The paper aims to assess the association between Hepatitis B Virus infection and colorectal liver metastasis by conducting a meta-analysis. The relevant studies were searched until 24 July 2020, Studies that assessed the correlation between HBV infection and CRLM were recruited. A random effects model was applied to calculate the odds ratio (OR) with 95% confidence interval (CI). All data analyses were performed by STATA 12.0 software. Ten studies involving 17529 participants were included in the study. The results shown that there was obvious association between HBV infection and CRLM . The study type and case–control rate may be the main causes of heterogeneity. In addition, HBV infection had no association with extrahepatic metastasis or prognosis of patients with CRLM. Sensitivity analyses confirmed that the results were stable, and Egg’s test indicated that there was no publication bias. Patients with HBV infection have the reduced risk of CRLM.  Colorectal cancer (CRC) is one of the most common malignant tumors, with the third highest incidence rate and the second highest mortality rate worldwide . It is eMany scholars have observed less tumor metastasis in the injured liver, including fatty liver, cirrhosis, and chronic hepatitis B infection . ChronicIn recent years, some studies have explored the relationship between HBV infection and CRLM . Qiu et So far, the association between HBV infection and CRLM is still unclear. Therefore, we summarize the existing evidences and conduct a meta-analysis to comprehensively assess the risk of CRLM in patients with HBV infection.A comprehensive literature search was conducted by two independent investigators (RQ.L and WH.K). Relevant studies were systematically searched in the PubMed, EMBASE and Web of Science until 31 October 2020. The following keywords were used: ‘colon cancer’, ‘colon neoplasm’, ‘colon tumor’, ‘colon carcinoma’, ‘rectal cancer’, ‘rectal neoplasm’, ‘rectal tumor’, ‘rectal carcinoma’, ‘colorectal cancer’, ‘colorectal neoplasm, ‘colorectal tumor’, ‘colorectal carcinoma’, ‘Hepatitis B Virus’, ‘HBV’, ‘hepatic metastases’, ‘liver metastases’. Boolean operators, such as ‘OR’ and ‘AND’, were used to combine the above keywords. No language restrictions and manually search for references in the included studies.The inclusion criteria were as follows: (1) assessed the association between HBV infection and CRLM. (2) offered the numbers of positive/negative liver metastasis persons in the HBV infection groups and control groups, and (3) more than 20 patients with HBV infection were included in the study. The exclusion criteria were as follows: insufficient data studies, animal experiments, letters, case reports and review were excluded.Two researchers extracted the data independently (RQ.L and TX.D). The following data were extracted: first author name, publication year, country, study design, age, male/female, the number of patients with liver metastases and non-liver metastases in the HBV group, the number of patients with liver metastases and non-liver metastases in the control group, the number of patients with extrahepatic metastases in the HBV group, and the number of patients with extrahepatic metastases in the control group. All studies were evaluated by the Newcastle-Ottawa Scale (NOS) in meta-analyses .2. If I2 was <50%, a fixed-effect model was used, and if I2 was ≥50%, a random-effects model was applied. Odds ratios (OR) and corresponding 95% CI were used to analyze the relationship between HBV infection and CRLM. Meta-regression and subgroup analyses were conducted to explore the sources of heterogeneity. The publication bias was evaluated by Egger’s test. All data analyses were performed using by STATA 12.0 . P value <0.05 was considered statistically significant.Heterogeneity was assessed based on IThe association between Hepatitis B Virus infection and colorectal liver metastasis is still unclear. Therefore, we summarize the existing evidences and conduct a meta-analysis to comprehensively evaluate the association between therefore and colorectal liver metastasis. We firstly searched the designated database to identify the relevant articles and extracted relevant data for meta-analysis. We found that patients with Hepatitis B Virus infection have the reduced risk of colorectal liver metastasis. In addition, HBV infection had no association with extrahepatic metastasis or prognosis of patients with colorectal liver metastasis.A total of 410 articles were initially collected from specified database. Three hundred and forty-five articles were screened for further information after removing 65 duplicates. Three hundred and twenty-six articles were further excluded after screening the titles and abstracts. Eventually, ten articles which investigated the association between HBV infection and CRLM were recruited in the meta-analysis. The flow diagram of the literature search is presented in The articles included in the meta-analysis comprised two cross-sectional study and eight case–control studies. Two studies were conducted in non-Asian countries, and eight in Asia. There were 17529 participants in the included studies, with the number of participants per study ranging from 356 to 7187. The NOS scores ranged from 5 to 7, with a mean score of 6.4. The characteristics of the included studies are summarized in 2 = 90.5%). The result showed that there was a significant reduced risk of CRLM in HBV Infection patients . The forest plot is displayed in The random-effects model was applied due to the marked heterogeneity . The forest plot is displayed in Among the included studies, six studies explored the association between HBV infection and extrahepatic metastasis. The meta-analysis indicated that there was no correlation between HBV infection and extrahepatic metastasis  with random-effects model . The forest plot is displayed in We performed sensitivity analysis to check the stability of the results. The results were consistent with the overall analysis, indicating that the results were stable . Egger’sAs is well known for us, the study is the first meta-analysis to comprehensively explore the relationship between HBV infection and CRLM. The results indicated that HBV infection was closely correlated with CRLM . Subgroup analysis confirmed that HBV infection can reduce the risk of metachronous colorectal liver metastases . We also conducted analysis according to different countries, and the results revealed that whether in China or Itlay, HBV infection was significantly related to CRLM. Regression analysis revealed that study type and case–control ratio may be sources of heterogeneity. Zhao et al. suggested that HBV infection was one of the prognostic factors of CRLM . The comThe mechanisms of HBV infection on CRLM are complicated. Lisa firstly discovered that liver cirrhosis was not conducive to the growth of metastatic tumors . HepatitSeveral limitations existed in our study. Firstly, the included studies are all retrospective studies, and it is difficult to determine the causal relationship between HBV infection and CRLM. More prospective controlled trials are necessary to validate our findings. Secondly, the results should be treated with caution due to the apparent heterogeneity. Thirdly, most of the included studies are from Asia. The conclusions should be more suitable for Asians, especially for China. Studies on the association of HBV infection with colorectal liver metastasis risk in different regions should be performed. Fourthly, some risk factors that affect colorectal liver metastasis such as diabetes, alcoholism, obesity and smoking cannot be extracted, and the meta-analysis could not be able to exclude their influence. Furthermore, we have not been able to distinguish whether there is a difference in the effects of hepatitis B cirrhosis and chronic hepatitis B on CRLM.The study also has some advantages. Firstly, our study is the first comprehensive meta-analysis about the effect of HBV infection on CRLM, and the results have higher statistical power and are more persuasive. Secondly, sensitivity analysis revealed that the results were stable. Additionally, we discovered the factors that caused high heterogeneity. More importantly, there is no possible publication bias.This meta-analysis confirms that Patients with HBV infection have a reduced risk of CRLM based on current evidence. Undoubtedly, large-scale prospective studies are necessary to validate the present results and seek strategies to prevent CRLM in the future.


