The present study aimed to conduct a meta-analysis of previously published studies in order to clarify the association of long noncoding RNA (lncRNAs) LINC00673 rs11655237 C> T polymorphism with cancer risk.Systematic review and meta-analysis.Electronic databases of PubMed, EMBASE, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, and Wanfang Database were used to search relevant studies. Studies published up to October 20, 2019 were included. The included studies were assessed in the following genetic model: allelic model, homozygote model, Heterozygote model, dominant model, recessive model. Data syntheses were conducted using STATA 12.0.Participants with various types cancers were included.Odds ratio (ORs) and 95% confidence interval (CIs) were calculated to assess the risk of tumor.P < .001), homozygous model , heterozygous model , dominant model  and recessive model . Subgroup analysis also demonstrated that polymorphisms at this site also increased the risk of neuroblastoma.Seven articles including 7 case-control studies, 7423 cases and 11,049 controls were adopted for meta-analysis. Our result demonstrated that LINC00673 rs11655237 C> T was related to the cancer among all model including allelic model (T vs C: pooled OR = 1.24, 95% CI = 1.16–1.41, Our results find that rs11655237 contributed to occurrence of cancer in all models in Chinese population. Other sites of the gene and the interaction of genes with the external environment were not analyzed.•Small sample size may be the biggest research defect, which may affect the result and lead to incorrect conclusions.•The subjects included in the study are all Chinese, so racial bias is inevitable and affects the outcome. Lung cancer is the most common cause of cancer-related deaths worldwide, accounting for 19% of all cancer-related deaths. Smoking, drinking, unhealthy diet and lack of exercise are recognized as major cancer risk factors worldwide. Of course, some carcinogenic infections, including Helicobacter pylori, human papillomavirus, hepatitis B virus, and hepatitis C virus, can greatly increase the risk of cancer. If cancer can be detected and diagnosed early, it can not only reduce cancer mortality, but also improve survival rate and greatly improve the quality of life of cancer patients.Cancer is the second leading cause of death in the world, with about one-sixth of deaths caused by cancer, and about 70% of cancer deaths occur in low- and middle-income countries.,5 Most of the current research is focused on lncRNA and MicroRNA (miRNA), and there is currently insufficient understanding of the interaction between lncRNA, miRNA and mRNA (messenger RNA). There are some reports that the mechanisms of lncRNA, miRNA and mRNA in the development of cancer and their interactions.–8 The miRNA-mRNA-lncRNA network provides clues for understanding the mechanism of tumors and developing novel diagnostic and therapeutic strategies.Non-coding RNAs (ncRNAs) are RNAs that do not encode proteins. These RNAs can be transcribed from the genome, but they are not translated into proteins, and they can perform their biological functions at the RNA level. ncRNAs can be classified in length, and lncRNAs are >200 nt in length. The number of lncRNAs has an absolute advantage in ncRNAs. Compared with the encoded protein gene, it has higher tissue-organ specificity and can be found in blood, urine, tumor tissue, or some other tissues or body fluids, and has the potential to become Biomarkers for cancer diagnosis, prognosis and treatment. There are also studies that point out that the lncRNA TC0101441 can induces epithelial-mesenchymal transition in epithelial ovarian cancer metastasis. So the lncRNAs may be involved in many biological processes that regulate tumorigenesis and cancer metastasis. There are also reports that there is a relationship between the lncRNAs polymorphisms and the risk of cancer. Research by Moschovis et al suggested that polymorphisms of these 2 lncRNAs polymorphisms (PVT1 rs1561927 and HOTAIR rs4759313) implicated in pancreatic carcinogenesis. Yuan et al prove that single nucleotide polymorphism rs114020893 of NEXN-AS1 at 1p31.1 may contribute to lung cancer susceptibility.The long noncoding RNAs  are increasingly becoming a research hotspot. Studies have pointed out that the lncRNA DLX6-AS1 can promote cell growth and invasiveness in bladder cancer.We found a lot of studies on LINC00673 rs11655237 C>T polymorphism and tumor susceptibility, however, there is some controversy about its relationship with tumor susceptibility. Therefore, we performed this meta-analysis to more comprehensively and precisely assess the association between the LINC00673 rs11655237 C> T polymorphism and cancer risk.A Medical Subject Headings method was used to retrieve subject terms from databases. “LINC00673” or “SLNCR1” and “rs11655237” and “polymorphism” or “mutation” or “variant” and “cancer” or “carcinoma” or “tumor” or “neoplasms” were used as keywords. The keywords were used as searching terms for PubMed, the Cochrane Library, Embase databases, Web of Science, China National Knowledge Infrastructure, and Wanfang Databases. Studies published up to October 20, 2019 were included. Selected articles were not confined to any language publications.The articles included in this study must meet the following criteria:independently published cohort design or case–control studies.sufficient information for calculating the odds ratios (ORs) with its 95% confidence intervals (CIs).The relationship between the LINC00673 rs11655237 polymorphism and cancer is evaluated in the study.Hardy-Weinberg equilibrium (HWE).The exclusion criteria were as follows:reviews, letters, editorials, and case reports.genotype frequency was not clear.family-based studies.not in HWE.Two researchers (Liang and Ke) independently evaluated and extracted information from eligible studies. The data extracted included the following information: the first author’s name, year of publication, the source of specimens of cases; genotyping method, cancer type, total number of cases and controls, genotype of the cases and controls, HWE was calculated from the study data. If the two investigators have any different opinions, submit the dispute to the third investigator (Zhang) until a consensus was reached.http://www.ohri.ca/programs/clinical_epidemiology/nosgen.Pdf). This scale is based on three aspects: selection of the study sample ; comparability of the sample groups  and; ascertainment of exposure/ outcome . The higher the score, the better the quality of the document, the scores range from 0 (worst) to 9 (best) score. the highest is 9 points; the definition of ≥6 points for high quality literature.The Newcastle-Ottawa Scale Quality Assessment Scale was used to assess the methodological quality  was adopted. Otherwise, the fixed-effects model (the Mantel-Haenszel method) was applied. We also performed a subgroup analysis based on cancer type. Sensitivity analyses were performed to examine possible changes when single studies were excluded. Moreover, we used Begg’s funnel plot and Egger’s test to investigate the potential publication bias in the meta-analysis.We evaluated the association between the LINC00673 rs11655237 polymorphism and risk of cancer by using different comparison models: allelic model (T vs C), homozygous model (TT vs CC), heterozygous model (CT vs CC), recessive model (TT vs CT+ CC), and dominant model (CT + TT vs CC). HWE in the controls of each study was evaluated with the Goodness-of-fit Chi-squared test, and P-values were 2-sided, and P < .05 was considered that the result was statistically significant.All the statistical analyses in this meta-analysis were conducted with STATA software . All the –20 The flow of the study is shown in Figure After searching the database based on search terms, 113 related studies were retrieved, including 74 from PubMed, 13 from EMBASE, 1 from Cochrane Library, 24 from Web of Science, 0 from China National Knowledge Infrastructure, and 1 from Wanfang Databases. First, delete duplicate records, obviously irrelevant articles, duplicate articles and review and meta-analysis, of which 77 studies were deleted. Of the remaining 36 studies, the 29 papers were excluded after reading the full text, 19 were not in compliance with the research criteria, and 10 were insufficient in frequency information. Finally, 7 articles including 7 case-control studies, 7423 cases and 11,049 controls were identified as suitable for meta-analysis.Seven case-control studies were published between 2014 and 2019, and they were all conducted in China, these studies are all about Asian studies. The tumor types included in the study were Wilms tumor, hepatoblastoma, gastric cancer (GC), neuroblastoma, cervical cancer, pancreatic cancer. The genotype frequencies of both case and control groups were obtained from the original study. The source of the control population was all hospital-based. HWE was calculated from the genotype of the control population, and all studies are consistent with HWE. The Newcastle-Ottawa Scale quality score shows that all 7 studies were all “high quality.” All the studies applied TaqMan probe technology (TaqMan). The characteristics of the included studies are shown in Table P < .001; homozygous model (TT vs CC): OR = 1.54, 95% CI = 1.36 to 1.76, P < .001; heterozygous model (CT vs CC): OR = 1.24, 95% CI = 1.16 to 1.32, P < .001; dominant model (CT + TT vs CC): OR = 1.28, 95% CI = 1.20 to 1.36, P < .001; recessive model (TT vs CT+ CC): OR = 1.42, 95% CI = 1.25 to 1.61, P < .001. A significant association between LINC00673 rs11655237 gene polymorphisms and cancer risk was observed under all the 5 genetic models . Subgroup analysis based on tumor type, we found no significant changes in heterogeneity under all genetic models. Subgroup analysis also shows that a significant association between the LINC00673 rs11655237 gene polymorphism and neuroblastoma risk. Forest plot shows the association between LINC00673 rs11655237 polymorphism and cancer risk in Figure P value of the Egger’s test are >0.05 in all models. The publication bias of the dominant model (CT + TT vs CC) is shown in Figure The sensitivity analysis was performed to evaluate the influence of each study on the merged OR. Finally, there is no qualitative change in the corresponding merged ORs. This reinforces the certainty and reliability of the results. The sensitivity analysis between LINC00673 rs11655237 polymorphism and cancer risk is shown in Figure The progression of cancer is a complex process that is the result of interactions between human genetic factors and external surroundings factors. Physical carcinogens (such as ultraviolet), chemical carcinogens (such as aflatoxin), and biological carcinogens  are external factors in cancer risk. The genetic factors of cancer risk are mainly the relationship between gene polymorphism and tumor susceptibility, and the interaction between genes and the environment. The causes of cancer’s occurrence and development are not fully understood. But genetic polymorphism may explain it in the field of genetics.P = .029). The results of LI et al showed that the polymorphism of LINC00673 rs11655237 C> T increased the risk of neuroblastoma in Chinese children . Zhao et al found that rs11655237 polymorphism