The extent of surgical treatment for most patients with thyroid cancer (TC) remains controversial and varies widely. As an emerging technology, genetic testing facilitates tumor typing and disease progression monitoring and is expected to influence the choice of surgical approach for patients with TC. Recent genome-wide association studies (GWASs) have identified that rs2439302 (8p12) variants near NRG1 are associated with TC risk; however, the results remain inconclusive. Therefore, we aimed to perform a meta-analysis to clarify the association between rs2439302 variants and the risk of TC.We search eligible studies using Pubmed, Scopus, Embase, Web of Science, and Cochrane library by July 2021. We analyzed the pooled OR and the corresponding 95% confidence interval (95% CI) of the included studies and then conducted subgroup analysis according to the ethnicity. We also performed a sensitivity analysis to validate the findings.This meta-analysis finally included 7 studies involving 6,090 cases and 14,461 controls. Results showed that the G allele of the rs2439302 polymorphism was a significant risk factor of TC in Allele (G/C), Dominant (GG+GC/CC), Recessive (GG/GC+CC), Homozygote (GG/CC), Heterozygote (GC/CC) models, with pooled ORs of 1.38 , 1.51 , 1.52 , 1.90 , and 1.40 , respectively. The subgroup analysis showed that rs2439302 polymorphism was associated with higher TC risk in different ethnicities with OR > 1. The sensitivity analysis exhibited that the results were stable by omitting any included studies.The study revealed that rs2439302 variants were associated with higher TC risk and may have a major influence on the choice of operative approach for patients with TC. Being the most prevalent malignancy in the endocrine system, thyroid cancer (TC) has become a serious disease threatening the health of the human being. Nearly 52,890 cases of TC were predicted to be diagnosed in the United States in 2020 . MoreoveWith the sharing of the single nucleotide polymorphism (SNPs) database represented by the International HapMap Project and the establishment and improvement of high-throughput genotyping technology, Genome-Wide Association Studies (GWASs) have become an important strategy for studying genetic mechanisms of complex diseases such as TC –10. Some−9) in 2011. Subsequently, associations between the rs2439302 polymorphism with TC risk and clinical parameters in different populations have been investigated (The SNP rs2439302 was within the first intron of NRG1 (gene encoding neuregulin 1) on 8p12. Julius Gudmundsson first demonstrated that rs2439302 was significantly correlated with TC , we conducted the systematic literature search for relevant articles from databases including Pubmed, Scopus, Embase, Web of Science, and Cochrane library, by the end of July 2021. Since the study only extracted data from published studies, ethical approval was not required. The review was not registered.The search terms we used in this study were as follows: “rs2439302,” “8p12,” “polymorphism,” “variation,” “variant,” “thyroid cancer,” “carcinoma of thyroid,” “thyroid carcinoma,” “thyroid neoplasm,” and “thyroid malignancy.” All the search records were limited to human studies and the language was restricted to English. The inclusion criteria were as follows: (1) used a case-control design; (2) evaluated the association between rs2439302 polymorphism and TC; (3) provided the number of rs2439302 genotypes or provided sufficient data to calculate the number of rs2439302 genotypes; (4) provided the odds ratios (OR) estimates and their 95% CIs or provided sufficient data to calculate the OR and 95% CI; (5) published in English or Chinese. We excluded the following studies: (1) duplicated publications; (2) irrelevant studies; (3) meta-analysis or review; (4) no access for full text; (5) case reports; (6) no associated data for extraction. As for the articles in which no relevant data are available, we contacted the corresponding authors to achieve the original data.An independent review of the included studies by 2 scientists was performed. The following parameters were extracted from the studies: the family name of the first author, the year of publication, the country of the population, ethnicity of the population, detailed number of the population, and specific genotype frequency of the population.I2 test were used for assessing the heterogeneity between studies. Higher I2 values indicated higher levels of heterogeneity . The fixed-effects model was used when the p-value was >0.05, while the random-effects model was used when the p-value was <0.05. The Egger's test and Begg's funnel plot were used to analyze the publication bias. A sensitivity assessment was performed to reveal whether the ethnicity exerted an effect on the findings. All p-values were two-sided, p < 0.05 were considered statistically significant. The statistical analysis was conducted using R software.We used the odds ratios (OR) and 95% confidence interval (95% CI) for the assessment of the association between the rs2439302 variants and TC. Five different models used were as follows: (1) G vs. C , (2) GG plus CG vs. CC (dominant model), (3) GG vs. CC plus CG (recessive model), (4) GG vs. CC (homozygous model), and (5) GC vs. CC (heterozygous model). The Chi-square test was used to analyze the Hardy-Weinberg equilibrium (HWE) for the control. Chi-square-based Q statistic and n = 2), no full text (n = 3), review (n = 1), no associated data (n = 4), and case report (n = 1). Finally, 7 studies involving 6,090 cases and 14,461 controls met our inclusion criteria . The TC risk correlated with the G allele was 1.38 times higher than that associated with the C allele  in other ethnicities and an OR of 1.42 (95% CI 1.31–1.54) in Asians . The remWe also conducted sensitivity analysis by omitting one of the included studies. The results indicated the significant association between rs2439302 polymorphism and TC, which was existed in all the five models in the sensitivity analysis , OR > 1.p > 0.05). These findings revealed the stability and credibility of our conclusions of the meta-analysis.We then carried out Begg's funnel plot and Egger's test to assess the publication bias of the studies. The funnel plots of the Allele, Dominant, Recessive, Heterozygote, and Homozygous models are symmetrical inverted funnels , which sThyroid cancer is a multifactorial disease that involves genetic mutation and environmental changes . Currentp = 0.016), and multifocality status of the tumor  (P = 0.038)  ; Further= 0.038) . The aboIn order to determine the TC risk under different genotypes, this meta-analysis analyzed the TC risk with rs2439302 based on different genetic models such as Allele (G/C), Heterozygote (GC/CC), Homozygote (GG/CC), Dominant (GG+GC/CC), and Recessive (GG/CG+CC). Results showed that the risk of TC associated with the G allele was 1.38 times higher than that of the C allele . In addition, this significant correlation between rs2439302 and TC also exists in the Dominant model , Recessive model , Homozygote model , and Heterozygote model . Subgroup analysis in different ethnicities was then carried out to investigate rs2439302 polymorphism in TC. The TC risk was significantly associated with the G allele compared with the C allele with an OR of 1.34 (95% CI 1.19–1.51) in other ethnicities and OR of 1.42 (95% CI 1.31–1.54) in Asians. It was also found that the rs2439302 polymorphism and TC were also significantly correlated based on subgroup analysis in the Dominant model, Recessive model, Homozygote model, and Heterozygote model. These findings from the sub-group analysis revealed that Asiana and other populations with rs2439302 polymorphism showed a comparable high risk for TC. Finally, the publication bias and sensitivity analysis indicated the stability of this meta-analysis.via the Begg's and Egger's tests, the funnel plots of the Dominant and Recessive models were asymmetrical inverted funnels. Thus, publication bias may have been inevitable. Therefore, further analysis using larger sample size, a standardized unbiased method, and better-matched controls are required to obtain a more convincing conclusion.Here, we found the vital association between rs2439302 and TC risk. However, some limitations still exist. First, owing to the lack of detailed information, the number of studies involved in this subject is small, which may lead to a lack of statistical capacity and hinder meaningful analysis of the results. Second, the effect of heterogeneity on the results could not be avoided even if a random-effects model was used. This heterogeneity may have been caused by factors such as a source of control, genotyping method, gene-environment interactions, and sample size. Third, although we found no publication bias Taken together, the present study indicated a significant association between rs2439302 and TC risk. Furthermore, we show that the Chinese populations have a higher risk than the Japanese and USA populations.The original contributions presented in the study are included in the article/MG and JX conceived and designed the experiments. YG and WZ performed the search and collected the data. YG and RH analyzed the data. YG and CZ interpreted the results and drafted the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.This work was supported by grants from the National Natural Science Foundation of China (81802674), Natural Science Foundation of Zhejiang Province (LY21H160049), Medical Health Science and Technology Project of Zhejiang Provincial Health Commission , and Zhejiang Province Postdoctoral Research Excellence Funding Project (ZJ2021167). The funders 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.