I2 = 7%, P for Cochrane's Q test = 0.37). During a mean follow‐up of 9.7 months, 216 (39.3%) cases of recurrent AF occurred. Results of the meta‐analysis showed that anxiety was independently associated with an increased risk of AF recurrence after catheter ablation . Subgroup analyses did not show that differences in study characteristics including study design, ethnicity of the patients, sample size, AF type, anxiety evaluation method, follow‐up duration, or adjustment of LAD may significantly affect the association between anxiety and AF recurrence . Anxiety may be an independent risk factor for AF recurrence after catheter ablation. Whether alleviating anxiety mood could reduce the risk of AF recurrence after catheter ablation should also be investigated.Previous studies that evaluated the influence of anxiety on recurrence of atrial fibrillation (AF) after catheter ablation showed inconsistent results. We performed a meta‐analysis of cohort study to systematically evaluate the association between anxiety and AF recurrence after catheter ablation. Electronic databases of PubMed, Embase, and Web of Science were searched for relevant cohort studies from inception to January 20, 2021. We applied the random‐effect model to combine the results to incorporate the potential influence of heterogeneity among studies. Five cohort studies were eligible for the meta‐analysis, which included 549 patients with AF that received catheter ablation. No significant heterogeneity was observed among the included studies ( We applied a combined search term of “anxiety” OR “tension” OR “posttraumatic stress disorder” OR “panic” OR “phobia” OR “phobic” OR “worry,” with “atrial fibrillation” OR “AF,” and “ablation” OR “catheter” OR “pulmonary vein isolation” OR “PVI” OR “recurrence.” We only considered studies published in English. As a complementation, we also searched the reference lists of the related original and review articles for potential relevant studies.2.2Studies that fulfilled all of the criteria were considered to be eligible for the meta‐analysis: (1) designed as cohort studies; (2) patients with AF that were scheduled for catheter ablation were included; (3) anxiety was evaluated for the AF patients before the ablation procedure and considered as exposure; (4) documented the incidence of AF recurrence during follow‐up in AF patients with and without anxiety; (5) reported the multivariate‐adjusted risk ratios (RRs) for the recurrence of AF in patients with anxiety as compared to those without anxiety, at least for age and gender. Anxiety was evaluated and validated in accordance with the criteria applied in the original articles. We did not apply restrictions of minimal sample sizes or follow‐up durations for the potentially included studies. For repeated reports of the same cohort, latest studies with the longest follow‐up duration were included. For studies reported RRs of different adjusting levels, the most adequately adjusted data were extracted.2.3Two authors (H. D. and L. Y.) performed database search, data extraction, and quality assessment independently. If discrepancies occurred, consultation with the third author (Z. H.) was indicated to resolve them. The following data regarding study characteristics were recorded: (1) study information ; (2) patient characteristics ; (3) methods for the evaluation and validation of anxiety; (4) details of catheter ablation procedures; (5) follow‐up durations; and (6) methods for the validation of the AF recurrence outcome. We evaluated the quality of the included studies using the Newcastle–Ottawa Scale.2.4p values, and were logarithmically transformed to stabilize variance and normalized the distribution.Q test and I2 test were performed to evaluate the heterogeneity among studies.I2 > 50% indicates significant heterogeneity. A random‐effect model was applied for the meta‐analysis since it incorporates the potential influence of heterogeneity and thereby could retrieve a more generalizable result.p < .05 was considered as statistically significant. RevMan  and STATA software  were used for the statistical analyses.Data of RRs and their corresponding standard errors were calculated from 95% confidence intervals (CIs) or 33.1The processes of database search and study identification were presented in Figure 3.2The characteristics of the included studies were presented in Table 3.3I2 = 7%, P for Cochrane's Q test = 0.37). During a mean follow‐up of 9.7 months, 216 (39.3%) cases of recurrent AF occurred. Results of the meta‐analysis showed that anxiety was independently associated with an increased risk of AF recurrence after catheter ablation . Predefined subgroup analyses did not show that differences in study characteristics including study design, ethnicity of the patients, sample size, AF type, anxiety evaluation method, follow‐up duration, or adjustment of LAD may significantly affect the association between anxiety and AF recurrence  patients had AF recurrence. No significant heterogeneity was observed among the included studies (9.3% pati3.4Funnel plots for the meta‐analysis of the association between anxiety before procedure and AF recurrence after catheter ablation were shown in Figure 4In this meta‐analysis, by pooling the results of relevant cohort studies, we found that anxiety is independently associated with an increased risk of AF recurrence after catheter ablation. Further results by excluding one study at a time confirmed the stability of the findings, which was not driven by a certain included cohort. In addition, subgroup according to the study design, ethnicity of the patients, sample size, AF type, anxiety evaluation method, follow‐up duration, and adjustment of left atrial dimension did not show a significant influence on the association of interest, which further validated the robustness of the findings. Taken together, these results suggested that anxiety is an independent risk factor for AF recurrence after catheter ablation. These findings should be validated in large‐scale prospective studies. Moreover, in view of high incidence of AF recurrence after catheter ablation in current real‐world practice, potential effects of psychotherapy and anxiolytics on AF recurrence after catheter ablation in patients with anxiety should be evaluated.To the best of our knowledge, this study is the first meta‐analysis that evaluated the association between anxiety and AF recurrence after catheter ablation. The strengths of the study include the strict inclusion criteria and comprehensive data analysis. Only cohort studies were included, which thereby could provide a temporary relationship between anxiety and AF recurrence. Besides, only data with multivariate adjustment were used, which could derive an independent association between anxiety and AF recurrence after catheter ablation. In addition, both sensitivity and subgroup analyses were used to confirm the robustness of the finding. Finally, no significant heterogeneity was found among the included cohort studies, which also reflected the consistency of the study design of the included cohorts. Previous studies also found that anxiety was independently associated with increased risks of early AF recurrence after cardioversion,Currently, it remains unknown whether interventions such as psychotherapy or anxiolytics could reduce the risk of AF recurrence in patients with anxiety. Interestingly, it has also been shown that anxiety is also associated with poor QoL in AF patients after catheter ablation,5Some limitations of our meta‐analysis should be mentioned. First, limited studies were included, particularly for the subgroup analysis. Accordingly, the results of subgroup analysis should be interpreted with caution. Second, the follow‐up durations of the included cohorts varied between 3 and 12 months, whether anxiety is associated with long‐term recurrence of AF after catheter ablation remains unknown. Third, various instruments were used for anxiety evaluation among the included studies. The optimal instruments for anxiety evaluation among these patients remain to be established. Moreover, although multivariate‐adjusted data were used, we could not exclude that some residual factors may confound the association between anxiety and increased risk of AF recurrence, such as concurrent use of statins.6In conclusion, the results of this meta‐analysis showed that anxiety is an independent risk factor for AF recurrence after catheter ablation. These findings should be validated in large‐scale prospective studies, and the potential effects of psychotherapy and anxiolytics on AF recurrence after catheter ablation in patients with anxiety should be evaluated.The authors declare that there are no conflict of interests.Hong Du and Lei Yang designed the study. Hong Du and Lei Yang performed database search, quality assessment, and data extraction. Hong Du, Hui Zhang, and Zheng Hu performed the statistical analysis. All authors interpreted the results. Hong Du and Zheng Hu drafted the manuscript. All authors critically revised the manuscript and approved the submission of the study.Supporting information.Click here for additional data file.


In serum lipids, total cholesterol levels are frequently reported associated with the exposure of PFCs. Among PFCs, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) exposure increased the risk of CVDs than other types of PFCs. Although the risk of PFOA and PFOS were positively associated with CVDs and their risk factors, more observational studies shall be carried out to identify the long-term effects of these contaminants in premature CVDs development in patients.Perfluorinated compounds (PFCs) are non-biodegradable synthetic chemical compounds that are widely used in manufacturing many household products. Many studies have reported the association between PFCs exposure with the risk of developing cardiovascular diseases (CVDs). However, those reports are still debatable, due to their findings. Thus, this review paper aimed to analyse the association of PFCs compound with CVDs and their risk factors in humans by systematic review and meta-analysis. Google Scholar, PubMed and ScienceDirect were searched for PFCs studies on CVDs and their risk from 2009 until present. The association of PFCs exposure with the prevalence of CVDs and their risk factors were assessed by calculating the quality criteria, odds ratios (ORs), and 95% confidence intervals (CIs). CVDs risk factors were divided into serum lipid profile (main risk factor) and other known risk factors. The meta-analysis was then used to derive a combined OR test for heterogeneity in findings between studies. Twenty-nine articles were included. Our meta-analysis indicated that PFCs exposure could be associated with CVDs (Test for overall effect:  PFCs consist of at least one perfluoroalkyl moiety CnFn+1 attacd groups . For thed groups ,7,8. Thed groups . The pred groups . The PFCd groups . It was d groups . After fd groups . The Eurd groups . Unfortud groups ,17.PFOS and PFOA are the most commonly detected PFCs found in the serum, plasma or tissue ,19,20. PThe accumulation of PFOS in the liver has been associated with hepatotoxicity . BesidesSeveral studies have