significantly increased GC risk in the Chinese population , and a significant interaction was found between rs11655237 and Helicobacter pylori infection (P = .006). Yang et al found that the LINC00673 rs11655237 C> T polymorphism can increase the risk of hepatoblastoma . Gao et al showed that LINC00673 rs11655237 C> T polymorphism was not significantly associated with Wilms tumor susceptibility under all the tested genetic models . Wang et al found rs11655237 significantly increased susceptibility of cervical cancer in a Chinese population . Zheng et al pointed out that LINC00673 rs11655237C>T is associated with pancreatic cancer susceptibility and indicates that, CT genotype carriers have a 28% increased risk of pancreatic cancer compared with CC genotype . We found that Gao’s research conclusions are inconsistent with other people’s research conclusions. There may be two reasons, first, the sample size is too small; second, selection bias and information bias are inevitable in their retrospective study. We conducted a meta-analysis of the above literature and found that the LINC00673 rs11655237C>T polymorphism can increase the risk of cancer . Subgroup analysis also demonstrated that polymorphisms at this site also increased the risk of neuroblastoma.LINC00673 is located at 17q24.3, which exhibits a high frequency of loss of heterozygosity. The relationship between LINC00673 rs11655237C> T polymorphism and cancer susceptibility has been demonstrated. Zhang et al pointed out that the rs11655237 T allele was positively associated with neuroblastoma and could confer neuroblastoma susceptibility (OR =1.80, 95% CI = 1.06–3.06,  Secondly, LINC00673 is able to reinforce the interaction of PTPN11 with PRPF19, an E3 ubiquitin ligase, and promote PTPN11 degradation through ubiquitination, which causes diminished SRC-ERK oncogenic signaling and enhanced activation of the STAT1-dependent antitumor response. In addition LINC00673-v4 augmented the interaction between DDX3 and CK1ε and thus the phosphorylation of dishevelled, which subsequently activated WNT/β-catenin signaling and consequently caused aggressiveness of cancer. Of course, lncRNAs can also regulate the invasion, proliferation, and metastasis of tumor cells through other pathways.–26 All of the above studies provide reliable evidence that lncRNALINC00673 plays an important role in the development, progression, and metastasis of various cancers.LncRNAs play a crucial role in the development and progression of tumors. It increases tumor risk and may be related to the following signaling pathways: Firstly, LINC00673 was found to regulate MARK4 expression by mutagenizing miR-515-5p, thereby inhibiting the Hippo signaling pathway, finally, the transcription factor Yin Yang 1 binds to the LINC00673 promoter and increases its cis transcription.However, there are some limitations that exist in our meta-analysis. In our meta-analysis, only the relationship between the polymorphism of LINC00673 rs11655237 C> T and the susceptibility of tumor was studied. Other sites of the gene and the interaction of genes with the external environment were not analyzed. Small sample size may be the biggest research defect, which may affect the result and lead to incorrect conclusions. The subjects included in the study are all Chinese, so racial bias is inevitable and affects the outcome.In conclusion, our meta-analysis showed that the LINC00673 rs11655237 C> T polymorphism can increase cancer susceptibility. Given the current limitations of this meta-analysis, a larger sample size for further research is needed in the future and multiple ethnic participants should participate to clarify the association between LINC00673 rs11655237 C> T polymorphism and cancer risk.Conceptualization: Xingxuan Ma.Data curation: Hongyu Zhang, You He.Formal analysis: Xingxuan Ma.Investigation: Liuhua Ke.Methodology: Ka Liang.Project administration: Ka Liang.Software: Baixiu Wu, Ka Liang, Liuhua Ke, Xingxuan Ma, Changliu Luo.Supervision: Liuhua Ke.Visualization: Liuhua Ke.


Since 2011, three large-scale genome-wide association studies (GWAS) have confirmed that the CD2AP rs9349407 polymorphism is significantly connected with Alzheimer’s disease (AD) in individuals of European descent. Subsequently, this association has been replicated in European populations, but is unclear whether it can be replicated in Chinese. Recently, the correlation between rs9349407 and AD in the Chinese population has become a research hotspot.To explore the association between rs9349407 polymorphism and AD in the Chinese population.Firstly, based on the exclusion and inclusion criteria, we selected 11 independent studies from 8 articles exploring the correlation between rs9349407 variation and AD in Chinese. Secondly, we conducted a meta-analysis based on fixed and random effect models and conducted a heterogeneity test. Thirdly, we used the additive model, dominant model, and recessive model for subgroup analysis.P = 7.45E-03), which is consistent with the effect observed in Caucasian populations. Additionally, subgroup analysis showed that rs9349407 under the additive model  and dominant model  were also significantly correlated with AD susceptibility, but not under the recessive model .We demonstrated that the CD2AP rs9349407 polymorphism increases AD susceptibility in Chinese populations (OR = 1.33, 95% CI = 1.08–1.64, These existing data suggest that rs9349307 is significantly correlated with the susceptibility to AD in the Chinese population, but future studies with large samples are needed to confirm our findings. Alzheimer’s disease (AD) is a neurological illness with an insidious onset and progressive development . It is cSince AD was first diagnosed in the early twentieth century, genetic risk factors and their roles in the pathogenesis of AD have become the focus of genetic association studies . In addiP = 1.20E-02). Another large 3-stage analysis of the GWAS datasets of European descent individuals by P = 1.20E-06). In contrast to the results of GWAS, P = 7.20E-01). Simultaneously, numerous researchers have also extensively explored and researched the potential correlation between rs93349407 mutation of the CD2AP gene and genetic risk of AD in Asian populations.In a large-scale GWAS of AD, P = 8.50E-01). In the following years, five independent studies by three scholars . It’s worth noting that P = 1.50E-02). Furthermore, three additional studies . In addition to the preceding study, the meta-analysis concluded by P = 8.78E-07).scholars  found no studies  in ChineIn conclusion, we found that previous and recent research on the association between the rs9349407 mutation of the CD2AP gene and the risk of AD in the Chinese population has not reached the same conclusion. The conflicting results may be influenced by several factors. The main reasons may be due to the lack of meaningful data caused by the small sample size of candidate gene research in each study and the genetic heterogeneity of the rs9349407 polymorphism in AD among different populations. Therefore, by collecting all published studies that meet the inclusion criteria in the Chinese population, we conducted a comprehensive and updated meta-analysis of 11 studies, including 4,173 AD individuals and 6,137 control individuals, to evaluate the relationship more accurately between the rs9349407 mutation of the CD2AP gene and the risk of AD in the Chinese population.1 China National Knowledge Infrastructure (CNKI2), PubMed,3 Web of science,4 and Wanfang.5 Keywords “AD,” “CD2AP,” “rs9349407,” and “China or Chinese” were used to select all possible studies. The literature search ended on 1 April 2022. In addition, we conducted a manual search of references cited in published articles to identify other studies that had been initially overlooked.We conducted a comprehensive literature search of five databases, including Google Scholar,The following criteria were used to determine the included published studies: (1) the selected studies were published before 1 April 2022; (2) the selected studies must evaluate the relationship between rs9349407 variation of the CD2AP gene and AD; (3) the experimental design of the included studies was case-control design and provided the number of cases in the case group and the control group; (4) the selected studies must provide the number of rs9349407 alleles or genotypes or sufficient data to calculate the number of rs9349407 genotypes, or (5) the included studies must provide an odds ratio (OR) and a 95% confidence interval (CI), or provide relevant data to calculate the OR and a 95% CI; Studies that do not meet either of the above inclusion criteria will be excluded.P-value .According to the inclusion criteria listed above, we independently and carefully extracted relevant information from all eligible studies. When there are different data extraction results, first try to solve them through discussion. If there is still no consensus, it is up to other authors to decide. Extracted data, including (1) the name of the first author; (2) the year of publication; (3) the population; (4) the numbers of AD cases and controls; (5) the numbers of rs9349407 genotype distribution of cases and controls; (6) basic information of the study, such as OR, 95% CI and The rs9349407 polymorphism of the CD2AP gene contains two types of variants (G and C). G is the major allele and C is the minor allele. We hypothesized that G and C were high and low risk factors for AD, respectively. In this meta-analysis, we used an allele model to evaluate the relationship between rs9349407 and AD. Dominant model (GG + GC vs. CC), additive model (GG + CC vs. GC) and recessive model (GG vs. GC + CC) were also used for analysis of this study only in the studies that provided GG, GC, and CC genotype data .Q test and I2 statistics {I2 = [Q-(K-1)]/Q × 100%}. The Q statistic approximately follows an X2 distribution with k-1 degrees of freedom . P < 0.10 and I2 > 50% indicated the existence of heterogeneity. In addition, based on the results of the heterogeneity test, fixed-effect models or random-effect models were selected to calculate the OR and 95% CI of the meta-analysis to assess the degree of genetic association. If the P-value of the Q test is <0.10 and I2 > 50%, indicating significant heterogeneity, the random-effects model is used to calculate the OR of the meta-analysis. In contrast, if the heterogeneity between studies is not significant, a fixed-effects model is used. The significance of pooled OR was determined by the Z test, in which PZ < 0.05 shows an obvious statistical difference. All statistical methods were performed using R.6The heterogeneity between studies was assessed by Cochran’s P < 0.05 represents significant publication bias)  . In thisAs shown in I2 = 77%, P < 0.01, recessive model (GG vs. GC + CC) I2 = 79%, P < 0.01, and additive model (GG + CC vs. GC) I2 = 72%, P < 0.01. Therefore, the three gene models have obvious heterogeneity, so the random effect model is selected for meta-analysis. However, the heterogeneity of the dominant model (GG + GC vs. CC) I2 = 39% and P = 0.14 was not obvious, so the fixed effect model was selected for analysis. Through this analysis, we found that the overall data, including 4,173 cases and 6,137 controls, showed a significant correlation between rs9349407 variation