was, first, that the results were based exclusively on observational studies, many of which were of retrospective case-control design, and which, by default, are considered low quality in the GRADE approach. Theoretically, observational studies can be upgraded to moderate quality if there is a large effect size or a strong dose-response relationship, but these criteria were not met for any of the included results.Secondly, we considered whether the exposure (processed meat) was measured accurately. Using our updated meta-analysis of CRC as an illustration of what we assume is representative across cancer outcomes , we coulGuideline to recommending on unprocessed red meat and processed meat consumption by Johnston and colleagues [Third, because assignment to high or low processed meat consumption is not random, as it would be in trials, we considered if there had been appropriate control for confounding , including those that are unmeasured or might involve time-varying confounding. Even in the most well-conducted prospective observational studies, unobserved or residual confounding can still be present, and known confounders may still be measured imprecisely and/or using non-validated methods. In our updated meta-analysis on CRC , all butlleagues , in whicFinally, considering the loss to follow-up (the risk of bias associated with missing data) and selective outcome reporting, our updated meta-analysis of CRC indicated that 75% of the eligible studies had a moderate to serious risk of missing data, and about half of the studies had issues with bias in the selection of the reported results.Limitations to the GRADE approach in evidence of diet and health, such as processed red meat and cancer, have been proposed by Qian et al. . Since iThus, the recommendation to reduce the consumption of processed meat and meat products to protect against cancer in the general population does not seem to be convincingly substantiated on the evidence that is methodologically strong. Clearly, there is still a lack of randomized trials evaluating the effect of lowering processed meat intake, and while such trials may be infeasible, cohort studies do not lend strong support for an association.


CDKN2B-AS1) variants rs1333049 G/C and rs4977574 A/G and the risk of coronary heart disease is unclear. We conducted an update analysis incorporating odds ratios and 95% confidence intervals to assess the correlation. Furthermore, we used in silico analysis to investigate the genes and proteins that interact with CDKN2B. Fifty case-control studies with a sample size of 35,915 cases and 48,873 controls were involved. We revealed that the rs1333049 C allele could increase the risk of coronary heart disease in the overall analysis . In subgroup analysis, positive correlations were detected in studies involving West and East Asians and in population-based control studies. The rs4977574 G allele was also a risk factor for coronary heart disease . These results indicate correlation of CDKN2B-AS1 rs1333049 G/C and rs4977574 A/G variants may be correlated with the risk of coronary heart disease.The relationship between Cyclin-Dependent Kinase Inhibitors 2B Antisense RNA 1 (Abbreviations CDK: Cyclin Dependent Kinase; CCND: G1/S-specific cyclin-D; CDKN: Cyclin Dependent Kinase Inhibitor; GWAS: Genome-wide association study; CDKN2B-AS1: Cyclin-Dependent Kinase Inhibitors 2B Antisense RNA 1; CHD: Coronary heart disease; MAF: minor allele frequencies; HWE: Hardy-Weinberg equilibrium of controls; CI: confidence interval; COL8A2: Collagen type VIII alpha 2 chain; HB: Hospital-based; ORs: odds ratios; ITGA11: Integrin subunit alpha 11; LTBP: Latent transforming factor beta binding protein; PB: Population-based; IBC: Itmat Broad Care; NA: Not applicable; PCR-RFLP: polymerase chain reaction-restriction fragment length polymorphism; MI: Myocardial Infarction; SNP: single nucleotide polymorphism; SMAD: Mothers against decapentaplegic homolog; RT-PCR: Real-time polymerase chain reaction; UK: United Kingdom  Coronary heart disease (CHD) is characterized by coronary artery stenosis and leading to occlusion. This disease is one of the leading causes of disability and death globally . The exaCDKN2B-AS1) also known as Antisense Noncoding RNA in the INK4 locus (ANRIL) is a potential CHD candidate gene located within the CDKN2A-CDKN2B gene cluster on human chromosome 9 (9p21.3). CDKN2B-AS1 can also encode a large antisense non-coding RNA, and prior studies have suggested the role of CDKN2B-AS1 gene in the progression of CHD by regulating the expression of CDKN2B and other genes in cardiac tissue [CDKN2B-AS1 in vascular smooth muscle could affect the expression of extra-cellular matrix remodeling genes, indicating a pivotal role in vascular function [CDKN2B-AS1 expression