documented the effects of high concentrations of PFCs on humans ,16,36, yMost studies investigated the presence of PFCs in patients of CVDs or with CVDs risk factors, such as serum lipid profile, diabetes mellitus, hypertension, atherosclerosis and obesity ,18,19,20PRISMA guidelines for systematic reviews and meta-analyses  were folThe following electronic database was searched for articles that had evaluated the association between PFCs exposure with CVDs and their risk factors between January 2009 and till present with English language restriction: Google Scholar, PubMed and Science Direct. This search used Google Scholar using this strategy:  and  or (“explode ‘atherosclerosis’ text word”) or (“explode ‘metabolic risk’ text word”) or (“explode ‘obesity’ or ‘body weight’ text word”) or (“explode ‘hypercholesterolemia’ text word”) or (“explode ‘hypertension text word”) or (“explode ‘hyperlipidemia’ text word”). A similar strategy was used in searches on PubMed and ScienceDirect. For Google Scholar, ‘Advance Search’ was further applied with; find articles with all the words ‘cardiovascular disease’, with the exact phrase “perfluoroalkyl compounds” and without the word ‘animal’. Abstracts were screened independently by two investigators (SSAS and SHSAK).Publication Type. Research and review articles were eligible. Conference Proceedings was excluded.Typesof studies. Randomised controlled trials (RCTs), cohort and cross-sectional studies were eligible. A narrative review and systematic review were excluded.Types of participants. Studies of adults (older than 18 years), adolescents (aged 10–18), children (aged 2–9) and infants. Animal and plant were excluded.Types of interventions. Studies that compared PFCs exposure with healthy or non-healthy humans.A selection was made for the PFCs exposure only. No restrictions were made regarding concentrations, duration of exposure, type of CVDs and type of CVDs risks.Types of outcomes. Studies were eligible if they assessed either (1) comparing non-diseased and CVDs patients (2) comparing healthy and CVDs risk population (3) comparing healthy and metabolic syndrome population (4) ascertained the prevalence of one or more manifestation of CVDs or CVDs risks diagnosis (5) provided quantitative estimation on the association between PFCs exposure and CVDs/their risk outcomes, including odds ratios (ORs) with 95% confidence intervals (CIs) or mean, standard deviation (SD) or difference in mean and sample size in healthy and non-healthy population.To be eligible, studies had to meet the following conditions:Eligible studies were assessed independently by two reviewers using a structured form to abstract information about the objectives, (country and year of publication), study subjects , CVDs/their risk exposures (method of ascertainment and definitions used) and main conclusion. Discrepancies were resolved by discussion or consultation with co-authors .The review protocol planned a separate analysis for PFCs exposure for (1) association of PFCs exposure with CVDs, (2) association of PFCs exposure with CVDs risks and (3) association of PFCs exposure with serum lipid. The OR from the highest quartile of PFCs exposure in each PFCs category associate with CVDs (95% CIs) were selected for the rest of the articles, whereas data of mean (ng/mL), standard deviation (SD) and sample size of PFCs concentration in healthy and non-healthy were selected only for Predieri et al.,2015 . As for If at least two studies were available on a specific outcome, meta-analysis were calculated using Comprehensive Meta-Analysis V3. A random-effects model was used to analyse statistical heterogeneity between studies . Meta-anect size .I2 statistics, a measure on how much variance between studies can be attributed to differences between studies rather than chance (1) I2 = 0.30%: No heterogeneity; (2) I2 = 30–49%: Moderate heterogeneity; (3) I2 = 50–74%: Substantial heterogeneity; and (4) I2 = 75–100%: Considerable heterogeneity [p value ≤ 0.10 was regarded to indicate significant heterogeneity [Heterogeneity was explored using the ogeneity . A p valogeneity .Subgroup and meta-analysis were performed where PFOS, PFOA and PFHxS were selected base on the most highly studied PFCs by previous researchers .p < 0.1 [Publication bias was assessed by visual analysis of funnel plots, generated using Comprehensive Meta-Analysis V3, if at least 10 studies were included in a meta-analysis . Roughlyp < 0.1 . ‘Trim ap < 0.1 . The ‘Trp < 0.1 , a funnep = 0.02) and considerable heterogeneity (I2 = 91.6% p < 0.0001) (p < 0.0001) and considerable heterogeneity (I2 = 85.8% p < 0.0001) (p = 0.12) and substantial heterogeneity (I2 = 72.1% p < 0.0001) (p = 0.47) and substantial heterogeneity (I2 = 58.56% p = 0.007) (p < 0.0001) and substantial heterogeneity (I2 = 60.13 p < 0.0001) (p < 0.0001) and considerable heterogeneity (I2 = 85.2%p < 0.0001)  . Strong  0.0001) . When st 0.0001) . No evid= 0.007) . In cont 0.0001) . Strong  0.0001) .There is evidence of heterogeneity between the studies investigating PFCs exposure with CVDs, serum lipid profiles (CVDs main risk factor) and other risk factors. This is further confirmed by the funnel plots, where a symmetrical funnel shape is obtained . In the funnel plot, the log ORs represents the natural logarithm of the OR of the individual studies, whereas the standard error represents the standard error in the natural logarithm of the ORs of the individual studies.p = 0.18), p = 0.12) and p = 0.10) suggesting that the plots are symmetry. Whereas significant asymmetry plot is observed in p = 0.04) and 12 .In Egger’s linear regression test, the intercept results indicate that the deviation from zero is not significant for In ‘trim and fill’ analysis, three studies were trimmed, and 20 possible missing studies (black spot) is indicated in the funnel plot  and not on specific CVDs [In the National Health and Nutrition Examination Survey (NHANES) (1996–2000 and 2003–2006), there is an increase in PFOA for CVDs and peripheral arterial disease in a cross-sectional study of 1216 adults. Age, sex, race, smoking history, body mass index, diabetes mellitus, hypertension and serum cholesterol were selected as independent confounders in the study . Anotherfic CVDs . The diffic CVDs . Individfic CVDs ,89,90. Tp < 0.001) [p = 0.002–0.003), whereas these associations were negative in men when analysed base on gender. Both experiments reported a sex-specific role of PFCs in atherosclerosis [The Carotid Intima-Media Thickness (CIMT) test is used to detect an individual risk of atherosclerotic disorder. The test measures the thickness of the carotid artery inner two layers; the intima and media. A previous cross-sectional study detected four types of PFCs  in random 644 serum samples from Taiwanese adolescents and young adults. Among the four types, PFOS was found to be significantly increased when CIMT increased (< 0.001) . In anot< 0.001) . Linear clerosis ,78. Testclerosis . These sInconsistent findings were observed in previous studies regarding the association of PFCs exposure with CVDs and their risk factors. Four out of eighteen studies had concluded that PFCs exposure is not associated with CVDs and their risk factors ,58,92 T. From thAlthough PFOA, PFOS and PFHxS were the most studied PFCs associated with human health, as demonstrated by many previous researchers , only PFOne previous study demonstrated that almost all PFCs exposure was not associated with CVDs except for PFHP . Althougp = 0.003). TRAP-6 activates the release of cytosolic calcium of platelets, necessary for the degranulation of platelets and important for the conformation and aggregation of platelets [A recent finding has demonstrated that impaired platelet aggregation, due to PFOA may lead to CVDs risk . The reslatelets . P-seleclatelets . Human slatelets . The latlatelets . The in latelets . Intereslatelets  This furMeta-analysis is suggesting that there is a need to understand the causative link between PFCs exposure and CVDs at the cellular level. Currently, limited studies are available. A recent finding has demonstrated that microRNAs (miRNAs) such miR-101-3p, miR-144-3p and miR-19a-3p are found to be downregulated when exposed to PFCs in a study involving 239 women drinking water contaminated by firefighting foam. In silico functional analyses suggested that these PFCs-associated miRNAs were annotated to cardiovascular function and disease . EpigeneThere are several limitations to this study. Firstly, the number of studies included in this work was not large enough to conclude that PFCs exposure is associated development of premature CVDs. Secondly, the number of studies included in this work was not large enough to separate the data into low versus high levels of PFCs exposure or comparing the risk, due to continuous exposure. Thirdly, we are unable to identify PFCs exposure association with serum lipid profile by stratify analysis of both forest plots and funnel plots as the data was not large enough. If more data are available, the analysis will be much clearer and more understandable. Fourthly, T1DM and T2DM were pooled together in previous studies when the researchers analysed the association of PFCs exposure with these CVDs risk factors ,60. FromOur synthesis of adequately designed studies showed a significant association of PFCs exposure with CVDs and their risk factors among children and adults. To our current finding, no available studies on infants for PFCs and CVDs. The heterogeneity between the ORs, indicates true effectiveness between populations. The important highlight in this meta-analysis is, each previous study had concluded a specific type of PFC(s) could be associated with CVDs. However, all the insignificant data of PFCs exposure were included and could not be discriminated during the meta-analyses. This eliminates the possibility of bias in selecting eligible papers that favours CVDs and their risk factors. Our analysis demonstrated that PFOS exposure association with CVDs and their risk are statistically significant. More in vivo and in vitro studies are needed on understanding the mechanism of PFCs exposure effects in the human heart, since several correlations and epidemiological studies do not fully elucidate what exactly happens at the cellular levels. The most recent finding that gives an insight into the cellular event is the effect of PFCs exposure on the platelet aggregation. How PFCs exposure is related to impaired platelet aggregation and leads to CVDs risk can be expanded by understanding the mechanism involving P-selectin and TRAP-6. Several important factors need to be alerted in future studies, such as gender, race and heterogenous lipoprotein subspecies, since these factors were observed to contributes to the inconsistent findings in investigating PFCs exposure association with CVDs and their risk factors.Among PFCs, PFOA and PFOS exposure increased the risk of CVDs than other types of PFCs. Although the risk of PFOA and PFOS exposure was positively associated with CVDs and their risk factors, more observational studies shall be carried out to identify the long-term effects of these contaminants with premature CVDs development.