and the genetic risk of AD in allele model   08–1.64) , additiv08–1.64) . In the 08–1.64) . More deSince there was a great degree of heterogeneity among the studies on the rs9349407 variation of the CD2AP gene, the stability of the results was determined by the results of sensitivity analysis. We conducted a sensitivity analysis by removing and including studies one by one, and the analysis results are shown in P < 1.00E-04). Therefore, the shear complement method was used to evaluate its impact on the meta-analysis results. Two studies were filled in the right side of the funnel plot, which showed a completely symmetric inverted funnel plot   . FurtherIt is reported for the first time from GWAS that the CD2AP rs9349407 polymorphism is significantly associated with AD of Caucasian descent to continuous duplication in the Caucasian population . All theAlthough a link between CD2AP deficiency and glomerular pathology has been described, little is known about the function of CD2AP in the brain. The following evidence suggests that the potential pathways of CD2AP in the pathogenesis of AD mainly include four aspects. (1) CD2AP is connected to AD neuroinflammation; CD2AP is expressed in brain neurons and microglia, the central nervous system’s primary immune cells. In AD patients and mouse models, microglia dysfunction has also been identified . (2) CD2N = 10,310; 4,173 AD individuals and 6,137 healthy controls) based on the above 11 studies. In this study, it was revealed that the CD2AP rs9349407 polymorphism in the allele model can increase the susceptibility to AD in the Chinese population, which is consistent with the effect observed in the Caucasian AD cohort. In addition, subgroup analysis showed that rs9349407 variation under the additive model and the dominant model was also significantly correlated with AD susceptibility in the Chinese population , while no correlation was found between them in the recessive model (GG vs. GC + CC: P = 7.44E-02). In conclusion, this updated meta-analysis provides strong evidence for the involvement of the CD2AP rs9349407 variant in AD susceptibility in the Chinese population.Since 2013, the correlation between rs9349407 and AD in the Chinese population has become a research hotspot in recent years. In this paper, we searched five databases, including PubMed, Google Scholar, and CNKI, based on strict inclusion and exclusion criteria and found 11 independent studies with case-control experimental design as the deadline was on 1 April 2022. Although the above studies assessed the potential association between rs9349407 and AD risk in the Chinese population, no consistent conclusion were published. For example, six studies  did not Nevertheless, there are some inevitable limitations to this study, and we hope that future research can avoid them as much as possible. First, the sample size of the included studies is quite limited, which may have varying degrees of impact on the reliability of some subgroup analysis results. Therefore, further large-scale replication studies in the Chinese population are still needed. Second, unpublished studies may be unintentionally excluded from our meta-analysis and more sensitive populations were selected in the small sample studies, which may lead to publication bias. Third, our results are uncorrected estimates and do not consider the influence of confounding factors such as age, gender, environment, education level, and lifestyle habits. Therefore, if there is more detailed personal data, we can conduct a more accurate hierarchical analysis to eliminate the interference of confounding factors and prove our conclusion. The fourth is that AD is a complex disease about the interaction between genes and genes as well as between genes and the environment. However, the studies included in our meta-analysis did not assess the interaction between the rs9349407 variant of the CD2AP gene and other genes or the environment. The last limitation is related to the diagnosis of AD. At present, the diagnosis of AD is mostly based on DSM, CERAD, NINCDS-ADRDA, and other diagnostic criteria, most of which do not provide pathological evidence for further confirmation. Therefore, misdiagnosis and missed diagnosis of AD cannot be ruled out in the included studies. Although this meta-analysis has limitations, it is the most comprehensive meta-analysis to date of the association of the rs9349407 variant of the CD2AP gene with susceptibility to AD in the Chinese population.In conclusion, this meta-analysis indicates that there is a significant correlation between the rs9349407 variant and AD risk in the Chinese population. However, more detailed genetic studies on AD with a large sample size are still needed to further prove our conclusion in the future.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.SG and G-YL designed the study. SG, J-WH, Y-NZ, XL, TW, Z-FH, and J-YS analyzed the data. SG, J-WH, Y-NZ, XL, TW, Z-FH, and G-YL wrote the manuscript. J-YS and B-LS put forward constructive modification suggestions and participated in the revision of the article. All authors contributed to the article and approved the submitted version.


Cancer and cardiovascular disease remain leading causes of death and disability worldwide, which places a heavy burden on public health systems and causes widespread suffering. Because these entities have highly overlapping risk factors, including hyperlipidemia, hypertension, diabetes, obesity, smoking and other lifestyle factors, many studies have reported that they have similar etiological mechanisms. Accumulating evidence indicates that there is an increased risk of cardiovascular disease among cancer survivors compared with the general population. However, whether cancer is associated with an increased risk of cardiovascular disease remains controversial.We will conduct and report the meta-analysis strictly based on the Cochrane Handbook for Systematic Reviews and the Meta-analysis of Observational Studies in Epidemiology guidelines combined with the Preferred Reporting Items for Systematic Reviews and Meta-analysis for Protocols (PRISM-P). This meta-analysis was registered with PROSPERO (registration number CRD42022307056). We will search for studies published from database inception to December 1, 2021, regardless of language or date, in three electronic databases  to identify and appraise cohort studies examining the relationship between cancer and subsequent cardiovascular disease risk. The literature screening, inclusion and data extraction will be conducted independently by two investigators using pre-designed standardized data extraction forms. A senior investigator will be consulted in cases of disagreement. We will assess risk of bias in the included cohort studies using the Newcastle–Ottawa Scale (NOS). Quantitative synthesis will be conducted using a random-effects model. To explore potential sources of heterogeneity, we will carry out multiple sensitivity analysis, meta-regression and subgroup analysis according to baseline characteristics. Publication bias will be evaluated through visual inspection of funnel plot asymmetry as well as by Begg's rank correlation test and Egger's weighted linear regression test. Cancer and cardiovascular disease remain the leading causes of death and disability worldwide, which places a heavy burden on public health systems and causes widespread suffering –6. It haCancer and cardiovascular disease have highly overlapping risk factors, including hyperlipidemia, hypertension, diabetes, obesity, smoking and other lifestyle factors –15, and www.crd.york.ac.uk/prospero).We will conduct and report our meta-analysis strictly based on the Cochrane Handbook for Systematic Reviews and the Meta-analysis of Observational Studies in Epidemiology guidelines combined with the Preferred Reporting Items for Systematic Reviews and Meta-analysis for Protocols (PRISM-P)  Supplem. Details*/malignanc*/carcinoma AND cardiovascular diseases/coronary disease/stroke/myocardial infarction/myocardial ischemia/heart failure AND cohort study/longitudinal study/follow-up study/prospective study/retrospective study  or EMBASE Subject Heading (Emtree) terms along with free-text words that are associated with cancer and cardiovascular disease. The following search keywords and search logic will include cancer/tumor/tumor/oncology/neoplasmWe will include studies with the following inclusion criteria in qualitative analyses: (1) studies involving a prospective or retrospective population-based cohort; (2) participants diagnosed with cancer but no history of cardiovascular disease or not diagnosed with cardiovascular disease at the time of participant enrolment based on the International Classification of Diseases, Seventh to Tenth Revision (ICD 7–10) criteria in the population-based cohort and diagnosed with one type of cardiovascular disease during the subsequent follow-up period; (3) studies reporting risk estimates, including relative risk (RR), hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals (CIs), or studies that can provide relevant data to be used to estimate risk ratios. We will exclude hospital-based cohort studies and those with inadequate data to estimate risk ratios.Data extraction will be conducted independently by two investigators using pre-designed standardized data extraction forms and crosschecked by a third investigator. Disagreements will be resolved by consensus. The following study characteristics will be abstracted: first author, publication year and design, geographic region, observation period, participant age at cancer diagnosis, comparison population, criteria of diagnosis for cancer and cardiovascular disease, study findings and risk estimates of the association of cardiovascular disease with cancer.The risk of bias for the included studies will be assessed using the Newcastle–Ottawa scale (NOS) tool according to three major aspects: representativeness of the patients, ascertainment of exposure and outcomes and adequacy of follow-up . A totalI2 statistic will be employed to quantify the proportion of the total variation leading to heterogeneity, where an I2 > 50% indicates substantial heterogeneity . The summary RR among cancer survivors compared with that among the non-cancer population accompanied by its 95% CI will be defined as the primary outcome. Given the expected large heterogeneity for the participants, study design, and clinical and methodological aspects among the included studies, we will adopt the DerSimonian–Laird random-effects model to calculate risk estimates . RR willogeneity .post-hoc: study design, geographic regions, methodological quality, outcome division, age, sex, attained age, adjuvant therapy, cancer site and cardiovascular disease type. In addition, sensitivity analysis will be carried out by removing one study at each time and repeating the analysis to evaluate whether any individual study considerably influences the summary estimates. Meta-regression will also be performed to explain the effects of heterogeneity. We will explore the possibility of publication bias with visual inspection of a funnel plot and with Begg's rank correlation test and Egger's weighted linear regression test if 10 or more studies are included in the meta-analysis .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.