in atherosclerotic lesions can promote atherosclerosis and thrombosis [CDKN2B-AS1 gene are associated with atherosclerosis-related diseases, including CHD.Cyclin-Dependent Kinase Inhibitors 2B Antisense RNA 1  is considered as a non-protein-coding variation located on chromosome 9p21.3 adjacent to Cyclin-Dependent Kinase Inhibitor 2B (CDKN2B). Up to now, the A to G variation can be correlated with early onset of CHD. This variation affects the expression level of CDKN2B in many tissues including coronary artery smooth muscle cells [CDKN2B-AS1 polymorphisms and coronary artery disease. One analysis involved only 9 studies based on the rs1333049 variant [CDKN2B-AS1 rs1333049 C and rs4977574 G allele can be used as a marker for the diagnosis or prognosis of CHD. The aim of the present research was to identify all eligible case-control studies to comprehensively investigate the correlation of CDKN2B-AS1 polymorphisms and CHD [in silico analysis to investigate the genes and proteins that interact with CDKN2B.Polymorphisms of d cancer . Prior sle cells . For rs1le cells ,15. Mostle cells ,17. In 2 variant  and the  variant . Up to n and CHD . FurtherA literature search of Embase, PMC, Google Scholar, and Chinese Wanfang databases for relevant published articles was performed using the search term (‘rs4977574’ OR ‘rs1333049’ OR “CDKN2B antisense RNA” OR “CDKN2B-AS” OR “9p21” OR “ANRIL”) AND (“variant” OR “variant” OR “SNP”) AND . The most recent search update was 1 June 2020. Besides the use of databases, eligible studies were also retrieved by searching the references cited in the published articles.CDKN2B-AS1 rs1333049 and rs4977574 variants and CHD; (b) Study providing available genotypic frequencies of 9p21 region polymorphisms; and (c) Full text in English or other languages. Major exclusion criteria were (a) Duplicated studies using the same data; (b) Absence of a control group; and (c) No relevant to CDKN2B-AS1 variants and CHD.A publication was included in the analysis only if it met the following criteria: (a) Case–control study addressing the relationship between CDKN2B-AS1 variants, evaluation of Hardy-Weinberg equilibrium (HWE), and the genotyping method. In addition, studies including Asian population were divided into East Asia and West Asia. Two investigators independently carried out data extraction and quality evaluation and differences between them were resolved by discussions until a consensus was reached.Information retrieved from the included studies was as follows: First author name, date of publication, region, and ethnicity of populations used, primary outcome, source of the control samples, total sample size, gene distribution of CDKN2B-AS1 rs1333049 and rs4977574 variants and CHD susceptibility was investigated using odds ratios (ORs) together with 95% confidence intervals. Five genetic models were adopted to assess the likelihood of CDKN2B-AS1 polymorphisms. For SNP rs1333049 G/C, the allele comparison represents C-allele versus (vs.) G-allele; heterozygous contrast refers to CG vs. GG; homozygous contrast represents CC vs. GG; dominant model represents CC + CG vs. GG; and recessive model refers to CC vs. CG + GG. For SNP rs4977574 A/G, the five genetic models were G-allele vs. A-allele, GA vs. AA, GG vs. AA, GG+GA vs. AA, and GG vs. GA + AA. Cochran’s Q statistic was performed to calculate the heterogeneity between ORs. If the probability (P) value < 0.05 was considered as statistically significant, indicating heterogeneity among studies. In this case, a random-effects model was adopted. Otherwise, we carried out a fixed-effects model. The HWE P value was calculated using the Fisher’s exact test, with a P value < 0.05 indicating significant bias. Stratification analyses were carried out to investigate the strength of ethnicity, control source, and type of primary outcome. Begg’s funnel plot was adopted to assess the potential publication bias. P < 0.05 represents the significance exists. Sensitivity analyses were used to test the reliability of the included studies. All statistical methods were referring to the STATA 11.0 software of StataCorp .Strength of the correlation between https://www.ncbi.nlm.nih.gov/snp). The protein–protein interactions of CDKN2B were investigated using the STRING tools (https://string-db.org/cgi/input.pl).Differentially expressed genes between the CHD and control groups in the overall population were evaluated using an online database. Moreover, we checked the minor allele frequencies (MAFs) in worldwide populations based on the online database . For East Asians, the ratio was 1.32 . For myocardial infarction groups, the ratio was 1.25 . The ratio was 1.38 in myocardial infarction groups  and rs4977574 (P > 0.05). Furthermore, we conducted sensitivity analysis