Acute appendicitis is one of the most common surgical emergencies worldwide. Clinical scoring system systems have been developed to diagnose acute appendicitis, but insufficient to predict the complication. The amount of serum biomarkers elevates in response to acute inflammation, which could be beneficial for diagnostic tools. Accordingly, a meta-analysis was conducted to evaluate the efficacy of platelet indices, including mean platelet volume (MVP) and platelet distribution width (PDW) as potential biomarkers for the diagnosis of a diagnosis of acute appendicitis.The dataset was defined by searching for articles published until December 2020 from PubMed, EMBASE, Google Scholar and the Cochrane database. The meta-analysis was performed using Review Manager Software version 5.4.1.The final analysis was made from 9 studies, including 3124 patients. The results demonstrated that lower MPV values was significantly associated with acute appendicitis (odds ratio (OR) = 0.81, 95% confidence interval (CI) = −1.51 to −0.11, P = 0.02), but not associated with complicated appendicitis by comparing it with the control  and non-complicated appendicitis groups . The present study failed to demonstrate the diagnostic value of PDW for the prediction of appendicitis and its complication.The results of the meta-analysis strongly indicate that a lower MVP values could function as a marker for predicting the acute appendicitis. •Platelet play an important role in the response to systemic inflammation and sepsis.•Inflammatory process activated platelets destruction consequence in the release of small platelets into bloodstream.•This studycompared the association between the platelet indices and the diagnosis of acute appendicitis.•Lower mean platelet volume(MVP) is a significant diagnostic marker for acute appendicitis. The annual incidence of acute appendicitis is 9.4 per 10,000 people and is continuing to increase in newly industrialized countries . Urgent Several clinical scoring systems have been developed to diagnose acute appendicitis with greater than 80% sensitivity and specificity among high-risk patients, such as the Alvarado score, Appendicitis Inflammatory Response (AIR) score, and RIPASA  score. Nevertheless, the clinical scoring system insufficiently diagnoses acute appendicitis and appears to be unreliable at differentiating between complicated and uncomplicated disease .Radiological methods include ultrasonography and computed tomography (CT) scans which have become valuable diagnostic tools. Point of care ultrasound (POCUS) is preferable for initial investigations and has a sensitivity and specificity for diagnosing AA of 91% and 97%, respectively . The lowComplete blood count (CBC) is one of the most common basic laboratory tests to determine inflammatory pathology. Leukocytosis and the neutrophils shift to the left are associated with acute appendicitis. The amount of several biomarkers elevate in response to acute inflammation, including C-reactive, Neutrophil-Lymphocyte ratio (NL-ratio), and Platelet-Lymphocyte ratio making them reliable tools in the identification of non-complicated and complicated appendicitis .Platelet indices play an important role in the response to systemic inflammation and sepsis . High inAlthough several studies report the usefulness of platelet indices in the diagnosis of acute appendicitis, there has been a significant degree of inconsistency in the findings of these studies. The present study conducts a meta-analysis based on the published literature in an attempt to clarify and evaluate the efficacy of platelet indices (MPV and PDW) as a potential biomarker for a diagnostic test of acute appendicitis and complications.22.1Electronic literature searches were performed on PubMed, Embase, Google Scholar, and the Cochrane database. The search terms ‘platelet indices’, ‘biomarkers’, ‘acute appendicitis’, and ‘complicated appendicitis’ were used as keywords to identify all English-language studies published through to December 2020 that evaluated the role of platelet indices (MPV and PDW) as a biomarker in the diagnosis of acute appendicitis and in the prediction of complicated appendicitis. Meta-analysis was performed according to the PRISMA 2020 statement, a guideline for reporting systematic reviews . The qua2.2The study inclusion criteria were as follows: (1) Studies published in English; (2) Acute appendicitis proven by the pathologic diagnosis; (3) Clarification of complicated appendicitis as gangrenous or perforated appendicitis; (4) Clarification that the control group were patients with non-diagnosis of acute appendicitis or normal appendix through operative or pathological findings; and (5) Measurement of platelet indices to compare between control and non-complicated or complicated appendicitis groups. The exclusion criteria were: (1) Non-English language articles; (2) review articles; (3) studies involving pediatric patients (aged < 15 years); and (4) no continuous variable data reported. The quality of the studies included in the meta-analysis was further evaluated using the Newcastle-Ottawa scale. The maximum possible score is 9 points which represents the highest methodological quality .2.3The two reviewers independently extracted the following information from the selected studies: Author names, country of origin, year of publication, study design, number of patients, patient characteristics, levels of MPV and PDW, and clinicopathologic diagnosis of acute appendicitis. Extracted data was cross-checked to reach consensus and then entered into a computerized spreadsheet for analysis.2 statistic was used to test for heterogeneity between the included studies (p < 0.05 is considered for significant heterogeneity).Meta-analysis was performed using Review Manager software, version 5.4.1 which was provided by the Cochrane Collaboration . Cochrane's chi-square-based Q-statistic test was applied to assess between-study heterogeneity. An IThe association between platelet indices (MPV and PDW) with the diagnosis acute appendicitis and the prediction of complicated appendicitis by comparing with the control group was analyzed using continuous variable data (mean ± SD) with inverse variant methods to generate a pooled odds ratio (OR). The OR was considered statistically significant at the p < 0.05 level and the 95% confidential interval (CI) did not include the value 1.The authors adopted the random-effects model, which is a more conservative way to calculate ORs, assumes a high level of variety between studies, and uses a weighted average of the effects reported in different studies to calculate levels of association. Publication bias was assessed by visual examination of a funnel plot, while asymmetry was formally assessed using both Egger's linear regression test and the rank correlation test (Begg's test).3The initial search identified a total of 101 potential articles. After screening, nine articles that matched the researchers’ criteria were deemed suitable for inclusion in the meta-analysis . The PRIPatients with hematologic disorder and severe comorbidities such as liver disease, heart failure, and peripheral vascular disease, which may affect the levels of MPV and PDW, were excluded from all of the included studies. Blood samples were obtained from the patient's admission time or within 24 h after diagnosis of acute appendicitis and drawn into tubes containing EDTA or citrate to analyze complete blood count and platelet indices using an automated hematologic analyzer. The Newcastle-Ottawa scale found that all the studies included in the meta-analysis were of moderate to good quality (6–8 stars). The characteristics of the nine included studies are shown in 3.12 = 97%, p < 0.00001). A forest plot displaying the association between MPV and diagnosis of acute appendicitis is illustrated in Fig. 3.Seven studies ,25,27,293.22 = 0%, p = 0.57) or publication bias (Egger's test [P = 0.807] or the rank correlation test [P = 0.734]) observed in this analysis.Four studies  reported2 = 0%, p = 0.14) and publication bias [Egger's test (P = 0.949) or the rank correlation test (P = 1.000)] was not observed.Additional analysis was conducted with four observational studies ,26,28,293.32 = 98%, p < 0.0001). No evidence of publication bias was identified by either Egger's test (P = 0.744) or the rank correlation test (P = 0.602).Three studies ,26,27 wi2 = 80%, p = 0.02).Two studies ,27 inves2 = 96%, p < 0.00001). A summary of the association between platelet indices (MPV and PDW) and the diagnosis of acute appendicitis and prediction of complicated appendicitis is illustrated in The final analysis was conducted from two studies ,27 which4. In addition, the most common mistaken diagnoses are typically correlated with young females with gynecological conditions (25–64.3%) [Appendectomy is the most common emergency surgical operation worldwide. Normal histopathologic findings of the appendix (negative appendectomy) reported an incidence of 8.47–9.5% which may increase mortality by up to 1.93% in male patients . In addi5–64.3%) . Evaluat5–64.3%) . In an aPlatelet indices consist of the mean platelet volume (MVP) and platelet distribution width (PDW) is a biomarker of platelet activation, which is inexpensive, comfortable, and can be rapidly measured by an automated hematology analyzer.Interleukin-6 (IL-6) is excreted during the inflammatory period in acute abdominal pain such as AA and ovarian torsion which may contribute to platelet sequestration and destruction, leading to activation of megakaryocytes in the bone marrow to release young platelets into circulation. Thus, large platelets should be found in the early inflammatory phase, then the progression into the late phase of sepsis. Meanwhile, small-sized platelets should be detected in CBC analysis and indicate complicated intrabdominal infection. This finding may lead to low sensitivity of MPV and PDW in the diagnosis of AA in some previous studies ,34.9 L, in which sensitivity and specificity were 59.0% and 59.5%, respectively [P = 0.003). However, the level of MPV also decreased in non-complicated appendicitis patients, but the interpretation of this finding may be limited by the positive results from small sample studies [. This evidence supports the efficacy of MPV as a biomarker for the diagnosis of acute appendicitis.The meta-analysis results investigated whether MVP and PDW are biomarkers for the diagnosis of acute appendicitis and the prediction of complicated appendicitis. The results demonstrate that MPV is significantly lower among acute appendicitis groups compared to control groups. Similar to Ceylan et al. the MPV value significantly decreased in non-complicated appendicitis subjects with a cutoff level of 9.9500 × 10ectively . Shen et studies . This evNevertheless, the results of the present study fail to demonstrate the diagnostic value of MPV for the prediction of complicated appendicitis. There appears to be lower MPV values among complicated appendicitis groups, but not at a significant degree of difference from the control and non-complicated appendicitis groups. This finding could be explained by: 1) The severity of inflammation and sepsis; 2) Timing of blood samples obtained; and 3) Only three of the nine included studies ,26,29 exDuring the early phase of inflammation, large platelets are released from the bone marrow. The progression of the high-grade inflammatory activity resulted in the large platelets get sequestrated and destroyed in the inflammatory zone, and small platelets become dominant.Furthermore, MPV may enlarge during the sepsis period due to platelet activation instead of increasing the production of young platelets from megakaryocytes which takes time ,37,38.9/L should be a valuable diagnostic marker of acute appendicitis with a 76.3% sensitivity and 93.1% specificity [In contrast to the association between MPV and acute appendicitis, the pooled analysis of recent literature demonstrates that PDW has no diagnostic value in acute appendicitis and is unable to predicts its complication. Fan et al. described that increasing PDW at the cut-off level 15.1 × 10cificity . The difcificity ,40.The results of the present study were somewhat complicated since significant heterogeneity was identified in the meta-analysis of the association between MPV and PDW with the diagnosis of acute appendicitis and PDW with complicated appendicitis. The heterogeneity observed in the meta-analysis can be explained by: 1) Differentiation in the patient exclusion criteria for each study; 2) Timing of blood samples obtained varied from patients presenting time to within 24 h after diagnosis; 3) Waiting time for blood analysis varied from 10 min to 2 h; and 4) The disparity of hematology analyzers and the reference values of each study. Additionally, the data was adjusted to mimic the heterogeneity in the analysis of MPV and complicated appendicitis and adopted a random-effects model to calculate the OR in order to compensate this effect for a more conservative result.The major limitations of the present study include several potential sources of publication bias, for instance the inclusion of only English language publications, studies that indicate continuous variable outcomes may lead to missing relevant articles, and only observational retrospective studies were considered. Finally, most of the patients in this analysis were from Asian populations and does not represent a global clinicopathological correlation between platelet indices and acute appendicitis. Nonetheless, evidence of publication bias was not observed from the Egger's linear regression test and rank correlation test results.5This study demonstrates that lower MPV values can have a significant role in the diagnosis of acute appendicitis, but failed to determine severity. The researchers suggest the use of MPV as a biomarker along with the clinical scoring system in patients with suspected acute appendicitis for greater diagnostic accuracy. Nevertheless, PDW was not found to be useful as a diagnostic marker and prediction of complicated appendicitis.Not commissioned, externally peer-reviewed.No.Tullavardhana Thawatchai: Concepts, Design, Definition of intellectual content, Literature search, Clinical studies, Data analysis, Statistical analysis, Manuscript review, Guarantor, Sanguanlosit Sarat: Design, Definition of intellectual content, Literature search, Data acquisition, Statistical analysis, Manuscript preparation, Manuscript review, Guarantor, Chartkitchareon Anuwat: Definition of intellectual content, Literature search, Data acquisition, Data analysis, Manuscript editing.10.13039/100009570Srinakharinwirot University, ThailandThe study received grant supports from This study is a systematic review and meta-analysis: no need for ethical approval.Name of the registry: THAWATCHAI TULLAVARDHANA.Unique Identifying number or registration ID: reviewregistry1131.https://www.researchregistry.com/browse-the-registry#registryofsystematicreviewsmeta-analyses/registryofsystematicreviewsmeta-analysesdetails/60744d3e348b8b001c745bfa/Hyperlink to your specific registration (must be publicly accessible and will be checked): Associated Professor Thawatchai Tullavardhana.The authors declare no conflicts of interest.