According to relevant clinical research, dietary and circulating antioxidants vitamin A are connected with the risk of breast, cervical, and ovarian cancer in women. However, there was inconsistency between the findings. We completed this meta-analysis at the right moment to address this contradiction of the problem.  Web of Science, Embase, and PubMed databases were searched using the proposed search strategy and filtered using the inclusion and exclusion criteria as well as the NOS quality score. As of May 2022, low intake or low concentration was used as a control, and odds ratio (OR) or relative risk (RR) and ninety-five percent confidence intervals (95% CI) were extracted for high intake. Stata 12.0 was used to process the data. I2 = 56.1%) and serum or plasma . Subgroup analyses were performed according to cancer type, diet or supplements, serum or plasma, study type, and geographic regions.  Our meta-analysis included a total of 49 studies, 29 on breast cancer, 10 on ovarian cancer, and 10 on cervical cancer. There were 38 case-control studies included, with 25,363 cases and 42,281 controls; there were 11 cohort studies included, 1,334,176 individuals were followed up, and finally 9496 obtained cancer. The pooled OR value results were as follows: diet or supplements (OR = 0.83, 95% CI 0.76-0.90,  In North American and Asian populations, high dietary consumption of vitamin A or supplements decreases the incidence of three cancers in women, with breast and ovarian cancers being more significant. However, high circulating vitamin A concentrations were not significantly connected with the risk of the three malignancies. With the development of science and technology and the progress of society, women's health has been paid more and more attention by people. However, the incidence and mortality of malignant tumors have gradually increased and become a major killer endangering human health , 2. AmonAccording to studies, excessive generation of reactive oxygen species (ROS) in the body has been linked to the emergence and progression of a number of chronic and degenerative disorders, including Alzheimer's disease, cardiovascular disease, digestive system diseases, and malignant tumors , 13. NorSince the new century, with the deepening of research on the role and mechanism of antioxidants, the great medical prospects of antioxidants have been revealed and attention has been paid to the association between antioxidant intake and various cancers . VitaminUtilizing the Embase, Web of Science, and PubMed English databases, two writers (Han X and Zhao R) independently searched the literature for vitamin A and human breast, cervical, and ovarian cancer risk. The key search terms were as follows: “Vitamin A” or “Retinol” or “All-Trans-Retinol” or “All Trans Retinol” or “Nutrients” paired with “Breast cancer” or “Cervical cancer” or “Ovarian cancer”. The search period was from inception to May 2022. In addition, to avoid possibly overlooked papers, we carefully examined references from pertinent reviews, meta-analyses, and so on. The language included in this study was restricted to English. The third writer resolved the search debate between the two writers.The following standards were applied to determine inclusion studies: (1) the patients were definitely diagnosed with breast cancer or ovarian or cervical cancer; (2) the types of included studies were prospective cohort studies and case-control studies; (3) the subjects of the studies were human clinical studies, excluding cell and animal trials; (4) the correlations between circulation or dietary vitamin A levels and supplement doses and the incidence of breast, ovarian, and cervical cancer were the connections of interest; and (5) containing data indicating the risk of the disease: odds ratio (OR) or relative risk (RR) and ninety-five percent confidence intervals (95% CI). We applied the following exclusion criteria: (1) reviews or meetings or letters to the editors or abstracts, (2) studies on animals, (3) repeat studies, (4) research into other malignancies, (5) lack of data on RR or OR, and (6) other kinds of vitamins.Two writers completed quality assessment and extracted pertinent data on the included research, respectively. The following basic information was included: the first author's name, publishing year, region, age, cancer type, kind of study design, sample size, OR or RR, and 95% CI, covariates involved in correction. The differences between the two writers Han X and Zhao R were discussed and decided by other writers. The NOS score was utilized to judge the quality of each article, and studies with scores more than or equal to 6 points were eligible for inclusion in this meta-analysis.Q and I2 tests to analyze the heterogeneity of the studies. If the Q-test (PQ), P value < 0.1, or I2 > 50%, indicating significant heterogeneity among the research, a random-effects model was utilized. On the contrary, a fixed-effects model was utilized. Forest plots were used to show the combined outcomes of this meta-analysis, and Begg's funnel plot and Begg's test were used to evaluate the publication bias of the studies. Finally, the stability of the combined data was tested using sensitivity analysis. All the above calculations were analyzed using the Stata 12.0 software for Windows, and P < 0.05 was regarded as statistically significant.From the included studies, the cancer risk HR, OR, or RR of the highest intake was extracted one by one against the lowest intake (or the lowest concentration in the circulation). In the original study, prospective cohort studies mostly used RR values or HR values to assess the risk of morbidity and case-control studies mostly used OR values to evaluate the risk of morbidity. Since the differences among the three are small, all risk results are presented as ORs to better combine and calculate the study results. In addition, we performed n = 2905), including PubMed (n = 1021), Web of Science (n = 988), and Embase (n = 896). Endnote was used to remove duplicates leaving 1189 articles. After reviewing the article titles and abstracts, 1092 were excluded because they were not related to the study subjects, article type, or study purpose. 97 full texts needed to be downloaded, of which 48 were excluded after initial examination because of unqualified article quality or lack of important data. Finally, 49 publications that fully satisfied the inclusion criteria and were of sufficient quality were included in our meta-analysis. Perform related literature search in 3 major databases using the specified search methods: total  reduced a woman's risk of three cancers by 17% , we chose a random-effects model for pooling. We subgroup analyzed the kind of cancer and discovered a significant inverse relationship between high vitamin A consumption and breast cancer incidence , we chose the fixed-effects model to combine effect sizes. Our subgroup analysis by types of malignant tumor found that high concentrations of circulating vitamin A were not significantly associated with the incidence of breast  in the prevention of cervical, breast, and ovarian cancer. In the past century, retinol and its derivatives have attracted much attention due to their wide range of physiological functions, which can affect cell differentiation, proliferation, and apoptosis, further affect individual growth and aging, and play a vital physiological role in a variety of biological activities . The occSeveral meta-analyses have previously been conducted to investigate the link between dietary or circulating vitamin A and the incidence of breast, ovarian, or cervical cancer. In 2011, Fulan et al. did a meta-analysis of diet vitamin A intake and breast cancer incidence, discovering that high vitamin A intake lowers the incidence of breast cancer by 17%, which is similar to our findings . The resI2 = 56.1%, P < 0.001), while there was no apparent heterogeneity in the combined data of circulating vitamin A . In meta-analysis, heterogeneity is inescapable, and it is our crucial responsibility to identify and investigate its causes. Firstly, when the heterogeneity is large, we choose the random-effects model for effect size combination; secondly, we determine the source of heterogeneity through detailed subgroup analysis. For diet and supplements, we subgroup analyzed by tumor type and found that the heterogeneity of ovarian cancer combined was low, and the heterogeneity of cervical cancer and breast cancer was high; we subgroup analyzed by study type and found that the heterogeneity of the cohort study combined was low, while the heterogeneity of case-control study was high; we subgroup analyzed by diet or supplements and found that the heterogeneity of diet combined was high, while the heterogeneity of supplement was low; finally, we conducted a subgroup analysis by geographic location and discovered that the heterogeneity was high in Asia and low in North America, Oceania, and Europe. Furthermore, various objective factors, such as ethnicity, nutritional structure, economic development status, and HPV vaccination status, may enhance heterogeneity. This may be followed by heterogeneity due to nonuniform methods and details of the study itself and inconsistency between diet and vitamin A concentration assessment tools or scales. The inconsistency in the specific dose limit for high intake and low intake is an important cause of heterogeneity. Therefore, strict and unified inclusion and exclusion criteria, large multicenter randomized controlled trials, or cohort studies are needed to more clarify the relationship between vitamin A and the three cancers in women. We tested the studies used for our meta-analysis for bias by Begg's tests and Begg's funnel plots and found that there may be some publication bias. The reason may be that we only searched the English language database and not the databases of other language kinds, resulting in some studies not being included. It is also possible that there were some unpublished results that we could not retrieve and include. As a result, our findings should be interpreted with care.We discovered heterogeneity in the combined data of dietary and vitamin A supplements with the risk of the three cancers in women  is frequently used in relevant clinical trials, which raises our concerns about the toxicity of excessive intake of vitamin A. Cases have been reported in which excessive intake of vitamin A can lead to acute toxic reactions, including headache, nausea, vomiting, diarrhea, blurred vision, depression and anxiety, and other symptoms of nerve damage –65. In aIn North American and Asian populations, higher dietary consumption of vitamin A or supplements lowers the incidence of three cancers in women, with breast and ovarian cancers being more significant. However, high circulating vitamin A concentrations were not significantly linked to the incidence of the three malignancies. Moderate increases in dietary vitamin A intake or supplements are recommended to prevent the development of these cancers in high-risk groups for these three cancers. From this point of view, vitamin A, as one of the typical antioxidants, has a promising medical application, and multicenter prospective cohort studies or large randomized controlled trials are encouraged to verify the above conclusions.