by removing single studies. Single study did not have an impact on the significance of ORs for both rs1333049 G/C  and rs43049 G/C ) polymorCDKN2B-AS1 variants rs1333049 and rs4977574 and the risk of CHD has been previously reported; however, a comprehensive analysis of the relationship was not available. Several meta-analyses have pooled the data of various studies; however, the number of studies included was insufficient. In 2018, Xu et al evaluated six articles on CDKN2B-AS1 SNP rs4977574 indicating increased likelihood of CHD due to the variation [et al in 2019 evaluated the association between SNP rs1333049 and CHD using 7 studies and reported increased risk of CHD with rs1333049 in the East Asian population [CDKN2B-AS1 variants rs1333049 and rs4977574 and the risk of CHD. Our analysis revealed a significant association of rs1333049 G/C and rs4977574 A/G variants with the likelihood of CHD, when all studies were pooled together.CHD is still the main cause of mortality globally and imposes a huge social and economic burden ,60. The ariation . Hu et apulation . The preP value = 0.17, OR = 0.87, 95% confidence intervals = 0.72–1.06; dominant comparison, P value = 0.14, OR = 0.83, 95% confidence intervals = 0.64–1.07; recessive genetic model, P value = 0.28, OR = 1.25, 95% confidence intervals = 0.84–1.86) [CDKN2B-AS1 rs1333049 G/C and rs4977574 A/G variants were not correlated with higher risk in African patients with CHD [CDKN2B-AS1 rs1333049 G/C variant in Africans is 0.21. It is lower than that in other populations and global average. Similar result was indicated for the rs4977574 A/G variant. A possible reason is that CDKN2B-AS1 rs1333049 G/C and rs4977574 A/G variants may be not associated with the CHD susceptibility in African population. Additionally, an online database was employed to explore differentially expressed genes between the CHD and control groups. We found that expression of LTBP2, ITGA11, and COL8A2 correlated with the expression of CDKN2B in CHD. The online database contains scant data on the specific mechanism of these genes. Future functional analyses and in vitro experiments are needed to demonstrate the correlations in detail.For the SNP rs1333049, C allele was a risk factor for both West Asians and East Asians in the subgroup analysis by race. In the stratified analysis by source of control population, there is a positive correlation between rs1333049 variant and population-based studies. In a subgroup analysis based on disease type, we observed that individuals carrying CC allele had an increased susceptibility of coronary artery disease and myocardial infarction patients’ group. Our conclusion is not consistent with the meta-analysis performed by Xie et al, who observed no positive relationship between this variant and susceptibility of myocardial infarction groups  . A possi84–1.86) . In strawith CHD . EvidencCDKN2B-AS1 rs1333049 G/C and rs4977574 A/G variations. Although the DerSimonian and Laird method was employed [in vitro and in vivo analyses. Third, the study does not include adjusted analysis for sex, lifestyle, and smoking exposure, which may have helped in better segregation and evaluation of the different groups.The current analysis has several limitations. First, we observed significant heterogeneity in the overall analysis when evaluating the employed , potentiCDKN2B-AS1 rs1333049 C allele and rs4977574 G allele is correlated with the risk of CHD. These polymorphisms may serve as genetic biomarkers for CHD, especially in people of East and West Asian ancestry.Taken together, our study demonstrates that


To investigate the relationship between preoperative proteinuria and postoperative acute kidney injury (AKI).We performed a search on databases included PubMed, Embase, the Cochrane Library, and Web of Science, from December 2009 to September 2020. Data extracted from eligible studies were synthesized to calculate the odds ratio (OR) and 95% confidence interval (CI). A fixed or random effects model was applied to calculate the pooled OR based on heterogeneity through the included studies.p < 0.001). Subgroup analysis showed that both preoperative mild proteinuria  and preoperative heavy proteinuria  were independent risk factors for postoperative AKI. The heterogeneity was combined because its values were lower. Further subgroup analysis found that preoperative proteinuria measured using dipstick was an independent risk factor for postoperative AKI . Finally, preoperative proteinuria was an independent risk factor for postoperative AKI in the non-cardiac surgery group  and cardiac surgery group This meta-analysis of 11 observational studies included 203,987 participants, of whom 21,621 patients suffered from postoperative AKI and 182,366 patients did not suffer from