There is evidence that diet and nutrition are modifiable risk factors for several cancers, but associations may be flawed due to inherent biases. Nutritional epidemiology studies have largely relied on a single assessment of diet using food frequency questionnaires. We conduct an umbrella review of meta-analyses of observational studies to evaluate the strength and validity of the evidence for the association between food/nutrient intake and risk of developing or dying from 11 primary cancers. It is estimated that only few single food/nutrient and cancer associations are supported by strong or highly suggestive meta-analytic evidence, and future similar research is unlikely to change this evidence. Alcohol consumption is positively associated with risk of postmenopausal breast, colorectal, esophageal, head & neck and liver cancer. Consumption of dairy products, milk, calcium and wholegrains are inversely associated with colorectal cancer risk. Coffee consumption is inversely associated with risk of liver cancer and skin basal cell carcinoma. Diet and food intake have been associated with a risk of developing different types of cancer but individual nutritional epidemiology studies are prone to inherent bias. Here, the authors perform an umbrella review of meta-analyses of observational studies and show the level of evidence for associating food and nutrients to cancer risk. The World Cancer Research Fund (WCRF) Third Expert Report concluded that diet and nutrition, including obesity and low physical activity, are modifiable risk factors for several cancers2. However, reported meta-analytic estimates from observational studies might not represent causal associations but may emerge due to biases common across studies, such as exposure measurement error, residual confounding, and publication bias, subsequently diminishing the strength of aggregated scientific evidence5.Cancer is one of the most frequent causes of morbidity and mortality worldwide, and 18.1 million incident cases and 9.6 million deaths were estimated for 20186. An evaluation of the robustness of this evidence is required to inform public health policy. Therefore, we conducted an umbrella review to systematically evaluate the robustness of the observational meta-analytic evidence across a large number of food and nutrient associations with risk of cancer at 11 anatomical sites. We further evaluated whether additional research is or is not warranted to change the inferences from the existing meta-analyses using an adaptation of research synthesis methods.Nutritional epidemiology is particularly prone to measurement error, as the consumption of foods and nutrients is based on participants’ self-reported data often provided at single point in time and the conversion of foods consumed into nutrient intake is based on food composition databases that might be inaccurateHere we show that only few single food/nutrient and cancer associations are supported by strong or highly suggestive meta-analytic evidence, and future similar research is unlikely to change this evidence.n = 779; 91%) used a continuous exposure contrast, whereas only 81 used a dichotomous contrast (top versus bottom category or use versus no use)  followed by lung and stomach cancers . The median number of cancer cases in a meta-analysis ranged from 388 for gallbladder cancer to 4526 for breast cancer. The median number of individual studies within a meta-analysis ranged from 2.5 for gallbladder cancer to 6 for CRC and breast cancer, and the overall minimum number of individual studies was 2 and the maximum was 33. The summary descriptive characteristics of the included meta-analyses by type of dietary exposure are presented in Supplementary Data N = 184 and 141, respectively) followed by meat/eggs and beverages . The median number of individual studies within a meta-analysis was 5 and was similar for different dietary exposures with the exception of fats/fatty acids, where the median was 11. The overall median number of cancer cases in a meta-analysis was 2152 and ranged from 1038 for phytochemicals to 9955 for fiber.Overall, 860 meta-analytic comparisons were included. Most meta-analyses (P < 0.05) based on the random-effects model. The percentage of nominally significant meta-analyses ranged from 0% for gallbladder cancer  to 74% for head and neck cancer  meta-analyses showed significant results, whereas only 25 (3%) meta-analyses remained significant at a threshold of 10−6  were nominally statistically significant (I2 > 50%). Head and neck cancer had the largest proportion of meta-analyses with high heterogeneity (40%) that was substantially reduced after excluding a pooling project of case–control studies, whereas gallbladder cancer had no meta-analysis with high heterogeneity followed by CRC and stomach cancer with 20% each (Table I2 ≤ 25%) was >52%. However, only 46 (5%) associations had a 95% prediction interval that excluded the null value (Table Approximately one fourth 26%) of the included meta-analyses had high heterogeneity (6% of theogeneity 0% that wSixty-nine (8%) meta-analyses showed evidence of small study effects bias Table , which wn = 5 associations), dietary calcium (n = 1), dairy products (n = 2), milk (n = 1), and whole grain products (n = 1). Specifically, total alcohol consumption was positively associated with risk of CRC (summary relative risk (RR) per 10 g/day [~1 drink], 1.07; 95% confidence interval (CI), 1.05–1.08), and identical associations were observed for beer consumption and CRC and total alcohol consumption with colon cancer risk. Consumption of dairy products , milk , calcium , and whole grains  was inversely associated with risk of CRC. Total alcohol consumption  and similarly wine consumption were positively associated with risk of postmenopausal breast cancer among current users of menopausal hormone therapy and postmenopausal breast cancer, respectively.Only 10 meta-analyses 1.2%) were supported by strong evidence , followed by coffee (n = 2), fruits (n = 1), and vegetables (n = 1). Alcohol consumption was positively associated with different subtypes of breast cancer and CRC, esophageal cancer in men , head and neck cancer , and liver cancer mortality . Coffee consumption was inversely associated with risk of liver cancer  and skin basal cell carcinoma , and intake of fruits and vegetables was inversely associated with risk of pharyngeal  and oral cancer , respectively. When we excluded a pooling project of 20 case–control studies from the meta-analyses of dietary factors with risk of head and neck cancer, we observed an attenuation of the evidence for most of the results  presented highly suggestive evidence , (ii) inverse associations of total dietary  and soluble fiber  and risk of breast cancer, (iii) inverse associations of serum retinol and α-carotene concentrations and fruit, folate, and vitamin C consumption with risk of lung cancer, (iv) positive associations of alcohol and red/processed meat with lung cancer, (v) inverse association of coffee consumption and melanoma risk in women, (vi) positive associations of alcohol consumption and serum vitamin D with basal cell carcinoma of skin, and (vii) positive associations for pickled vegetables and salty foods and risk of stomach cancer. A total of 182 meta-analyses (21%) were supported by weak evidence, and the remaining 613 (71%) meta-analyses did not have nominally statistically significant findings.Forty-two (4.9%) meta-analyses had suggestive evidence, 18 of which pertained to associations that already received strong or highly suggestive evidence but were performed for different types of the same exposure and/or different subtypes of same outcome Fig. . NotableAmong the 65 meta-analyses that achieved strong, highly suggestive, or suggestive evidence, the median fail-safe number (FSN) was 23 range: 4–159) for meta-analyses with suggestive evidence, 111 (range: 38–856) for highly suggestive and 67 (range: 32–369) for strong evidence  to detect a statistically significant summary estimate using either the random-effects estimate  or the estimate of the largest study   was evaluated, but they contained on average relatively few studies (median = 5) and a moderate number of cancer cases (median = 2152). Less than 30% of the included associations on diet and cancer risk reported a nominally statistically significant summary random-effects estimate. When a lower P value threshold (P < 10−6) was used, the proportion of significant associations decreased to 3%, indicating potential dearth of existing robust associations. Approximately 1 in 4 associations showed large heterogeneity (I2 ≥ 50%). When we calculated the 95% prediction intervals, which further account for heterogeneity, we found that the null value was excluded in only 5% of the associations, an estimate that was mostly driven by the low percentage of nominally significant meta-analyses. Moreover, in 8% of the associations the summary estimates were inflated due to small study effects and in 15% the observed number of significant results was larger than the expected, indicating that the risk of reporting and other biases in this literature is relatively low, yet these tests had low power, as many meta-analyses included a small number of studies. The latter summary description of the robustness of the evidence seems to apply for most dietary exposure categories and cancer outcomes, with one notable exception. A larger proportion (11%) of alcohol and cancer associations (compared to other diet-cancer associations) is supported by strong statistical evidence, but potential evidence for existence of bias is also present in the alcohol and cancer associations shown by larger likelihoods of high heterogeneity, small study effects, and excess significance bias. When the FSN and CP research synthesis metrics were used, they indicated that additional similar research is unlikely to change current evidence for most associations with few exceptions that pertained mostly to currently observed null associations between dietary factors and understudied malignancies.Several dietary factors have been clearly associated with risk of obesity, type 2 diabetes, and cardiovascular disease2. Specifically, most associations that were supported by strong or highly suggestive evidence in the current umbrella review were also supported with convincing evidence by WCRF. Exceptions were the inverse associations of coffee consumption with skin cancer and fruit and vegetable consumption with head and neck cancer, which received limited suggestive evidence by WCRF and highly suggestive evidence in this umbrella review, but the majority of the evidence for associations with head and neck cancer stemmed from case–control studies. There were a few associations that received convincing evidence grading by WCRF but were ranked lower in the current umbrella review. Specifically, we graded the consumption of red and/or processed meat with risk of CRC and salty foods with stomach cancer risk with suggestive evidence, because they had summary association P values of approximately 10−4 and did not reach the strict threshold of 10−6. The recent evaluation of the literature for the health effects of red and processed meat consumption conducted by the NutriRECS consortium