XRCC1, XRCC2 and XRCC3 genes with susceptibility to thyroid cancer (TC). We conducted a comprehensive meta-analysis to explore the association of polymorphisms at We searched PubMed, EMBASE, Web of Science, and CNKI for relevant available studies. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of the associations. XRCC1 Arg399Gln, 13 studies with 3,234 cases and 4,807 controls on XRCC1 Arg280His, 13 studies with 2,956 cases and 3,860 controls on XRCC1 Arg194Trp, five studies with 1,287 cases and 1,422 controls on XRCC2 Arg188His, 13 studies with 2,488 cases and 3,586 controls on XRCC3 Thr241Met, and six studies with 1,828 cases and 2,060 controls on XRCC3 IVS5-14 polymorphism were selected. Polled data revealed that the XRCC1 Arg399Gln, Arg280His, Arg194Trp, XRCC2 Arg188His and XRCC3 Thr241Met and IVS5-14 polymorphisms were not significantly associated with an increased risk of TC. Stratified analyses by ethnicity showed that the XRCC1 Arg399Gln polymorphism was associated with TC risk in Caucasians, but not in Asians. A total of 67 studies including 17 studies with 6,806 cases and 5,229 controls on XRCC1 Arg399Gln, Arg280His, Arg194Trp, XRCC2 Arg188His, XRCC3 Thr241Met and IVS5-14 polymorphisms were not associated with risk of TC in the global population. Further well-designed investigations with large sample sizes are required to confirm our results.Our meta-analysis indicated that the  Thyroid carcinoma (TC) is the most common endocrine malignancy and accounts for 0.5–1.5% of all cancer cases in the United States . The incidence of TC has increased globally in recent decades, especially among younger adults. Its incidence and mortality rates are varied by 8–12 fold and 2–6-fold, respectively . In the United States of America (USA), deaths from TC alone account for more deaths than all of the other endocrine malignancies with annual incidence of 6.6% between 2000 and 2009 is the highest among all cancers . TC is more common in women than in men, but men are twice as likely as women to die from this cancer . The Papillary Thyroid Carcinoma (PTC) is the most frequent subtype of thyroid malignancy which constitutes approximately >85% of all cases . The etiology and development of TC is a result of complex interactions between genetic and environmental factors . Continuously exposed to a wide range radiation is a well-established risk factor for TC, which such radiation include certain radiation therapy and radiation fallout from power plant accidents of atomic bombs .XRCC1, XRCC2, XRCC3 DNA repair genes are associated with an increased risk of TC in in different populations . However, no conclusive result has been reported due to the conflicting results among different studies. Therefore, a meta-analysis of all available studies will help to obtain a more convincing result, because some of these studies were based on small sample size, thus, subgroup analysis ethnicity may also yield more meaningful results . Here, we performed a meta-analysis of all eligible case-control studies published to date, to assess the association of XRCC1, XRCC2 and XRCC3 polymorphisms with susceptibility of TC globally.There is increasing evidence suggests that damage to human DNA might initiate the cancer, which caused by external agents such as chemical agents, ionizing radiation and UV . To date, several genetic variations that have a fundamental role in the carcinogenesis of different subtypes of TC have been reported . DNA repair is essential for the maintenance of genomic integrity, which is of primary importance in the general and specialized functions of cells, as well as in the prevention of carcinogenesis . Some genes of the X-ray repair cross-complementing (XRCC) family are an essential part of the BER and homologous recombination (HR) DNA repair pathways responsible for DNA double strand breaks caused by normal metabolic processes and/or exposure to ionizing radiation, and have been reported to be associated with development of TC . Previous studies have reported that X polymorphisms of Publication SearchXRCC1, XRCC2 and XRCC3 genes polymorphisms with TC risk up to October 01, 2020. Combinations of the following keywords were used in the search: (‘’Thyroid Cancer’’ OR ’’Thyroid Carcinoma‘’ OR ‘’Papillary Thyroid Cancer ‘’ OR ‘’Follicular Thyroid Cancer’’ OR ‘’Hurthle Cell Cancer’’ OR ‘’Medullary Thyroid Cancer’’ OR Anaplastic Thyroid Cancer’’) AND (‘’X-Ray Repair Cross-Complementing Protein I’’ OR ‘’XRCC1’’ OR ‘’rs1799782’’ OR ‘’Arg194Trp’’ OR ‘’rs25487’’ OR ‘’Arg399Gln’’ OR ‘’rs25489 OR ‘’Arg280His’’) AND (‘’X-Ray Cross Complementing Group II’’ OR ‘’XRCC2’’ OR ‘’Arg188His’’ OR ‘’rs3218536’’) AND (‘’X-Ray Cross Complementing Group III’’ OR ‘’XRCC3’’ OR ‘’Thr241Met’’ OR ‘’rs861539’’) AND (‘’Gene’’ OR ‘’Genotype’’ OR ‘’Allele’’ OR ‘’Polymorphism’’ OR ‘’Single Nucleotide Polymorphisms’’ OR ‘’SNPs’’ OR ‘’Variation’’ OR ‘’Mutation’’). In addition, to prevent the loss of any important data, we reviewed the bibliographical references list of retrieved studies, reviews and previous meta-analyses. The whole search process was carried out in English, Chinese, Portuguese, Russian and Persian. When overlapping data on the same cases were included in more than one publication, only the one with the larger sample size was selected.Ethical approval or patient consent was not required because this is a meta-analysis in which all data were extracted from published data. A comprehensive computer search was carried out independently by two authors, in PubMed, Web of Knowledge, Web of Science, Embase, Scientific Information Database (SID), WanFang, VIP, Chinese Biomedical Database (CBD), Scientific Electronic Library Online (SciELO) and China National Knowledge Infrastructure (CNKI) database to collect the case-control studies that investigated the association Inclusion and Excluding CriteriaXRCC1, XRCC2 and XRCC3 genes with TC; 3) provide both genotype and allele distributions inpatients and controls for estimation of combined odds ratios (OR) and 95% confidence intervals (CI); and 4) full text studies on human. Accordingly, Studies were excluded if they: 1) abstracts, reviews, editorials, comments or animal studies; 2) case only studies; 3) linkage studies and family based studies; 4) did not provide the numbers of genotypes; 5) animal and in vitro studies; and 6) contained overlapping data. If the full text article or a study did not published detailed data regarding the genotype distribution in cases and controls, the corresponding authors of the study were contacted for unpublished data.The studies included in the meta-analysis were required to meet the following criteria: 1) Case-control study of TC cases and healthy subjects; 2) studies evaluated the association of polymorphisms at Data ExtractionTwo authors worked independently to extract all data from all eligible studies based on the inclusion criteria. Any disagreement was resolved by further discussion until a consensus about valid data was reached. The publication details collected included: first author’s name, year of publication, ethnicity , country of origin, genotyping methods, numbers of cases and controls, frequencies of genotypes in cases and controls, minor allele frequency (MAF) in controls, and Hardy-Weinberg equilibrium (HWE) in controls. The ‘‘mixed’’ group means mixed or unknown populations. Moreover, when publications included sample of more than one ethnicity or population, the data was extracted separately according to ethnicities. The publications did not reported necessary data, as well as genotype frequencies; we contacted the corresponding authors by email to request the missing data.Statistical AnalysisXRCC1, XRCC2 and XRCC3 genes and TC risk was estimated by calculating pooled odds ratios (OR) with 95% confidence intervals (CI). The significance of the summary of pooled data was tested using a Z-test in which P-values less than 0.05 were considered to be statistically significant. The association of the XRCC1, XRCC2 and XRCC3 polymorphisms with TC risk was evaluated under models, i.e., allele (B vs. A), homozygote (BB vs. AA), heterozygote (BA vs. AA), dominant (BB+BA vs. AA) and recessive model (BB vs. BA+AA), respectively. The between studies heterogeneity was performed using the chi-square-based Cochrane Q-test, in which P-value less than 0.10 was considered significant. In addition, we have used I2 to statistically measure the heterogeneity and indicate the percentage of variance of the heterogeneity. A fixed-effect model (Mantel-Haenszel method) was used to pool ORs and 95% CI when there was no significant heterogeneity. Otherwise, a random effects model (the DerSimonian and Laird method) was used. The Pearson’s χ2 test was applied to test the Hardy-Weinberg equilibrium (HWE) in healthy controls with the significance set at P<0.05. Sensitivity analysis was performed by iteratively omitting one study at a time to determine the effects of individual study on overall data and stability of the results. Moreover, sensitivity analysis was performed by removing those studies did not in agreement with HWE in control groups. Stratification analysis was performed based on ethnicity , source of controls (HB or PB), genotyping methods and HWE status. The publication bias of the individual studies on XRCC1, XRCC2 and XRCC3 polymorphisms and TC risk was assessed visually inspecting the Begg’s funnel plot for asymmetry and the Egger’ linear regression test statistically. Egger`s linear regression test was used to evaluate the symmetry of the funnel plot in order to minimize the subjective influence of the visual inspection assessment, in which bias was considered with P<0.05 in Egger’s test. Statistical analyses were performed using Comprehensive Meta-Analysis (CMA) software version 2.0 . Two-sided P-values < 0.05 were considered statistically significant.The strength of the association between different polymorphism of Characteristics of included studiesXRCC1 (n=43), XRCC2 (n=5) and XRCC3 (n=19) polymorphisms met our inclusion criteria . Detailed characteristics and genotype distribution of eligible studies are summarized in XRCC1 Arg399Gln, 13 studies with 3234 cases and 4807 controls on XRCC1 Arg280His, 13 studies with 2956 cases and 3860 controls on XRCC1 Arg194Trp, five studies with 1,287 cases and 1,422 controls on XRCC2 Arg188His, 13 studies with 2,488 cases and 3,586 controls on XRCC3 Thr241Met, and six studies with 1,828 cases and 2,060 controls were on XRCC3 IVS5-14 polymorphism. Subjects in 26 of the included case-control studies were belonged to Caucasians while those in the remaining studies were Asians. Five different genotyping methods were used in these studies including PCR-RFLP, TaqMan, iPLEX Assay, MassARRAY, and ARMS-PCR. The genotype distributions in the healthy controls of 21 studies were not consistent with HWE  and dominant , but not in Asians. Subgroup analyses by ethnicity still did not find a significant for association of XRCC1 Arg280His and Arg194Trp polymorphisms and TC risk . The XRCC1 protein has no known catalytic activity, but serves an important component of the base excision repair (BER) pathway via its role as a central scaffolding protein physically associated with DNA ligase III at its COOH terminus . More than 300 validated polymorphisms in the human XRCC1 gene are listed in the dbSNP database, of which, the most extensively studied SNPs are Arg399Gln (exon 10), Arg280His (exon 9) and Arg194Trp (exon 6) polymorphisms in different cancer . Our results revealed that the XRCC1 Arg399Gln, Arg280His and Arg194Trp polymorphisms were not significantly associated with risk of TC in the global population. However, subgroup analysis showed that the XRCC1 Arg399Gln polymorphism was associated with risk of TC in Caucasians, but not in Asians. To date, several meta-analyses have been performed to undertake the association of polymorphisms in XRCC1 in development of TC.Human XRCC2 gene is paralogue of RAD51 plays a pivotal role in the homologous recombination repair (HRR) machinery, maintenance of the genome integrity and the control of genomic rearrangement processes causes to the chromatid breaks . XRCC2 gene is located on human chromosome 7q36.1, consists of three exons, which are distributed 29 DNA repair over a 30 kb region. In exon 3, an Arg188His polymorphism (rs3218536) has been identified on the coding region of XRCC2 as potential cancer susceptibility loci in recent studies, although association results are controversial. However, the potential phenotypic effects of this polymorphism are currently unknown. Previous epidemiological studies that examined the XRCC2 Arg188His polymorphisms with TC risk have provided controversial results. For example, Yan et al., (2020) reported that there was no significant association between XRCC2 Arg188His polymorphism and TC risk in a Chinese population. However, Fayaz et al., reported that XRCC2 Arg188His polymorphism is associated with an increased risk of TC in an Iranian population. To the best of our knowledge, this was the first meta-analysis to evaluate association of the XRCC2 Arg188His polymorphism with TC risk. Our results revealed that there was no significant association between XRCC2 Arg188His polymorphism and TC risk in the overall population.Human XRCC3, also known as CMM6, is a member of the RecA/Rad51-related protein family that participates in HRR to maintain chromosome stability which was originally identified by its ability to complement the DNA repair defect . Human XRCC3 gene is located on chromosome 14q32.3, contains 10 exons (its seven exons lie in the region taking 13.5 kbp) and spans 21 kbp length . In this meta-analysis, our pooled data showed that the XRCC3 IVS5-14 and Thr241Met polymorphisms were significantly associated with an increased risk of TC in the overall population. Moreover, subgroup analysis showed that there was no a significant association between the XRCC3 IVS5-14 and Thr241Met polymorphisms and an increased risk of TC. Unlike our results, Lu et al., in a meta-analysis of eight studies with 963 TC cases and 1,942 controls reported that the XRCC3 Thr241Met polymorphism was associated with the risk of TC in the global population, but they did not observe significant association in by ethnicity . On the basis of availability of five more studies with 2,589 cases and 3,596 controls on XRCC3 Thr241Met polymorphism and TC, our results more reliable and powerful results than the previous meta-analysis.Human XRCC2 Arg188His polymorphism with susceptibility to TC. Second, our results were inconsistent with the previous meta-analysis on XRCC3 Thr241Met polymorphism association with TC risk might be due to including large sample size. Finally, no publication bias was found in the present study and sensitivity analysis also indicated that no single study yield obvious impact on the pooled results, which indicating that the results of the present meta-analysis are statically robust.The present meta-analysis has some novelty and advantages. First, to the best of our knowledge, this study was the first meta-analysis to comprehensively evaluate the association of XRCC2 Arg188His and XRCC3 IVS5-14 polymorphisms with TC risk, which leads to the improper publication bias for these polymorphisms. Second, in the meta-analysis all of the included studies were on the Caucasian and Asians, and there was no study in African and mixed populations among the eligible studies. Therefore, need to further studies on a large scale on African and mixed populations to verify this result. Third, the study might have experienced the publication bias due to the inclusion of English and Chinese literature, which could have limited the published evidences. Fourth, the control group of several studies was not in accordance with HWE, which may be attributed to the reason as genotyping error. However, deletion of those studies did not change the results of quantitative synthesis, suggesting the robustness of results. Fifth, our pooled ORs were based on un-adjusted data for potential covariates such as age, sex, lifestyle, exposure and environmental factor, which might have affected the accuracy of the results, though no sufficient information available for most of studies included in the meta-analysis. Finally, TC is a multi-factorial disease from complex interactions between environmental factors and genetic factors. In this meta-analysis, we had insufficient data to conduct an evaluation of such interactions for the role of XRCC1, XRCC2 and XRCC3 polymorphisms and factors in TC development.Despite above mentioned advantages, the current meta-analysis has some limitations which should be addressed. First, the sample size is still relatively small, which might not enough statistical power to explore the real association of the XRCC1 Arg399Gln, Arg280His, Arg194Trp, XRCC2 Arg188His, XRCC3 Thr241Met and IVS5-14 were not significantly associated with an increased risk of TC in global population. However, subgroup analyses by ethnicity showed that the XRCC1 Arg399Gln polymorphism was associated with risk of TC in Caucasians, but not in Asians. Taking into account the aforementioned limitations, further studies are highly needed in the future.In summary, the present meta-analysis suggested that the Conceived and designed the study and experiments: MM, SAD, SMT. Performed the experiments: FA and JJNAnalyzed the data: HN and SAD. Contributed reagents/materials/analysis tools: SHS and SK. Wrote the paper: HN, MM and FA. All authors reviewed the manuscript.


