The association between psoriasis and the risk of aortic aneurysm is still unclear.Patients with psoriasis have a higher risk of aortic aneurysm than healthy individuals.PubMed, Embase, and Scopus from inception to 20 July 2019 were searched. We included cohort studies if they reported estimate effects on the risk of aortic aneurysm in patient with psoriasis. We used Newcastle‐Ottawa Scale to evaluate methodology quality of eligible studies. Random‐effect meta‐analyses were used to estimate the overall risk. Subgroup analyses were conducted for analysis of influencing factors.I2 = 53.1%). The risk is not statistically different between patients with severe psoriasis  and patients with mild psoriasis . The risk was not statistically increased in female patients , patients ≥50 years old , and patients with diabetes .After a view of 2207 citations, we included three large cohort studies enrolling 5 706 525 participants in this systematic review. Psoriasis patients have an increased risk of development of aortic aneurysm (hazard ratio [HR]: 1.30, 95%confidence intervals [CI], 1.10‐1.55, Current evidence from observational studies suggests that psoriasis increases the risk of aortic aneurysm, and screening of aortic aneurysm might be considered among psoriasis patients. Chronic aortic vascular inflammation is believed to lead to destruction of the aortic media and to vascular smooth muscle cell dysfunction as a result of the release of a range of proteolytic enzymes, such as matrix metalloproteinases and cysteine proteases, oxidation‐derived free radicals, cytokines, and related products.22.1The systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) guidelines. We conducted a systematic search on PubMed, Scopus, and Embase for relevant full‐text articles published before July 20, 2019. We did not set any language limitation in the literature search. Search terms  authors, (b) published year, (c) participants, (d) exposure, (e) definition of psoriasis severity, (f) outcomes, (g) controls, (h) follow‐up, (i) unadjusted and adjusted estimates with corresponding 95% confidence interval (CI), (j) adjustment of covariates, and (k) baseline characteristics of study population .2.4We applied the Newcastle‐Ottawa Scale (NOS) to appraise the methodological quality of included studies. The scale is a scoring system covering three perspectives of methodology: selection of study population; comparability; and ascertainment of outcome and exposure. We did not exclude any study on the basis of quality appraisal. Two investigators (Xinyu Yu and Xin Feng) individually assessed the quality of eligible studies, and a senior investigator (Shiyi Cao) solved the discrepancies.2.5I2) test.I2 values ranged from 0% to 100% and I2 < 50% was considered as low heterogeneity, and I2 value 50% to 75% as moderate heterogeneity, and I2 > 75% as statistically high heterogeneity. When we analyzed the overall risk of AA in patients with psoriasis and the overall HR was not provided, we used fixed‐effect meta‐analysis to calculate overall HR from separate HR. Due to the limited number of included study, we did not conduct a sensitivity analysis. We performed subgroup analyses to find whether other factors  influence the final estimates. We conducted a meta‐regression analysis to test the difference between subgroups. We used Student t test to compare the differences in mean values between two groups, and we conducted Chi‐square test to evaluate the significant difference of baseline factors in two groups. All P value were two‐tailed and P < .05 was set as the significance level. All analyses were conducted in Stata version 14.0 and forest plots were prepared in R version 3.6.1.Unadjusted and adjusted hazard ratios (HRs) with corresponding 95%CI were extracted from included studies. We used adjusted HRs to reduce the impact of confounding factors on estimate effects. There was obvious heterogeneity in study methodology and definition of psoriasis severity between included articles. Therefore, we just used random‐effect meta‐analysis to evaluate the risk of AA in groups with psoriasis. Statistical heterogeneity was quantified by using the inconsistency index I2 test.133.1The searching strategy is displayed in Figure 3.2I2 = 53.1%) for the risk of AA in patients with different degrees of psoriasis. Increased risks of AA were also observed in patients with mild  and severe  psoriasis. There was no significant difference between risks of these two groups (P = .278).Forest plots of meta‐analyses were prepared as shown in Figure 3.3I2 = 97.3%), and patients with diabetes .According to the subgroup analysis Table , psorias4This is the first systematic review and meta‐analysis to estimate the risk of AA in patients with psoriasis considering the effect of disease severity of psoriasis on the risks. It showed that psoriasis patients are more susceptible to AAs compared to the general population, and the risk does not increase with the severity of psoriasis. Moreover, the association was not significant in female patients, patients ≥50 years old and patients with diabetes.There was low to moderate statistical heterogeneity within meta‐analyses and subgroup analyses. Definitions and inclusion criteria of exposure and outcome were slightly different between included studies (see Supplementary Table 18FDG‐PET/CT,Psoriasis is an immune‐mediated inflammatory disease associated with cardiometabolic comorbidities.From a preventive point of view, AA screening is strongly suggested recently.When interpreting results of this systemic review, several strengths and limitations should be considered. We conducted subgroup analyses to test the robustness of the results, and we found that age, gender, and comorbidities affect the association. However, we failed to conduct sensitivity analyses and a meta‐regression of influencing factors for lack of enough studies. There is moderate heterogeneity in meta‐analyses and subgroup analyses, and results of this systematic review should be interpreted carefully.5Our findings indicate a higher incidence of AA in patients with psoriasis compared to the general population, and the risk does not increase with the disease severity of psoriasis. Whether AA screening is effective and feasible in patients with psoriasis still requires further research.The authors declare no potential conflict of interest.Supplementary Table 1 Newcastle‐Ottawa scale for assessing the methodological quality of included studiesSupplementary Table 2. Baseline characteristics of the study populationPRISMA check listClick here for additional data file.


MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis.A common genetic variant near We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models.pz = 4.8×10–5) and diagnosis of NAFLD  in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis  in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (pz = 0.002) and lower serum triglycerides (pz = 1.5×10–4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD.Data from 1,066,175 participants  across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI  was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including ‘cirrhosis’). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change (‘variant’) in one gene  to assess the role of rs641738C>T near •rs641738C>T positively associated with liver fat, ALT, fibrosis and HCC.•rs641738C>T negatively associated with serum triglycerides.•Consistent associations found in studies of Caucasian populations only. Since the first genome-wide association study (GWAS) of liver fat,O-acyltransferase domain-containing 7 (MBOAT7) was initially identified as a genome-wide significant risk variant for alcohol-related cirrhosis ,,PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), and 17β-hydroxysteroid dehydrogenase type 13 (HSD17B13), it was not identified to have genome-wide significance for liver fat or serum alanine aminotransferase (ALT).,,rs641738C>T near membrane-bound MBOAT7, which belongs to a family of genes that encode specific acyl donors and acceptors.MBOAT7 encodes lysophosphatidylinositol acyltransferase 1 (LPIAT1), which contributes to the regulation of free arachidonic acid in cells.,MBOAT7 at both the mRNAMBOAT7.Rs641738 is located a few hundred base pairs downstream of the 3′-untranslated region of p = 0.005). Follow-up studies of European subjects corroborated the initial findings, and suggested a role in development of HCC.,,In NAFLD, the rs641738C>T variant was first demonstrated to be associated with increased hepatic fat content and severity of fibrosis in individuals of European descent.MBOAT7 cause autosomal recessive mental retardation 57 (Online Mendelian Inheritance in Man #617188) and no liver phenotype has been reported in these patients to date.,MBOAT7 are associated with HCC in NAFLD.In addition, bi-allelic loss-of-function mutations in MBOAT7 were to be investigated as a drug target in NAFLD.In summary, the association between rs641738C>T and hepatic fat content, as well as its effects on severity of NAFLD, remain unclear. Moreover, the broader metabolic effects of this SNV, including its association with markers of insulin resistance and dyslipidaemia, have not been assessed. Understanding the broader metabolic effects of rs641738C>T is important if Here, we conducted a large meta-analysis to determine whether rs641738C>T influences the development or stage of NAFLD and related traits.Two data sources were included in the meta-analysis: (i) studies that looked at the effect of the variant on traits of interest by genotyping the variant; and (ii) look-up from GWAS of traits of interest.MBOAT7 or membrane-bound-o-acyltransferase) or (rs641738 or rs626283) or (TMC4)’. In addition, HuGe Navigator Phenopedia was searched using terms related to liver disease , with inclusion/exclusion criteria applied to potentially eligible full texts.www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018105507).HuGENet guidelines2 >0.98 in European and American populations2 = 0.92 in Guzman et al.in vitro studies and investigations involving animals, fish and invertebrates were excluded. Studies that investigated liver disease of other aetiologies were also excluded. There was no restriction on ethnicity or ancestry. The types of study eligible for inclusion were case-control, cohort, GWAS, systematic reviews and meta-analyses. Preprint and abstract publications were not eligible for inclusion. Several studies reported on the same cohort (or patient sample) in more than 1 article. In these instances, data only from the larger of the overlapping cohorts were included in analyses. A full list of overlapping cohorts and articles is provided in Studies were included if genotyping of rs641738C>T [or rs626283G>C  was evaluated as a dichotomous variable where radiological , MRI, and proton density fat fraction (PDFF). Non-invasive assessment of hepatic fat content was also assessed using semiquantitative scoring in the Fenland cohort, as previously described,Individual participant-level histology data were extracted according to the NASH Clinical Research Network scoring systemParticipant demographics and characteristics meta-data were collected from each study, including sex, age, ethnicity, presence of type 2 diabetes mellitus (T2DM), and body mass index (BMI). Where possible, individual patient-level data were obtained.The authors of 59 studies were contacted for additional data or clarification, of whom 49 replied. Data from 11 potentially relevant studies could not be included, which are listed in the Additional details regarding cohorts with genome-wide data, the Avon Longitudinal Study of Parents and Children (ALSPAC)Database searches identified 1,167 articles , of whicIn total, 1,066,175 individuals  were included in the meta-analysis. Most studies were in adults  and in individuals from predominantly Caucasian populations . Of the 42 studies included, 14  reported data on liver histology.,,Studies were generally of high quality, although, in 5 studiesOne previous meta-analysis was included,pz = 4.8x10–5) standard deviations in inverse-normalised liver fat  reported data on hepatic fat as a continuous variable assayed by CT or MRI. On meta-analysis, rs641738C>T was associated with higher liver fat in studies in Caucasian populations using an additive model of inheritance, with a per T-allele change of β 0.034 (95% CI 0.018–0.051), iver fat , whereasGiven the difference in sensitivity and specificity