DRD2 Taq A1 allele and severe alcoholism in JAMA, there has been an explosion of genetic candidate association studies, including genome-wide association studies (GWAS). To develop an accurate test to help identify those at risk for at least alcohol use disorder (AUD), a subset of reward deficiency syndrome (RDS), Blum’s group developed the genetic addiction risk severity (GARS) test, consisting of ten genes and eleven associated risk alleles. In order to statistically validate the selection of these risk alleles measured by GARS, we applied strict analysis to studies that investigated the association of each polymorphism with AUD or AUD-related conditions, including pain and even bariatric surgery, as a predictor of severe vulnerability to unwanted addictive behaviors, published since 1990 until now. This analysis calculated the Hardy–Weinberg Equilibrium of each polymorphism in cases and controls. Pearson’s χ2 test or Fisher’s exact test was applied to compare the gender, genotype, and allele distribution if available. The statistical analyses found the OR, 95% CI for OR, and the post risk for 8% estimation of the population’s alcoholism prevalence revealed a significant detection. Prior to these results, the United States and European patents on a ten gene panel and eleven risk alleles have been issued. In the face of the new construct of the “preaddiction” model, similar to “prediabetes”, the genetic addiction risk analysis might provide one solution missing in the treatment and prevention of the neurological disorder known as RDS. Since 1990, when our laboratory published the association of the  The purpose of this article is to provide the scientific basis for the potential incorporation of genetic addiction risk  and psychological profiling analyses for an emerging novel concept referred to as the “preaddiction” severity index, as encouraged by both the National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA).Addiction scientists and clinicians face an incredible challenge in combatting the current opioid and alcohol use disorder (OUD/AUD) pandemic worldwide. Despite significant progress, the death toll from narcotic overdoses managed to reach over 100,000 fatalities in the United States in 2021 and could reach 165,000 in 2022. NIDA and NIAAA continue to struggle with the generation of novel approaches to combat the severity of the current substance abuse epidemic. FDA-approved medication-assisted treatments (MAT) work primarily by blocking dopamine release and function at the pre-neuron in the nucleus accumbens , and wheWhile the highest in the United States, drug overdose deaths are a problem internationally, and extraordinary solutions are needed. Short-term opioid substitution therapy can reduce harm. However, long-term patients can be locked into a lifetime of substance use disorders (SUD) . AlternaThere is increasing movement to opt for the non-addicting narcotic antagonist Naltrexone to treat Alcohol Use Disorder (AUD). Recent studies have shown that Naltrexone is beneficial by attenuating craving via “psychological extinction” and reducing relapse. Buprenorphine is currently the MAT of choice, but injectable Naltrexone plus an agent to improve dopaminergic function and tone may renew interest amongst addiction physicians and patients. Even with the extended injectable option, there is still poor compliance. As such, our group described an open-label investigation in humans showing improvement in naltrexone compliance and outcomes with dopamine augmentation with the pro-dopamine regulator KB220 262 days) compared to naltrexone alone (37 days) , where the minor allele was in association with lower mean scores on the EAI questionnaire (0.67 ± 0.92) as compared to the major (T) allele (0.76 ± 0.98) [Analysis showed a significant association between  ± 0.98) .Previous genetic association studies of addictions have mainly focused on one specific type of SUD. The Hungarian study  aimed toCNR1 gene (rs806380) and the DRD2/ANKK1 gene (rs1800497) also showed association with the “lifetime other drugs” variable. CNR1 codes for cannabinoid 1 receptors that offer high expression in regions with proven involvement in reward, addiction, and cognitive function [rs806380 SNP in intron 2 of CNR1 is associated with cannabis dependence. However, the majority of the participants also met the criteria for alcohol dependence. The rs806380 SNP has also been linked to the development of cannabis dependence symptoms [CNR1 has also been positively associated with intravenous drug use and cocaine, amphetamine, and cannabis dependence [In addition, the presented genetic association analysis was carried out as a part of the PGA study assessing several types of addictions in a sample of 3003 adolescent participants. As previously stated, the association analyses of 32 SNPs and four substance use and seven potentially addictive behaviors revealed 29 nominally significant associations, nine of which survived the FDRbl correction for multiple testing. Polymorphisms in the function . The rs8symptoms . A micropendence . rs1800497 SNP of ANKK1, also known as the Taq1A polymorphism, has been widely studied in psychiatric disorders. Numerous studies have linked Taq1A to reduced DRD2 densities and binding affinity [Taq1A polymorphism has been significantly associated with nicotine dependence [The affinity ,71, implpendence ,73, smokpendence , alcoholpendence ,76, heropendence ,78, and pendence ,80.rs1800955 of the DRD4 gene and the mean scores on the SCOFF questionnaire assessing eating disorders. This SNP, also known as -521C/T, is a variant in the promoter region upstream of the DRD4 gene and has a putative role in regulating transcriptional activity [rs1800955 [rs1800955 polymorphism of DRD4 has also been proposed in the GARS test by Blum et al. [DRD2 A1 allele (rs1800497) have been associated with heroin addiction [Finally, the results revealed an association between activity . Furthers1800955 . Previous1800955 ,84. The m et al. , which im et al. . This SNddiction  and contddiction .These alleles were proposed for a GARS panel in case–control studies, specifically for alcoholism  see ref for furtDRD1, 2, 3, 4), DAT1, SLC6A4, COMT, MAO-A, GABRB3, OPRM1, and some SNPs and point mutations chosen to reflect a hypo dopaminergic trait. The genes determined to negatively influence the net release of dopamine at the brain reward site were chosen from thousands of association studies providing clear evidence of the specific risks for all addictions [To develop this patented GARS test, the ten reward candidate genes selected included the dopamine receptors . It is noteworthy that only the DRD2 gene polymorphism  had a significant Pearson correlation using days on treatment . Importantly, this twofold increase is significant for compliance with treatment. Blum’s research team methodically assessed the impact of polymorphisms from five possible genes and their potential as targets for the development of a DNA-customized nutraceutical KB220Z to combat obesity, with particular emphasis on body re-composition as measured by BMI. Blum’s group developed an early version of the GARS specifically directed towards glucose craving and, as such, included specific alleles: DRD2 Al; MTHFR C 677T; 5HT2a 1438G/A; PPAR-γProl2Ala and Leptin Ob1875 < 208 bp. Pre- and post-hoc analyses revealed a significant difference between the starting BMI and the BMI following an average of 41 days (28–70 days) of KB220Z intake in the 21 individuals. Additionally, the average pretreatment weight in pounds was 183.52 compared to the post-treatment weight of 179, a statistically significant (p < 0.047) change. In this particular group, 53% lost, on average, over 2.5% of their starting weight. These studies in obesity are presented to provide some idea of the potential success of utilizing customized nutrigenomic-based solutions, which may pave the way to treating and preventing RDS-like behaviors in the future [Previously, our laboratory started with the mindset of designing a study with which to evaluate DNA customization with nutritional solutions for both wellness and especially weight management, as one RDS example. In terms of nutrigenomics, a number of studies should be mentioned to serve as the rationale for developing customized DNS-guided pro-dopamine regulation utilizing KB220 as a basis ,108,109.e future ,108,109.Unfortunately, despite the enormous efforts of the federal government to help fund and develop and deliver certain treatments (MAT) for victims of SUD, albeit not a magic bullet or “cure,” treatment penetration rates are less than 20% . In an aIt is noteworthy that Volkow (Director of NIDA) and Koob (Director of NIAAA) are encouraging the psychiatric field to include the concept of “preaddiction” as a plausible new inclusion for the DSM. Relevant to this suggestion is the possibility of developing a test to help categorize mild, moderate, or high risk for future addictive-like behaviors. With this in mind, based on our initial work and now with many other global scientists, the preaddiction classification is best captured with the construct of dopamine dysregulation  or specifically in reward deficiency or net hypodopaminergia at the meso–limbic brain reward circuitry . CurrentIndependent of the appropriate name, similar to the idea of “prediabetes,” we want to develop a reliable method that allows for the early identification of people at risk for future serious issues with substance and non-substance behavioral addictions (preaddiction). Therefore, we are hereby proposing the GARS test along with the RDSQ29  pencil aThe GARS test was utilized to assess the potential risk of preaddiction in patients who, following an injury, for example, received powerful opioids to relieve pain and continued to be prescribed an analgesic for more than a year. In this study, Moran et al.  utilizedIn addition, an estimation based on these previous literature results provided herein, while not representative of all association studies known to date, this sampling of case-control studies displays significant associations between alcohol and drug risk. In fact, Blum et al.  presenteIn another investigation, Fried et al.  utilizedThe risk of all addictive drug and non-drug behaviors, especially in the unmyelinated PFC of adolescents, is important and complex. Many animal and human studies show the epigenetic impact on the developing brain in adolescents compared to adults. Some reveal an underlying hyperdopaminergia that seems to set our youth up for risky behaviors by inducing high quantities of pre-synaptic dopamine release at reward site neurons. In addition, altered reward gene expression in adolescents caused epigenetically by social defeat, like bullying, can continue into adulthood. In contrast, there is also evidence that epigenetic events can elicit adolescent hypodopaminergia. This complexity suggests that neuroscience cannot make a definitive claim that all adolescents carry a hyperdopaminergic trait. The primary issue involves the question of whether there exists a mixed hypo- or hyper-dopaminergia in this population. One investigation by Blum et al.  utilizedDRD2 Taq A1 allele and severe alcoholism in JAMA, there has been an explosion of genetic candidate association studies, including GWAS. To develop an accurate test to help identify those at risk for at least AUD, Blum’s group [χ2 test or Fisher’s exact test was applied to compare the gender, genotype, and allele distribution if available. The statistical analyses found the OR, 95% CI for OR, and the post risk for 8% estimation the population’s alcoholism prevalence revealed a significant detection. The OR results showed significance for DRD2, DRD3, DRD4, DAT1, COMT, OPRM1, and 5HTT at 5%. While most of the research related to GARS is derived from our laboratory, we are encouraging more independent research to confirm our findings.Since 1990, when our laboratory published the association of the ’s group  applied Inquiry into the neurobiology of addictive disorders has consistently pointed to the altered brain mesolimbic dopaminergic and other neurotransmitter circuits subserving reward and motivation. Even in the era of GWAS, the SUD field remains uniform. However, given the uncertain genetic- vs. acquired nature of the observed alterations. To that end, a multi-center study utilized GARS criterion validity against the backdrop of the ASI-MV in 393 polydrug abusers. Blum and associates  found a Finally, to reiterate our understanding of the daunting polygenicity of mental illness, Hyman  discusseterra incognita” [Additionally, the successful exploitation of results from genetics will require past avoidance of long-successful reductionist approaches to the investigation of gene function, a commitment to supplanting much research now conducted in model organisms with human biology, and the development of new experimental systems and computational models to analyze polygenic causal influences. In this regard, our laboratory has already started the process by developing behavioral addiction risk assessment (BARS/GARS) testing in psychiatry ,78,79,80cognita”  and a reThe idea of preaddiction, which was first introduced in 1971 and thus not a new term , while aIn fact, there can be clinical presentations where a lesser number of criteria are present, but these criteria are indicative of the presence of “addiction.” Second, the clinical presentations that are captured by mild and moderate severity are given a valid medical diagnosis as per the DSM-5. This should warrant appropriate clinical interventions . If the aim of the introduction of the concept of “preaddiction” is to offer appropriate interventions to those at risk of developing “addiction” later in life, then these individuals need to be identified using criteria that do not overlap with an existing diagnostic category . To be clear, in fact, RDS occurs at birth due to DNA genetic antecedent risk, which could set up individuals to be at high risk, which is actually equivalent to preaddiction. Of course, via epigenetic insults due to subsequent SUD, the polymorphic DNA antecedents could compound the risk. To assist the readership, we developed DRD2 Taq A1 allele and severe alcoholism in JAMA, there has been an explosion of genetic candidate association studies, including GWAS. To develop an accurate test to help identify those at risk for at least AUD, a subset of RDS, Blum’s group developed the GARS test, consisting of ten genes and eleven associated risk alleles. In order to statistically validate the selection of these risk alleles measured by GARS, we applied strict analysis to studies that investigated the association of each polymorphism with AUD or AUD-related conditions, including pain and even bariatric surgery, as a predictor of severe vulnerability to unwanted addictive behaviors, published since 1990 until now. This analysis calculated the Hardy–Weinberg Equilibrium of each polymorphism in cases and controls. Pearson’s χ2 test or Fisher’s exact test was applied to compare the gender, genotype, and allele distribution if available. The statistical analyses found the OR, 95% CI for OR, and the post risk for 8% estimation of the population’s alcoholism prevalence revealed a significant detection [Since 1990, when our laboratory published the association of the etection . It is retection , could bPrior to these results, the United States and European patents on a ten-gene panel and eleven risk alleles have been issued. In the face of the new construct of the “preaddiction” model, similar to “prediabetes”, the genetic addiction risk analysis might provide one solution missing in the treatment and prevention of the neurological disorder known as RDS.