To examine tear function in patients with diabetes mellitus (DM).Systematic review and meta-analysis.We searched Embase and PubMed from database inception to March 16, 2022. We included observational studies that compared tear function between patients with and without DM. Tear function was measured using invasive tear breakup time (ITBUT) and Schirmer’s 1 test. Pooled results are presented as standard mean difference (SMD) with 95% confidence interval (CI) based on random-effects models.We included 59 studies  comparing the tear function between patients with and without DM. This meta-analysis indicated that patients with DM had worse tear function than those without DM , and the results remained consistent in patients with different types of DM  and from different ethnic backgrounds . Patients with DM under poor glycemic control had worse tear function than those of the non-DM group , whereas there were no significant differences in tear function between patients with DM under optimal glycemic control and non-DM groups.We found that patients with type 1 or type 2 DM had significantly reduced tear function. The level of tear function could be determined by glycemic control, and therefore, our findings suggest that glycemic control in patients with DM is critical for maintaining tear function.https://www.crd.york.ac.uk/prospero, identifier CRD42021250498. Diabetes mellitus (DM), a leading public health issue, affects more than 240 million people worldwide, and this number is expected to reach 370 million by 2030 . In addiPatients with DED often complain of a burning sensation, photopsia, foreign body sensation, soreness, itchiness, redness, and blurred vision. The corneal complications of DED include superficial punctate keratitis, neurotrophic keratopathy, and epithelial defects. In fact, both DM and DED are risk factors for corneal infection, scarring, perforation, and irreversible tissue damage . DM incrA previous systematic review and meta-analysis by Lv et al. indicated that tear function is worse in patients with DM than in individuals without the disease, but we recommend that more detailed subgroup analyses should be considered to deal with the impacts of the clinical heterogeneity within the included studies, especially as regard different types of DM . For exaIn this study, we aimed to systematically examine the evidence on tear function in patients with DM; specifically, we evaluated tear function in these patients by conducting different subgroup analyses, including type of DM, age, ethnicity, and glycemic control status.This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines . The stuWe searched Embase and PubMed for relevant records from the inception of these databases to March 16, 2022. The search strategy is presented in Inclusion criteria for studies were as follows: (a) study groups included participants with DM, including type 1 DM, type 2 DM, GDM, and unclassified DM, and the control groups included participants without DM; (b) study outcome assessments used common tests to assess DED severity ; and (c)We included two tests for DED severity as study outcomes . First, To evaluate differences in tear function within different subgroups of DM types, age, ethnicity, and DM control status, we further compared (1) tear function in the pertinent DM group with type 1 DM versus type 2 DM versus GDM versus unclassified DM; (2) mean participants’ age as those <65 versus >65 years old; (3) participants’ ethnicity as Asian versus non-Asian; and (4) mean glycosylated hemoglobin (HbA1C) levels as <7% versus >7%.Two investigators (YKK and ETL) independently extracted data regarding the study region, inclusion period, trial design, subgroups, sample size, mean age, sex ratio , DM duration, and HbA1C levels from the included studies. The outcome data for the meta-analyses included Schirmer’s 1 test and ITBUT. Because the outcomes of study interest were continuous data, we first extracted the mean and standard deviation (SD) from the included studies for the meta-analyses. If the included studies only reported the standard error (SE) or interquartile range (IQR), we calculated the SD using the formula SE = SD/√N and IQR/1.35, respectively , 20. If Two investigators (YKK and ETL) independently assessed the study quality using an adapted form of the Newcastle–Ottawa Quality Assessment Scale for observational studies . This sc2 values to measure statistical heterogeneity among the studies. Furthermore, we performed subgroup analyses to evaluate the differences in tear function in patients with different types of DM, age, ethnicity, and HbA1C levels. We considered absolute SMDs of <0.2, 0.2–0.5, and >0.8 as small, medium, and large differences in DED severity, respectively, between the DM and control groups  based on the random-effects model. We used Review Manager 5.4 software provided by the Cochrane Collaboration Network for the meta-analysis . We calcl groups . ResultsWe initially identified 466 records from Embase (n = 329), PubMed (n = 134), and three additional studies from the reference lists of previous literature. After applying our inclusion and exclusion criteria, we included 60 reports from 59 studies in this systematic review and meta-analysis Figure 1The 59 studies contributed 7,234 eyes of participants with and without DM from China  –44, TurkDetails of the risk of bias assessment are presented in 2: 95%) and Schirmer’s 1 test result .In this meta-analysis, 59 studies of DM evaluated severity of DED 3 9, 2525–82. Co2: 96%), type 2 DM , and unclassified DM . No statistical differences in ITBUT were found in participants with GDM .This meta-analysis included 41 studies that evaluated ITBUT in relation to DM type , 80, 82.2: 91%) and type 2 DM . However, no statistical differences were found in participants with unclassified DM  or GDM .There were 41 studies of DM where Schirmer’s 1 test results were evaluated , 77, 82.2: 96%), whereas no statistical differences in ITBUT were found among elderly participants .2: 92%) and elderly participants .The 36 studies of DM where Schirmer’s 1 test results were evaluated in relation to age are shown in 2: 95%) and non-Asian patients with DM .There were 41 studies of DM that evaluated ITBUT together with ethnicity , 80, 82.2: 89%) and non-Asian patients with DM .With regard to Schirmer’s 1 test results, 41 studies included ethnicity , 77, 82.2: 97%) and good control of DM .Twenty-one studies of DM investigated ITBUT in relation to HbA1C levels , 80, 82.2: 83%), but no statistical differences were found in participants with good control of DM .Twenty studies evaluated Schirmer’s 1 test results with HbA1C levels , 75, 82.Based on the meta-analyses of ITBUT and Schirmer’s 1 tests, this study indicated that patients with DM presented with worse tear function than those without DM. More importantly, our findings could be the first summarized evidence on tear function within different DM subgroups. For example, unlike types 1 and 2 DM, we found patients with GDM had similar tear function to control groups. Moreover, patients with DM with good glycemic control had similar tear function to those without DM. However, tear function was similar in Asian and non-Asian patients with DM.The influence of chronic hyperglycemia, such as in type 1 and type 2 DM, on DED has been elucidated by several mechanisms, including microvascular changes of the lacrimal gland, a reduced lipid layer in tear film composition, a high grade of conjunctival squamous metaplasia, an increased inflammatory process, and a low goblet cell density , 84. HowPrevious evidence regarding the role of ethnicity in tear function suggested that Asian populations were associated with higher risk of DED , 85, 86.2: 95%; 2: 83%; Early studies reported age as a significant risk factor for decline of tear function, because it is associated with lacrimal gland atrophy with lymphocyte infiltration, eyelid laxity, and meibomian gland dysfunction –93. In tCompared with previous systematic review with meta-analysis , this prIn conclusion, this systematic review and meta-analysis found that patients with type 1 or type 2 DM had worse tear function compared with the non-DM groups. The level of tear function could be determined by glycemic control. Our findings suggest that glycemic control in patients with DM is critical for maintaining tear function.The original contributions presented in the study are included in the article/Y-KK contributed to study planning, performed the systematic review search, and wrote the manuscript. S-CS performed study conception and meta-analysis and reviewed/edited the manuscript. E-TL contributed to study planning and implementation of supplemental analyses and reviewed/edited the manuscript. L-YP contributed to study planning and reviewed/edited the manuscript. LY contributed to study planning, wrote the methods, and reviewed/edited the manuscript. C-CS contributed to study conception and planning and reviewed/edited the manuscript. C-CS is the study guarantor. All authors contributed to the article and approved the submitted version.This research received the research grant MW#70986493 from Alcon Services AG, Taiwan Branch, Taiwan. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Epidemiological studies have been conducted on the relationship between systemic rheumatic diseases (SRDs) and dementia. Therefore, we focused on determining the extent of alliances bounded by SRDs, along with the risk of dementia.2 statistics. The quality of the included studies was assessed using the Newcastle-Ottawa Scale. Funnel plots were used to calculate the risk of bias.Two independent reviewers assessed all studies retrieved from the PubMed, EMBASE, Scopus, and Web of Science databases between January 1, 2000 and November 30, 2021. Only observational studies that estimated the possibility of dementia in participants with SRD were considered. The random-effects model was applied to forecast pooled risk ratios (RRs) and 95% confidence intervals (CI). Heterogeneity among the studies was evaluated using the Q and ISeventeen observational studies with 17,717,473 participants were recruited. Our findings showed that among the participants with SRDs, those with osteoarthritis, systemic lupus erythematosus, and Sjogren’s syndrome were highly related to an elevated risk of dementia . However, participants with rheumatoid arthritis (RA) were not associated with an increased risk of dementia .This systematic review and meta-analysis demonstrated an increased dementia risk among SRDs participants, except for RA. Dementia is a common neurological disorder associated with impaired performance in daily activities , 2. The Systemic rheumatic diseases (SRDs) such as osteoarthritis (OA), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjogren’s syndrome (SS) are chronic inflammatory conditions that are common causes of disability . Over thRegarding the current evidence of SRDs, little information can be gathered if SRDs are related to dementia. Thus, we examined the relationship between SRDs and dementia risk through an updated systematic review of evidence .The Preferred Reporting Items for Systematic Reviews and Meta-analyses  guidelinAn extensive search was conducted in the PubMed, MEDLINE, Embase, and Web of Science databases for studies evaluating the association of dementia with SRDs and dementia risk. A search strategy was developed based on the PICO  questions, and two expert authors  assisted in developing the search strategies, which are provided in To analyze the possibility of dementia incidence and diminish potential bias, our primary target included only randomized controlled trials (RCTs). However, no RCTs have been published on this topic. Therefore, we included observational studies  to reduce the recall bias. Our inclusion criteria were as follows: (1) all observational studies that evaluated the association between dementia and SRDs, (2) provided accurate information about their methodology, and (3) reported the risk estimates of dementia. We considered studies with proven diagnoses of dementia and SRDs, based on clinical guidelines or standard diagnostic codes. If studies were published as cross-sectional, case reports, editorials, review articles, or non-human studies, they were excluded. The same two expert authors (Y.-C.W. and M.