To systematically evaluate the risk factors of early‐onset seizures after stroke, in order to better provide evidence‐based results for early detection, identification, targeted prevention, and treatment of this disease.PubMed, EMBASE, The Cochrane Library, CNKI, and WanFang databases were searched to collect relevant studies on the risk factors of early‐onset seizures after stroke from January 2010 to January 2020. Meta‐analysis of all included studies was performed by using RevMan version 5.3 and Stata version 14.0 software.p < .00001], cerebral infarction with hemorrhagic transformation  and intracerebral hemorrhage ‐related factors showed greater association with the occurrence of early‐onset seizures after stroke.Eighteen case–control studies with a total sample size of 13,289 cases, including 813 cases with early‐onset seizures after stroke, and 12,476 cases with non‐early‐onset seizures after stroke were included. The results of meta‐analysis showed that cortical involvement [Odds Ratio (OR) = 5.00, 95%Confidence Interval (CI) , These findings suggest that cortical involvement, intracerebral hemorrhage, and cerebral infarction with hemorrhagic transformation are important predictors and risk factors for early seizures after stroke, while the patient's gender, age, NHISS score, alcoholism, smoking, high blood pressure, diabetes, atrial fibrillation, dyslipidemia, receiving surgical treatment, and reperfusion therapy showed no association with the occurrence of early‐onset seizures after stroke. These findings suggest that cortical involvement, intracerebral hemorrhage and cerebral infarction with hemorrhagic transformation are important predictors and risk factors for early seizures after stroke, while the patient's gender, age, NHISS score, alcoholism, smoking, high blood pressure, diabetes, atrial fibrillation, dyslipidemia , receiving surgical treatment and reperfusion therapy showed no association with the occurrence of early‐onset seizures after stroke. PubMed, EMBASE, the Cochrane Library, CNKI, and WANFANG databases were searched to identify relevant studies. The search was conducted from January 2010 to January 2020 using the search terms “after stroke”, “cerebral hemorrhage”, “brain ischemia”, “early seizures”, “risk factors”, and “factors”. The search words and keywords were also joined for conducting the search. The reference lists of eligible publications were manually checked to identify any other potential studies.2.22.2.1Each database (between 2010.01 and 2020.01) publishes one or more of the risk factors for early‐onset seizures after stroke in Chinese and English, such as gender, age, NIHSS score at admission, alcoholism, smoking, hypertension, diabetes, atrial fibrillation, dyslipidemia, hemorrhagic transformation, cortical injury, stroke subtype, receiving surgical treatment, etc.Research subjects: studies that included patients with early‐onset seizures after stroke (ES group) and those with non‐early‐onset seizures after stroke (no‐ES group).Diagnostic criteria: International League Against Epilepsy for ES is defined as the appearance of seizures symptoms within 7 days after a stroke, and the criteria for appearance of seizures symptoms within 14 days (2 weeks) after a stroke are also adopted by the researchers ], or the above data can be calculated.In case of publication of multiple articles by the authors from the same institution using overlapping sample data, only recent studies or studies with more complete information are selected.2.2.2Summary report, meeting abstracts, commentaries, republished articles, etc.Literature with no clear sample source, no control group, or inconsistent control group definition.Studies on children.Studies with Newcastle‐Ottawa Scale (NOS) score of ≤4.2.3The literature was screened according to the inclusion and exclusion criteria, and the following information was extracted: the first author's name, publication time, nationality of study population, total number of samples in case and control groups, average age, possible risk factors, details of exposure factors, etc.2.4Two investigators (MA Sitian and WANG Huan) have independently evaluated the risk of bias of included studies. If there are inconsistent opinions, then a third author (YANG Yongfeng) was contacted for decision. Third‐party opinions will be looked out if still differences exist. The bias risk evaluation of case–control studies was done using the NOS scale in order to evaluate the quality of literature included, in which a score of 9 points, ≥ 7 points were considered as high‐quality, 4 to 6 points were considered as medium‐quality articles, and ≤3 points were considered as low‐quality articles Table .2.5I2 was used to evaluate heterogeneity. When p > .1 and I2 < 50%, a fixed‐effects model is used. Otherwise, a random‐effects model was used. A subgroup analysis was performed based on factors such as sample size, country, and region to find the source of heterogeneity. In case–control studies, the odds ratios (OR) was used as the effect scale and its 95% confidence intervals (CI) was calculated at the same time, with p ≤ .05 as statistically significant difference. The man differences (MD) were used as the effect scale for continuous variables, and its 95% CI was calculated at the same time. The difference was statistically significant with p ≤ .05. Sensitivity analysis was used to calculate combined OR value and 95% CI, and compared the two sets of results to show whether the results are stable. Egger funnel chart was drawn using Stata version 14.0 software, and publication bias was evaluated by Egger p value result and whether the funnel chart was symmetrical or not. If p > .10 and funnel chart showed no obvious asymmetry, this indicated no obvious publication bias. Otherwise, publication bias was indicated.Statistical analysis was performed using Review Manager version 5.3 software. 33.1A total of 1,258 documents were initially retrieved, and after the elimination research layer by layer, 18 studies were finally included , so the fixed effects model was adopted; the characteristic factors of NIHSS at admission were heterogeneous , so the random effects model was adopted. Meta‐analysis results show that  = 2.46 , p = .29]. Research suggests that there is significant heterogeneity in alcoholism factors, so subgroup analysis is carried out according to sample size and different countries  was used, and the results showed no statistical significance .Four studies , and the fixed‐effects model was adopted. While the two factors of diabetes and atrial fibrillation are heterogeneous , and the random‐effects model was adopted. The results of meta‐analysis showed no statistically significant association between the above factors and ES, suggesting hypertension, diabetes, atrial fibrillation, and dyslipidemia as not risk factors for ES.Meta‐analysis on the relationship between the underlying disease factors related to hypertension, diabetes, atrial fibrillation, and dyslipidemia and the occurrence of ES Table  was condThe study found significant heterogeneity in the factors of diabetes and atrial fibrillation, so we further conducted a subgroup analysis of different sample sizes and countries Table . This ca3.3.4I2 = 83%, p < .000 01) was observed, and random‐effects model was used. The results showed that the composition ratio of cortical damage in ES group was greater than that in the no‐ES group [OR (95% Cl) = 5.00 ]. The difference was statistically significant (p < .01), indicating cortical injury as a risk factor for ES after stroke.Ten Bian,  studies The study found that there is significant heterogeneity in cortical damage factors, so we further conducted subgroup analysis according to different sample sizes Figure  and regiI2 = 0), and fixed‐effects model was used. The results showed that OR (95% Cl) = 2.77 , suggesting statistical significance and indicating that hemorrhagic transformation is a risk factor for ES.Six , and random‐effects model was used. The results showed that the probability of ES patients in cerebral hemorrhage group was greater than that in the cerebral infarction group [OR (95% Cl) = 1.83 ]. The difference was statistically significant (p < .01), indicating cerebral hemorrhage as a risk factor for ES.Eleven  is obvious, so we further analyze the subgroups according to the total sample size and different regions (Asia/Europe/Africa). The results revealed that the total sample size and the population of different continents have no influence on the outcome indicators. However, comparison of OR between the states through data showed Asia [OR (95% Cl) = 1.72 ], Europe [OR (95% Cl) = 2.01 ], and Africa [OR (95% Cl) = 1.75 ], and it can be found that ES caused by cerebral hemorrhage more likely occurs in the European population, followed by Africa and finally Asia  = 1.22 , p = .56], suggesting surgical treatment as not risk factor for ES.Two studies Bian,  have invI2 = 0, p = .50), so the FE model was used for meta‐analysis The results were not statistically significant , suggesting that reperfusion therapy has nothing to do with the occurrence of ES.Two articles  as a risk factor for ES after stroke through systematic review and meta‐analysis. But our study showed no statistical significance between alcoholism and ES. Therefore, whether alcoholism is related to the occurrence of ES, whether it acts as a risk factor for ES and the underlying mechanism of alcoholism that leads to seizures requires further research.With regard to alcoholism, due to inconsistent results of fixed‐effects and random‐effects calculations, the results of meta‐analysis remained unstable. This is because too few study samples were included, or the definition of alcoholism is still inconsistent or not described. Researcher Zhang et al.  have fou4.1There are still many deficiencies that should be acknowledged in this study and are as follows: (1) all the included studies are retrospective case‐control studies; (2) in several studies, reports have shown that seizures were recorded by family or caregivers during the follow‐up period; (3) some risk factors involving less literature, such as four articles on alcoholism and atrial fibrillation and two on surgical treatment, might lead to a certain bias in the meta‐analysis; (4) regarding the definition of ES, most of the studies included e seizures that occurred within 7 days after stroke onset according to the definition of the International League Against Epilepsy, but a few studies did not follow the definition of the International League Against Epilepsy, leading to some bias; and (5) the studies included 11 countries with three continents, with a large geographical span, large differences in climate and human environment, and might not be representative of a single country. Therefore, future multi‐center, large‐sample epidemiological studies are needed to further clarify the risk factors for ES after stroke.5In summary, the results of this meta‐analysis indicate that cortical injury, cerebral infarction with hemorrhagic transformation, and cerebral hemorrhage are closely related to the occurrence of ES, and are risk factors and important predictors for the occurrence of ES. Medical staff can refer to the results of this study to identify early, targeted risk groups of early‐onset seizures after stroke, reduce early incidence of seizures in patients after stroke and thus improve the quality of life of patients and their families.The authors declare that they have no competing interests.FAN Xiaoxuan and MA Sitian contributed to the conception of the study; MA Sitian 、WANG Huan 、YANG Yongfeng and WANG Kai performed the selection of documents and the evaluation of document quality; FAN Xiaoxuan and MA Sitian contributed significantly to analysis and manuscript preparation; MA Sitian performed the data analyses and wrote the manuscript; ZHAO Xiaoping and FAN Xiaoxuan helped perform the analysis with constructive discussions.Not applicable.Not applicable.https://publons.com/publon/10.1002/brb3.2142.The peer review history for this article is available at