Network meta-analysis of deaths from various underlying diseases after COVID-19 infection. This study included more than 10 research centers with the same level of care. In total, 1,676 subjects were included in our study, including 1,122 men and 554 women, patients diagnosed with COVID-19, and combined with underlying diseases; provided data on the number of deaths from related diseases, such as hypertension, diabetes, heart disease, cerebrovascular disease, malignant tumor, chronic kidney disease, chronic liver disease, and respiratory disease. The comparison RR between hypertension and different diseases shows that it is  compared with diabetes, compared with coronary heart disease , compared with cerebrovascular disease , compared with malignant tumor , and compared with chronic kidney disease , compared with chronic liver disease , compared with respiratory diseases , RR values are >1, which is statistically significant. The surface under the cumulative ranking curve (SUCRA) showed that the ranking of disease mortality from high to low was hypertension> diabetes> heart disease> cerebrovascular disease> respiratory disease> chronic kidney disease> malignant tumor> chronic liver disease. The study that hypertension, diabetes, and heart disease are the top three risk factors for patients infected with COVID-19, and management of these patients should be strengthened to improve the prognosis of patients. Ethical approval and patient consent are not required as this study is a meta-analysis based on published studies. The results of this network meta-analysis will be submitted to a peer-reviewed journal for the publication. So far in the 21st century, human beings have witnessed deadly pandemics related to novel coronaviruses, including SARS, Middle East Respiratory Syndrome (MERS), and COVID-19. All these viruses that cause acute respiratory infections are highly contagious in nature and/or cause high mortality .Although the gradual popularization of vaccines has a positive effect on the prevention and control of the spread of COVID-19, it still cannot prevent the occurrence of new deaths, with millions of related deaths reported at the time of preparation of the manuscript , 5. The Since the outbreak of the COVID-19 pandemic, a large number of studies have reported risk factors related to severe disease or mortality rates, and the combination of underlying diseases in infected persons has been considered to be associated with mortality. However, there have been no systematic reports of related deaths among COVID-19 infected persons under various underlying diseases. Among the factors related to the mortality rate of COVID-19, the specific risk of death of infected persons under various underlying diseases is not clear.In addition, the incidence rate of chronic diseases in each country is different, and the population of each country is also different from the target population of this study of chronic diseases. The purpose of this article is to calculate the death rate of novel coronavirus under different chronic diseases through scientific statistical methods, establish a network diagram through mesh meta-analysis, fit the model, and eliminate heterogeneity. Calculate the mortality of patients with novel coronavirus under different basic diseases.Network meta-analysis is a relatively new statistical method, which can be combined and ranked based on the effect of multiple interventions and risk factors. Exclude the heterogeneity of various articles, so as to select the best intervention measures and risk factors. In order to better solve the heterogeneity of risk factors in various regions and articles, observational mesh meta-analysis has emerged as a more novel statistical method, which is divided into the Bayesian school and frequency school. This article creatively uses observational mesh meta-analysis to explore the differences in mortality under various basic diseases of novel coronavirus. Excluding the different incidence rate and heterogeneity of articles in various regions, we finally come to the basic disease that has the highest impact on the mortality of novel coronavirus.A network meta-analysis using a Bayesian framework will be implemented in this study. This protocol of network meta-analysis will be performed on the basis of the Preferred Reporting Items for Systematic review and Meta-Analysis Protocol (PRISMA-P), and the reporting of the following network meta-analysis will obey the PRISMA extension statement for reporting of systematic reviews incorporating network meta-analysis of healthcare interventions. In this article, Bayesian mesh meta-analysis method is used. First, the whole document screening process is made, and the flow chart is drawn, and the basic information of different documents is drawn, eliminating unsuitable and low-quality literature, determining the final inclusion of literature and extracting relevant data. Second, the mesh relationship diagram is drawn through the model, and the action size of each risk factor is clarified through the network relationship diagram. Different network diagrams and the size of circles in the diagram represent different relationships between different basic diseases. The effect of Bayesian model is evaluated by using the trajectory diagram and density diagram. Only when there is a good fitting, convergence, and diagnostic diagram can the calculation results of this model be used and the RR value is taken to compare each risk factor in pairs, and the League map is drawn. Through the RR value, the maximum influencing factor is found. The influence probability of each risk factor is calculated by the Bayesian model, and finally, the value of this study is evaluated by the heterogeneity test. We searched seven databases, namely, PubMed, Embase, Cochrane, Google Scholar, Wanfang, VIP, and CNKI, and the search time was set from 1 January 2020 to 12 December 2021. The keywords used in our search include COVID-19, mortality, death, novel coronavirus, novel coronary pneumonia, death factors, death, and comorbidities.Patients were not involved in the design, conduct, reporting, or dissemination plans of this research.The inclusion criteria in the study were: patients diagnosed with COVID-19 and combined with underlying diseases, provided data on the number of deaths from related diseases, no restriction on the type of study. The exclusion criteria were: animal experiments; duplicate studies; meta-analyses, reviews, guidelines, and letters.Data were extracted by two independent investigators in accordance with pre-determined information extraction tables . Any differences were negotiated and resolved with a third investigator.A total of 113 articles were retrieved from the databases, and 23 articles were obtained through other means. After removing duplicates, 96 articles were obtained and 76 of them were left after the preliminary screening of titles and abstracts. We read the remaining 76 articles in full text and finally determined to include 33 articles see .P ≥ 0.05 obtained from the analysis by node splitting method indicated no significant inconsistency, and the consistency model would be used for analysis. The rank probability plot was employed to rank the mortality of different diseases. Direct and indirect comparisons between different diseases were presented by drawing a network diagram, and publication bias was tested using an adjusted funnel plot.The Newcastle–Ottawa Scale (NOS) was used to assess the quality of the cohort studies, which was divided into eight items in three blocks, namely, selection, comparability, exposure assessment or outcome assessment. The total score of NOS in cohort studies is nine points, and a score of ≥6 is generally considered as a high-quality study. The American Institute for health care quality and Research (AHRQ) is a quality evaluation of cross-sectional studies, including 11 items, which are answered with “yes,” “no,” and “unclear,” respectively. If the answer is “no” or “unclear,” the score of this item is 0; If the answer is “yes,” the score of this item is 1 point. Evaluation criteria: (1) low quality 0–3 points; (2) Medium quality 4–7 points; (3) High quality 8–11 points. Gemtc 0.8 program package of R 4.0 software and JAGS software were adopted combined with the Markov Chain Monte Carlo (MCMC) method to conduct Bayesian network meta-analysis. Relative risk (RR) was used as the effect size for binary data, and the 95% prediction interval (CI) was calculated. In total, three Markov chains were selected for the initial value setting, and the total number of iterations was set at 10,000. The first 6,000 annealing times were used to eliminate the influence of the initial value, and sampling started after 6,001 times. Iterative convergence was determined by calculating the potential scale reduction factor (PSRF) and the Gelman Rubin Brooks diagnosis method, and the convergence was better with the reduction factor tending to 1. For the closed loop, the node analysis model was used to detect the inconsistency. The characteristics of the included 33 articles are shown in P>0.05, so we chose the consistency model for subsequent network analysis. It can be seen from the trajectory diagram and density diagram that the MCMC chain of the model fits well, the fluctuation of a single chain cannot be recognized by the naked eye, and the convergence degree is good. The bandwidth value and calculation result of the density diagram are obviously small, and the curve is stable and smooth, which also proves that the model fits well, which is shown in the figure below A total of 33 studies reported the mortality of underlying diseases, and the network meta-analysis involved eight diseases, namely, hypertension, diabetes, coronary heart disease, cerebrovascular disease, malignant tumor, chronic kidney disease, chronic liver disease, and respiratory disease. The reticular relationship of mortality of different underlying diseases complicated with COVID-19 is shown in The relative mortality results of different diseases are presented in The rank probability of the mortality of different diseases is shown in The COVID-19 pandemic poses a major threat to human health on a global scale,as multiple systems can be affected after infection. With the accumulation of epidemic prevention experience, vaccination, and popularization of epidemic prevention knowledge , the curThis study found that hypertension is the leading risk factor for the death of people infected with COVID-19. Yin et al.  retrospeBased on the literature retrieval results, the current study is the first network meta-analysis to explore the correlation between various underlying diseases and COVID-19 deaths. Nevertheless, this study has the following limitations: first, this study included studies from China, Japan, South Korea, Iran, India, and Kuwait. There are differences in epidemic prevention policies, medical resources, and allocation of medical resources in different countries, which will lead to differences in epidemic prevention and control efficiency, treatment rate, and mortality rate . In thisCombined hypertension, diabetes, and heart disease are the top three high-risk factors for the poor prognosis of patients infected with COVID-19, and management of these patients should be strengthened to improve the prognosis of patients. The results of this study need to be further verified by studies with a larger sample size. Through this study, we can know the mortality of COVID-19 under different basic diseases. From the basic level, it can provide direction for the basic research on the prognosis of novel coronavirus, and explore the pathological mechanism of novel coronavirus and hypertension. With the current large-scale vaccination, the reduction of adverse prognostic events of the novel coronavirus, and the emergence of new novel coronavirus strains, we can see that more energy can be put into financial and material resources which are put into the study of clinical manifestations and prognosis of different strains of novel coronavirus.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.JY and ML drafted the manuscript. RZ revised the manuscript critically for important intellectual content. All authors gave final approval of the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved, made substantial contributions to the conception and design of the work, and the acquisition, analysis, and interpretation of data for the work.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.