-S.L.) independently examined all the topics and abstracts of the retrieved manuscripts using predefined criteria. Subsequently, the entire content of possible articles was screened for acceptability. Any differences during the study screening were resolved through discussion with the principal investigator until a final decision was made.The same expert authors  separately extracted the following data: author name (first author only), publication year, origin, database, population characteristics, study period, participant selection process, adjusting factors , number of participants, and outcome of interest (dementia). We collected only data on adjusted risk estimates, including risk ratios (RRs), odds ratios (ORs), and hazard ratios (HRs) with 95% confidence intervals (CIs). To examine the risk of bias for the included articles, the Newcastle-Ottawa Scale was applied by the same expert authors. All controversies within the period of data extraction and the possibility of bias calculation were finalized through a dissertation with other authors.2 statistic was used to evaluate appropriate heterogeneity between studies. I2 statistics ranging from 0–25%, 25–50%, 50–75%, and 75–100% were expressed as very low, low, medium, and high heterogeneity, respectively  of our study. We calculated the overall RRs of dementia and utilized the HRs and ORs from the included studies. Pooled RRs with corresponding CIs were analyzed using a random-effects model to reduce considerable clinical heterogeneity. The Iectively , 22. We The PRISMA selection flowchart is presented in the International Classification of Diseases (ICD) Ninth and Tenth Revision. The modified covariates of all encompassed studies are presented in The basic characteristics of the results and important outcomes are outlined in NOS assessment was used to examine risk bias in the selected studies. The methodological study quality was divided into two categories  according to the NOS value. In total, 11 studies had low risk bias, five had moderate risk bias, and one had high risk bias. However, the general quality of evidence was high in the meta-analysis  compared to those without SS Figure 42 statistic among these studies was 89.61%, indicating a high risk of heterogeneity.In total, ten studies examined the risk of dementia among participants with RA. Participants with RA were not related to any dementia risk  compared to those without RA Figure 52 = 81.10, Q = 5.29, tau2 = 1.10). For participants aged <65 years, the adjusted pooled RR was 1.23; 95% CI: 0.96–1.56 and the heterogeneity in these studies was very low . However, the risk of dementia among SLE patients was higher in female in comparison with male . However, the risk of excessive dementia was significantly higher in male than females among SS participants (RR: 1.24 vs RR: 1.11).To the best of our knowledge, this is the first meta-analysis examining the association between SRDs and dementia. An analysis based on 17 observational studies showed that SRDs, such as OA, SLE, and SS, were associated with an increased risk of dementia. However, no relationship was found between RA and the risk of dementia.The relationship between chronic inflammation and dementia is well established. SRDs such as OA, SLE, and SS, which trigger systemic or organ-specific inflammation, can induce cognitive impairment , 36. ThePrevious studies have also shown that the level of serum IL-1b is extremely high in dementia participants compared to controls , 49. IncThe primary advantage of the present study is the utilization of an extensive search strategy to identify and select studies and to evaluate the risk bias using standard guidelines, thereby minimizing selection bias. An expert researcher  and an epidemiologist developed the search strategy, which was further validated by three senior faculty members. Our study had some limitations. First, all the studies used diagnostic codes. Therefore, selection bias might exist. Second, the majority of these studies were published in Asian countries, which might have introduced some geographical bias. Third, no study has reported the duration of SRDs or the risk of dementia. Therefore, we were unable to calculate the effect of time on the risk of dementia. Fourth, our analysis could not categorize dementia subtypes  with SRDs due to a lack of data. Fifth, a significant heterogeneity was observed in the meta-analysis. Different study designs, geographical regions, and confounding factors may have contributed to this heterogeneity. Therefore, a random effects model was utilized because it could estimate the mean value of the distribution of effect sizes for heterogeneous populations. We also conducted subgroup analyses based on the study design and methodological quality .This systematic review and meta-analysis found that SRDs, such as OA, SLE, and SS, were associated with an increased risk of dementia. However, no significant association was observed between RA and dementia.The original contributions presented in the study are included in the article/Y-CW and W-MK proposed the research idea and wrote the draft. M-SL and C-CW performed the analysis. AP-HH supported and contributed the literature review. Y-CW, M-SL, and W-MK helped revise the manuscript. M-SL and AP-HH provided clinical suggestions. Y-CW and W-MK supported data analysis and prepared the manuscript for submission. 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.


To identify, critically appraise, and synthesize evidence on the effect of quality of dietary fat intake and different classes of fatty acids on the risk of Alzheimer’s disease (AD) and dementia in adults aged ≥50 years.We searched MEDLINE, EMBASE, Cochrane Central of Controlled Trials, and Scopus for clinical trials and prospective cohort studies published until May 2021. Two reviewers independently screened retrieved literature, extracted relevant data, and performed risk of bias assessment. Classes of fatty acids included were saturated fatty acids (SFAs), trans fatty acids (TFAs), monounsaturated fatty acids (MUFAs), poly-unsaturated fatty acids (PUFAs), and their subtypes and sources. Given between-study heterogeneity, we did not perform meta-analyses but narratively described findings from the studies.From 4,491 identified records, five articles (based on four prospective cohort studies) met the inclusion criteria. Three studies had an overall serious risk of bias, while one study had a moderate risk. Overall, we found no robust association between intake of any fatty acids type and the development of AD and dementia. For example, for SFA and TFA, there was contradictory associations reported on AD: one study found that each unit increase in energy-adjusted intake of SFA  and TFA  was associated with a decreased risk of AD, but not dementia. For PUFA, one study found that higher quintile intake of marine-based n-3 PUFA was associated with a decreased risk of AD. The intake of other fatty acids was not associated with the outcomes. The certainty of the overall evidence was inconclusive.We found no clear association between the intake of various classes of fatty acids and the risk of AD and dementia in adults. More well-designed prospective studies are required to clarify these findings. Beyond genetic predisposition, lifestyle and environmental factors, like diet, are thought to play a role in the development of Alzheimer’s disease and dementia.The role of dietary fats has been of focus in recent decades, because of their role in inflammation.By performing a systematic review of previous, we found no evidence that intake of dietary fatty acids plays any important role in the development of Alzheimer’s disease and dementia in adults aged ≥50 years.In recent decades, emerging evidence shows that the origin of Alzheimer’s disease (AD) and related dementias goes beyond genetic predisposition caused by the E4 allele of apolipoprotein E (ApoE) –9. Cleara priori (In updating the 2012 Nordic Nutrition Recommendations (NNR), the role of fat quality in the pathogenesis of AD and related dementias was one of the prioritized topics among the systematic reviews commissioned by NNR Committee. The criteria for prioritization of topics were published a priori , 19, whia priori published systematic review guidelines developed for the NNR 2022  was developed in collaboration with the authors, led by BN and JD. There were no exclusions by publication date or language. The reference list of included studies was also screened to identify potentially eligible studies. We did not include the gray literature because of its uncertain methodological quality  of the team, working independently. Literature screening was first piloted with approximately 10% of the obtained titles and abstracts before full literature screening on the remaining 90% of the papers. If at least one of the assessors voted for inclusion, the paper was included in the full text screening. Potentially eligible papers were retrieved and read in full text by the two reviewers. Discrepancies between assessors were resolved by discussion or arbitration by a senior member of the research team (AÅ).We developed and piloted a data extraction form, which was used to extract relevant data from the full-text papers by three reviewers working independently . Any discrepancies in the data extraction were resolved by discussion. The data extraction form included a minimum of the following items: the full reference, eligibility, methods, participants and settings; interventions/exposures; outcomes; main results; and confounding variables. Nutrition-specific elements, such as intake levels/doses, food sources, method for dietary assessment, validation of the dietary assessment method, food composition database used, and assessment of nutrition status, were also extracted. The study is the unit of interest; duplicate papers from the same study were extracted as one study, where relevant.Two reviewers (BN and LB) independently evaluated the risk of bias in all included studies. Any discrepancies were resolved by discussion. Since no RCTs were retrieved, assessment of risk of biased was based on the ‘Risk of Bias for Nutrition Observational Studies’ (RoB-NObS) tool (developed by the USDA’s Nutrition Evidence Systematic Review [NESR]) alone , which iWe performed a narrative synthesis of the included studies by describing the characteristics and context of the studies, their strengths and limitations, heterogeneity (in study characteristics and results), and relevance. Following the recommendations of the Agency for Healthcare Research and Quality (AHRQ) and the Cochrane Handbook, our a priori criteria to perform meta-analysis stipulated that more than three independent RCTs or five cohort studies must be available on each specific question for a meta-analysis to be undertaken –28. In aconvincing body of evidence was established as strong enough to support a causal relationship or lack of a relationship in which several conditions are met, including evidence coming from more than one study type. A probable body of evidence was supported when strong enough to support a probable causal relationship, and there was evidence from at least two independent cohort studies, no unexplained heterogeneity between or within study types, good-quality studies to confidentially exclude possible random or systematic errors, and evidence for biological plausibility. A limited – suggestive was supported when there was evidence from at least two independent cohort studies: a consistent direction of effect and evidence for biological plausibility. A limited – no conclusion evidence was established if the evidence is so limited that no firm conclusion could be made. An evidence strong enough to support a convincing absence of a causal relationship was considered substantial effects unlikely.Strength of evidence was categorized according to the World Cancer Research Fund’s grading: ‘Convincing’, ‘Probable’, ‘Limited – suggestive’, ‘Limited – no conclusion’, ‘Substantial effects unlikely’ , 20. TheA total of 2,146 records were retrieved from the database searches after de-duplication; of which 2,109 were excluded after title and/or abstract screening. Of the 37 full-text papers evaluated, five met the criteria to be included in the review  –33. FiguIn total, 530,576 participants were analyzed across the four included independent studies, with mean age range at baseline of 63–76 years. The participants were mainly healthy adults recruited from the general