yielded very similar (to this umbrella review) positive associations for red/processed meat and CRC risk12 but graded the certainty of evidence as low, because they used the GRADE system to assess quality of evidence where evidence from observational studies is ranked lower compared to randomized controlled trials (RCTs)13. The associations of alcohol intake with risk of kidney and stomach cancer were graded with weak evidence in the current umbrella review, because they had summary P values of 10−2 and 10−3 but also high between-study heterogeneity and evidence of excess significance bias. The association of alcohol consumption with risk of premenopausal breast cancer was graded with convincing evidence by WCRF, but this assessment did not consider a more recent pooled analysis that rendered the overall association as not significant14.Our grading of the evidence suggested that there are a limited number of dietary factors that are robustly associated with specific cancers, which agrees with the evidence grading performed independently by the WCRF16. The obesogenic effects of a high calorie diet and lack of physical activity could account for about 10–15% of the cancer burden, whereas about 5% may be attributable to alcohol and another 5% to specific dietary factors combined 16. The current umbrella review supports the notion that there are a limited number of energy-balance independent dietary factors that are robustly associated with cancer risk. However, it is critical to continue and enhance research efforts and investments in this field, because diet is a ubiquitous exposure and changes in diet may modify cancer risk. The conduct of nutritional epidemiologic research on cancer has many limitations and challenges. Cancer is a group of diseases with long latency periods, but assessment of dietary intakes is usually performed only at one or at few time points in several well-established cohort studies, which may lead to underestimation of some diet and cancer associations. In addition, previous research has mostly focused on studying associations of single nutrients and foods, for which it may be difficult to decipher their independent effects and may not be biologically important in isolation, but synergistic effects of numerous foods into overall dietary patterns may matter more.It has been estimated that diet and nutrition could account for 20–25% of the worldwide cancer burden17. Biological mechanisms linking alcohol consumption to breast cancer would mainly involve altered circulating and intracellular estrogen concentrations and subsequent proliferation of estrogen receptors (ER) in mammary epithelial cells18. More specifically, alcohol consumption has been associated with increased circulating estrogen and androgen concentrations in observational studies and RCTs, and ethanol promotes the proliferation of ER+ but not ER− breast cancer cells leading to a 10–15-fold increase in the transcriptional activity of ER18. Chronic alcohol intake has been further associated with oxidative stress, intestinal dysbiosis, and hyperpermeability to luminal bacterial products, which may lead to the development of CRC21, alcoholic liver disease, and liver cancer. The direct carcinogenic effects of acetaldehyde and its metabolites is another potential mechanism for cancer onset, as acetaldehyde rapidly binds to DNA and proteins and produces DNA adducts, which results in DNA point mutations18.There is ample evidence in agreement with the results of the current umbrella review suggesting that alcohol is a major risk factor for several cancers, including breast, CRC, esophageal, head and neck, and liver cancer22, in agreement with the results of the current umbrella review. Dairy products may lead to lower CRC risk due to their high calcium concentration23; calcium forms in the colonic lumen insoluble soaps by binding to tumor-promoting free fatty acids and bile acids24. Other pathways include regulation of cell proliferation, differentiation and apoptosis through the preservation of intestinal epithelial cell integrity, and maintenance of immune homeostasis in the gut21. Apart from the role of calcium, studies have shown that lactic acid bacteria may absorb mutagens from cooked foods, deactivate intestinal carcinogens, and reduce intestinal inflammation25.The current literature supports an inverse association between consumption of dairy foods and CRC risk27. Studies have shown that consumption of whole grains reduce fasting insulin concentrations, which is an established risk factor for CRC21. In addition, dietary fiber shortens the bowel transit time, dilutes the colonic contents, and promotes the anaerobic fermentation of the intestinal bacteria29. As a result, the carcinogenic substances are in contact with epithelial cells for a short period of time, while short chain fatty acids like butyrate are produced that reduce the conversion of primary bile acids to secondary and also inhibit cell proliferation and promote cell apoptosis29.The current umbrella review found strong evidence to support the inverse association of whole grain products and CRC risk. Whole grain products are rich in dietary fiber and other nutrients and substances with potential anticancer properties30. We found highly suggestive evidence that coffee intake was inversely associated with risk of liver and skin basal cell carcinoma. The beneficial effects of coffee consumption might be due to the antioxidant and anti-inflammatory properties of its phytochemical compounds that may protect against diseases triggered by inflammation like cancer30. Additionally, coffee consumption has been linked with a better profile of markers of liver injury that could be another mechanism though which coffee may lower liver cancer risk32.Coffee is one of the most commonly consumed beverages at a global level and its association with several outcomes has been extensively investigated33, but they are inconsistent and allow some degree of arbitrariness. The criteria we used for grading evidence should not be considered causal criteria, especially when used individually, but we think that they are useful for identifying biases when used together. We further applied two established research synthesis metrics, the CP and FSN, to determine whether or not further research can provide a meaningful contribution to the existing meta-analytic evidence in an effort to guide the future research agenda and public health policy. The application of these metrics should not be interpreted as stopping research altogether but rather to focus future research to address current evidence gaps.We applied several statistical criteria and sensitivity analyses to evaluate the strength and validity of the evidence for the association between food and nutrient intake and risk of 11 cancers using the most extensive systematic review to date from the WCRF Continuous Update Project (CUP). Several different methods exist for rating quality of evidenceImportant limitations should also be considered in the interpretation of our findings. Our review relied on already published studies that were included in the meta-analyses performed by the WCRF CUP through 2018. Some studies may have been missed, although this is unlikely given the extensive literature search conducted. We evaluated all study-specific results that were reported in the meta-analyses, namely, primary cancer incidence and/or mortality, histological and anatomical cancer subtypes, and analyses by sex, menopausal status, smoking, and hormone replacement therapy, but we may have missed other sub-analyses that were not reported with sufficient study-specific data.37. Furthermore, RCTs in this field need better strategies to monitor and enhance adherence and a long duration of follow-up appropriate for cancer outcomes, which can pose serious challenges for their conduct38.In addition, the current umbrella review was based on results derived only from observational studies. Evidence from RCTs is essential to identify potential causal associations in epidemiology. However, there is a lack of adequately powered RCTs in the field of nutritional epidemiology, and those that do exist have in general failed to support protective associations39. There is also the issue of estimating the intake of dietary factors  that not only depends on multiple episodically consumed food items but also on nutrient databases that may further contribute to measurement error. Furthermore, if the statistical models are adjusted for additional factors, such as additional dietary variables, that are also measured imprecisely, the risk estimates may become attenuated, inflated, or can even change direction40.Another important issue is that observational studies in nutritional epidemiology have largely relied on food frequency questionnaires (FFQs) to measure the consumption of the different dietary factors (most studies are in European-descent populations) and a small percentage of studies have included other methods such as 24-h recalls usually in combination with an FFQ. However, this approach is prone to measurement error, especially in the case of assessing intake of non-habitually consumed items , which in prospective studies usually results in risk estimates attenuated toward the null and a loss of statistical power41. However, multiple measurements, up to 6 days for less frequently consumed foods, are needed to get a more precise and correct assessment of an individual’s usual intake42. The use of mobile phone pictures of all foods consumed and image recognition software for the analysis regarding type of food and amount could be a useful future tool, but this method is still under development43. The second option is the use of biomarkers of intake either directly in the analysis or as a calibration tool for the self-reported assessments45. Unfortunately, there is currently a limited number of such biomarkers, and therefore there is a big need for additional biomarkers to be identified, probably through high-dimensional metabolomic profiling or other omics platforms46 Calibration of the biomarker to the true intake would be also required within a feeding study to obtain unbiased estimates47.Several methods have been proposed to reduce measurement issues in assessing dietary intake. The first approach includes the use of reference methods, such as the 24-h recallFinally, the statistical tests we used to assess bias do not prove its definitive presence or its exact source. However, our estimates are likely to be conservative, as a negative test does not exclude the potential for bias.The association between diet and risk of cancer has been extensively studied. Taking into account the inclusion of only observational studies and the limitations of the dietary assessment methods that may bias risk estimates, we found strong or highly suggestive evidence to support: (a) the positive association of alcohol consumption and risk of colon, rectum, breast, esophageal, head and neck, and liver cancer, (b) the inverse association of calcium, dairy, and whole grain consumption and risk of CRC, and (c) the inverse association of coffee consumption and risk of liver and skin basal cell carcinoma. Other associations could be genuine, but substantial uncertainty remains. Additional similar