postoperative AKI. The combined results demonstrated that preoperative proteinuria is an independent risk factor for postoperative AKI (adjusted OR = 1.65, 95%CI:1.44–1.89, Preoperative proteinuria is an independent risk factor for postoperative AKI and in instances when proteinuria is detected using dipsticks. The reported incidence of AKI after surgery ranges from 1 to 30% . PostopePostoperative AKI can be caused due to multiple reasons; hypovolemia, low systemic vascular resistance due to anesthesia or caval compression, and direct injury to the urinary system are all common events during surgery that can possibly harm the kidney. Factors that prolong the duration of renal ischemia and intraoperative hypotension during surgery are key determinants of postoperative AKI. In 2018, the perioperative quality initiative conducted a review of the literature from 1952 to 2017 and concluded that an intraoperative MAP below 60–70 mmHg was associated with an increased risk of AKI and mortality [p < 0.001). In cardiac surgery, preoperative proteinuria has been shown to be associated with postoperative AKI regardless of the baseline renal function [Proteinuria has been reported to be associated with AKI in various clinical settings. Some studies have indicated that baseline proteinuria is an independent predictor for contrast-induced AKI ,9. Javiefunction . A meta-function . However2.2.1.Meta-analyses of study-level observational data were undertaken and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . Two ind2.2.The inclusion criterias are as follows: (a) proteinuria was tested using a dipstick or urine albumin to creatinine ratio (ACR). To classify the severity of proteinuria, we defined negative cases as “no proteinuria”, trace to 1 as “mild proteinuria”, and 2–4 as “heavy proteinuria”;  original research article based on an epidemiologic study performed on humans; and (d) available information on the relationship between preoperative proteinuria and postoperative AKI.Whereas the exclusion criterias are as follows:  no surgery; (d) case reports and reviews; (e) cross-sectional study; (f) note, letter, and Editorial; (g) conference abstract; (h) nephrectomy.2.3.Two reviewers independently read the full text of the manuscripts and quality assessment, and data extraction are carried out independently, and disagreements are resolved through consensus. The trials in the meta-analyses included are defined by the 9-star Newcastle-Ottawa Scale  to evalu2.4.I2 statistics. When heterogeneity is lower (I2 < 50%), a Mantel–Haenszel fixed-effects model is applied for OR estimation. When heterogeneity is higher (I2>50%), a Mantel–Haenszel random-effects model is applied for OR estimation. Subgroup analysis is implemented based on the degree of preoperative proteinuria, different detection methods for preoperative proteinuria, and different types of surgery. Begger's funnel plot is carried out if the studies are more than ten. Egger's linear regression test is employed to check possible publication bias. The value of p is lower than 0.05 considered statistically significant. All statistical analyses are carried out using STATA 14 software .To investigate the relationship between preoperative proteinuria and postoperative AKI, the odds ratio (OR) of each study is calculated. The forest plot is used to describe the OR (95% CI). We assess heterogeneity among studies using the 3.3.1.The literature search is carried out on the PubMed, EMBASE, Cochrane Library, and Web of Science databases. We identify 123 records and use the information available in the title and abstract to filter the articles for the first time. The following are excluded: 10 duplicate records, 8 conference abstracts, 8 case reports, 6 notes, letters, or editorials, 18 reviews, 1 non-surgical record, 9 non-preoperative proteinuria records, 25 non-postoperative AKI records, 20 unrelated records, 1 record with children as participants, 3 nephrectomy records, and 4 records are excluded for other reasons. Therefore, we identify 10 records including 11 studies totally and report studies for our meta-analysis  Figure .The twelve studies include 203,987 participants, among whom 21,621 patients suffered from postoperative AKI and 182,366 patients do not. Among them, eleven studies evaluates the relationship between preoperative proteinuria and postoperative AKI, six studies investigates the relationship between the degree of preoperative proteinuria and postoperative AKI, eight studies uses the dipstick method to detect proteinuria, two studies uses the urine ACR to detect proteinuria, six studies investigates the relationship between preoperative proteinuria and postoperative AKI in cardiac surgery, four studies evaluates the relationship between preoperative proteinuria