population or community. All the four studies were prospective cohort studies. Two of the studies were conducted in the USA , one in Of the four included studies, three received an overall serious risk of bias grading –32, whilOverall, most studies showed no putative association between SFA intake and risk of AD and dementia, except for the studies by Engelhart et al. and Kivipelto et al. . EngelhaThere were no statistically significant associations between the intake of MUFA and the risk of AD or dementia in any of the four included studies . The rolWith one exception, the studies showed no putative association between total PUFA, n-3 PUFA, or n-6 PUFA and the risk of developing AD and dementia. Kivipelto et al. found that only the second versus first quartile of the intake of total PUFA was associated with a decreased risk of developing dementia . AlthougIn the study by Engelhart et al., one SD-increment in the intake of energy-adjusted TFA was associated with a reduced risk of developing AD  but not with total or vascular dementia. However, higher quintiles of TFA intake were not statistically significantly associated with AD mortality in the study by Zhuang et al. .limited – no conclusion.On the association between SFA and the development of AD and dementia, given the contradictory evidence and the high risk of bias, we considered the certainty of this evidence as limited – no conclusion, due to tendencies toward contradictory findings.Given the absence of any statistically significant association between MUFA and AD and dementia, we considered this evidence as limited – no conclusion.Of the four studies included, two showed a trend, generally statistically non-significant, toward an increased risk of AD and dementia with the intake of PUFA, while two showed the opposite effect. On the basis of contradictory findings, we considered the certainty of this evidence as limited – no conclusion. On the association between TFA and the development of dementia, only one study considered this question, but found no statistically significant effect; hence, we considered this evidence as limited – no conclusion, since there was no basis to support a convincing presence or absence of a causal relationship.Of the two studies that investigated TFA, one showed a significantly reduced risk between TFA intake and AD, but one showed a statistically non-significant tendency toward a decreased risk. We considered the certainty of this evidence as Very few studies were identified fulfilling the eligibility criteria. Overall, we found no robust association between the intake of any fatty acid type and the development of dementia or AD. For SFA and TFA, there was even contradictory associations reported on specifically AD. There was no clear association between MUFA and PUFA and their subtypes, and AD and dementia. In the light of these findings, we considered the overall evidence on the role of fatty acids in the development AD and dementia to be at best inconclusively limited.We followed established processes for undertaking robust systematic reviews. The NNR 2022 Committee, a priori, established criteria for the prioritization and selection of a systematic review topic . To enhaThree of the four included studies were graded as having serious risk of bias –32, whicTwo previous systematic reviews reported mixed results on the association between the intake of dietary fats and the risk of cognitive outcomes. In the study by Barnard et al., who included also two of the studies included in the present review, the association between SFA and TFA and dementia was synthesized in prospective cohort studies . The autAdvances in our understanding of the disease mechanisms for AD and related dementias show that they are diseases with complex pathogenesis, involving a complex interplay of genetic, environmental, and lifestyle risk factors. The dietary fat quality, especially a higher intake of SFA/TFA, has been proposed to be linked with risk of dementia, including AD . PotentiWe found no putative association between the intake of various classes of fatty acids and their subtypes and the development of adverse cognitive outcomes in adults. If any potential effect exists, we consider such at best inconclusively limited. More long-term prospective cohort studies may help to clarify and elaborate on these observations.Funding was received from the Nordic Council of Ministers and governmental food and health authorities of Norway, Finland, Sweden, Denmark, and Iceland.Prospero registration number CRD42021235829.Click here for additional data file.


Heatwaves are becoming more frequent and may acutely increase the risk of stillbirth, a rare and severe pregnancy outcome.Examine the association between multiple heatwave metrics and stillbirth in six U.S. states.th percentile) during the exposure window, as well as a continuous measure of mean temperature during the exposure window modeled using natural splines to allow for nonlinear associations. State-specific odds ratios (ORs) and 95% confidence intervals (CI) were estimated using conditional logistic regression models. State-specific results were pooled using a fixed-effects meta-analysis.Data were collected from fetal death and birth records in California (1996–2017), Florida (1991–2017), Georgia (1994–2017), Kansas (1991–2017), New Jersey (1991–2015), and Oregon (1991–2017). Cases were matched to controls 1:4 based on maternal race/ethnicity, maternal education, and county, and exposure windows were aligned . County-level temperature data were obtained from Daymet and linked to cases and controls by residential county and the exposure window. Five heatwave metrics  were created using different combinations of the duration and intensity of hot days , three of the five heatwave metrics examined were not associated with stillbirth. However, four consecutive hot days during the previous week was associated with a 3% increase in stillbirth risk , and a 1 °C average increase over the threshold was associated with a 10% increase in stillbirth risk . In continuous temperature analyses, there was a slight increased risk of stillbirth associated with extremely hot temperatures (≥ 35 °C).Most heat wave definitions examined were not associated with acute changes in stillbirth risk; however, the most extreme heatwave durations and temperatures were associated with a modest increase in stillbirth risk.The online version contains supplementary material available at 10.1186/s12940-022-00870-y. Stillbirth is a rare, severe birth outcome that affects 1 out of every 160 births in the United States –6, but on = 5047), Auger et al. reported that the odds ratio for a temperature of 28 °C the day before death, compared to 20 °C, was 1.16  , . It is important to note that a one degree increase in this metric is extremely large, and a value for HW3 that was greater than 1 only occurred on average 1.04 days per year across counties (0.2% of days). Estimates were elevated for HW3 in all states except New Jersey, where there was no association between heatwaves and stillbirth, regardless of the definition used. This classification of a heatwave represented the most extreme definition used and incorporated both the duration and magnitude of the heatwave in the previous week, as well as county-specific thresholds. To put this into context, in Florida the average temperature in the previous week would have to be over 29.0 °C, whereas in Oregon this would only be an average degrees over 22.3 °C. Although the two temperatures differ in magnitude, they had a similar effect on the risk of stillbirth within each state , providing some evidence that local extreme temperatures are important to consider instead of an overall absolute temperature measure.An unexpected finding from our analyses was the suggestive association between extreme cold temperatures during the exposure window and stillbirth, especially in states where temperatures below 0 °C are more common. In Kansas and New Jersey, the ORs for stillbirth associated with a temperature of 0 °C, compared to 20 °C, were 1.11 , and 1.10 , respectively [pooled OR(CI): 1.02 ]. This finding is similar to results by Ha et al., who reported that chronic exposure to cold temperatures during pregnancy increased the risk of stillbirth more than chronic exposure to hot temperatures; however the authors did not find evidence that acute exposure to cold temperatures increased the risk of stillbirth . When teAlthough race/ethnicity is an unlikely confounder in this context due to purely temporal contrasts of exposure, we examined race/ethnicity as a possible effect modifier and observed some evidence that there was an increased risk of stillbirth among non-Hispanic black mothers, which is consistent with previous studies examining racial differences in the association between environmental exposures and birth outcomes , 22, 23.We hypothesized that stillbirths after 28 weeks gestation would be more sensitive to the acute effects of extreme temperatures, but despite the potential etiologic differences between early and late stillbirths, we did not find evidence that the timing of the stillbirth in pooled or state-specific results changed the conclusions. Across states, there were differences in the proportion of stillbirths that were delivered before 28 weeks compared to the proportion that were delivered after 28 weeks. However, when looking at stillbirths as a percent of all pregnancies (Supplemental Table Acute risk factors for stillbirth are difficult to investigate because the timing of the fetal death is unknown, and instead studies must rely on the date of delivery. Because of this, there may have been misclassification of the exposure, using the week before delivery instead of the week before fetal death. Most fetal deaths occur within two days of delivery , meaningThis is the largest study to date that has examined the association between acute heatwaves and stillbirth. Even with this extremely large sample, estimates were often imprecise due to both heatwaves and stillbirths being rare events, but associations were estimated with more precision than previous studies. We used a geographically diverse sample to examine multiple heatwave metrics that took into account county-level thresholds and local acclimatization; results varied by how heatwaves and temperatures were operationalized. We found evidence that only the most extreme heatwave definitions and continuous temperature metrics were associated with a modest increase in the risk of stillbirth. These results are important in the context of increasing global temperatures and highlight a potential risk-factor for stillbirth that is likely to become more common in the future. Although heatwaves are not a modifiable risk factor, healthcare providers should be aware of the potential effects of extreme temperatures and should counsel patients to take preventive measures during periods of extreme heat. Future studies are needed to support our findings and should aim to assess the association between acute heatwaves and stillbirth using a variety of heatwave and temperature metrics in large, geographically diverse populations.Additional file 1: Supplemental Figure 1. County-level 7-day mean temperature distribution by state, 1991-2017. Supplemental Table 1. Rate of stillbirth across states. Supplemental Table 2. Odds ratios and 95% confidence intervals for the association between heatwaves and stillbirth in California, Florida, Georgia, Kansas, New Jersey, and Oregon. Supplemental Table 3. Odds ratios and 95% confidence intervals for the associations between heatwaves and stillbirth by maternal race, by state. Supplemental Table 4. Odds ratios and 95% confidence intervals for the association between heatwaves and stillbirth by the timing of the stillbirth, by state. Supplemental Table 5. Select estimates for continuous temperature model, reference 20°C. Supplemental Table 6. Select estimates for continuous percentile model, reference 50%. Supplemental Figure 2. Comparison of continuous temperature model versus categorical temperature model, pooled results. Supplemental Figure 3. Comparison of continuous percentile model versus categorical temperature model, pooled results. Supplemental Table 7. Odds ratios and 95% confidence intervals for categorical temperature model. Supplemental Table 8. Odds ratios and 95% confidence intervals for categorical percentile model.