research is unlikely to change current evidence for most associations with few exceptions that pertained mostly to currently observed null associations between single dietary factors and understudied malignancies. Future research should instead focus on new and improved methods  to measure the time-varying nature of nutrition, the role of early life diet, the assessment of overall diet patterns, the investigation of the biological processes involved in the diet–cancer associations, the study of molecular cancer subtypes and outcomes after cancer diagnosis, and the interaction of diet patterns with the rest of the exposome . For public health and policy, efforts should be targeted to deter the known major diet-related risk factors for cancer, particularly obesity and alcohol consumption.2, which is one of the most rigorous and systematic analysis of the scientific research on the associations of diet, nutrition, adiposity, and physical activity with risk of cancer development and survival. We focused on meta-analyses investigating the association of all diet-related exposures and risk of cancer development or death at 11 anatomical sites , the meta-analyses of which were conducted by WCRF CUP since 2015. The WCRF systematic review for cervical cancer was published in 2018 but did not include meta-analyses for dietary variables and was thus excluded from the current paper48. The relevant umbrella reviews for prostate and endometrial cancer49 have been published separately50, and WCRF meta-analyses for pancreatic and ovarian cancers were conducted in 2011 and 201352 and were considered outdated and not included in the current assessment.Data was extracted from the WCRF Third Expert Report2. Case–control studies were included only in the meta-analyses for head and neck cancer54. RCTs were retrieved, but they were too few and the assessed interventions were usually irrelevant to specific dietary intakes; therefore, they were not included in the WCRF CUP meta-analyses. More details on the literature search strategy, search terms, and inclusion/exclusion criteria of the WCRF CUP reports are provided in Supplementary Information.The literature search for the WCRF CUP reports was conducted in MEDLINE, and primarily prospective cohort studies, which are considered to represent the highest level of observational evidence, were included in the meta-analysesFor all the meta-analyses present in the WCRF reports, we extracted the following information at the meta-analysis level: dietary factor, contrast of comparison, and cancer outcome. At the individual study level, we extracted the first author’s surname, year of publication, sex, number of cases and total cohort size (or controls), study design, RRs, and 95% CIs. When this information was not available in the WCRF CUP meta-analyses, it was extracted from the individual studies. Eight authors  performed the data extraction, which was verified independently by four authors  and any disagreements were resolved by discussion.The appraisal of the evidence was based primarily on comparisons with a continuous exposure contrast, as it was considered a more standardized way of presenting and synthesizing estimates from individual studies. For associations where the WCRF CUP reports provided results only in the form of top versus bottom or use versus no use comparisons, we used this information instead.55. The between-study heterogeneity was quantified with the I2 statistic56. To take further into account the heterogeneity among studies, we also estimated the 95% prediction intervals, representing the range in which the effect estimate from a future study addressing the same association is expected to lie57. Substantial inconsistency could reflect either genuine heterogeneity between studies or bias.We used a random-effects model to estimate the summary associations and the 95% CIs for each dietary factor and cancer comparison58, by applying the Egger’s regression asymmetry test59. We considered as an indication of small study effects when the Egger’s P value was ≤0.10 and the point estimate of the largest study  in the meta-analysis was smaller in magnitude than the summary estimate. We examined whether the observed number of studies with nominally statistically significant results  within a meta-analysis differed from the expected60. The expected number of significant results in each meta-analysis was estimated from the sum of the statistical power estimates for each individual study, using an algorithm from a non-central t distribution and the estimate of the largest study in each meta-analysis as the plausible effect size for the tested association61. A P value ≤0.10 indicated evidence of excess significance.We evaluated whether there was an indication of inflated summary estimates due to small study effects63. Briefly, associations were considered to be supported by strong evidence if all the following criteria were met: the meta-analysis included >1000 cancer cases, a threshold that provides 80% power for hazard ratios ≥1.20 , a threshold that might substantially reduce false positive findings in a field where low prior probability exists that any single food/nutrient is associated with cancer66; absence of high heterogeneity (I2 < 50%); 95% prediction intervals excluded the null value; no evidence of small study effects and excess significance bias. Associations supported by highly suggestive evidence had meta-analyses with >1000 cases; a random-effects P value ≤10−6, and the largest study in the meta-analysis was nominally statistically significant. Associations based on meta-analyses with more than 1,000 cases and a random-effects P-value ≤10−3 66 were categorized as suggestive evidence. The remaining nominally significant associations were graded as weak evidence. We further evaluated the percentage of individual studies in each major (not for food subgroups and cancer subtypes) meta-analysis that adjusted for age, sex (except for breast cancer), smoking, adiposity, and physical activity.Meta-analyses showing nominally significant associations were categorized into four evidence groups, namely, strong, highly suggestive, suggestive, and weak evidence, as previously detailed68. We further applied the CP approach using the effect of the largest study in the observed meta-analysis as an alternative estimate. For the nominally statistically significant meta-analyses, we determined the number of future studies of average null effect and average weight needed to detect a non-statistically significant summary estimate by calculating Rosenberg’s FSN69.To determine whether or not further similar research in diet and cancer may provide a meaningful contribution to the existing evidence, we adapted research synthesis metrics, the FSN and CP. For the nominally non-statistically significant meta-analyses, we quantified the number of future studies  required to achieve a CP of at least 80% to detect a nominally statistically significant effect size equal to the observed meta-analytic summary estimate assuming that the heterogeneity of the updated meta-analysis did not changeAll data were collected in MS Office 365 and the statistical analyses were conducted using Stata version 14 and R version 4.03.Further information on research design is available in the Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization.Supplementary InformationPeer Review FileDescription of Additional Supplementary FilesSupplementary Data 1Supplementary Data 2Supplementary Data 3Supplementary Data 4Supplementary Data 5Supplementary Data 6Supplementary Data 7Reporting summary


Meta-analyses of cross-sectional studies suggest that patients with psychosis have higher circulating levels of C-reactive protein (CRP) compared with healthy controls; however, cause and effect is unclear. We examined the prospective association between CRP levels and subsequent risk of developing a psychotic disorder by conducting a systematic review and meta-analysis of population-based cohort studies. Databases were searched for prospective studies of CRP and psychosis. We obtained unpublished results, including adjustment for age, sex, body mass index, smoking, alcohol use, and socioeconomic status and suspected infection (CRP > 10 mg/L). Based on random effect meta-analysis of 89,792 participants (494 incident cases of psychosis at follow-up), the pooled odds ratio (OR) for psychosis for participants with high (>3 mg/L), as compared to low (≤3 mg/L) CRP levels at baseline was 1.50 . Evidence for this association remained after adjusting for potential confounders . After excluding participants with suspected infection, the OR for psychosis was 1.36 , but the association attenuated after controlling for confounders . Using CRP as a continuous variable, the pooled OR for psychosis per standard deviation increase in log(CRP) was 1.11 , and this association further attenuated after controlling for confounders  and excluding participants with suspected infection . There was no association using CRP as a categorical variable . While we provide some evidence of a longitudinal association between high CRP (>3 mg/L) and psychosis, larger studies are required to enable definitive conclusions. Second, meta-analyses of population-based longitudinal studies suggest that prenatal maternal infection, including bacterial5, respiratory6, or genital and reproductive infections8, are associated with a two- to fivefold increased risk of schizophrenia in the offspring. Third, meta-analyses of cross-sectional studies have reported raised levels of several inflammatory markers and elevated specific cell counts in patients with schizophrenia as compared to controls16.Several lines of evidence implicate infection and inflammation in the pathogenesis of schizophrenia and related psychotic disorders. First, childhood infections involving the central nervous system18 and psychiatric disorders25. Meta-analyses of cross-sectional studies reported that circulating CRP levels are higher in schizophrenia compared to healthy controls, with medium to large effect sizes26. Our recent meta-analysis15 supports small to medium effect sizes in medication-naïve first-episode psychosis patients. However, cross-sectional studies cannot ascertain the direction of the association, i.e., whether elevated CRP predates or follows psychosis.C-reactive protein (CRP) is an acute-phase protein and an archetypal inflammatory marker that has been used most extensively as a proxy for systemic inflammation in studies of physical27. Furthermore, population-based longitudinal studies are less prone to sampling bias, a common issue for cross-sectional designs, which often include hospitalized patients27. A number of population-based studies have reported a longitudinal association between higher CRP levels at baseline and risk of psychosis at follow-up34. However, there are important issues that need to be considered to allow more definitive conclusions. For example, there is heterogeneity in sample age with some studies conducted in relatively young34 and some in relatively older populations30. While these studies have controlled for various confounders, variables included varied from study to study. Third, not all studies excluded participants with suspected infection, as measured by