and postoperative AKI in non-cardiac surgery .3.2.Of the ten articles, nine records are cohort studies and one record is a case-control study. One article score 7 points, seven articles scores 8 points and two articles scores 9 points in the literature quality evaluation .3.3.3.3.1.p < 0.001, p for heterogeneity = 0.018, and I2 =53.4)  .3.4.3.4.1.p < 0.001, p for heterogeneity = 0.093, and I2=47.1) and mild proteinuria  are independent risk factors for postoperative AKI , while in the ACR detection group, proteinuria is not an independent risk factor for postoperative AKI   .3.4.3.p = 0.002, p for heterogeneity = 0.018, and I2=70.2), in the cardiac surgery group, proteinuria is also an independent risk factor for postoperative AKI   .3.5.p = 0.001 < 0.05) (The funnel plot is suggested by the Egger’s linear regression test. There are some publication bias observed on the relationship between preoperative proteinuria and postoperative AKI ( < 0.05) .4.Postoperative AKI is a common complication of surgical operation, which occurred due to a variety of factors. It includes the surgery timing , proper intraoperative hemodynamic monitoring and management, and early postoperative intervention . ChronicProteinuria is a common clinical manifestation of chronic kidney disease, as well as its relationship with AKI has also been confirmed by more and more studies. The pathophysiological explanation of the association between proteinuria independent of baseline glomerular filtration rate (GFR) and risk factors of primary diseases, especially the existence of AKI by hypertension or diabetes mellitus (DM). The first possibility is that proteinuria is thought to be caused by acute kidney infection or immune inflammation. Secondly, the possibility is that proteinuria can lead to hypoalbuminemia, and then the decrease of inflation pressure caused by hypoalbuminemia lead to the contraction of intravascular volume and susceptibility to AKI. In our meta-analysis, the comprehensive results demonstrate that preoperative proteinuria is an independent risk factor for postoperative AKI.As we all know, different degrees of proteinuria mean that patients are in different pathological states. Those who with severe proteinuria are more likely to have DM, hyperuricemia, higher creatinine level and lower estimated-GFR level, which indicates that the kidney is more vulnerable to damage. However, recent studies have found that neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1are up-regulated in damaged renal tubules, which have been confirmed to predict AKI and unrelated to the degree of proteinuria. In our meta-analysis, no matter the degree is mild or heavy, patients with preoperative proteinuria have a higher risk of postoperative AKI. The incidence of AKI in preoperative mild proteinuria group and preoperative heavy proteinuria group is low heterogeneous, so we combined them.Dipstick proteinuria and urine ACR are two methods to detect proteinuria. In subgroup analysis, dipstick proteinuria is an independent risk of postoperative AKI, while urine ACR is not. The detection limit of dipstick protein is 150 mg/L, and the clinical ACR ≥ 30 mg/g is the diagnostic standard of early diabetic nephropathy. The detection of dipstick protein is easy to detect, and it is not affected by urine pH and urine specific gravity . Recent There are many risk factors that can lead to acute kidney injury after operation. The incidence of AKI after cardiac surgery is as high as 30% . SubgrouThe advantages of our meta-analysis include comprehensive search, large sample size, and inclusion of the latest research with high quality of methodology. The result in this research is a suggestion both in scientific viewpoint and in clinical practice. Our meta-analysis have some limitations. First of all, the number of included researches was not abundant and there was publication bias. Secondly, ten studies were cohort studies and one was case-control study. Methodological differences can increase heterogeneity. Thirdly, the method of meta-analysis is collect the values of OR or RR from the logistic regression model by the adjustment of other risk factors for each study, and then use them to analyze. However, different studies are adjusted for different risk factors. Most of the studies are adjusted for at least age, sex, race, diabetes, heart failure and drugs. Besides, for instance, Coca’s study also adjusted for the type of operation and Nishimoto1’s study not only adjusted for the type of operation, but also adjusted for the minimum systolic blood pressure (SBP) during operation, SBP triangle during operation. These will also increase heterogeneity.5.Proteinuria is closely associated with the progression of renal function. Recent studies have found that preoperative proteinuria is associated with postoperative renal function progression, postoperative cardiovascular complications, and the need for renal replacement therapy . In this