Strong positive associations were observed between PSC and risk of CCA, hepatobiliary cancer, liver cancer, gastrointestinal cancer, pancreatic cancer, CRC, total cancer, and all-cause mortality, but not for cardiovascular disease.A diagnosis of primary sclerosing cholangitis (PSC) has been associated with increased risk of hepatobiliary cancers, colorectal cancer and all-cause mortality in several studies, while associations with cardiovascular disease have been inconsistent. We conducted a systematic review and meta-analysis of published cohort studies on the topic to summarize these associations. PubMed and Embase databases were searched up to January 13th, 2020. Cohort studies on PSC and risk of cancer, cardiovascular disease, or mortality were included. Summary relative risks (RRs) and 95% confidence intervals (95% CIs) were estimated using random effects models. The summary RR (95% CI) comparing persons with PSC to persons without PSC was 584.37 (269.42–1267.51, I In absence of effective medical treatment, the majority of patients will gradually develop liver cirrhosis and end-stage liver disease, where liver transplantation represents the only curative option for patients with end-stage disease. PSC is a rare disease with an incidence of 0.4–0.7 cases per 100,000 in the UK2 and a prevalence of 3.9–16.2 per 100,0001. Little is known about the causes of the disease, but genetic risk factors suggest a role of immune-mediated mechanisms in the disease development as there is genetic overlap with autoimmune diseases, such as type 1 diabetes, coeliac disease, rheumatoid arthritis, sarcoidosis and psoriasis3. Inflammation in the colon is a predominant risk factor for PSC with concomitant inflammatory bowel disease being reported in up to 60–80% of PSC patients1. Higher intake of coffee has been found to be inversely associated with PSC5, which is partly consistent with the protective effect of coffee on liver cirrhosis and liver cancer6. Smoking has shown a paradoxical inverse association with risk of PSC9, however, it is unclear if this finding is causal as most of the available studies are of retrospective case–control study design, which may be prone to recall and selection bias.Primary sclerosing cholangitis (PSC) is a chronic disease of the biliary tree characterized by progressive inflammation, and fibrotic stricturing of the bile ducts13, 117–177 for hepatobiliary cancer15, 78 for gallbladder cancer13, and 22–42 for liver cancer13. In addition, several studies have suggested increased risk of gastrointestinal cancer overall16, pancreatic cancer17, colorectal cancer18, total cancer14 as well as all-cause mortality15. A potential association between PSC and cardiovascular disease (CVD) has been more unclear with only a limited number of studies published on the subject19. However, the available data on risk of cancer, cardiovascular disease and mortality in PSC have to our knowledge not yet been summarized. Therefore, to provide more stable estimates of risk of cancer, cardiovascular disease and mortality in patients with PSC we conducted a systematic review and meta-analysis of the published cohort studies on the topic.Prospective cohort studies have suggested strong positive associations between PSC and increased risk of several gastrointestinal cancers with extreme relative risks (RRs) in the range of 200–1560 for cholangiocarcinoma20.We searched the PubMed and Embase databases up to January 13th, 2020 for eligible studies. The search terms used are found in the We included published retrospective and prospective cohort studies that investigated the association between PSC and the risk of cancer, cardiovascular disease and all-cause mortality. Estimates of the relative risk (RR) had to be available with the 95% confidence intervals (CIs) in the publication. A list of the excluded studies and exclusion reasons is found in The following data were extracted from each study: The first author’s last name, publication year, country where the study was conducted, study period, sample size, number of cases, age, exposure (PSC) and subgroups , comparison, RRs and 95% CIs for patients with PSC compared to persons without the condition, and variables adjusted for in the analysis. DA extracted the data and AS double-checked the data for accuracy.21 which takes into account both within and between study variation (heterogeneity). The average of the natural logarithm of the RRs was estimated and the RR from each study was weighted using random effects weights.We calculated summary RRs (95% CIs) for the association between PSC and risk of cancer, cardiovascular disease, and mortality using the random-effects model by DerSimonian and Laird2 statistics22. Cochran’s Q is calculated as the weighted sum of squared differences between individual study effects and the pooled effects across studies, with weights being those in the pooling method. I2 is a measure of how much of the heterogeneity that is due to between study variation rather than chance. I2-values of 25%, 50% and 75% indicates low, moderate and high heterogeneity respectively. The Newcastle–Ottawa scale was used to assess the quality of the included studies23.Heterogeneity between studies was evaluated using Q and I24 and Begg–Mazumdar’s test25. Egger’s test is a statistical test for asymmetry of the funnel plot and is a linear regression in which the standard normal deviate (estimate divided by its standard error) is regressed against its precision (inverse of standard deviate). Begg’s test is a test of the interdependence of variance and effect size using Kendall’s method. Sensitivity analyses were carried out excluding one study at a time from the analyses to assess whether the summary estimates were driven by a very large study or a study with an extreme results. The statistical analyses were conducted using the software package Stata, version 13.0 software .Publication bias was assessed using Egger’s test19  for cholangiocarcinoma13  for hepatobiliary cancer  for liver cancer  for gastrointestinal cancer16  for pancreatic cancer17  for colorectal cancer18  for total cancer16  for all-cause mortality15  for CVD19  across outcomes is provided in Fig. % CIs acr13. A study from New Zealand reported RRs of 117.6 (95% CI 24.2–343.6) for nonmelanoma skin cancer, 4.3 (95% CI 0.5–15.4) for lung cancer, 4.1 (95% CI 0.5–14.8) for breast cancer, 1.2 (95% CI < 0.1–6.7) for prostate cancer, and 0.8 (95% CI < 0.1–4.6) for renal cell carcinoma15. A Swedish study reported a RR of 2.2 (95% CI 0.1–12.5) for stomach cancer14.For several cancers there was only one study available and meta-analyses were therefore not possible. A study from Finland reported a RR of 78.3 (95% CI 21.3–200) for gallbladder cancerWe conducted sensitivity analyses removing one study at a time from each analysis, however, the summary estimates were largely similar across these sensitivity analyses 6 this association is not sufficiently strong to fully account for the RR of 30 for liver cancer among patients with PSC. On the other hand, if smoking is truly protective for PSC this would most likely lead to negative confounding for cancer and mortality as smoking is strongly positively associated with both these outcomes. One study which additionally adjusted for smoking status found associations which were slightly weaker than the remaining studies, however, within that study the smoking-adjusted hazard ratios were slightly stronger than the unadjusted hazard ratios2. This suggests that other differences perhaps due to study design and/or analyses could have contributed to the slight difference in results between this study and the remaining studies. Considering the very strong observed associations as well as the specificity of the associations (particularly between PSC and liver cancer and CCA), it seems perhaps less likely that confounding by lifestyle factors could fully account for these strong associations. However, we cannot exclude the possibility that other shared risk factors  could explain a proportion of the associations. The prevalence of inflammatory bowel disease (IBD) is high in PSC27 and it is possible that the association between PSC and CRC could be partly explained by IBD. However, previous studies suggested that patients with both PSC and IBD had a 3.4-fold increase in CRC risk compared to patients with only IBD, suggesting that PSC increases CRC risk beyond what is solely due to IBD28. One study excluded cases of small duct PSC from the analyses10, however, exclusion of that study (or any other study) did not materially alter the observed associations. Misdiagnosis of common bile duct cholangiocarcinoma as pancreatic head cancer could be a potential explanation for the association with pancreatic cancer.The meta-analysis has some limitations which need to be mentioned. The number of studies included in each analysis was low, and therefore we cannot exclude the possibility that some of these findings may slightly change when additional studies accrue. In most of the sensitivity analyses excluding one study at a time, no single study accounted for the observed associations, and strong positive associations remained across most analyses. For several cancers we only identified one study which met our inclusion criteria and we were therefore not able to conduct analyses for these cancers. This includes gallbladder cancer, which is known to be strongly related to PSC29 and could result in oncogenic mutations. Some reports have shown mutations in loci with tumor suppressor function, such as p16INK4a, both in PSC cases without cholangiocarcinoma and PSC cases with cholangiocarcinoma30. Mutations, homozygous deletions or inactivation by methylation in p16INK4a have also been observed across several cancers, e.g., pancreatic, esophageal, bladder and liver cancer and familial melanoma32, homozygous deletions in bladder, kidney, pancreas and ovary tumors35, and inactivation through methylation in cancers of the breast, prostate, head and neck, and hepatocellular carcinomas39. The ErbB receptor kinase family are strong mediators of development of sporadic CCA, and interact with COX-2, interleukin-6, VEGF and Met activating not only their own pathway, but enhancing that of others40. It has been shown that ErbB2 is increased in patients with PSC as well as hepatolithiasis 41.Several biological mechanisms or pathways may explain why PSC is associated with increased risk of cancer and mortality. Pro-oncogenic processes resulting from chronic biliary inflammation and cholestasis with accumulation of bile acids is suspected to contribute to the development of CCA, possibly through induction of nitric oxide synthase and nitric oxide generation, which promotes oxidative DNA damage and inhibits DNA repair42, and chronic intestinal inflammation may increase risk for CRC in the 60–80% of patients with PSC that have concomitant inflammatory bowel disease27. PSC is known to be related to pancreatitis43, which is an important risk factor for pancreatic cancer44.Progressive inflammation and scarring of the liver parenchyma in more advanced PSC may increase risk of liver cancer development through upregulation of proliferative signaling pathwaysThe current findings are concerning given the strength of the observed associations and the rather poor survival rates for several of these cancers, particularly in CCA, liver cancer and pancreatic cancer. The results underscore the need for effective cancer surveillance in this patient group, as well as identification of markers for early diagnosis of cancer. In addition, implementation of primary prevention strategies by identification of potentially modifiable risk factors or pharmaceutical targets involved in cancer development are warranted.In conclusion, this meta-analysis suggest that PSC is a very strong risk factor for CCA and liver cancer, but is also strongly associated with total gastrointestinal, pancreatic, colorectal, and total cancer risk as well as all-cause mortality. Although further studies are needed for a more comprehensive assessment of the association across a larger number of outcomes and with adjustments for additional confounding factors, the current findings clearly indicate that PSC patients need to be followed up closely with regard to cancer risk.Supplementary Information.