a fixed CRP threshold33. Therefore, a more streamlined analysis across cohorts with consistent adjustment for key confounders is required.Longitudinal studies can disentangle the directionality of the association between exposure and outcome, and therefore can help to address the issue of reverse causation35, and in line with previous psychiatric research22. Second, to examine the potential effect of confounding, we used results from each cohort before and after adjusting for the same set of confounders including age, sex, body mass index (BMI), measures of socioeconomic status (SES), smoking, and alcohol use. We repeated the analysis after excluding participants with baseline CRP levels >10 mg/L to minimise potential confounding by acute inflammation/infection35. Finally, to examine the effect of age we carried out sub-group analyses by age.In this study, we aimed to examine the longitudinal associations between circulating CRP levels and subsequent risk of psychotic disorders by carrying out a systematic review and meta-analysis of population-based prospective studies. We examined the nature of this longitudinal association in a number of ways. First, we used CRP both as a continuous and a binary variable. For the latter, we defined CRP levels >3 mg/L as “high” in line with the American Heart Association and the US Centers for Disease Control and Prevention criteria for CRP use in population-based research34. Two of these studies examined the associations of childhood CRP levels with the risk of psychotic disorder in adulthood in the ALSPAC birth cohort34. Of the two, we included the study with the longer follow-up34. Consequently, four studies were included in meta-analysis34. Please see Supplementary Fig. 1 for the PRISMA diagram of study selection.The literature search yielded 303 studies, out of which five met the inclusion criteria34, while two involved older adults (mean age at the outcome of 64–78 years)30. Samples were, on average, 60.2% male (range: 44.5–100%). The mean percentage of white ethnicity across studies was 99.7% (range: 98.7–100%).The studies included in the meta-analysis comprised 89,792 participants, with 494 incident cases of psychosis, drawn from separate areas of Europe. Please see Table 34, CRP was measured at age 9, and psychosis was assessed at age 24 using a semi-structured face-to-face interview . Point estimates were slightly larger for the childhood/adolescence samples; see Fig. p = 0.04), and after additional adjustments for alcohol consumption, smoking levels and SES ; see Fig. The meta-analytic unadjusted OR for psychosis at follow-up in participants with high CRP (>3 mg/L) as compared to low CRP (≤3 mg/L) at baseline was 1.50 ; all ps >0.25).There was no evidence of significant heterogeneity in any of the analyses . See Fig. p = 0.36). The fully adjusted model showed a pooled OR of 1.07 ; see Fig. The meta-analytic unadjusted OR for psychosis at follow-up per SD increase in baseline CRP as a continuous value was 1.11 ; all ps >0.05).There was no evidence of significant heterogeneity in any of the analyses .Compared to those with low baseline CRP (<1 mg/L), the OR for psychosis at follow-up was 0.93  for medium (1–3 mg/L) and 1.49  for high (>3 mg/L) CRP. The overall pooled OR for psychosis for CRP ≥1 mg/L as compared to <1 mg/L was 1.18 . See Supplementary Fig. 2.After adjusting for all potential confounders, the aOR for the medium CRP group was 0.90  and that for the high CRP group was 1.27 . The overall aOR for CRP ≥1 mg/L as compared to <1 mg/L was 1.07 ; see Supplementary Fig. 3, panel A. Evidence for this association weakened after adjusting for age, sex and BMI  and on further adjustments for alcohol consumption, smoking levels and SES ; see Supplementary Fig. 3, panels B and C.After excluding subjects with suspected infection (CRP > 10 mg/L) at baseline, the meta-analytic unadjusted OR for psychosis at follow-up in participants with high CRP (>3 mg/L) as compared to low CRP (≤3 mg/L) at baseline was 1.36 ; see Supplementary Fig. 4, panel A. The 95% confidence interval widened after adjusting for age, sex and BMI . The fully adjusted model showed a pooled OR of 1.00 ; see Supplementary Fig. 4, panels B and C.After excluding subjects with suspected infection (CRP > 10 mg/L) at baseline, the meta-analytic unadjusted OR for psychosis at follow-up per SD increase in baseline CRP was 1.07  at baseline, the results were similar to the primary analyses, indicating no association between high or medium CRP levels and psychosis risk .36; see Supplementary Table 15, all studies were rated as ‘good quality’.All included studies were rated ≥7 on the Newcastle-Ottawa Scale for study quality  are associated with an increased risk of psychosis at follow-up. However, we found no association between CRP and psychosis using CRP as a continuous variable (per SD increase), or using CRP as a categorical variable . Overall, the effect sizes were slightly larger for younger compared with older samples, but our analysis included a limited number of studies and a relatively small number of cases. Therefore, in the future larger samples will be required before definitive conclusions can be drawn about the true existence of longitudinal associations between CRP and psychosis risk, and the potential effects of age of onset.Using CRP as a binary variable, we report an increase of 50% in the odds of developing psychosis for those with high (>3 mg/L), as compared to low (≤3 mg/L), CRP levels at baseline in unadjusted analyses. The availability of unpublished results allowed us to examine the effects of a number of important confounding factors, including suspected infection (CRP > 10 mg/L) at baseline (time of blood sampling). In addition to sex, age and BMI, we included relevant social and lifestyle factors, including alcohol consumption, smoking, and SES. Our results suggest that evidence for an association between high, as compared to low, CRP levels at baseline and risk of psychosis at follow-up remained after adjusting for potential confounders. After excluding participants with suspected infection, defined as having CRP > 10 mg/L at baseline, the evidence for an association remained only in the unadjusted, but not in the adjusted, analyses.37, and in patients with chronic schizophrenia38. CRP levels have also been reported to correlate with psychotic symptom severity14. Potential explanations for the null findings in sensitivity analyses excluding subjects with CRP > 10 mg/L at baseline, and using CRP as a categorical variable , may include limited statistical power due to a smaller number of cases overall, or in each category. We also observe no associations using CRP as a continuous variable. It is possible that the CRP-psychosis association is non-linear, as we observe an association using CRP as a binary variable but not using CRP as a continuous variable. In future, further studies with a larger number of cases will be required to test whether an association exists, and, if so if it is linear or non-linear.Our findings, that dichotomous CRP levels (>3 mg/L) could be longitudinally associated with a higher risk of psychosis, are consistent with evidence from previous cross-sectional studies. These have found elevated CRP levels in first-episode psychosis as compared to healthy controls14. Our findings are consistent with these results. We provide some evidence for a longitudinal association between high CRP levels at baseline and increased risk of psychosis at follow-up. However, this epidemiological evidence is at odds with recent findings from Mendelian randomization (MR) studies that used genetic variants as proxies for CRP to examine whether the CRP-psychosis association is likely to be causal or could be attributable to confounding. Using genetic variants associated with CRP levels, MR studies have reported that genetically predicted higher CRP levels are associated with a decreased risk of psychosis41. This is puzzling, given that case-control studies have consistently reported higher CRP levels in psychosis patients, and further research is required to understand the exact mechanisms.A number of meta-analyses have reported that patients with schizophrenia and related psychotic disorders have higher CRP levels compared to controls42. The MR results could also be a consequence of not taking into account other inflammatory markers that influence CRP levels. For instance, a recent MR study by Perry and colleagues reported that, after controlling for genetically predicted levels of IL-6, IL-6 remained associated with schizophrenia while the apparent protective effect of CRP on schizophrenia risk completely attenuated43. This highlights the importance of considering the immune system as a highly interlinked and complex entity rather than looking at individual biomarkers in isolation.There may be a number of potential explanations for the divergent findings between epidemiological and MR studies. For instance, it has been proposed that a genetic predisposition for a decreased acute phase response (as reflected by lower CRP levels) might increase the risk of psychosis by increasing susceptibility to infection44. Further research is needed to test whether treating inflammation has broader therapeutic benefits in psychosis, and if the benefits might extend to all or just to a subgroup of patients with psychosis.Evidence supporting a role for inflammation in psychosis may inform novel approaches to the treatment and prevention of this condition. A meta-analysis of clinical trials of anti-inflammatory drugs given as an adjunct to antipsychotics shows that the addition of anti-inflammatories results in greater improvements in positive and negative symptoms of psychosis, as compared to antipsychotic monotherapy47 and sex48 are separately associated with schizophrenia risk and levels of CRP. A higher BMI has been associated with increased CRP levels50, and BMI shows differential associations with psychosis risk depending on age. A low BMI in childhood is associated with an increased risk of psychosis51. Patients with psychosis tend to have higher BMI as a group possibly due to lifestyle and other factors, including metabolic effects of certain antipsychotic drugs52. BMI levels have also been associated with differing psychiatric outcomes in first-episode psychosis53, though this association was not replicated54. In addition, we included smoking and alcohol use as potential confounders, both of which are known to increase levels of inflammatory markers and are also associated with psychosis risk55. Finally, SES is an important correlate of psychosis risk47.Among the strengths of this work, all the included studies were rated as “good quality” according to Agency for Healthcare Research and Quality standards. There was little evidence of heterogeneity in the meta-analyses. We used harmonized, unpublished results from each cohort to specifically address confounding, and we were able to run sensitivity analyses excluding subjects with suspected infection. We examined associations separately in cohorts including early- and late-onset psychosis. Our choice of potential confounders was informed by previous research. Both age56.Limitations of the work include the small number of studies available to