of modalities used to assess liver fat, a subanalysis by modality of imaging was performed. No significant differences were observed between studies using CT, MRI, or MRS for quantification of liver fat .pz = 0.08; A similar trend was observed using CAP and semiquantitative ultrasound to assess steatosis severity in 12,224 adults  using a recessive model of inheritance (pz = 0.003). Subgroup analysis by modality of diagnosis found that the 95% CIs for all modalities overlapped, except for MRI-PDFF, which had only 1 study (pz = 0.0017) using a recessive model of inheritance.Data from a range of diverse modalities were used to assess the effect of this variant on the diagnosis of NAFLD, to reflect real-world diagnostic practice. rs641738C>T was associated with NAFLD as a trait  and when using the Trim and Fill method to account for this bias, the positive association remained but was attenuated  bias (vs. S3) on liver biopsy  showed that rs641738C>T was not significantly associated with the presence of severe steatosis  found that rs641738C>T was not associated with the presence of NASH on biopsy in adults , showed a borderline positive association with rs641738C>T in Caucasian populations , using an additive genetic model.Liver biopsy data on the presence of advanced fibrosis were available from 8 studies . Our primary outcome, presence of advanced fibrosis in adults (stage F0–F2 vs. F1–F4) was also borderline positively associated with rs641738C>T overall  as well as in non-Caucasian populations as a subgroup  found that the presence of any fibrosis (F0 subgroup .vs. CT + TT) of inheritance  reported on the development of HCC in patients with NAFLD. rs641738C>T was associated with increased odds of HCC in NAFLD only when using a dominant model (CC pz = 0.002), which was observed in Caucasian populations but not in non-Caucasian populations on subanalysis  were available for meta-analysis to investigate the effect of rs641738C>T on ALT. The variant showed a positive association with ALT  increase in untransformed ALT: 0.18 IU/L higher ALT per T-allele in this variant  was +0.32 IU/L , rs641738C>T was not found to be significantly associated with a change in ALT; for example, the mean difference using a recessive model (CC + CT pz = 1.5×10–4), which was observed in Caucasian populations but not in non-Caucasian populations on subanalysis  found that rs641738C>T was associated with lower triglycerides , which was not observed in non-Caucasian populations  found rs641738C>T to be positively associated with total cholesterol in Caucasian populations  were used in the meta-analysis. rs641738C>T was not significantly associated with the diagnosis of NAFLD, liver fat content, stage of liver histology, or serum biochemistry in children .vs. NAFL  and presence of fibrosis lipid metabolism, conceptually similar to other SNVs at GWAS significance in alcoholic and non-alcoholic liver disease, namely TM6SF2 and PNPLA3. Later studies found the variant to influence the full spectrum of fatty liver disease, from steatosis to NASH, to fibrosis, cirrhosis, and HCC.,A 2-stage GWAS initially identified rs641738C>T as a genome-wide significant locus for alcohol-related cirrhosis.PNPLA3 p.I148M and TM6SF2 p.E167K, the 2 strongest steatogenic variants.PNPLA3, HSD17B13, mitochondrial amidoxime reducing component 1 (MTARC1), and TM6SF2. This might account for the absence of this variant (or others near MBOAT7) from GWAS for NAFLD in the general population.,,,,p value) was too small to be identified as significant genome-wide. The marginal positive effect on hepatic triglyceride content suggests that this variant acts through alterations in the composition as well as quantity of hepatic lipid.We found that rs641738C>T was associated with higher liver fat content, higher ALT, and with higher odds of NAFLD diagnosis, fibrosis, and HCC, particularly in Caucasian adults and in the homozygous ‘TT’ genotype. The effect sizes of rs641738C>T reported here are small compared with those of MBOAT7. Results from the GTEx Consortium showed a strong negative association with T-allele,et al.MBOAT7 protein expression correlated with mRNA in liver biopsies from Mancina et al.,et al.MBOAT7 encodes LPIAT1, a 6-transmembrane domain protein involved in acyl-chain remodelling of membranes that influence intracellular membrane composition and circulating phosphatidylinositols.MBOAT7 as the causal gene for this SNV.The function of this variant is still relatively poorly understood and there is conflicting evidence as to whether rs641738C>T is associated with changes in the hepatic expression of MBOAT7 is the causal gene underlying the association with liver disease at the locus is supported by the observation that mice deficient for MBOAT7 have altered hepatic concentrations of polyunsaturated phosphatidylinositol.MBOAT7 (but not TMC4) increases the severity of NAFLD in mice fed a high-fat diet.,The hypothesis that e.g. for liver fat and ALT). Other genetic variants are known to impact all-cause mortality in a recessive manner, notably variants that perturb homeostatic iron regulator protein (HFE).These analyses suggest that rs641738C>T impacts the severity of NAFLD through a recessive model of inheritance, although some analyses using an additive genetic model were suggestive of a role ,We found no evidence of an effect of rs641738C>T on insulin resistance (the key driver of hepatic steatosis) as determined by unaltered fasting insulin concentrations. GWAS meta-analyses of T2DM have implicated p.I148M in et al.A strength of this meta-analysis is the large number of individuals with liver biopsy-derived phenotypic data as well as the use of population-based GWAS data. The larger number of included studies and participants is likely to account for the different conclusions reached in this study compared with the previous meta-analysis by Xia An important