To identify the association between albuminuria and dementia or cognitive impairment.The literature search was performed to identify relevant scientific studies through August 2019, including PubMed/Medline and EMBASE. For inclusion, the studies had to fulfil the following criteria: population-based cohort, case–control or cross-sectional studies; quantifying an association of albuminuria with cognitive impairment or dementia; and reported odds ratio (OR), and the corresponding 95% confidential interval (95% CI). Random effects model was used to yield pooled estimates.A total of 16 studies  were included in the meta-analyses. Based on the fully adjusted estimates, albuminuria was associated with a significant higher risk of cognitive impairment or dementia. Furthermore, the same trend existed for cognitive impairment and dementia, respectively. In addition, both of Alzheimer’s diseases (AD) and vascular dementia (VaD) were significantly associated with albuminuria.Albuminuria was significantly associated with cognitive impairment and dementia. Corresponding to an earlier subclinical time-point in kidney disease progress, albuminuria may be a potential factor predicting the future occurrence of dementia.The online version contains supplementary material available at 10.1007/s10157-021-02127-3. There is an increasing number of people diagnosed with dementia worldwide, comprising major public health concerns . Among iAs a marker of renal microvascular disease, albuminuria often occurs in the presence of hypertension and diabetes mellitus (DM), and shares common risk factors with dementia, including increasing age, elevated systolic blood pressure (SBP), and increased levels of inflammation factors , 7. PrevThe literature search of computerized databases was performed to identify relevant scientific studies through August 2019, including PubMed/Medline and EMBASE. Two search themes were combined with the Boolean Operator “And”. The first Boolean search used the terms of “albuminuria”, “proteinuria” or "kidney disease", and the second theme was cognitive impairment using subject headings, including “dementia”, “cognition”, “cognitive impairment”, or “Alzheimer’s disease”. In addition, the reference lists of identified studies were scanned to enhance the searches. This meta-analysis was designed, conducted and reported following the pre-determined protocol in accordance with the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines .Hongqin Li and Baoshan Gao independently assessed the eligibility of each searching result. Full texts of selected articles were reviewed to further identify eligible studies included in the study, after screening all the potential articles with reading titles and abstracts. The disagreement was resolved by discussion. For inclusion, the study had to meet the following criteria: adult participants with aged ≥ 18; longitudinal studies (cohort or case–control) or cross-sectional studies; quantifying an association of albuminuria with cognitive impairment or dementia; and reported odds ratio (OR), and the corresponding 95% confidential interval (95% CI). Studies with (1) involvement of solely children/adolescents and referring exclusively to hemodialysis patients, or patients with chronic autoimmune disorders or HIV-infected, (2) in vitro and animal studies, (3) reviews, case reports, abstracts, editorials, and comments would be excluded.Shuailin Zhao and Ruiyu Wang extracted data from all eligible studies respectively, with any disagreement resolved by consensus. For each relevant study, the following data were extracted: the first author’s last name, year of publication, study design, geographic location, sample size, median age, gender composition, clinical characteristics , exposures, outcome assessment, and analysis results. We adopted an evaluation system based on Newcastle–Ottawa scale (NOS) to assess the quality for both longitudinal and cross-sectional studies .Albuminuria was defined by albumin-to-creatinine ratio (ACR) or 24-h urinary albumin excretion; cut-off points of either , or  were used . MicroalTwo major outcomes were examined, including dichotomized cognitive impairment/ dementia outcomes and continuous cognitive function measures. The first included cognitive impairment, defined by validated instruments, and dementia based on clinical diagnostic criteria. Various validated neuropsychological tests were used to evaluate continuous cognitive function. The diagnosis of dementia, and classification of Alzheimer’s diseases (AD) and vascular dementia (VaD) were based on clinical diagnostic criteria.Q