include in the meta-analysis. Therefore, formal assessment of publication bias was not appropriate, as Cochrane recommends that “tests for funnel plot asymmetry should be used only when there are at least 10 studies included in a meta-analysis”Further, it is possible that studies with null findings were not published. The limited number of studies also precluded the use of meta-regression to explore further potentially confounding effects such as age at onset, which was instead represented as an exploratory subgroup analysis.13, a meta-analysis including both inpatient and community samples), and in depression .Our sample included a total of 494 incident cases of psychosis, of which 114 had high CRP levels at baseline (>3 mg/L), which represents 23% of the psychosis sample. This is very close to the meta-analytic estimate of the prevalence of high CRP in psychosis  at baseline and greater risk for developing psychosis at follow-up. There was some indication that the effect sizes were larger for younger compared with older samples. However, these analyses included a limited number of cases of psychosis, and the results using CRP as continuous or categorical variables were largely null. In future, further studies with a larger number of cases are required before definitive conclusions can be drawn about the longitudinal association between CRP and psychosis risk.58. Two separate databases, PubMed and Google Scholar, were searched from their inception to the 1st of September 2020 for published, prospective studies of CRP levels and schizophrenia or related psychoses using the following search terms (* denotes wildcard terms):We conducted a systematic review in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines AND (CRP OR “C-reactive protein” OR hs-CRP) AND (schizophreni* OR psychosis OR psychotic).59. As suggested in ref. 59, the first 200 search results from Google Scholar were screened. The search was limited to studies based on human participants. The electronic search was complemented by hand-searching of meta-analyses and review articles and by contacting study authors. Abstracts were screened, and full texts of relevant studies were retrieved.Google Scholar was used as a source of grey literatureLongitudinal study design with data on CRP at baseline and psychosis at follow-up.CRP levels measured in plasma or serum at baseline using a standard laboratory method.Psychosis or schizophrenia assessed at follow-up using a standardized methodology; e.g., interview-assessed, or clinical diagnosis from electronic health records.Population-based samples, e.g., cohort or community-based, representative of the general population.The inclusion criteria were:Cross-sectional studies or longitudinal studies based on particular groups of individuals selected on the basis of, e.g., a specific demographic characteristic, diagnosis of a certain disease/disorder, or a specific infection.Non-human subjects.Studies exclusively based in settings other than community .The exclusion criteria were:When multiple articles were identified from a single cohort, the article with the largest sample or longest follow-up was included. Two authors (LB and EFO) independently applied the inclusion/exclusion criteria and selected the final studies for this review.For each study, we extracted information on the OR for psychosis at follow-up, sample size, number of incident cases of psychosis at follow-up, length of follow-up, cohort, method of case ascertainment, country, age at baseline (CRP sampling), age at follow-up (psychosis diagnosis), sex, ethnicity, and definition of outcome.a binary variable (>3 mg/L versus ≤3 mg/L);a continuous variable, after log-transformation to correct right skew (per standard deviation [SD] increase);a categorical variable . Authors were also asked to provide unadjusted and adjusted ORs after excluding subjects with potential infection at baseline (defined as CRP > 10 mg/L). In addition, in the study by Wium-Andersen et al.60.The methodological quality of each included study was assessed using the Newcastle-Ottawa Scale (NOS) for cohort studies34 were assessed for psychosis at age 24, but it is unclear when the outcome had first occurred. Register-based studies often relied on hospitalization primarily to identify cases31. While hospitalization is a useful proxy for illness time of onset, it may still not accurately reflect exact time of onset as not all patients are hospitalized and often there is a considerable delay between illness manifestation and help-seeking from healthcare professionals.Random effects models were used to meta-analyse ORs in order to address differences due to methodology and sample size. ORs were used as the preferred statistic over others , due to uncertainties around the exact time of outcome in some samples. For instance, ALSPAC cohort participants61. ORs were log-transformed for meta-analysis and then back-transformed for plotting in forest plots. Meta-analyses of ORs were carried out using the metafor package62 in R63.Random effects models were fitted using the restricted maximum-likelihood estimator, which has been shown to be effective in small meta-analytic samples where sample sizes are significantly diverseI2 statistic, which reflects the percentage of the variability in effect estimates that is due to heterogeneity. Heterogeneity was tested using Cochran’s Q Test64. p < 0.05 two tailed was considered statistically significant. Publication bias could not be assessed due to the small number of included studies.Heterogeneity between studies was measured using the Supplementary Information


A large randomized placebo-controlled trial reported in two articles  has demoOn the other hand, two meta-analyses  based onFinerenone exerts its renal protective effects in patients with T2D and CKD mainly by reducing inflammation, fibrosis, and albuminuria , while t−1–1.73 m−2 and/or urine albumin-creatinine ratio >300 mg/g (2), or renal death. If this composite outcome was not available, we used another composite renal outcome similar to this one instead. MACE was defined as a composite of CVD, nonfatal MI, or nonfatal stroke. If nonfatal MI and stroke were not available, we used total MI and stroke instead.We conducted this network meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension statement for network meta-analyses . The stu300 mg/g . Seven oWe searched Embase, PubMed, and Cochrane Central Register of Controlled Trials (CENTRAL) to identify related articles published before March 26th, 2021. The search terms that we mainly used were “Type 2 diabetes,” “Chronic kidney disease,” “Diabetic kidney disease,” “Diabetic nephropathy,” “SGLT2 inhibitors,” “Gliflozins,” “Sotagliflozin,” “Empagliflozin,” “Canagliflozin,” “Ertugliflozin,” “Dapagliflozin,” “Finerenone,” “Cardiovascular outcome*,” “Renal outcome*,” and “Randomized controlled trial.” Two authors independently performed study selection, data extraction, and risk of bias assessment. Risk of bias assessment was performed according to the Cochrane risk of bias assessment tool . When th2 statistic was calculated to measure statistical heterogeneity. If I2 was more than 50%, we would report random-effects results. Otherwise, we would report fixed-effects results. Network meta-analysis was done using the restricted maximum likelihood method within the frequentist framework. We completed all the data analyses in Stata/MP (version 16.0), with implementation of conventional meta-analysis via the metan command and implementation of network meta-analysis via a series of network commands.From included articles, we extracted the aggregated two-category data  to conduct conventional meta-analysis and network meta-analysis, respectively. Treatment effects were presented as risk ratio (RR) and 95% confidence interval (CI). Conventional meta-analysis was done using the fixed-effects inverse variance method and the random-effects DerSimonian and Laird method , respectWe finally included 14 articles  reportin2 = 0%; 2 = 0%; 2 = 52.7%; 2 = 0%; 2 = 0%; 2 = 15.9%; 2 = 56.6%; Conventional meta-analysis results showed that in patients with T2D and CKD, compared to placebo, SGLT2 inhibitors significantly reduced the risks of KFP  and HHF  than finerenone in patients with T2D and CKD. This suggests the obvious superiority of gliflozins over finerenone in preventing renal failure and heart failure events among this vulnerable population.Although network meta-analysis results in this study revealed that gliflozins had similar risks of MACE, nonfatal MI, CVD, and ACD compared to finerenone, conventional meta-analysis results in this study revealed that gliflozins versus placebo significantly reduced the risks of these four outcomes. On the contrary, the FIDELIO-DKD trial  revealedIn the conventional meta-analyses of gliflozins, there was no heterogeneity or only mild heterogeneity found for the five outcomes of KFP, HHF, MI, CVD, and ACD, which suggests that it is a class effect that gliflozins reduce these outcomes. Oppositely, in the conventional meta-analyses of gliflozins, there was substantial heterogeneity found for the two outcomes of MACE and stroke. This may suggest that some gliflozins could reduce MACE and stroke in patients with T2D and CKD, whereas others could not. Similarly, previous studies have already revealed that the effects of gliflozins on MACE and stroke are drug-specific effects . TherefoIn this study, gliflozins were observed with greater reductions of cardiorenal events, especially renal and cardiac failure events, than finerenone, for which the possible reason is as follows: finerenone produces cardiorenal protection mainly by its anti-inflammatory and antifibrotic effects and the function of reducing albuminuria , whereasThree previous meta-analyses  demonstrThis study has several limitations. First, we did network meta-analyses based on indirect comparisons, and therefore, our findings require to be validated by head-to-head trials comparing gliflozins with finerenone. Second, gliflozins involved much more subjects than finerenone. This imbalance in patient numbers limited the statistical power of this network meta-analysis. Accordingly, an updated meta-analysis including more subjects treated with finerenone is needed. Third, although we extracted the outcome data of patients with T2D and CKD from gliflozins and finerenone’s trials, the cardiorenal risk of participants was possibly different among included trials. There is a need for further analysis adjusting relevant cardiorenal risk factors. Last, this study focused on cardiorenal efficacy outcomes and did not assess safety outcomes associated with gliflozins or finerenone. Thus, future studies assessing the safety of these two drug classes are meaningful.Given the above limitations of this study, its findings may suggest that among patients with T2D and CKD, SGLT2 inhibitors are more effective than finerenone in reducing renal and cardiovascular endpoints, especially renal and cardiac failure events. However, further validation by head-to-head trials comparing finerenone with gliflozins would be beneficial. Moreover, there is a need for further studies to assess whether finerenone combined with a gliflozin yields more cardiorenal benefits than the respective monotherapy.