There is growing evidence that sepsis survivors are at increased risk of developing new-onset atrial fibrillation, acute kidney injury, and neurological diseases. However, whether sepsis survivals increase the risk of dementia or cognitive impairment remains to be further explored.The objective of this study was to determine whether sepsis survivals increase the risk of dementia or cognitive impairment.We searched PubMed, Cochrane Library, Web of Science, and EMBASE databases for cohort studies or case-control studies from their inception to November 5, 2021. The quality of this study was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS). The Stata software (version 15.1) was used to calculate the odds ratio (OR) of dementia or cognitive impairment in sepsis survivals. Subgroup and sensitivity analyses were performed to assess the source of heterogeneity. Funnel plots and Egger’s test were used to detect the publication bias.I2 = 96.4%, p = 0.001). However, there was no obvious association between sepsis survivals and the risk of cognitive impairment . Subgroup analyses showed that severe sepsis was associated with an increased risk of dementia or cognitive impairment ; such risk was higher than that of other unspecified types of sepsis .Eight studies  involving 891,562 individuals were included. The quality assessment results showed that the average score of NOS was over 7, and the overall quality of the included studies was high. Pooled analyses indicated that sepsis survivals were associated with an increased risk of all-cause dementia (OR = 1.62, 95% CI = 1.23–2.15, Sepsis survivals are associated with an increased risk of all-cause dementia but not with cognitive impairment. Appropriate management and prevention are essential to preserve the cognitive function of sepsis survivors and reduce the risk of dementia. Sepsis is a life-threatening organ dysfunction resulting from a dysregulated host response to infection , which hDementia is regarded as a global public health problem, affecting around 50 million individuals and resulting in a cost of 1% of global gross domestic product (GDP) . It is eThere is increasing evidence that sepsis survivals are at an increased risk of developing new-onset atrial fibrillation , acute kThis study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines , and theWe systematically searched the PubMed, EMBASE, Cochrane Library, and Web of Science databases without language restrictions from their inception to November 15, 2021. The Medical Subject Headings (MeSH) terms and keywords used in the search were as follows: (“sepsis” OR “septicemia*” OR “septic shock*” OR “severe sepsis*” OR “systemic inflammatory response syndrome” OR “SIRS” OR “septic” OR “septicaemic shock”) AND (“dementia” OR “Alzheimer’s disease” OR “cognitive decline” OR “cognitive impairment” OR “cognitive disorder” OR “cognitive dysfunction”). The references of the included studies and existing systematic reviews were hand-searched to find additional relevant articles. The full search strategy is included in The included studies were required to meet the following criteria: (1) cohort or case-control study design; (2) the exposed group consisting of sepsis survivals with dementia or cognitive impairment, and the control group consisting of patients without sepsis; (3) the risk of dementia or cognitive impairment as the outcome, expressed as an adjusted odds ratio (OR); and (4) population-based study design. In this study, all types of dementia, such as vascular dementia, senile dementia, Alzheimer’s disease, and mixed dementia, were included.Exclusion criteria were as follows: (1) conference abstracts or study protocols; (2) duplicate publications; and (3) studies with incomplete data or no relevant outcome.Two reviewers (SL and XL) independently screened the literature. Initially, duplicate and irrelevant publications were excluded based on their title and abstract. Later, each of them independently read the full text of each potentially eligible article and finally identified all studies. In case of disagreement, discussions were conducted with a third investigator (JS Li) until consensus was reached.Two reviewers (SL and XL) independently extracted the following data using predesigned forms according to the guideline for data extraction for systematic reviews and meta-analysis , includiThe Newcastle-Ottawa Quality Assessment Scale (NOS)  was usedI2 value, and p < 0.1 or I2> 50% was considered to indicate heterogeneity; in such instances, the random-effects model was adopted. Otherwise, the fixed-effects model was employed. We performed subgroup and sensitivity analyses to verify the robustness of the overall results and explore the sources of heterogeneity. The funnel plots and Egger’s regression test were used to detect the publication bias.The Stata software (version 15.1) was used to conduct the data analysis. We extracted data on the adjusted OR and 95% CI from each study to assess the risk of dementia or cognitive impairment in sepsis survivals. We assessed heterogeneity using the chi-square test and n = 4) (n = 15), and articles with no related outcome (n = 1)  , confere (n = 1) . FinallyWe included eight studies  involvinThe NOS scale was used to assess the quality of the included studies, and the results are shown in I2 = 96.4%, p = 0.001; I2 = 96.4%, p = 0.000), we performed a sensitivity analysis by omitting each study to explore the source of heterogeneity and found that the overall results were relatively robust (p = 0.786) indicated a low possibility of publication bias in this meta-analysis.A total of six studies  assessedy robust . A visuay robust . The EggI2 = 97.8%, p = 0.043; Three studies  assessedI2 = 87.4%, p = 0.306; Two studies  evaluateI2 = 75.3%, p = 0.008; I2 = 97.6%, p = 0.029; Three studies  evaluateIn this systematic review and meta-analysis of observational studies, we compiled current evidence on the association between sepsis survivals and the risks of dementia or cognitive impairment in 891,562 individuals from eight population-based studies . We founThis study found that sepsis survival could increase the risk of dementia, which is consistent with the results of previous studies. Consistent with previous findings, it is noteworthy that no significant association was found between sepsis survival and the risk of cognitive impairment in our meta-analysis . HoweverSubgroup analyses showed that severe sepsis was associated with a higher risk of developing dementia than other unspecified types of sepsis, which is largely consistent with the results suggested by Only two of all included studies  showed tThe pathophysiological mechanism of the association between sepsis and dementia or cognitive impairment remains largely unclear ; neverthThe heterogeneity of the included studies was large, which may be attributed to the following reasons. The experimental data of the studies included in the analysis were small, and only two studies analyzed the relationship between sepsis and the risk of cognitive impairment, which might have affected the accuracy of the results. Therefore, studies with larger sample sizes and more cohort studies with long-term follow-up are needed to clarify the association. Furthermore, the diagnostic criteria of sepsis and dementia were inconsistent, such as ICD-9 or ICD-9-CM, or ICD-10, and the disease diagnosis mainly depended on electronic health records, which may lead to the deviation of results. In addition, the different confounders adjusted for each study may be another source of heterogeneity.To the best of our knowledge, our review is the first meta-analysis to include only studies of sepsis survivals and the risk for dementia or cognitive impairment, which may contribute to the accurate assessment of whether sepsis survivals are associated with an increased risk of dementia or cognitive impairment. Admittedly, there were several limitations in our study. First, the number of included studies was limited; thus, we could not perform subgroup analyses on the type of dementia to demonstrate the risk of different types of dementia in sepsis survivals. Second, the included studies showed significant heterogeneity in terms of study design, population size, and definitions of sepsis, dementia, and cognitive impairment. Therefore, the potential effect of heterogeneity on the results should be taken into account when interpreting our results. Third, the generalizability of the findings of the included studies should be concerned. As the studies were conducted in the United States, China, Germany, and Sweden, regional bias is a valid possibility.Sepsis survivals are associated with an increased risk of all-cause dementia but not with cognitive impairment. Appropriate management and prevention are essential to preserve the cognitive function of sepsis survivals and reduce the risk of dementia.The original contributions presented in the study are included in the article/JL and XL contributed to design and conception of the article. SL and XL contributed to collection and assembly of materials, and drafted the manuscript. SL, XL, HZ, ZF, and LC contributed to data interpretation and analysis. XL, HZ, ZF, LC, YX, and JL revised the manuscript. All authors reviewed and approved the final version 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.


Daratumumab has shown clinical benefit in multiple myeloma. We aimed to evaluate the safety and efficacy of adding daratumumab to backbone anti-myeloma treatments. Systematic search was performed up to August 2021 to identify randomised controlled trials comparing the outcomes of backbone therapy with and without daratumumab in relapsed/refractory and newly diagnosed myeloma . Odds ratios (ORs) and hazard ratios (HRs) were calculated with 95% confidence intervals (CIs). Primary outcomes were death or disease progression, minimal residual disease (MRD) negativity, and stringent complete response (sCR). Secondary outcomes were complete response or better and safety endpoints prespecified in the study protocol: PROSPERO (CRD42020222904). In NDMM, MRD negativity [OR = 3.61 (CI 2.33–5.61)] and sCR [OR = 2.29 (CI 1.49–3.51)] were more likely and death or disease progression [HR = 0.47 (CI 0.39–0.57)] was less likely to occur with daratumumab compared to control. Regarding RRMM, MRD negativity [OR = 5.43 (CI 2.76–10.66)] and sCR [OR = 3.08 (CI 2.00–4.76)] were more likely and death or disease progression was less likely [HR = 0.50 (CI 0.37–0.67)] with daratumumab compared to control. The addition of daratumumab has shown high clinical efficacy and acceptable toxicity profile for the treatment of NDMM and RRMM regarding the endpoints examined. In the early 2000s, the approval of modern therapeutic options, such as immunomodulatory drugs (IMiD) and proteasome inhibitors (PI), greatly improved the relative survival rate in MM2. Although new innovative agents have brought a considerable breakthrough, this disease’s the treatment is still a challenging pursuit because of the frequent relapses. The 5-year survival rate is only 52.2%, despite the tremendous advances and continuous evolving therapeutic strategies3 Over the past decade, monoclonal antibodies were also proved to be an essential part of the therapeutic arsenal, especially in combination with the aforementioned novel agents4.Multiple myeloma (MM) is the second most common haematologic malignancy, accounting for 1% of all cancers5.CD38 is overexpressed on myeloma cells’ surface, making this transmembrane glycoprotein a good target for immunotherapy in MM. Daratumumab is a CD38-targeted human IgG monoclonal antibody that exerts its antineoplastic effect through complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity and phagocytosis, programmed cell death after crosslinking, and inhibition of ectoenzyme function of CD386). Furthermore, new regimens including daratumumab are evaluated by ongoing clinical trials .This agent was approved as a monotherapy for relapsed MM by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2015 and 2016, respectively. Additionally, daratumumab is also indicated for combination therapy  or with lenalidomide and dexamethasone in patients who have received at least one prior therapy7. Similar benefit of daratumumab was found by Wang et al. regarding CR or better in relapsed/refractory MM (RRMM)8. In another meta-analysis, Giri et al. revealed longer PFS in patients receiving daratumumab both in NDMM and RRMM regardless of cytogenetic risk9. The publication by Cao et al. focused on RRMM. Their results also suggested that daratumumab- based therapies enhance PFS in RRMM regardless of patient's baseline characteristics or previous therapeutic agents10. Another meta-analysis also investigated the impact of cytogenetic risk on the PFS benefit provided by the addition of daratumumab. They observed an increased PFS in RRMM patients with daratumumab; however, they did not reveal benefit of that agent in high genetic risk NDMM11. Similarly to that publication, the findings of two other studies could not support the survival benefit of daratumumab in high cytogenetic risk NDMM13.Since the FDA and EMA approved daratumumab, its incorporation into myeloma treatment regimens has significantly improved the outcomes of myeloma treatment including stringent complete response (sCR) and minimal residual disease (MRD) negativity, translating to prolonged progression-free survival (PFS) and overall survival (OS) with a relatively safe toxicity profile. Recent meta-analyses have assessed the safety and efficacy of daratumumab as an addition to