practical consideration is the population frequency of this variant in different ethnicities. The mean allelic frequency of the effect (T) allele is highly variable: from 0.24 in East Asians compared with 0.53 in those of South Asian ancestry.Although this analysis did include data from individuals of multiple ethnicities (and genetic ancestries), we only found evidence of an effect of this variant in Caucasian individuals. This is consistent with the initial discovery and it is likely that rs641738C>T is a proxy for the true causal variant. However, because of differences in patterns of linkage disequilibrium, we cannot exclude the possibility that a different nearby locus is associated with liver-related phenotypes in individuals of other genetic ancestries.e.g. with advanced fibrosis) in children, the analyses did not show a trend congruous with those in adults. Paediatric NAFLD has a different histological phenotype to that of adults  and, therefore, it is plausible that this is a true lack of association in children with NAFLD.A limitation of using meta-analysis for a single variant is the lack of adjustment for population stratification. When further genome-wide data are available, a formal GWAS meta-analysis might be able to address this. We found significant differences between adult and paediatric histological analyses. Although there were fewer clinical events (e.g. CT), we have underestimated the effect size associated with this variant.Data from multiple diagnostic or imaging modalities were combined in several analyses. Although we observed minimal heterogeneity between modalities, these techniques have differing accuracy for the diagnosis of steatosis, which has the potential to affect results. The subgroup analysis of hepatic fat by modality suggested a marginally greater effect size in studies using MRS, which is regarded as a highly sensitive technique. There is potential that, through the inclusion of other modalities , a European Paediatric Research Society award and a 10.13039/501100000290Children's Liver Disease Foundation grant. The EU-PNAFLD is supported by an EASL Registry Grant. 10.13039/100000002NIH grants: R01HD028016 (S.C.), R01DK111038 (S.C)., R01DK114504 (N.S.), DK091601 (J.K.D.) and UL1TR001105 (J.K.). Supported by the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) of the 10.13039/100000062National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ; the 10.13039/100006108National Center for Advancing Translational Sciences ; and the 10.13039/100000062NIDDK . This study was supported by the German Federal Ministry for Education and Research (BmBF) through the Livers Systems Medicine (LiSyM) project. This work was supported by grants from the Swiss National Funds (SNF no. 310030_169196) and the 10.13039/501100011595Swiss Foundation for Alcohol Research (SSA) to F.S. This Raine Study was supported by the 10.13039/501100000925National Health and Medical Research Council of Australia . The UK 10.13039/501100000265Medical Research Council and 10.13039/100004440Wellcome (grant ref: 102215/2/13/2) and the 10.13039/501100000883University of Bristol provide core support for ALSPAC. ALSPAC GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. A comprehensive list of grants funding is available on the ALSPAC website ; this research was specifically funded by grants from 10.13039/501100000265MRC and 10.13039/501100000280Alcohol Research UK (MR/L022206/1) and 10.13039/100000002NIH (5R01AA018333-05) to K.W.M.A. and M.H. L.V. was supported by MyFirst Grant 10.13039/501100005010AIRC n.16888, Ricerca Finalizzata Ministero della Salute RF-2016-02364358, Ricerca corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico. German 10.13039/501100002347Federal Ministry of Education and Research (BMBF LiSyM 031L0051 to F.L.). P.L. is supported by grants from the 10.13039/501100006306Sigrid Jusélius Foundation and the 10.13039/501100009708Novo Nordisk Foundation. The Fenland study was funded by grants to the MRC Epidemiology Unit . R.B. and M.K. are employees of and shareholders in Perspectum Diagnostics Ltd. C.A.P. is funded by a 10.13039/100010269Wellcome Trust Clinical PhD Programme (206274/Z/17/Z). J.M.B. is supported by the Spanish 10.13039/501100004587Carlos III Health Institute  co-financed by 10.13039/501100008530Fondo Europeo de Desarrollo Regional (FEDER) and La Caixa Scientific Foundation (HR17-00601). Research from the GUARDIAN Study was supported DK085175 and DK118062, and phenotyping in IRASFS was supported by HL060944, HL061019, HL060919 and HL060894 IRASFS from the 10.13039/100000062National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). H.Y. is funded by a 10.13039/501100000361Diabetes UK RD Lawrence fellowship (17/0005594). Q.M.A. and A.D. supported by the 10.13039/501100009058EPoS (Elucidating Pathways of Steatohepatitis) consortium funded by the 10.13039/501100007601Horizon 2020 Framework Program of the 10.13039/501100000780European Union under Grant Agreement 634413. Q.M.A., A.D., L.V. and A.G. are members of the LITMUS (Liver Investigation: Testing Biomarker Utility in Steatohepatitis) consortium funded by the 10.13039/501100000780European Union10.13039/501100010767Innovative Medicines Initiative 2 (IMI2) Joint Undertaking under grant agreement 777377. Q.M.A. is a Newcastle 10.13039/100006662NIHR Biomedical Research Center Investigator.J.P.M. is supported by a Study concept and design: J.P.M.; acquisition of data: all; analysis and interpretation of data: K.T., J.K., S.S., L.V., J.P.M.; drafting of the manuscript: K.T., J.P.M.; critical revision of the manuscript for important intellectual content: all authors; statistical analysis: K.T., J.K., S.S., L.V., J.P.M.; obtained funding: J.P.M., S.C., N.S., J.K.D., J.K., P.L., J.M.B., C.A.P., H.Y., K.W.M.A., L.A., Q.M.A., A.D.K., T.B., G.S.G., C.H., J.H., J.L., P.E.M., T.A.M., N.D.P., S.R., J.I.R., E.K.S., S.S., A.T.H., L.E.W., L.V., H.Y.J., K.A.Y.; study supervision: J.P.M.C.E. reports receiving personal fees from Navitor Pharma and Novartis. The other authors declare no conflicts of interest that pertain to this work.Please refer to the accompanying