Oat supplementation interventions (OSIs) may have a beneficial effect on cardiovascular disease (CVD) risk. However, dietary background can modulate such effect. This systematic review assesses the effects of OSIs on CVD risk markers among adults, accounting for different dietary backgrounds or control arms.We included randomized clinical trials (RCTs) that assessed the effect of oat, oat beta-glucan-rich extracts or avenanthramides on CVD risk markers.2, ], weight , and waist circumference . RCTs on inflammation and/or oxidative stress markers were scarce and with inconsistent findings. RCTs comparing an OSI to heterogeneous interventions , showed lowered levels of glycated haemoglobin, diastolic blood pressure, HDL cholesterol and apolipoprotein B. The majority of included RCTs (81.1%) had some concerns for risk of bias.Seventy-four RCTs, including 4937 predominantly hypercholesterolemic, obese subjects, with mild metabolic disturbances, were included in the systematic review. Of these, 59 RCTs contributed to the meta-analyses. Subjects receiving an OSI, compared to control arms without oats, had improved levels of total cholesterol (TC) , LDL cholesterol , glucose , body mass index [− 0.13 kg/mDietary OSIs resulted in lowered levels of blood lipids and improvements in anthropometric parameters among participants with predominantly mild metabolic disturbances, regardless of dietary background or control. Further high-quality trials are warranted to establish the role of OSIs on blood pressure, glucose homeostasis and inflammation markers.The online version contains supplementary material available at 10.1007/s00394-021-02763-1. Cardiovascular diseases (CVDs) represent one of the leading causes of global mortality among adults and lifestyle modifications have emerged as a great opportunity to reduce their health burden . Hence, This work follows an established guide on conducting systematic reviews and meta-analyses for medical research , as wellTwo reviewers, who afterwards assessed the full-texts of potentially eligible studies, independently evaluated titles and abstracts. Two reviewers also independently extracted the relevant information using a pre-defined data extraction form. Any disagreement between reviewers was settled by reaching a consensus or by consulting a third reviewer. The quality of included RCTs was assessed by two independent reviewers using the Risk of Bias Tool for Randomized Trials (Rob 2.0) . Detaileχ2 statistic (Pq < 0.05 was considered as significant) and the I2 statistic, and was determined as low (I2 ≤ 25%), moderate (25% < I2 < 75%), or high (I2 ≥ 75%)  of the treatment effects in CVD risk markers were presented as summary outcome measures. For data reported as medians, ranges or 95% confidence intervals (CI), means and standard deviations were converted as described elsewhere . Random-2 ≥ 75%) . Study c2 ≥ 75%) . We perfn = 56, 75.7%) included individuals with some form of metabolic disturbance , metabolic syndrome, prediabetes, prehypertension, hyperlipidaemia), while only 18 RCTs were conducted in healthy individuals. The majority of the RCTs  investigated oat bran, meal or porridge supplementation, 13 RCTs reported on β-glucan- containing oat products and one investigated avenanthramides   , I2 = 55.6%, Pq = 0.09], body weight  and waist circumference (WC)  were lower in the OSI group compared to the control arm  , TC , HDL-C , and LDL-C  were lower in the OSI + DR group compared to DR alone arm , I2 = 55.9%, Qp = 0.06], respectively  BMI [WMD: − 0.13 kg/mp = 0.03) and TC (p = 0.51) tended to decrease, but WMD of HDL-C increased (p = 0.007), Supplemental Figs. 5–8. No evidence was found for publication bias of RCTs included in meta-analysis comprising five or more estimates .In subgroup analyses and meta-regression, only geographic location and sex were identified as potential sources of heterogeneity for TC and LDL-C analysis, respectively, . The leave-one-out analyses showed that findings on TC, HDL-C, LDL-C, TGs and glucose were not driven by any single study . Regressing continuous variables, such as age, duration of study and number of study participants, on WMD showed some evidence of linear trends between percentage of male individuals and WMD of HDL-C and LDL-C. With increasing proportions of male participants, WMD of LDL-C . Results on blood lipid parameters remained similar to the other two meta-analyses, showing lowered TC and LDL-C in an OSI group compared to the control arms Table . In addiThe scarcity of studies and the diversity of control arms across trials did not permit a meta-analysis of inflammation and oxidative stress markers. A summary of these results is available in Table p < 0.05) [In one study , daily s < 0.05) . While mIn this systematic review and meta-analysis, dietary OSIs were associated with some improvements in a subset of CVD risk markers independently of the dietary background or control arm Fig. . In partFindings of meta-analyses have shown that intake of oat products can lower blood lipids, mainly serum LDL-C concentrations, but with a relatively modest reductions, which were variable within the range of real-world intakes. The role of oat products on lipid profile has been extensively studied in previous meta-analyses of RCTs, involving normal or mildly hypercholesterolaemic adults , 27, 28.Oats can exert health benefits via bioactive phytochemicals with potent antioxidant and anti-inflammatory effects, such as phytosterols, tocols, flavonoids, avenanthramides and soluble fibres such as beta-glucans , 30. TheApart from the lowering effect of an OSI on TC and LDL-C, a significant decrease in HDL-C was observed in the meta-analysis of RCTs comparing OSI + DR vs. DR alone. A recent RCT  has repoA growing body of epidemiological studies –51 has cEffects of an OSI on BP were only observed for diastolic BP, in the case of OSI + DR vs. DR alone. This change ) was inconsistent in other types of interventions and not found in case of systolic BP. A similar inconsistency was observed for glucose homeostasis markers, where significant differences were observed for HbA1c only in RCTs comparing OSI + DR versus DR alone and for glucose for RCTs comparing OSIs vs. no OSIs. No significant differences were observed in any other intervention or in interventions comparing an OSI with heterogeneous controls, regarding any glucose homeostasis marker. A meta-analysis of RCTs evaluating the effects of oat products on glycaemic control among diabetic patients indicated that the effects of oats and oat beta-glucans on glycaemic control and insulin sensitivity are inconclusive . HoweverTo the best of our knowledge, this is the first study to provide a comprehensive analysis on the role of OSI on several CVD risk markers, accounting for background diet and control arms. To identify as many relevant studies as possible and reduce the risk of publication bias, a highly sensitive search strategy was used and additional resources were searched including the reference lists of included trials and relevant systematic reviews. Conventional funnel plots and Egger test estimates showed only a minimal publication bias; still, these methods are limited by their qualitative nature and we cannot exclude the possibility of measured or unmeasured publication bias. Location of study and percentage of male participants contributed to the heterogeneity of findings, and the OSI’s dose and duration were highly variable. Thus, future studies exploring the role of sex, ethnicity and cultural factors in the association of OSIs and risk of CVD are warranted. Our findings need to be interpreted cautiously, with considerations of the specific comparison food/diet. Also, only 36 out of 74 RCTs (48.6%) took isocaloric diet between arms into account, and whether these differences affect the results should be explored by future studies.Supplementation of diet with oat cereals improves CVD risk markers among healthy adults and those with mild metabolic disturbances, particularly by influencing serum total and LDL cholesterol, BMI and WC. The beneficial effects on TC and LDL-C were independent of the dietary background. The role of OSIs on BP, glucose homeostasis or other markers, could not be established.Supplementary file1 (DOCX 323 KB)Below is the link to the electronic supplementary material.