backbone treatments in MM. Xu et al. found that addition of daratumumab to first-line regimens  significantly improves PFS, compared to the same regimens alone, in NDMM. Furthermore, in their study, patients receiving daratumumab, compared to patients on the control arms, had a higher chance to achieve complete response (CR) rate or betterSince these studies' publication, more evidence has become available, allowing us to re-evaluate these results performing meta-analytic calculations and to assess new endpoints such as sCR or MRD negativity. Furthermore, our objective was to resolve the discrepancies between the findings in previous reports. Besides these goals, our meta-analysis aims to summarise evidence on daratumumab containing backbone regimens' safety profile compared to the same combinations without daratumumab.14. We fully adhered to our pre-study protocol registered in PROSPERO (CRD42020222904).We report this study in accordance with the PRISMA 2020 statement: an updated guideline for reporting systematic reviewsWe ran a systematic search in five electronic databases , dated from inception to August 3rd, 2021, with the query ‘(daratumumab) OR (humax-CD38) OR (humax-CD 38) OR  OR (anti-CD38) OR (antiCD38) OR (L01XC24) OR (945721–28-8) OR (DB09331) OR (4Z63YK6E0E) OR (D10777)’. No filter was applied. Reference lists of the eligible studies were also screened to identify relevant publications.15. κ values ≤ 0 were interpreted as no agreement, 0.01–0.20 as none to slight agreement, 0.21–0.40 as fair agreement, 0.41–0.60 as moderate agreement, 0.61–0.80 as substantial agreement, 0.81–1.00 as almost perfect agreement, and 1.00 as a perfect agreement15. Disagreements have been resolved by third-party arbitration.Two independent review authors assessed all records at title, abstract, and full-text level. At each level of selection, inter-rater reliability was evaluated by calculating Cohen's kappa coefficient (κ)Only randomised controlled trials (RCTs) that compared the outcomes of a daratumumab containing regimen with the same treatment without daratumumab in patients with MM were eligible for inclusion. Furthermore, eligible studies had to provide data on least one of the following outcomes in both treatment arms: death or disease progression, sCR, CR or better, MRD negativity, thrombocytopenia, neutropenia, lymphopenia, anaemia, second primary malignancy, peripheral neuropathy, hypertension, cardiac failure, ischemic heart disease, acute renal failure. If more publication reported on the same trial , the one that provided the most recent data was included in each outcome. If a study was not published in full-text article, the record was deemed ineligible for inclusion.Two independent review authors extracted the following data from the full text and corresponding supplementary information of eligible articles: study name, first author, year of publication, Digital Object Identifier (DOI), title, number of patients in the study and each treatment group, age and gender distribution, number of patients with the above-listed outcomes. For death or disease progression, hazard ratios (HRs) with the corresponding 95% confidence intervals (CIs) were extracted. If there were available data, we collected information on high- and standard cytogenetic risk subtypes. High cytogenetic risk subtype was defined as t translocation, t translocation, or 17p deletion and standard cytogenetic risk subtype as patients lacking all of these. Data on NDMM and RRMM were collected and analysed separately.16. The risk of bias assessment comprises five main domains: randomisation process, deviation from the intended intervention, missing outcome data, and selection of the reported results. These were rated as low risk, some concerns, or high risk of bias. Disagreements have been resolved by an independent third investigator.Two independent review authors evaluated the quality of the included studies using the RoB 2: a revised tool for assessing risk of bias in randomised trialsBased on the approach proposed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Working Group, the certainty of the evidence was assessed by two review authors independently with the help of GRADE profiler software . Available from gradepro.org.). Disagreements have been resolved by third-party arbitration.17. If there was an overlap between the two study populations, the study with the higher patient number was included in the analysis. Statistical heterogeneity was analysed using the I2 and χ2 tests to gain probability values; p < 0.10 was defined to indicate significant heterogeneity. The I2 test represents the percentage of total variability across studies because of heterogeneity. I2 values of 30–60%, 50–90%, and 75–100% corresponded to moderate, substantial, and considerable heterogeneity, respectively, based on Cochrane's handbook18. Forest plots displayed the results of the meta-analysis. Trial sequential boundaries for cumulative meta-analyses and the meta-analyses were performed with Stata 16 SE (Stata Corp).Pooled odds ratios (ORs) and hazard ratios (HRs) were calculated for dichotomous outcomes. A random-effect model was applied in all analyses with the DerSimonian–Laird estimationNot required as data is not individualized and primary data was not collected. Not required as data is not individualized and primary data was not collected.The corresponding author accepts responsibility for releasing this material on behalf of any and all co-authors.30. Reasons for exclusion regarding full-text assessment are provided in Appendix A. The inter-rater reliability was rated as almost perfect or perfect at all steps of selection.A total of 13,521 records were identified, 12 of which proved to be eligible for inclusion in qualitative synthesis , standard-risk , and high cytogenetic risk MM  compared to the control treatment  ; and in the case of acute cardiac failure, acute renal failure, ischemic heart disease (one non-overlapping population each) , we have not found survival benefit in patients with high cytogenetic risk MM (low certainty).One of the main objectives of treatment in myeloma patients is to improve survival, both in NDMM and RRMM. In NDMM, the addition of daratumumab was associated with increased chance for PFS in each individual RCT and in our meta-analysis as well (moderate certainty). Regardless of these promising results, genetic risk stratification is a particularly important aspect of MM. About 15% of these patients carry myeloma with a high cytogenetic risk9, which had significant results in this analysis, incorporated their results from a conference abstract of the MAIA trial32 with a higher PFS benefit in the daratumumab arm compared to the one in other two publications12 and our paper. These three meta-analyses were more conservative and included only peer-reviewed full-text publications. Secondly, although all meta-analyses used the random effect model, the weights of the included studies slightly differ among the meta-analyses regarding this analysis. It has to be noted that the meta-analysis of Mohyuddin et al. did not reveal PFS benefit of adding daratumumab in high cytogenetic risk NDMM13; however that study did not use the HRs provided by the original publication and recalculated them from raw data. This resulted HRs that differed much from the ones calculated by the studies included. Thirdly, the four papers with neutral results used PFS values from more similar median follow up times  and the one with significant PFS benefit in this population used HR from the MAIA trial with a median follow up of 36.4 months. This heterogeneity could also contribute to the difference between previous publications and reflect on the long term PFS benefit of daratumumab. However, regardless of the discrepancy in these findings, our TSA analysis confirmed that the statistical power was insufficient in this subgroup analysis, it seems to be early to preclude the benefit on this outcome.The results about PFS benefit of daratumumab in high cytogenetic risk NDMM are controversial in the previous meta-analyses. We identified some possible explanations of this. Firstly, the paper of Giri et al.In RRMM, PFS benefit was also observed in the daratumumab group (low certainty). This benefit was also found in the standard cytogenetic risk (low certainty) and in the high cytogenetic population (moderate certainty) as well. Therefore, our finding supports the incorporation of daratumumab regardless of the results of the cytogenetic assessment.33. Based on this meta-analysis, patients on daratumumab have a better chance of achieving CR or better compared to control in NDMM (low certainty) and RRMM (moderate certainty). As modern therapeutic strategies led to deeper therapeutic response, sCR became an essential surrogate for survival endpoints34. Kapoor et al. found that patients achieving sCR had longer time to progression and longer OS after transplantation than those who only achieved CR, which underlines the prognostic significance of sCR34. Concerning sCR, we found that it is more likely to be achieved both in NDMM (low certainty) and RRMM patients (moderate certainty) receiving additional daratumumab compared to controls.Several studies support that a better therapeutic response translates into longer PFS and OS in MM35. Several studies have confirmed that MRD negativity is associated with improved survival both in patients with NDMM  and RRMM 29. In RRMM, MRD-negativity rates favoured daratumumab arm (moderate certainty). Regarding NDMM patients, the same associations were observed, and our pooled analyses support that the addition of daratumumab increases the chance of achieving MRD negativity (low certainty).Detection of MRD is emerging as an important tool to assess the efficacy of treatments in MM36 as the target of this antibody is expressed on haematopoietic cells37. In NDMM, both all grade and grade 3–4 lymphopenia (moderate certainty) and neutropenia (low certainty) were more likely to appear in patients on daratumumab. These were consistent with our RRMM population results; however, the chance for all grade thrombocytopenia and grade 3–4 thrombocytopenia was also found to be increased (low certainty). Regarding the likelihood of anaemia, no difference was demonstrated.Despite the enhanced cytotoxicity on myeloma cells, better survival results, and therapeutic response, safety concerns arise37. A previous meta-analysis demonstrated that the risk for peripheral neuropathy does not increase with the addition of daratumumab36. This study covered the literature until June 2019. Now all of their eligible studies have updated results; therefore, we could re-evaluate their findings and perform analyses on all grade and grade 3–4 neuropathy separately. Our results also support their finding.Besides the bone marrow, other tissues, like peripheral and central neurons, also express CD38 which could raise clinical concern38. In a population-based study of Sweden, the incidence of second primary malignancy was 5.5% after a median follow-up of 2.5 years39. These disorders mostly consist of mostly acute leukaemia or myelodysplasia and their incidence is about 2.19 times higher in MM compared to the general population39. Htut et al. found no increase in the incidence of second primary malignancies after the addition of daratumumab to backbone therapies36. We support their finding (very low certainty). However, as they pointed out, long-term follow-up results are required to confirm this observation.With the increasingly longer survival of MM, second primary malignancies gained more significance29. This enabled us to re-evaluate their results and to assess new endpoints such as MRD negativity and sCR and to evaluate RRMM with subgroup analyses, which have not been included in a meta-analysis yet. There are limitations in this meta-analysis, including that different backbone regimens are evaluated in the individual RCTs. This issue was addressed by lowering the level of evidence due to indirectness in each evaluation. As the Trial Sequential Analyses have pointed out, some assessments are exposed to the possibility of imprecision. The overall risk of bias was generally ‘low’; however, certain domains had ‘some concern’ evaluation. Publication bias could not be assessed because the number of studies included in each analysis was insufficient for statistical analysis.This study has multiple strengths and limitations. First of all, the research was conducted with rigorous methodology adhering to the latest methodological recommendations and we reported our analyses transparently. Furthermore, our results are consistent with previous meta-analyses on the topic. Nevertheless, many of new publications on the subject emerged since these reviews were published, counting the longer follow-up data for the studies included in the precedent meta-analyses and the results of the GRIFFIN trial, the LEPUS trial, and the APOLLO trialImplication for practice: our results support incorporating daratumumab in backbone therapies in MM which was associated with better therapeutic response and survival and favourable safety profile both in NDMM and RRMM.Implication for science: additional studies are needed to specify further the population that gains the most benefits from this treatment, especially in high cytogenetic risk NDMM, where the OIS was not reached.Daratumumab has shown high clinical efficacy and acceptable toxicity profile for the treatment of both NDMM and RRMM for the endpoints examined.Supplementary Information 1.Supplementary Information 2.Supplementary Information 3.