XRCC1 (X-ray repair cross-complementing protein 1) expression and its single nucleotide polymorphism XRCC1 rs25487 (G>A) may be related to radiotherapy-related cancer prognosis or radiation-induced side effects. However, this association is controversial. We performed a bioinformatic analysis and a meta-analysis to obtain comprehensive results.TCGA data sets and eligible publications published before November 31, 2020 were retrieved by searching the PubMed, Web of Science and CNKI  databases. ORs (odds ratios) and HRs (hazard ratios) with their corresponding 95% CIs  were calculated to evaluate associations. For XRCC1 single nucleotide polymorphisms, we employed three types of comparisons: GA vs GG, AA vs GG and GA+AA vs GG.Sixty nine articles with 10232 patients and 17 TCGA data sets with 2705 patients were included in the analysis. We observed that high XRCC1 expression was associated with an increased risk of minor treatment response and poor overall survival, XRCC1 rs25487 was associated with reduced risk of minor treatment response in esophageal cancer and an increased risk of high-grade side effects in head and neck cancer.The results suggest that XRCC1 expression and rs25487 polymorphism are prognostic factors for patients receiving radiotherapy-related treatment. Considering the insufficient treatment parameters provided and the various sample sizes in most of the studies, we suggest that genetic association studies related to radiation-based treatment should include more cancer types with sufficient statistical power and more detailed clinical parameters. Radiotherapy using ionizing radiation is among the main treatments used to control or kill malignant neoplasms. Ionizing radiation functions by creating double-strand breaks (DSBs) or by damaging cell membranes, which can lead to cell death. However, the responses to radiotherapy vary between different cancer types, or even between cancer cells inside a tumor . SeveralSince 2002, more than two-hundred published studies have reported an association between single nucleotide polymorphisms (SNPs) and cancer prognosis in patients receiving radiotherapy-related treatment. In the meantime, many studies have focused on the gene expression level, radiotherapy-related treatment response and cancer prognosis. According to our statistics, the key factors in evaluating prognosis mainly include survival , treatment response , and radiotherapy-related side effects . One of the important goals of these studies is to identify genetic factors that can be used to predict radiotherapy-related cancer prognosis . Among tTo address the issues of inconsistent conclusions and limited sample size, we performed meta-analyses that included the most comprehensive literature and obtained the largest sample size for this topic to date. To minimize the effect of publication bias, we collected data from published articles (including published Ph.D. and master’s theses) on the association between XRCC1 expression level and radiotherapy-related treatment response/cancer prognosis; we also explored the relationship between XRCC1 rs25487 polymorphism and radiotherapy-related treatment response/radiation-induced side effects.Eligible publications were retrieved by searching the PubMed, Web of Science and Chinese National Knowledge Infrastructure (CNKI) databases up to November 31, 2020. The search strategy was based on the following keywords: [(X-ray Repair Cross Complementing Protein 1(MeSH Terms)] AND Radiotherapy [MeSH Terms]) AND Neoplasms [MeSH Terms]. Studies focusing on the association between XRCC1 expression/XRCC1 rs25487 and radiotherapy-related cancer prognosis were screened for further analysis.via Kaplan Meier (K-M) curves; and (5) provision of the number of patients in the high/low XRCC1 expression group or with different genotypes in the case-control group.Two independent reviewers performed the inclusion assessment. The inclusion criteria were as follows: (1) an independent case-control or cohort study; (2) evaluation of the association between the XRCC1 expression level and radiotherapy-related treatment response/cancer prognosis; (3)evaluation of the association between XRCC1 rs25487 and radiotherapy-related treatment response/radiation-induced side effects in patients receiving radiotherapy-related treatment; (4) sufficient data on the relationship between XRCC1 expression and overall survival, with estimated hazard ratios (HRs) and 95% confidence intervals(CIs) determined by multivariate analysis and reported in the articles or available to be indirectly calculated Exclusion criteria: (1) studies without sufficient data associated with radiotherapy-related treatment response, overall survival (OS), or radiation-induced side effects, (2) duplicated publications, (3) studies based on animal models or cell lines, (4) other literature types: reviews, letters, abstracts, meta-analysis, case reports, etc.Two independent reviewers collected data from the studies included in the meta-analysis. The following data were collected: first author, publication year, cancer type, treatment, side effects, acute/late degree, evaluation criteria, cutoff value, follow-up period, survival outcome, HR (95% CI), number of patients in the high/positive XRCC1 expression group and low/negative XRCC1 expression group associated with treatment response, and number of patients in the case-control group and the association between XRCC1 rs25487 and treatment response/side effects. If survival rates were not obtained from multivariate analysis, the survival HR (95% CI) was indirectly retrieved from K-M curves using Engauge Digitizer software. This method