In the past decade, fibroblast growth factor 23 (FGF23) has been recognized as an important biomarker of cardiovascular diseases. This study aimed to assess the relationship between FGF23 and the risk of cardiovascular diseases (CVDs) in general populations.The protocol was registered prospectively in PROSPERO (CRD42021281837) and two authors independently searched for relevant studies in the PubMed, EMBASE, and Cochrane Library databases. The random effects model was applied.RR: 1.40, 95%CI: 1.03−1.89), stroke , heart failure (HF) , CVD events , cardiovascular mortality , and all-cause mortality . In the continuous analysis, per doubling of FGF23 was associated with increased risks of MI , stroke , HF , CVD events , cardiovascular mortality , all-cause mortality . Furthermore, the dose-response analysis demonstrated a potentially non-linear relationship between FGF23 and stroke, HF, and all-cause mortality. In contrast, a potentially linear relationship between FGF23 and cardiovascular mortality was observed (p for non-linearity = 0.73).In total, 29 prospective studies involving 135,576 participants were included. In the general population, the category analysis revealed that elevated FGF23 levels were related to increased risks of myocardial infarction (MI) (The present study suggests that increased serum FGF23 levels are positively related to CVD events and mortality in the general population. The clinical application of FGF23 levels to predict CVD risk requires further research. Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, resulting in 17.3 million deaths each year. The number of annual deaths is expected to exceed 23.6 million by 2030. Meanwhile, cardiovascular diseases are responsible for approximately 40% of deaths in the Chinese population  (Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone primarily secreted by osteocytes and osteoblasts. It participates in adjusting systemic phosphate homeostasis, vitamin D metabolism, and a-Klotho expression through the bone-kidney axis . FGF23 mne (PTH) , 7. In tne (PTH) , 9. Prevne (PTH) –13, but This review strictly followed the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) and G-Dose checklists guidelines , 2. The Two authors (PX and ML) performed a literature search using the PubMed, EMBASE, and the Cochrane Library databases, including articles published before 10 September 2022. Medical subject headings were combined with free-text terms for retrieval without language restrictions. The search conditions were as follows: “fibroblast growth-factor 23 OR FGF23 protein OR fibroblast growth factor 23 OR FGF23 protein OR phosphatonin OR tumor-derived hypophosphatemia inducing factor” And “cardiovascular diseases OR cardiovascular disease OR disease, cardiovascular OR diseases, cardiovascular OR myocardial infarction OR stroke OR heart failure OR atrial fibrillation OR coronary heart disease OR left ventricular hypertrophy OR hypertension.” The details of the search strategy are described in According to the PICOS  strategy, the inclusion criteria for this review were as follows:(1) The participants were adults from the general population (age > 18 years).(2) The studies compared high vs. low FGF23 levels.(3) The outcomes included all kinds of cardiovascular diseases .(4) Prospective cohort studies were included.RR) or hazard ratio (HR), and the corresponding 95% confidence interval (CI) were required. Prospective case-cohorts were regarded as prospective cohort studies  independently recorded the following information for each related study: first author, country, publication year, study design, sample size, sex, mean or median age, follow-up duration, FGF23 categories, outcomes reported, FGF23 measurement, HR was considered to be equivalent to RR. The adjusted RR was transformed to the natural logarithms (logRR) to fit a normal distribution, and the standard errors (SElog [RR]) were calculated according to the corresponding 95%CIs. The random effects model was applied to pool the risk estimates considering the heterogeneity of different cohort studies. When an included study compared the lowest level or the reference category of FGF23 with the higher categories (≥2 categories), the highest category was regarded as the high level, while the reference level or the lowest level was regarded as the low level. For the category analysis, the summary RRs and 95%CIs were calculated by comparing the highest level of FGF23 to the lowest level of FGF23. For the dose-response analysis, the method described by Greenland and Longnecker   developed by Xu and Doi  . FGF23 w and Doi , 19 was  and Doi , 21.Q test and the I2 statistic. For the Q statistic, P < 0.1 indicated significant heterogeneity. For the I2 statistic, <25% indicated low or no heterogeneity; 25%−50% suggested moderate heterogeneity; >50% was considered high heterogeneity  are detailed in We initially identified 3900  articles from the electronic literature search. After removing irrelevant and duplicate articles, a full-text review was performed for the remaining 87 potentially relevant studies. Ultimately, 29 articles were identified for the meta-analysis. The reasons for exclusion . Four studies reported continuous analysis .Four studies –26 reporanalysis –26; the RR: 1.20, 95%CI: 1.02−1.43, p = 0.03; p = 0.66, I2 = 0%). In the continuous analysis, the RR of stroke per doubling of FGF23 was 1.21 . Moreover, six studies performed a dose-response analysis . In the continuous analysis, the summary RR for a 20 RU/ml increment of FGF23 was 1.25 ; and the RR of HF per doubling of FGF23 was 1.24 . In addition, eight studies carried out a dose-response analysis . In the continuous analysis, the RR of CVD per doubling of FGF23 was 1.12 .Additionally, six studies , 36, 37 A few studies examined the relationship between FGF23 and other cardiovascular diseases, but the results were not pooled due to the scarcity of data. As shown in RR: 1.32).Three studies , 33, 43 Jovanovich et al.  found thRR: 1.46, 95%CI: 1.29−1.65, p < 0.00001; p = 0.50, I2 = 0%). In the continuous analysis, the summarized RR for a 20 RU/ml increment of FGF23 was 1.23 ; and the RR of cardiovascular mortality per doubling of FGF23 was 1.43 . Moreover, eight studies . The RR of all-cause mortality per doubling of FGF23 was 1.42 . Furthermore, nine studies were included in the dose-response analysis , follow-up duration (≤10 years vs. > 10 years), and FGF23 measurement (iFGF23 vs. cGFG23)  , 3.p = 0.394 and 0.530) and a Funnel plot , and a stratified analysis was performed to explore the sources of heterogeneity. No substantial heterogeneity was detected in the intact FGF23 subgroup. The differences in variable adjustment across studies might lead to an inaccurate estimation of the effect size. Although our analysis showed moderate heterogeneity, a robust association was observed between FGF23 levels and all-cause mortality.The findings were confirmed with a further analysis stratified by age (≤60 years vs. >60 years), follow-up duration (≤10 years vs. >10 years) and FGF23 types (iFGF23 vs. cGFG23). The results revealed a similar relationship between FGF23 and cardiovascular and all-cause mortality. Notably, most subgroups in this study did not exhibit heterogeneity, and no substantial changes were observed in the pooled RR: 1.25, 95%CI: 1.14−1.37) and CVDs  in hemodialysis patients. These significant associations support the predictive role of FGF23 in CKD patients. Remarkably, most of the included studies had adjusted for potential confounders, including age, estimated glomerular filtration rate and other risk factors. Consequently, a significant association was observed between FGF23 levels and CVD risk and mortality. Three cohorts . Collectively, our results provided compelling evidence for the close relationship of FGF23 levels with CVDs and mortality in the general population, independent of CKD status. These findings suggest that FGF23 may potentially be applied to predict the risk and mortality of CVDs, irrespective of kidney function.Gao and co-workers  reported cohorts , 37, 44 in vivo experiments by Hu et al.  . Faul etRR 1.46, 95% CI 1.38−1.55, p < 0.001), CVD  and renal events  in pre-dialysis CKD patients. Marthi et al.  intake levels in healthy people. Consequently, reducing the absorption of dietary phosphate can hypothetically decrease the circulating FGF23 concentrations. Commonly used phosphorus binders include Ca unclear .The mechanisms regulating FGF23 synthesis are poorly understood. Blocking the main FGFR isoform FGFR4 may reduce the cardiotoxic effects of FGF23, but does not affect its physiological functions. The safety of this method in cardiovascular diseases has already been demonstrated in clinical trials. Conversely, FGF23 antibodies might cause greater side effects than clinical benefits in patients with renal dysfunction . OptimalTraditional biomarkers such as troponin I and T have been widely used in clinical practice for the diagnosis of MI. FGF23, as a novel candidate biomarker of cardiovascular risk, is positively correlated with classical biomarkers of cardiac damage but does not directly depend on them . In addiAdditionally, FGF23 may potentially predict the prognosis of cardiovascular diseases. Song et al.  have repThis review only included prospective studies, avoiding recall bias. Most of the included studies had a large sample size and had adjusted for potential confounding factors, such as age, gender, race, smoking, BMI, and basic disease histories. Nevertheless, the limitations of this study should be acknowledged. Firstly, our results were based on observational studies and a causal relationship cannot be confirmed. The residual confounding factors and the unmeasured factors could not be ruled out completely due to the inherent nature of observational research. Secondly, the majority of the included studies were performed in the United States or Europe, and the applicability of our findings to the Asian population requires further research. Finally, some studies may have included CKD patients in the general population, affecting the reliability of our results.Overall, the increased serum FGF23 levels were associated with increased risks of CVDs and mortality in general populations. There was a potentially non-linear relationship between FGF23 and stroke, HF and all-cause mortality, whereas a potentially linear relationship between FGF23 and cardiovascular mortality was observed. Additional studies are needed to clarify the mechanism between FGF23 and CVDs in the general population. The clinical application of FGF23 levels to predict CVD risk requires further research.The original contributions presented in this study are included in the article/XL and PY were responsible for the entire project and revised the draft. PX, YZ, and ML performed the data extraction and statistical analysis, drafted the first version of the manuscript, and interpreted the data. All authors participated in the interpretation of the results and prepared the final version of the manuscript.