test and I2 statistics [P value of Q test < 0.05. We had stratified the AD and VaD for further analysis. Subgroup analyses by study design were carried out, to assess the potential influence on the association. Publication bias was assessed through the Egger’s test and funnel plots [The ORs were used as the common measure of association, and both relative risks (RRs) and hazard ratios (HRs) were considered equivalent to ORs . ORs andatistics . Heterogel plots , 18. Alln = 3); no ORs/HRs or the corresponding 95% CI (n = 17); review or editorial (n = 2) and HIV patients (n = 1). Another three eligible studies were identified through references of relevant publications.Our initial search yielded a total of 1106 unique citations, of which 36 articles were considered to be potentially relevant and identified to retrieval with full-text review , with a total of 127,296 participants  were included in the meta-analysis –34. AmonP < 0.05) as shown in Fig. P < 0.05) and dementia , respectively. In addition, both of AD and VaD were significantly associated with albuminuria . After excluding 5 cross-sectional studies, the pooled estimates for the remaining cohort studies revealed a significant association between albuminuria and cognitive impairment or dementia .Based on the fully adjusted estimates, albuminuria was associated with a significant higher risk of cognitive impairment or dementia . In addition, significant heterogeneity was identified for studies on cognitive impairment , whereas there was mild-to-moderate heterogeneity for studies with outcomes of dementia .There was significant heterogeneity for all studies included in this meta-analysis (P < 0.01).The funnel plot showed an obvious asymmetry Fig. . And theThis systematic review and meta-analysis suggested that individuals with albuminuria had significantly a higher risk of cognitive impairment or dementia. Stratifying by study design, the pooled results for all cohort studies revealed the same trend between albuminuria and risk of cognitive impairment or dementia.Our findings were consistent with the previous meta-analysis that albuminuria was independently associated with cognitive impairment and dementia , 35. As Although the mechanism underlying the relationship between albuminuria and dementia remained undermined, several plausible mechanisms may account for the association. First, proteinuria may act as a surrogate marker of oxidative stress, which plays an important role in the pathogenesis of dementia . Paragh The association of albuminuria and dementia probably indicates concurrent pathology in kidneys and brain. Although the mechanism is not fully understood, evidence has proven the association of chronic kidney disease and cognitive dysfunction , 43. HowAs an important method to reveal risk trends, meta-analysis provides a more precise risk estimates. In addition, most of the studies included in our meta-analysis adopted a cohort design, and the estimates with cohort studies separately were calculated, which might reduce the possibility of recall and selection bias. Moreover, the included studies contained various ethnicity, which might increase the generalizability of the findings. However, several limitations of this meta-analysis should be acknowledged. First, since only observational studies were obtained, there was a possibility that other factors might account for the association. In addition, compared with studies on dementia, the heterogeneity for studies on cognitive impairment was significant. Several methodologic issues might contribute to the substantial heterogeneity observed in the meta-analyses for cognitive impairment populations, including: (1) different criteria to measure albuminuria; (2) variation in study population ; (3) adjusting different confounders; and (4) different assessment tools of cognitive functioning, and one study only having continuous measures of cognition. Last, the results of the meta-analysis should be take cautiously since significant publication bias was revealed and the direct exchange of HR/RR to OR. Further evidence are warranted to verify our findings.In summary, albuminuria was significantly associated with cognitive impairment and dementia. Corresponding to an earlier subclinical time-point in kidney disease progress, albuminuria may be a potential factor predicting the future occurrence of dementia. Targeting the pathogenesis of albuminuria or treating modifiable risk factors may have clinical implications to prevent dementia, or delay disease progression.Supplementary file1 Supplementary Fig. 1. Forest plot of cohort studies assessing the relation between albuminuria and dementia or cognitive impairment (fully adjusted estimates) (TIF 61 KB)Below is the link to the electronic supplementary material.