was described in detail by Tierney et al. . A calcuThe Cancer Genome Atlas (TCGA) database was searched to further verify the relationship between XRCC1 expression and radiotherapy-related cancer prognosis. The patients were filtered out if they had not undergone radiotherapy and/or had no survival information. Overall survival was assessed using R software (version 4.0.3).To reduce the effect of specific parameters  on the association between rs25487 and treatment/side effects, we performed subgroup analysis if there were five or more studies. When we performed subgroup analysis for cancer, we classified by the type of tissue and the primary site. In treatment response, the patients in each study were divided into two groups according to their treatment response: minor treatment response (case group) and major treatment response (control group). Major treatment response refers to a complete/partial response  or grade <3 regression grade , and minor treatment response refers to stable/progressive disease , or a ≥25% increase in one lesion) or a ≥3 regression grade . We classified side effects by organ system and clinical dissection/irradiation region. Cystitis and proctitis were classified as bladder and/or rectal toxicity. Digestive system toxicity included dysphagia and radiation esophagitis. Anemia, leukocytopenia, neutropenia and thrombocytopenia were classified as hematological toxicity. Skin toxicity included radiation dermatitis and erythema. Telangiectasia, fibrosis or fat necrosis were classified as soft tissue injury.2) test were used to assess heterogeneity. If I2 <50%, the fixed effect model was chosen to combine data, otherwise the random effect model would be adopted. In the sensitivity analysis, the “metaninf” module was used to investigate the influence of each individual study on the overall meta-analysis summary estimate by omitting each study in turn. Begg’s rank correlation test and Egger’s linear regression test were chosen to assess publication bias and P<0.05 was considered statistically significant. All statistical analyses were performed using STATA 14.0 software .HRs and ORs, with their corresponding 95% CIs, were utilized to analyze the association between XRCC1 expression and prognostic indicators (OS) and treatment response, respectively. ORs and 95%CIs were also calculated to evaluate the association between XRCC1 rs25487 and treatment response/side effects. For XRCC1 rs25487 analysis, we used three genetic models to combine data: heterozygote model (GA vs GG), homozygote model (AA vs GG), and dominant model (GA+AA vs GG). A chi-squared test and Higgins’s . The association between XRCC1 and OS was assayed using data from six studies, and we found that high XRCC1 expression was significantly related to poor OS , However, heterogeneity was found to be relatively large . Seven studies reported data showing patient treatment response. The pooled OR indicated that high XRCC1 expression was closely related to an increased risk of minor treatment response . A heterogeneity test showed low heterogeneity among these studies  and in patients receiving radiotherapy only . In OS analysis, we found no relation between XRCC1 expression and OS in the cancer subgroup or treatment subgroup. To assess whether the combined results were affected by a single study, sensitivity analysis was performed by a single study by calculating the results when individual studies were omitted and determining if the result was within the CI. The results are shown in To further explore the prognostic value of XRCC1 expression in cancer patients who received radiotherapy, we retrieved expression data for radiotherapy-related cancer prognosis in all cancer types from TCGA data set. A total of 2705 patients with 17 cancer types, consisting of digestive, respiratory, urinary, female reproductive, head and neck, neurological, urinary, and soft tissue system cancers, were included in the analysis. The patients were divided into high- and low- XRCC1 expression groups according to the median XRCC1 expression value. Meta-analysis of all the studies indicated that high XRCC1 expression may be related to poor OS; however, the result was not statistically significant . No significant association was found between rs25487 and treatment response Table 3.Among all the included studies focusing on association between XRCC1 rs25487 and treatment response/side effects, adjusted data of side effects were available in seven studies, adjusted data of treatment response were available in two studies. Adjusted factors included age, tumor size, body mass index, adjuvant treatment, dose of radiotherapy, smoking status and so on. When we used adjusted data to analyze the association between rs25487 and side effects/treatment response, no significant association were found for both side effects analysis and treatment response analysis, which were consistent with our results when we used the crude data in corresponding studies. In the treatment response analysis, the GA genotype  was associated with a reduced risk of minor treatment response in esophageal cancer. The AA genotype  was associated with a reduced risk of minor treatment response when using grade ≥3 as the cutoff value Table 3.In the side effects analysis, an increased risk was found to be associated with the GA genotype  in head and neck cancer. The results further validated the results for the GA genotype  and GA+AA genotype , in terms of mucositis. Genotypes with variant alleles were associated with increased risks of side effects in patients receiving radiotherapy  or radio-chemotherapy . GA  and the GA+AA genotype  was found to be associated with an increased risk of acute side effects. Heterozygous and mutant homozygotes were also associated with an increased risk of side effects when using Grade ≥2 or ≥3 as the cutoff value Table 4.In the sensitivity analysis, we removed