IL6R) gene to the risk of multiple human diseases and phenotypes, yet have reported inconsistent results. We aimed to synthesize current knowledge of variants in the IL6R gene on the risk of diseases and phenotypes.Genetic studies have linked polymorphisms in the interleukin 6 receptor  related to the risk of four cardiovascular diseases , four inflammatory diseases , and concentration of four phenotypes . Furthermore, phenome-wide analysis verified that rs2228145 associated with asthma and dermatitis risk. Functional analyses indicated that these polymorphisms fall within exon, enhancer regions.We included 155 studies for evaluating the associations between 80 polymorphisms in the IL6R gene and highlights the pharmacological targeting potential of IL-6R on cardiovascular and inflammatory diseases.Our study comprehensively summarizes current data on the genetic architecture of the  IL6R) gene is located in chromosome 1q21.3 (Gene ID: 3570) (Interleukin (IL)-6 receptor (D: 3570) .IL6R gene are associated with a range of common diseases and phenotypes. In 2003, Kim et al. firstly identified seven single-nucleotide polymorphisms (SNPs) in the IL6R gene in the Korean population , rs4845625 , or rs7529229 , were also reported to be associated with the risk of many diseases, such as asthma (p = 2.4×10−8) (Other polymorphisms in the s asthma  and CVDss asthma . A GWAS .4×10−8) . Then, a.4×10−8) , coronar.4×10−8) , AAA, anIL6R gene were also suggested to be related to hematological inflammatory biomarkers and some conventional CVD risk factors. Several publications showed that the C allele of rs2228145 increased circulating soluble IL-6R (sIL-6R) and IL-6 concentrations by 34% and 15%, respectively  tests. Thirdly, we performed a phenome-wide analysis for independent variants with strong evidence using data from UK Biobank to uncover new relationships. Fourthly, we performed functional annotations for the variants in the IL6R gene using data from the Encyclopedia of DNA Elements Project (ENCODE), the 1000 Genomes Project, the Genotype-Tissue Expression (GTEx) Project, and other sources to provide clues for the pathogenesis of these associations.In addition to diseases, variants in the ectively , 9. Furtectively . With thple size –21. ThesThe methods used in the present study were based on guidelines proposed by the Human Genome Epidemiology Network (HuGENet) for a systematic review of genetic association studies and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) , 23. ThiIL6R published in English up to August 1, 2021. We also retrieved published reviews, meta-analyses, pooled analyses, and the included studies to identify additional publications.We systematically searched PubMed and Embase using keywords (“interleukin 6 receptor” OR “IL-6R” OR “IL6R” OR “interleukin-6 receptor” OR “IL-6 receptor” OR “rs2228145” OR “Asp358Ala” OR “D358A”) to identify the original genetic association studies of IL6R gene and human diseases or phenotypes; (iii) they directly provided risk estimates such as odds ratio (OR), relative risk (RR), hazard ratio (HR), and 95% confidence interval (CI), coefficient β and standard error (SE), or provided valid data to calculate these risk estimates under additive genetic model; (iv) or for publications investigating continuous quantitative phenotypes, they should provide mean and standard deviation (SD). When multiple studies use the same population, the most recent or the one with the largest sample size was selected. Studies without full text or sufficient information to calculate effect size were excluded. Two investigators (MZ and YB) independently assessed the eligibility of each publication, and disagreement was settled through discussion with the principal author (DG).Articles were eligible to be included if they met the following inclusion criteria: (i) they were observational studies conducted in humans; (ii) they investigated associations of genetic variants in p-value , mean concentrations of quantitative traits and SD for different genotypes, Hardy–Weinberg equilibrium (HWE) among controls, and genotyping methods.Three authors  independently extracted the data using a predesigned collection sheet including PMID, first author, publishing year, variants, major and minor alleles, source of population, ethnicity of the study population, study design, sample size of cases and controls, genotype and allele counts, matched information, effects of associations and the corresponding 95% CIs, regression coefficients, SE or In our study, the primary outcome was the risk of disease or categorical phenotypes, measured by OR/RR/HR and 95% CI under an additive genetic model. Due to the relatively low incidence of the events mentioned above, the effect size of OR, HR, and RR was deemed identical in this meta-analysis . For conQ test, and the I2 statistic was used to evaluate and quantify heterogeneity between studies (I2 ≥ 50%), while the fixed effects model was used if I2 < 50%. For variants that showed significant associations with relevant diseases or phenotypes, sensitivity analyses were conducted to examine whether the associations would be lost when a single study was excluded or when the first positive report or studies with deviation from HWE in controls were excluded. Begg’s test  on the outcome for each variant. We adopted the methods used in original studies if data were extracted from GWASs or large GWAS meta-analyses from collaborative studies. For heterogeneity assessment, we performed the Cochran’s  studies , 26. A rg’s test  and Eggeg’s test  were conp-value of less than 0.10 was considered significant as recommended. All the other statistical tests were two-tailed, and a p-value of < 0.05 was considered statistically significant unless otherwise stated.Statistical analysis was done using STATA, version 15 . Tests of heterogeneity and bias were two-tailed, and a Venice criteria were applied to evaluate the epidemiological credibility of significant associations identified by primary meta-analyses see . BrieflyWe also estimated the noteworthiness of the significant associations by calculating FPRP . A priorr2 > 0.80 was considered as significant using data from the 1000 Genomes Project  as significant, adjusted for multiple comparisons of variants and 778 phenotypes.We performed linkage disequilibrium (LD) analysis for variants significantly associated with risk of diseases and phenotypes in the present meta-analyses, and  Project . We then Project . We conscis-eQTL data in multiple tissues from the Blood eQTL browser  tool HaploReg v4.1  and the  browser , and the browser . The sigIL6R gene and the risk of human diseases and phenotypes. Of the 155 publications, 114 regarding the association between 67 variants in the IL6R gene and 102 diseases . Specifically, the coronary heart disease risk was negatively associated with minor allele of rs7529229 , rs4537545 , and rs2228145 . Atrial fibrillation risk was inversely associated with minor allele of rs7529229 , rs4537545 , and rs28638007 , but positively associated with rs4845625 . The abdominal aortic aneurysms risk was negatively associated with rs7529229 , but it was positively associated with rs4129267 . As for asthma, rs4129267  and rs2228145  were associated with increased risk of asthma. In addition, the CAD risk was positively associated with rs4845625 .We conducted 27 main meta-analyses to estimate associations of six variants in p > 0.05).Furthermore, rs2228145  was associated with decreased risk of aneurysm , atherosclerosis , rheumatoid arthritis , type 1 diabetes , CVD , type 2 diabetes , Crohn’s disease , and ulcerative colitis  while it was positively associated with dermatitis . However, we did not find significant associations between rs2228145 and risk of obesity, dengue, mental disorder, multiple myeloma, chronic obstructive pulmonary disease (COPD), and anterior cruciate ligament injury  (As shown in  < 0.05) Table 2.We also conducted meta-analyses for rs2228145 and 12 continuous phenotypes under a co-dominant model (I2 < 25%), ten associations revealed moderate heterogeneity (25% > I2 <50%) and 24 associations revealed strong heterogeneity (I2 > 50%). The results indicated that publication bias was found in three associations (p < 0.10), and a small study bias was found in nine associations (p < 0.10)  in the European population.Linkage disequilibrium analysis (p < 6.43 × 10-6. Variant rs4845625 and its highly correlated SNPs were significantly associated with four non-binary phenotypes of mean platelet (thrombocyte) volume, platelet count, mean corpuscular hemoglobin, and monocyte count.Therefore, phenome-wide association analysis was just conducted for two SNPs (rs2228145 and rs4845625) using data from UK Biobank. The results are shown in IL6R gene. In variant rs2228145, A to C transition is observed at position 358 in the IL6R gene, resulting in the alteration of amino acid from alanine to aspartate or valine. The C allele of rs2228145 is associated with inflammatory/autoimmune diseases as well as quantitative traits , indicating similar functional mechanisms in this ethnic group. According to LD analysis in the European population, cis-eQTL analysis was conducted for rs2228145 and rs4845625 , inflammatory or autoimmune diseases , and levels of inflammatory biomarkers . We then assigned strong cumulative evidence to 29 significant associations, which assessed ten variants in this gene related to the risk of five cardiovascular diseases, four inflammatory diseases, and the concentration of four phenotypes. Further analysis of functional annotation indicates that the strong variants might fall in putative functional regions.Our study summarizes the published data thus far on relationships between variants in the IL6R gene encodes a subunit of an IL-6R protein complex that exists in two forms, an mIL-6R and sIL-6R, resulting in different signal transduction mechanisms known as IL-6/IL-6R classic signaling and trans-signaling, respectively. These two models of signaling can mediate the anti-inflammatory  and pro-inflammatory  response of IL-6 , indicating that the functional mechanisms of these SNPs associated with diseases and phenotypes might be similar. In addition, the variant rs4845625  strongly associated with CAD is in weak or moderate LD with rs2228145 , reflecting that functional mechanisms of IL6R variants associated with CVD risk might be distinct. Additional studies are needed to investigate rs4845625 and its related SNPs affecting the development of CVD.LD analysis using data from the 1000 Genomes Project reveals that four variants  are highly correlated with rs2228145 in the European population . The funding agencies of this study had no role in study design, data collection, data management, data analysis, data interpretation, writing of the manuscript, or the decision for submission.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.