The changes of blood lipid levels in patients with Parkinson's disease (PD) and its clinical relevance remain unclear. We aimed to evaluate the potential association of blood lipid and the occurrence of PD, to provide evidence to the clinical treatment and nursing care of PD.  We searched PubMed, Medline, Web of Science, Cochrane Library, Wanfang Database, Weipu Database, and China National Knowledge Infrastructure for studies related to the blood lipid levels and PD until November 30, 2021. Two researchers independently screened the literature and extricated the data including the levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of included studies. RevMan5.3 and Stata 12.0 software were used for statistical processing and analysis. P=0.04), TG , HDL-C  and LDL-C  level in the PD patients was significantly lower than that of health controls. Sensitivity analysis indicated that the results were stable. No significant publication bias was found between the synthesized outcomes.  A total of 15 cohort studies with 9740 participants involving 2032 PD patients and 7708 controls were included. Meta-analysis indicated that TC (SMD = −0.29, 95% CI −0.55∼−0.03,  Lower blood TC, TG, HDL-C, and LDL-C level are associated with the occurrence of PD. Limited by sample size and study population, further high-quality, large-sample clinical trials in different areas are needed to further determine the relationship between blood lipids and PD in the future. Parkinson's disease (PD) is a common neurodegenerative disease, and the incidence of PD in people over 65 years old is nearly 2% –3. The cRecent studies –9 have sWe aimed to prepare and report this meta-analysis and systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) .The two authors searched PubMed, Medline, Web of Science, Cochrane Library, Wanfang Database, Weipu Database, and China National Knowledge Infrastructure CNKI) databases on all publicly published original documents related to blood lipid levels and PD up until March 5, 2022. The search strategy  publicly published case-control or cohort studies on the relationship between blood lipids and PD, and data such as sample size, mean, and standard deviation could be extracted; (2) the age of the research population was ≥18 years; (3) the diagnosis of PD met the diagnostic criteria, and the control group was matched non-PD population; (4) the language of the article was limited to English and Chinese.The literature exclusion criteria for this meta-analysis are as follows: (1) we removed reviews, case reports, meeting records, and animal and cell experiments; (2) repeated published articles; (3) reports in which data could not be extracted for statistical analysis.Two researchers independently reviewed the title and abstract of the literature for preliminary screening, and read the full text of the literature according to the inclusion and exclusion criteria to determine whether it was selected based on the inclusion and exclusion criteria.The data extraction of included studies in this meta-analysis was carried out independently by two researchers. The relevant data were extracted according to the data extraction table designed in advance, and the results were cross-checked. In case of disagreement, the third researcher would be introduced to discuss and resolve the disagreement. The extracted content mainly included: first author, publication year, region, research type, sample size, observation index including the TC, TG, HDL-C, and LDL-C level.This meta-analysis used the Newcastle–Ottawa Scale (NOS)  to evaluI2 < 50%, P > 0.05), the fixed effects model would be used. Otherwise, the random effects model would be used and the possible heterogeneity will be considered by conducting subgroup analysis and regression analysis. Standard mean difference (SMD) and 95% confidence interval (95% CI) were calculated for synthesized effect analysis, and forest plot was drawn, sensitivity analysis and publication bias assessment were performed. Sensitivity analysis was used to judge the stability of the results. A funnel chart and Begg's test were used to assess publication bias. In this meta-analysis, the difference was statistically significant with P < 0.05.This meta-analysis uses RevMan5.3 and Stata 12.0 software for statistical processing. We first conducted a heterogeneity test for the included studies. If there was no heterogeneity in the outcomes of included studies , therefore random effect model was applied for data synthesis. As showed in P=0.03).14 studies , 27–30 rI2 = 28%, P=0.18); therefore, the fixed effect model was applied for data synthesis. As shown in P < 0.001).11 studies , 27–30 rI2 = 59%, P=0.10); therefore, the random effect model was applied for data synthesis. As shown in P=0.02).10 studies , 28–30 rI2 = 93%, P < 0.001); therefore, the random effect model was applied for data synthesis. As shown in P=0.04).13 studies , 28–30 rP=0.612), HDL-C (P=0. 771), and LDL-C (P=0.606). Also, age had no significant effect on TC (P=0.147), HDL-C (P=0.096), and LDL-C (P=0.214). In addition, a subgroup analysis based on geographic location shows that the heterogeneity between Asian countries and non-Asian countries is very high. It can be seen that geographic location is not the main source of heterogeneity (P=0.131, TG: P=0.465; HDL-C: P=0.778, LDL-C: P=0.426, The results of TC, HDL-C, and LDL-C have high heterogeneity. To explore the potential sources of high heterogeneity, regression analysis was performed on variables such as age and gender. In the regression analysis, gender had no significant effect on TC (ogeneity . SensitiPD is a common neurological disease in middle-aged and elderly people, and its incidence is second only to Alzheimer's disease . PD is mα-synuclein, and the polymorphism of α-synuclein gene rs356219 is related to the pathogenesis of PD. The joint action of alpha-synuclein and lipid oxidation metabolites can cause mitochondrial dysfunction and cause the death of dopaminergic neurons, leading to the occurrence and development of PD [The lipids contained in plasma are collectively called blood lipids, which are the general term for neutral fats and lipids. Neutral fats include TG and TC, while lipids include phospholipids, glycolipids, sterols, and steroids, which are essential for basic metabolism of life cells substance , 44. TG nt of PD .Previous study has found that higher levels of TC, TG, and LDL-C levels are associated with a lower risk of PD . The posCholesterol is an important component of the cell membrane, has a dual role in structure and function, and can regulate a variety of signal pathways and cell functions . AbnormaIn conclusion, the results of this study show that hypolipidemia including lower TC, TG, HDL-C, and LDL-C may be related to the pathogenesis and development of PD. Statins are commonly used clinically lipid-lowering drugs, but whether statins are currently beneficial to patients with PD remains to be further studied. It is worth noting that there is still a lack of comparisons of different age groups in terms of nutritional status and different populations, and the associations between blood lipids and development of PD still need further investigations in the future.


I2 = 25.8%, P = 0.223), which appears to be related to a shift in nutritional behaviors in the countries. Significant results were also observed in subgroups with aspartame and a mixed intake of artificial sweeteners. Moreover, higher risk was observed for artificial sweeteners intake in all-cause mortality  and a J-shaped association between them was found. More data from well-conducted studies and clinical trials are required.Cancer has become a major challenge in the global disease burden. Artificial sweeteners are a class of chemical compounds that are used as food and beverage addition agent to replace sugar. However, the health effects of consuming artificial sweeteners are still unclear. This meta-analysis was performed to evaluate the role of artificial sweeteners on cancer. The databases PubMed, Cochrane Library, MEDLINE, Web of Science and EMBASE were searched up until July 2022. A Newcastle–Ottawa scale (NOS) was used to estimate the study quality. A total of 25 observational studies were included with a total of 3,739,775 subjects. The intake of artificial sweeteners had no apparent association with overall cancer incidence and mortality. However, in Europe, artificial sweeteners’ intake could increase the risk of cancer incidence (HR/RR = 1.07, 95% CI = ,  Cancer has become a major challenge in the global disease burden. A global estimate of 23.6 million new cancer cases and 10.0 million cancer deaths occurred in 2019, which represented a 26.3% and 20.9% increase in new cases and deaths, respectively ,5,6. TheNowadays, according to the latest report, there is at least a third of adults and children who consume artificial sweeteners regularly in the United States, Europe and Australia . It is dThe PubMed, Web of Science, MEDLINE, Cochrane Library and EMBASE databases were searched up to July 2022, and the used keywords included artificial sweetener, aspartame, artificially sweetened beverage (ASBs), cancer and tumor, to screen and identify published literatures. The search had no restriction on publication date or language. The detailed search strategy of PubMed that was performed is shown in The inclusion criteria were as follows: (1) exposure: using artificial sweeteners in food, drinks and packets; (2) overall or site-specific cancer incidence or mortality, or all-cause mortality as a consequence; (3) hazard ratio (HR) or risk ratio (RR) with 95% confidence interval (CI) for the association between artificial sweetener and any type of cancer incidence and mortality was estimated; (4) animal studies, in vitro studies, duplicates, reviews, or conference papers were excluded. Two researchers independently assessed all of the included studies, resolved disagreements via discussion and collected final eligible literatures .A literature review was conducted to extract the following data: publication year, first author, region, cancer type, usage of artificial sweeteners (including type and dose) and outcome of studies. Based on the Newcastle–Ottawa scale (NOS), the bias risk for the included study was estimated .I2 statistic and p < 0.05 was considered significant. In our study, random effects models were used in all of the analyses based on the level of heterogeneity. Egger’s test was employed to gauge publication bias, while the trim-and-fill approach was used to correct results and analyze the influence of bias on them , The idea behind artificial sweeteners was originally to replace the sugar so that using these products would reduce caloric intake, result in weight loss and reduce diabetes mellitus’ incidence . HoweverOur meta-analysis found a J-shaped association between artificial sweeteners intakes and all-cause mortality, which was also observed in some original studies and other similar meta-analysis ,51. ManyExisting evidence indicated that the artificial sweeteners’ intake could indirectly cause a reduction in sugar-sweetened beverages or foods, thus leading to a decrease in the cancer incidence rate related to them . AlthougIn subgroup analyses, we evaluated the effect of artificially sweetened beverages or aspartame intake alone. Aspartame, a well-known artificial sweetener, is now used as a sweetener and flavor enhancer in six thousand food products worldwide . NotablySome limitations existed in our study. Although almost all of the original literature included are large-scale, prospective studies with long-term follow-up, the reliability of causal conclusions may not be as robust because they are all observational studies. Although possible confounding factors were adjusted in the original studies, the findings should be cautiously interpreted given the existence of residual confounding. Meanwhile, more data are also required to evaluate the effects of other artificial sweeteners on cancer.Our meta-analysis indicated that artificial sweeteners’ intake could increase the risk of all-cause mortality, but the relationship was not observed in the risk of overall cancer incidence and mortality. However, in Europe, the consumption of artificial sweeteners could increase cancer incidence. More data from well-conducted studies and clinical trials are required to confirm the association.