the studies one by one to clarify their influence on the results. The confidence intervals for all the studies indicated that the results are stable. Encoded by XRCC1 (X-ray repair cross complementing 1) gene, XRCC1 plays a crucial role in the oxidative DNA damage repair through the base excision repair (BER) pathway and single-stranded break repair (SSBR) processes, after exposure to ionizing irradiation or alkylating agents . XRCC1 fTo the best of our knowledge, this is the first comprehensive meta-analysis with the largest sample size investigating both the relationship between XRCC1 expression and radiotherapy-related treatment response/overall survival and the association between the XRCC1 r25487 polymorphism and radiotherapy-related treatment response/radiation-induced side effects. The results demonstrated that high XRCC1 expression is correlated with poor treatment response. For OS, the pooled HRs showed a strong correlation between high XRCC1 expression and poor OS, indicating that high XRCC1 expression could be considered a risk factor in cancer patients receiving radiotherapy. To further validate the radiotherapy-related prognostic value of XRCC1, we performed a TCGA data review. The pooled HRs indicated that high XRCC1 expression tended to be correlated with poor OS, although the result was not statistically significant. However, interestingly, when we performed a TCGA analysis in different tumor types without considering therapeutic modalities, we found that high XRCC1 expression was significantly related to better OS, indicating that high XRCC1 expression is a protective factor in the undifferentiated treatment cancer population. Studies have demonstrated that XRCC1 facilitates efficient DNA damage processing, which is pertinent in patients undergoing radiochemotherapy. This is mitigated to a certain extent by non−specific DNA repair systems; therefore, high XRCC1 expression levels may increase the DNA repair capacity of tumor cells, leading to an increased tolerance to DNA damage induced by radiochemotherapy . All theNo high-throughput studies (such as GWAS) were found that reported a correlation between XRCC1 rs25487 and radiotherapy-related prognosis. However, given that many single variable studies with different sample sizes that drew different conclusions about the relationship between XRCC1 r25487 and radiotherapy-related prognosis, this meta-analysis is of special importance to obtain a more robust conclusion with higher statistical power. Overall, we found an increased risk of side effects  associated with the GA genotype and GA + AA genotype, compared to the GG genotype. Furthermore, the GA + AA genotype was found to be associated with acute and severe side effects, especially in terms of mucositis in head and neck cancer (HNC). PARP and PNK are two important enzymes in the BER pathway. The variant alleles of XRCC1 rs25487 might significantly change the affinity of the binding domain of PARR or PNK , which cThe era of advanced multimodality radiotherapy requires the development of approaches for tailoring treatments to the individual. Irradiation-related genomic biomarkers can contribute by identifying sufficient genetic variants associated with a patient’s risks of radiotherapy-related toxicity and cancer prognosis. Increasing clinical trials  are focusing on the relationship between genes and radiotherapy-related side effects, most of the results have not been released. One of our included studies is registered on the ClinicalTrials database (identifier: NCT01316328), which indicates no relationship between XRCC1 rs25487 and radiotherapy-induced fibrosis or fat necrosis in breast cancer patients. Our meta-analysis shows no relationship between XRCC1 rs25487 and radiotherapy-induced soft tissue injury, which confirmed the clinical trial results from a broader perspective with a larger sample size. The evidence above shows that it will be valuable that referencing our meta-analysis results when using the XRCC1 gene and XRCC1 rs25487 polymorphisms as biomarkers for patients receiving radiotherapy-related treatments in clinical practice.According to statistics, nearly 90% of patients suffer from different grades of mucositis during radiotherapy , which hHowever, some methodological issues should be taken into consideration. First, the sample size among the included studies ranged from 50 to 575, which is relatively small. Thirty-three studies had fewer than 100 patients and only five studies had more than 400 patients. Andreassen et al. reported that studies with small sample sizes were underpowered to detect SNPs with a modest impact on complication risk . TherefoOur meta-analysis suggested that high XRCC1 expression is associated with increased risk of minor treatment response and poor OS. XRCC1 rs25487 is associated with reduced risk of minor radiotherapy-related/radiation-induced treatment response in esophageal cancer and increased risk of mucositis in head and neck cancer. Considering the insufficient reporting of treatment parameters and the various sample sizes for different cancer types, we suggest that genetic association studies related to radiation-based treatment should include more cancer types and patients with sufficient statistical power and more detailed clinical parameters.The datasets supporting the conclusions of this article are included within the article and its additional files.ZL designed the study. LG, ML, and RS reviewed articles and collected data. LG performed statistical analysis. LG, ML, and RS wrote the manuscript. LQ and CC revised the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation of China (No.81802997), the HuBei Provincial Department of Science and Technology Innovation Group Programme (No.2019CFA034), The Free Exploration Foundation of the Hubei University of Medicine (No.FDFR201802).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.