The global spread of coronavirus has caused many physical and mental health problems throughout the world. Depression and anxiety are among the issues that people are experiencing abundantly, along with other mental health disorders, during this period. Cognitive behavior therapy (CBT) is one of the approaches that is effective on improving most of the psychological issues including depression and anxiety. The objective of this systematic review and meta-analysis was to assess the effects of CBT on depression and anxiety during COVID-19 pandemic period.I2 index; and in the case of heterogeneity presence, random effects model was used instead of fixed effects model. Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used for evaluating the quality of evidence.English databases such as Cochrane, PubMed, Google Scholar, Web of Science and Persian databases such as SID, MagIran and IranDoc were searched with a time limit of 2019 to 2022. Two researchers independently evaluated the quality of the entered studies based on Cochrane handbook. Subgroup analysis was conducted separately on the basis of being infected with coronavirus, not being infected with coronavirus, and having a history of depression or anxiety before the intervention and internet-based CBT for depression and anxiety. Meta-analysis results were reported using standardized mean difference (SMD) and 95% confidence interval (95% CI). Heterogeneity of studies was analyzed by means of P < 0.00001, I2 = 94%). In addition, mean score of depression in the intervention group was significantly lower than the control group . In addition, the results of subgroup meta-analysis showed that internet-based CBT was effective in reducing of depression  and anxiety . The evidence about the effectiveness of CBT on depression and anxiety compared with control group on the basis of GRADE approach had low quality.Totally, 2015 articles were analyzed of which 11 articles entered meta-analysis. The overall results of meta-analysis showed that mean score of anxiety in the group receiving CBT was significantly lower than the control group . The worldwide outbreak of coronavirus pandemic since 2019 became a very serious crisis for all people and posed many challenges for world health community as well as research and medical committees ) OR anxiety [MESH Terms]) AND cognitive behavior therapy [MESH Terms] at COVID-19One of the strategies used in this study to search in PubMed database is as follows:Two researchers (NZ and RH) independently investigated the titles and abstracts of the studies that were obtained via the search for a review study; if obtained data were not sufficient for decision making, the whole article was analyzed and any uncertainty about its suitability for being entered in the study was resolved through consulting with a third researcher (MM).The researchers extracted the data from the relevant studies on the basis of Cochrane handbook including: first author’s name, year of publication, country, characteristics and design of intervention, age of participants, sample size, type of intervention, type of control group, measuring tools, results and consequences, and then presented the data in Table Two researchers (NZ and RH) independently assessed risk of biases and again evaluated and resolved any inconsistencies via counseling with a third researcher (MM). The studies included were analyzed on the basis of Cochrane Handbook and in regard to six domains of bias  in three levels of low-risk, unclear, and high-risk and the results are presented in Table I2 index, and in cases with high heterogeneity, random effects model was used instead of fixed effects model. Subgroup analysis was conducted on the basis of being infected with coronavirus, not being infected with coronavirus, having a history of depression and anxiety before the intervention and internet-based CBT for depression and anxiety. Since the number of included studies in the meta-analysis of anxiety was more than 10 studies, publication bias was assessed with Egger’s test and funnel plot. A meta-regression analysis was performed to estimate the influence of the participants’ type  on heterogeneity.The Review Manger (RevMan) software of version 5.3 and Stata version 14.2 software  were used for meta-analysis and plotting bias forms. Because of the different tools that were used for measuring anxiety and depression, meta-analysis results were reported using standardized mean difference (SMD) and 95% confidence interval (95% CI). Heterogeneity of studies was analyzed by means of A total of 2015 articles were obtained from the search in different databases of which 1987 articles were excluded due to duplicates or the irrelevancy of their titles or after reviewing their abstracts. Of 28 remaining articles, 14 of the articles did not enter the systematic review due to the following reasons: Mohammadi et al.  articlesThe risks of biases of the entered studies are presented in Table Three of the studies were conducted in China , 33, 34,P < 0.00001) and heterogeneity level of I2 = 94% were obtained. Subgroup analysis results on the basis of being or not being infected with coronavirus or having a history of depression were as follows.Random-effects meta-analysis on 6 studies and 1269 participants showed that the mean score of depression in the intervention group was significantly lower than the control group . However, there was no statistically significant difference between two groups for those infected with coronavirus  and people with a history of depression . There were two studies that implemented CBT via the internet for depression. Subgroup analysis was conducted on these studies. The results of the meta-analysis showed that internet-based CBT was effective in reducing of depression   Fig. .Fig. 4MeP < 0.00001; I2 = 94%). Subgroup analysis results on the basis of being or not being infected with coronavirus or having a history of anxiety were as follows.Random-effects meta-analysis on 11 studies and 1859 participants showed that the mean score of anxiety in the intervention group was significantly lower than the control group  but for people infected  and not infected with coronavirus  there were no statistically significant difference between the intervention and control groups. There were 6 studies that assessed the effect of internet-based CBT on anxiety. Subgroup analysis was conducted on these studies. The meta-analysis results showed that internet-based CBT had a significant effect on anxiety  .The asymmetrical appearance of the funnel plot indicates the probable presence of publication bias in the anxiety-related studies Fig. . This waThe results of meta-regression model indicated that in both variables of anxiety and depression, none of the two groups (participants with corona and participants with anxiety) did not show significant difference compared to the participants without corona.The evidence about the effectiveness of CBT on depression and anxiety compared with control group on the basis of GRADE approach had low quality, so the results were close to reality with low reliability. The results of evaluation of evidence utilizing GRADE are shown in Table According to most of the studies, COVID-19 pandemic has a negative impact on individual mental health so different psychological approaches should have been used to improve society’s well-being. CBT is one of the effective approaches for psychological disorders. In the present study, the effects of CBT on people’s depression and anxiety in COVID-19 pandemic period were analyzed. Based on the overall results of meta-analysis, CBT had a significant effect on reducing anxiety and depression. Since we did not find systematic review studies on the effects of CBT on anxiety and depression in coronavirus period, we reviewed similar studies. No study was found that examined both outcomes so we have reviewed outcomes separately. There were some studies that evaluated the effect of CBT on the anxiety.Hall et al.  evaluateThere are a number of articles that evaluated the effect of CBT on depression. In a systematic review, Lopez-Lopez et al.  investigCBT is a therapeutic approach that is suggested for the treatment of depression and anxiety by Aaron beck. CBT helps the patients change their thoughts and through which leads to better feelings in them . Since nThe results of the subgroup meta-analysis showed that ICBT (internet-based CBT) is effective in reducing depression and anxiety. In the Farrer et al. study , ICBT waThis systematic review and meta-analysis has a number of weaknesses and strengths. One of the limitations was the small sample size of the included studies. In addition, we had just 11 studies which also limited our sub-group analyses. The other limitations of the present study were different study designs, participant’s ages and outcome measures. In addition, the most of the included studies did not clearly stated their methods of randomization and so were placed in unclear risk level in terms of randomization bias, just one study  was low One the strengths of the present study is that all of the included studies are at low-risk level in terms of reporting bias and attrition bias. Likewise, in the present systematic review, all age groups regardless of their sex entered the study, so the results are generalizable to all age groups and both sexes. Of other strengths of this study, we can refer to subgroup analysis.Meta-analysis shows that CBT is significantly effective on reducing depression and anxiety scores in COVID-19 pandemic period. Therefore, extensive use of this method during coronavirus pandemic and other similar pandemics is recommended. It is suggested that the effectiveness of other psychological approaches on the problems developed during the pandemic to be analyzed in other studies. Moreover, since the need for counseling and psychological interventions is inevitable due to psychological and mental disorders people experience during different kinds of crises such as natural or social crises or pandemics etc., it is recommended that governments and communities put paying enough attention to these methods on their agenda.