Background and Aims: The dietary inflammatory index (DII) is associated with non-communicable disease. We conducted an umbrella review to systematically evaluate meta-analyses of observational studies on DII and diverse health outcomes.Methods: We comprehensively searched the PubMed, Web of Science, and Embase databases to identify related systematic reviews and meta-analyses of observational studies. Those investigating the association between DII and a wide range of health outcomes in humans were eligible for inclusion. For each meta-analysis, we estimated the summary effect size by using fixed and random effects models, the 95% confidence interval, and the 95% prediction interval. We assessed heterogeneity, evidence of small-study effects, and excess significance bias.Results: The umbrella review identified 35 meta-analyses assessing associations between DII and various health outcomes: cancer (n = 24), mortality (n = 4), metabolic (n = 4), and other (n = 3). The methodological quality was high or moderate. Of the 35 meta-analyses, we observed highly suggestive evidence for harmful associations between digestive tract cancer, colorectal cancer, overall cancer, pharyngeal cancer, UADT cancer, and CVD mortality. Moreover, 11 harmful associations showed suggestive evidence: hormone-dependent cancer, rectal cancer, colon cancer, breast and prostate cancer, gynecological cancer, breast cancer, ovarian cancer, colorectal cancer, prostate cancer, all-cause mortality, and depression.Conclusion: DII is likely to be associated with harmful effects in multiple health outcomes. Robust randomized controlled trials are warranted to understand whether the observed results are causal.Systematic Review Registration: CRD42021218361 The dietary inflammatory index (DII) is a new dietary index developed to reflect the inflammatory potential of diet. It scores an individual's diet on a continuum from anti- to pro-inflammatory. This scoring system is based on the results of scientific publications rather than population means or recommended intakes. The literature includes studies on the relationships among dietary factors—including foods, nutrients, and other bioactive compounds—and six inflammatory biomarkers: C-reactive protein, interleukin (IL)-1b, IL-4, IL-6, IL-10, and tumor necrosis factor-α . The indIn this context, we performed an umbrella review of the evidence through current systematic reviews and meta-analyses of observational studies, to provide an overview of the range and validity of the published relationships between DII and health-related outcomes. We summarized the multiple health outcomes that have been associated with DII in meta-analyses, assessed the diverse bias in these meta-analyses, and identified which of the previously studied associations are supported by the strongest epidemiological evidence.Umbrella reviews perform in-depth evaluations of the quantitative results of meta-analyses of observational associations and the potential bias in these meta-analyses. Umbrella reviews comprehensively and systematically search and evaluate existing systematic reviews and meta-analyses and can readily be used by decision-makers in healthcare to understand a broad topic field .We systematically searched PubMed, Embase, and the Web of Science from inception until August 8, 2020, to identify systematic reviews and meta-analyses examining the association between DII and any health outcome. The search terms included DII, dietary inflammatory score, dietary score, inflammatory diet, inflammatory potential of diet, dietary inflammation potential, inflammatory potential intake, anti-inflammatory diet, pro-inflammatory diet, dietary pattern, diet-related inflammation, index-based dietary patterns, or DII, combined with systematic review or meta-analysis . We alsoStudies were included if they met the following criteria, established by using the PICOS strategy:Population: adults.Intervention/comparison: the DII .Outcomes: health outcomes .Study design: meta-analyses of observational studies .In addition, if an article performed different meta-analyses on more than one health outcome, each analysis was assessed separately. When two or more meta-analyses were available on the same scientific question, the one including the largest number of studies was selected.Studies were excluded if they met the following criteria, established by using the PICOS strategy:Population: non-adults.Intervention/comparison: not DII.Outcomes: any other outcome outside of the inclusion criteria.Study design: systematic reviews of observational studies without quantitative analysis, meta-analyses not reporting comprehensive data , or meta-analyses including primary studies are <3.Two independent authors (F-HL and MZ) extracted data from each eligible meta-analysis, and disagreements were resolved by the third author (Q-JW). First-author name, publication year, journal, number of total studies, study design, method of exposure ascertainment , and outcomes were abstracted from each included meta-analysis. From each observational study included in the meta-analysis, we further recorded the name of the first author, publication year, number of cases and controls (case–control study), sample size, measure of exposure , specific risk estimates, and 95% CIs.P-values by using both fixed- and random-effects models  included in a meta-analysis was larger than the expected number (E), by using the excess statistical significance test  was considered to indicate excess statistical significance for each meta-analysis  with nominally significant results  as convincing, highly suggestive, suggestive, weak, or non-significant associations. We considered convincing associations to have a statistical significance of P < 10−6 in a random-effects model based on >1,000 cases , P < 0.05 for the largest component study, a 95% PI excluding the null value, no heterogeneity (I2 < 50%), and no evidence of small-study effects (P > 0.10) or excess significance bias (P > 0.10). Highly suggestive evidence had a significance threshold of P < 10−6, a number of cases >1,000 , and a statistically significant effect observed in the largest study. Suggestive evidence was indicated by >1,000 cases  and P < 10−3 for random effects. Weak evidence was indicated by P < 0.05 for a significant association. No association was indicated by a P-value not reaching the significance threshold (P > 0.05).According to previous umbrella reviews , 23, we Association does not necessarily indicate causation. For associations with convincing or highly suggestive evidence, we performed a sensitivity analysis of only prospective cohort studies to investigate the temporality of the relationship between DII and any health outcome. All analyses were conducted in STATA, version 12.0.Overall, 10,154 publications were retrieved through the database search, and 45 were deemed eligible. Twenty-nine publications were excluded after full-text screening for different reasons . The finn = 2) and depression (n = 1). Twenty-eight meta-analyses compared the highest vs. lowest DII score, and seven meta-analyses reported health effects associated with a one-unit increase in DII score.P < 0.05 in 31 (89%) meta-analyses, whereas the summary fixed effects estimates were significant in 32 (91%) meta-analyses. When P < 0.001 was taken as a threshold for significance, 21 (60%) and 29 (83%) meta-analyses generated significant summary results according to the random and fixed effects models, respectively. However, when a more stringent threshold of significance (P < 1 × 10−6) was applied, the summary random effects estimates were significant in nine (26%) meta-analyses, and the summary fixed effects estimates were significant in 20 (57%) meta-analyses  of 35 meta-analyses.The effect of the largest study included in each meta-analysis is reported in our analysis . Twenty-I2 < 50%), 13 (37%) meta-analyses showed high heterogeneity (I2 = 50–75%), and 13 (37%) showed very high heterogeneity (I2 > 75%)  showed low heterogeneity (2 > 75%) . When 952 > 75%) .Evidence of small-study effects was observed in 19 (54%) of 35 meta-analyses on the basis of Egger's test . When taAmong the 16 articles included in our umbrella review, only two (13%) were rated as high quality (≥8 points) and 14 (87%) were defined as moderate quality (4–7 points), according to the AMSTAR criteria . In summWe performed a sensitivity analysis for associations supported by convincing and highly suggestive evidence, which was limited to meta-analyses of prospective cohort studies. Of the five associations included, three further associations met the criteria for highly suggestive evidence: the effect of DII on colorectal cancer (DII as a continuous variable), overall cancer, and CVD mortality. Two associations between DII and digestive tract cancer and overall cancer (DII as continuous variable) were downgraded to suggestive evidence .The present study is the first umbrella review to quantitatively estimate the existing evidence of the associations between DII and multiple health outcomes, including cancer, mortality, metabolic, and other outcomes . We provided a comprehensive overview of the current meta-analyses of observational studies and examined the methodological quality of the included meta-analyses and the quality of evidence for all these associations.The umbrella review comprised 16 published meta-analyses on a total population of more than 5.6 million participants. The methodological quality of the included meta-analyses was high/moderate. Highly suggestive evidence was observed for seven outcome variables, including digestive tract cancer, colorectal cancer, overall cancer, pharynx cancer, UADT cancer, and CVD mortality. Eleven outcomes associated with higher DII scores presented suggestive evidence. Additionally, 11 associations were supported by weak evidence.The most notable associations identified in our umbrella review were those between DII and diverse cancers; harmful associations of DII with digestive tract cancer, colorectal cancer, overall cancer, pharynx cancer, and UADT cancer were observed. Our results were in accordance with those of prior studies. A population-based multi case–control study in Spain  showed tWe found highly suggestive evidence that higher DII scores are associated with a higher risk of CVD mortality. Our results are in line with those from a published meta-analysis comprising 42,000 participants and 1,000 CVD cases, in which a higher DII score was found to increase the risk of CVD mortality . HoweverFurthermore, we observed suggestive evidence of a positive association between DII and depression. This association did not meet our criteria for convincing evidence, mainly because of the relatively low statistical significance. A systematic review examining DII and the risk of depression, published in 2019, has also reported that higher DII is associated with a higher risk of depression . Pro-infThis umbrella review is the first to provide a comprehensive critical appraisal of published systematic reviews and meta-analyses on all health outcomes for DII. In addition, we searched three databases through a rigorous strategy, and two authors independently extracted the information. Moreover, we used the AMSTAR criteria to assess the methodological quality of selected in our umbrella review, and all investigated meta-analyses achieved a moderate-to-high quality score, thereby suggesting that current meta-analyses evaluating the effects of the DII on health outcomes partially or almost fully complied with standards of methodological quality. We used the criteria of evidence grading to evaluate the evidence categorization.I2 < 50% as a criterion for convincing evidence, to assign the best grade of evidence to only robust associations without heterogeneity. Unfortunately, many of the meta-analyses included in our umbrella review showed high or very high heterogeneity. Second, fewer than 10 original studies were included in most (74%) of the meta-analyses in our study, thus potentially decreasing the power of Egger's tests and excess significance tests (Nevertheless, some limitations of our study must be discussed. First, assessment criteria for credibility, which were based on established tools for observational evidence, were used in our umbrella review. Although none of the components of the assessment criteria presented definite evidence of absence of reliability, they together indicated the susceptibility of the results to uncertainty and bias. To account for the discrepancies in the populations, study designs, or other characteristics of the studies included in the meta-analyses, we used an ce tests . Moreovece tests  to calcuce tests , which sce tests . HoweverIn summary, highly suggestive evidence exists for associations between DII and digestive tract cancer, colorectal cancer, cancer, pharynx cancer, UADT cancer, and CVD mortality. Although DII may be associated with an increased risk of other health outcomes, their relationships are uncertain according to our study. In the future, better designed studies are necessary to generate definite conclusions, and the association between inflammatory markers and health outcomes in a given population must be investigated.The corresponding author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.The data supporting the conclusions of this article can be directed to the corresponding author/s.Q-JW, SG, and Y-HZ conceived the study. F-HL, SG, and T-TG contributed to the design. F-HL and MZ conducted the literature search, literature screening, and extracted the data. HS, Y-TJ, and J-YZ performed the quality assessment. X-YL and CG performed the statistical analysis. F-HL and T-TG wrote the first draft of the paper. CL revised the manuscript for important content. SG is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria were omitted. All authors interpreted the data, read the manuscript, and approved the final vision.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.