Accumulating epidemiological evidence has shown the favorable associations between healthy dietary patterns and risk of glioma, although the results remain inconclusive.We therefore carried out a systematic review and meta-analysis to summarize the evidence from previous published studies, and to clarify the effects of healthy dietary patterns, typical healthy foods on glioma.Q test and I2 statistic. According to heterogeneity, the fixed-effects model or random-effects model was selected to obtain the relative risk (RR) of the merger. Subgroup analysis, sensitivity analysis and publication bias were also used for our analysis.PubMed, Web of Science, CNKI, and Wan fang data were searched from inception up to September 2022 for eligible studies. Two authors independently performed the literature search, study selection, data extraction, and quality assessment. Heterogeneity across studies was estimated using the Cochran’s P < 0.0001). Moreover, compared with the lowest intakes, the highest intakes of vegetables  and fruits  significantly reduce the risk of glioma. However, the intakes of fresh fish, nuts, whole grains, and dairy products showed no statistically significant associations with the risk of glioma (P > 0.05).Twenty-four articles that met the selection criteria, involving 7,278 glioma cases and 2,143,528 participants, were included in our analysis. There was a reduced risk of glioma in the highest compared with the lowest categories of healthy dietary patterns (RR = 0.58; 95% CI: 0.44–0.77; Findings from this systematic review and meta-analysis indicate that higher intakes of healthy dietary patterns, vegetables, and fruits are significantly associated with the lower risk of glioma. Further studies, particularly with prospective design, are required to confirm our findings. According to estimates from the International Agency for Research on Cancer (IARC) in 2020, the global incidence rate of brain cancer is 3.9 per 100,000 in males and 3.0 per 100,000 in females . MoreoveA growing body of evidence has suggested that dietary factors play the important role in the pathogenesis of glioma , 9. For P < 0.001) (a posteriori methods and odds of glioma (The considerable attentions in recent years have been focused on examining dietary patterns as a whole in relation to glioma risk . Up to d< 0.001) . Howeverf glioma . In contf glioma . Notablyf glioma . But, thThis systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines . HoweverA comprehensive literature search was performed for pertinent articles published in English or Chinese using the databases of PubMed, Web of Science, CNKI, and Wan Fang Data up to September 2022, with the following search terms:  AND . No publication date restrictions were applied in the retrieved process. Moreover, reference lists of all retrieved studies and the published review articles were also manually searched to identify any other studies that were not found in the initial database search.Titles and abstracts of all retrieved articles were assessed by two independent authors (LS and DY). Any inconsistencies were resolved by discussion with a third author until consensus. After all authors agreed on the relevant articles, the full-text versions of articles were reviewed against inclusion and exclusion criteria for this meta-analysis. Studies were included in this systematic review and meta-analysis if they met the following inclusion criteria: (1) original studies with observational design ; (2) the study was published in the English or Chinese languages; (3) the exposure of interest was healthy dietary patterns and typical healthy foods; (4) the outcome of interest was glioma in adults; (5) studies that reported risk estimates  of glioma and their corresponding 95% CIs were provided ; (6) If the data in original publication lacked sufficient detail, the corresponding author of the study was contacted for additional information by email. Studies were excluded based on the following criteria: (1) written in a language other than English or Chinese; (2) not performed on humans; (3) non-observational study, i.e., review articles, conference abstracts, case reports, editorials, and letters to the editor; (4) lack of sufficient data to obtain RR/HR/OR and 95% CI.Two authors (LS and DY) independently assessed the eligible studies. Among the selected studies, the following information was extracted, including the first author’s last name, year of publication, location, study design, age range/mean age for cases and participants, number of cases and controls or participants, methods used to identify dietary pattern, confounders adjusted for, and the OR, RR, or HR estimates with corresponding 95% CI for the highest vs. lowest categories of healthy dietary patterns or typical healthy foods.The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the included non-randomized studies in meta-analyses . This scI2 statistic were used to evaluate the potential sources of heterogeneity in all included studies. A P-value of Q-test ≤ 0.10 or I2 scores ≥ 50% indicated a presence of between-study heterogeneity, and the random-effects model by DerSimonian and Laird method was used to combine the effect size and 95% CI. Otherwise, the fixed-effects model was used (a priori vs. a posteriori), and the study quality (≥7 points and <7 points). Publication bias was evaluated visually with funnel plots and with the Begg’s or Egger’s tests . Given the incidence of glioma was relatively low, ORs and HRs were directly treated as RRs . Log-trawas used . If the ’s tests . Sensitin = 9); the outcome of interest was brain tumor and not glioma (n = 10); reported the same participants (n = 2); did not mention healthy dietary patterns or typical healthy foods (n = 6); animal studies (n = 2). Ultimately, 24 articles were eligible to be included in this systematic review and meta-analysis. Among these articles, 10 articles reported the association between healthy dietary patterns and risk of glioma, 13 articles reported the association between vegetables intake and risk of glioma, 16 articles reported the association between fruits intake and risk of glioma.a posteriori method . The heterogeneity among the included studies was apparent , and hence the effect was assessed using the random-effects model. There was an asymmetry in the funnel plot, and the Egger’s test (P < 0.0001) revealed a possible publication bias. Consistently, on the basis of the trim and fill algorithm, the adjusted value showed an inverse association between healthy dietary patterns and risk of glioma. Comparing the adjusted value (0.543) with the original estimate (0.581) indicates a small contribution of the study effect to the original results. The results from sensitivity analysis revealed that excluding an individual study did not change the significance of the results, indicating that the combined results are stable  . Sixteen articles reporting eighteen original studies were included, and P = 0.014). A random-effects model was used to assess the data, and there was evidence of heterogeneity . However, in pooled analyses of five studies, high intake of fresh fish was not associated with the risk of gioma , and there was moderate between-study heterogeneity   . Data fr= 0.134) . Likewis= 0.134) , whole g= 0.134) , and dai= 0.134)  showed tI2 = 0%). Besides, in T3 vs. T1 comparison studies, there was no evidence of heterogeneity between studies , and a significantly decreased risk of glioma was shown . For other healthy foods intake . For the study country, vegetables intake was statistically significant in Asian countries , where moderate heterogeneity . For study quality, vegetables and fruits intake were statistically significant in the studies with the study quality score < 7 . However, the heterogeneity was apparent for fruits intake . Similarly, for sample size, vegetables intake was statistically significant in the studies with sample size < 1,000 . For fruits intake, there was evidence of heterogeneity , and a significant decrease in the risk of glioma was shown in the studies with sample size < 1,000 . For fresh fish and whole grains intakes, because of the relatively small number of studies and limited reporting of subgroup results, we were unable to explore all potential sources of heterogeneity. In general, subgroup analyses revealed that several factors, e.g., study design, study quality, and methods used to determine dietary patterns are potential sources of heterogeneity.Significant heterogeneity was observed in healthy dietary patterns, vegetables, fruits and nuts intake and glioma risk. Thus, further subgroup analyses were carried out. For healthy dietary patterns , subgrous intake , subgrouP = 0.271; Egger’s test P < 0.01). Thus, we conducted the trim and fill analysis to adjust the pooled effect, and found that the results remained unchanged. Besides, for other healthy foods, the visual inspection of funnel plots revealed little evidence of asymmetry (not shown) and therefore little evidence of publication bias .The effect of individual studies on the pooled RR was evaluated by repeating the meat-analysis after eliminating each study in turn. The results showed a slight change in the relationship between healthy dietary patterns and glioma, when Kuan et al.’s study was excluded. Besides, no individual study had excessive influence on the association of typical healthy foods intake and glioma, when we removed a single study at a time. Hence, the results of this meta-analysis were relatively stable . The funThe quality of included non-randomized studies based on NOS criteria is shown in To the best of our knowledge, this is the first systematic review and meta-analysis to explore the associations between healthy dietary patterns, typical healthy foods and the risk of glioma. Based on 24 articles on healthy dietary patterns, typical healthy foods and glioma published from 1987 to 2022, involving 7,278 glioma cases and 2,143,528 participants, our meta-analysis results showed the significant inverse associations between healthy dietary patterns, vegetables and fruits intakes and risk of glioma, with substantial heterogeneity between studies. Meanwhile, other healthy foods including fresh fish, whole grains, nuts and dairy products had no significant effects on glioma. Subgroup analyses revealed that these associations depend on the study design, study quality, country, and methods used to identify dietary patterns. Collectively, our findings provide further evidence for an inverse association between healthy dietary patterns and glioma risk, and support the adoption of this pattern for the prevention of glioma.In 2020, GLOBCAN estimated that the overall age-standardized incidence rate of brain cancer was 3.9 and 3.0 per 100,000 for males and females, respectively . In addiP = 0.012). Our results are in line with a previous meta-analysis conducted by Li and his colleagues . By contrast, however, findings from a recent systematic review and meta-analysis of dietary factors and risk of glioma showed that fresh fish intake had no significant effect on the risk of glioma   . Even soP > 0.05). Inconsistent with our findings, Malmir et al. found an inverse association between legume and nuts consumption and odds of glioma . Although between-study heterogeneity is common in meta-analysis (In the present meta-analysis, we found the high between-study heterogeneity on the association between adherence to the healthy dietary patterns and risk of glioma (analysis , explorianalysis . FinallyThis study has its own strengths. First, this is the first systematic review and meta-analysis to comprehensively clarify the associations between healthy dietary patterns, typical healthy foods and the risk of glioma. This systematic review further adds to the current evidence on the protective effect of healthy dietary patterns against glioma. Second, the cases of glioma have been diagnosed through clinical manifestations and pathological section, avoiding misdiagnosis. Third, with a larger number of studies and the cases of glioma than the previous meta-analyses, this study had more statistical power to detect the significant associations between healthy dietary patterns, typical healthy foods and glioma. Fourth, the strengths of this study are the extensive literature screening with strict adherence to quality standard set out in PRISMA 2020 guidelines. We excluded some published studies that have been included in some previous meta-analyses but involved astrocytoma and other types of brain tumors , 14, 68.In conclusion, the present systematic review and meta-analysis shows that adherence to healthy dietary patterns may reduce the risk of glioma. Moreover, higher intakes of several typical healthy foods, such as fruits and vegetables are also inversely associated with the risk of glioma. Our findings provide a more comprehensive and reliable evidence for the protective role of healthy dietary patterns, typical healthy foods against glioma. This supports public health recommendations to increase the intakes of healthy dietary patterns and typical healthy foods for the prevention of glioma. However, further large prospective studies and randomized controlled trials are required to validate our findings in different populations.The original contributions presented in this study are included in the article/LS and FJ took responsibility for data integrity and the accuracy of data analysis and drafted the manuscript. FJ was responsible for study concept and design. LS and DY acquired the data. LS was responsible for analysis and interpretation of the data. DY performed the statistical analysis. All authors critically revised the manuscript for important intellectual content and approved the submitted version.