Background: Yogurt is known to be nutrient-rich and probiotic content, which gather optimism due to their potential role in preventing and managing cancers. The effect of yogurt consumption on colorectal cancer (CRC) is inconsistent.Objective: This study aims to investigate the association of yogurt consumption with the risk of CRC.Methods: Three databases, namely, PubMed, Web of Science, and Embase, were searched for all relevant studies from July 2021 on the association of yogurt consumption with CRC risk. We pooled the odds ratios (ORs) and their 95% CIs using a random-effects meta-analysis to assess the association.Results: Finally, 16 studies met the inclusion criteria and were chosen in the meta-analysis. Yogurt consumption was significant with lower risk of CRC risk in the overall comparison , in the cohort studies , and case-control studies . With regard to subgroup analyses by study region, cancer type, publication year, and sex, yogurt consumption significantly decreased overall CRC, colon cancer, and distal colon cancer risks. In stratified analyses, we observed significantly decreased CRC risk in Europe and Africa and published after 2010 and overall population. Sensitivity analysis indicated the result is stable and there is no publication bias in the meta-analysis.Conclusions: Overall, this study indicated that yogurt intake was related to a decreased risk of CRC. Colorectal cancer (CRC) is the third most common cancer among men and women in the world –4. Some Fermented food contains a large number of live microorganisms, so it can be used as probiotics to enrich the intestinal tract with beneficial bacteria. It helps the body to absorb nutrients and enhance immune function by preventing inflammation and stimulating phagocytosis . Yogurt To the best of our knowledge, previous reviews always included the small number of epidemiological studies and did not reach a consensus –64. In vThis study was presented according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 statements . We provPubMed, Embase, and Web of Science literature databases were searched dated up to July 2021, using the combinations of keywords related to yogurt and CRC. Keywords for exposure (yogurt consumption) included “yogurt,” “yogurt,” and “cultured milk products,” while keywords for the outcome (risk of CRC) included “colorectal cancer” and “colorectal neoplasms.” The detailed search terms used in each literature database are summarized in The inclusion criteria were (1) human (>18 years old) epidemiological studies  that focused on the association of yogurt consumption with an incidence of CRC, such as total CRC, colon or rectal cancer, or proximal or distal colon cancer; (2) studies provided estimates of the odds ratio [OR], relative risk [RR], or hazard ratio [HR] with their 95% CIs for the data synthesis or reported sufficient data that could be used to calculate the estimates was presented; and (3) studies evaluated the intake of yogurt through the use of validated food questionnaires. We excluded studies that (1) were not written in the English language; (2) were not original studies, such as review, meta-analysis, commentary, letter, or editorial; and (4) studies assessed CRC mortality as an outcome of interest.The following data were extracted from each chosen study: name of the first author, year of publication, country, study design (duration of follow-up for cohort studies), sample size, mean age of study participants, dietary assessment, outcome assessment, number of cases, categories of yogurt intake, reported risk estimates  with their 95% CIs, and the adjusted confounders in the final multivariable regression models. If two effect estimates based on the sex of study participants were reported in a study, we firstly pooled them using fixed-effect meta-analysis and then put the pooled estimate in the main meta-analysis. If studies report the crude and confounding adjusted risk estimates for CRC, we selected the effect estimates from the full-adjusted model.To assess the quality of each study, we applied the widely used quality assessment tool for an observational study, which is Newcastle-Ottawa Scale (NOS) . Two of I2 statistic  were used as the measures of the association of yogurt consumption with the risk of CRC. Following previous practices , 68, we tatistic  and the ogeneity . To testn = 128) was excluded. Nineteen studies that did not meet the inclusion criteria were excluded and produced a total of 16 studies were included in the systematic review and meta-analysis (35 studies were detailed assessed). The reference lists of all the 19 studies were also screened, and we found that all the potentially included articles were already chosen. Finally, a total of 16 studies were chosen for the systematic review and meta-analysis.A total of 484 studies  were chosen through the literature search . We exclI2 = 19.9%; P-heterogeneity = 0.217). When performed stratified meta-analyses  did not indicate the presence of publication bias  were conducted in European countries and the dairy products consumption varies greatly among different regions. Europe is the region with the highest dairy products consumption  has been shown to prevent tumor induction caused by 1,2-dimethylhydrazine in mouse models  the number of included studies is relatively small and thus precluded us perform meta-regression analysis to explore source(s) of heterogeneity. Moreover, we only included studies published in the English language so that some other language papers may be omitted; (2) we are unable to explore the dose-response curve of yogurt consumption with CRC risk due to the limited data provided by the included studies; (3) most of the included studies did not distinguish colon and rectal cancers and analyzed them together. In spite of these cancers are always considered together, potential etiological factors for colon and rectal cancers may be different and site-specific mechanisms of carcinogenesis have been indicated ; (4) altTo conclude, this systematic review and meta-analysis suggested that yogurt consumption is related to a lower risk of CRC. However, in consideration of the aforementioned limitation, these findings should be confirmed by further longitudinal studies with improved yogurt consumption assessment, better CRC, such as subtypes of CRC case ascertainment and comprehensive control of confounders in clarifying the association. If such a conclusion is supported, we would recommend regular yogurt intake as a healthy lifestyle behavior in decreasing the risk of CRC in adults.The original contributions presented in the study are included in the article/JSu and JSo conceived the idea, performed the statistical analysis, and drafted this meta-analysis. JY, LC, and ZW selected and retrieved relevant papers. MD and SY assessed each study. JSu was the guarantor of the overall content. CH and QB supervised the whole study process and contributed to the critical revision of the manuscript. All authors revised and approved the final manuscript.This study was supported by Anhui Province Natural Science Foundation (1908085MG233), Quality Engineering for Research Projects of the Anhui Province , and Key Projects of Natural Science Research of Anhui Provincial Department of Education (KJ2020A0163).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.


TMEM165 (transmembrane protein 165) gene with the risk of BD. Genotyping of the rs534654 was carried out using the tetra primers- amplification refractory mutation system-PCR (4P-ARMS-PCR) method in 203 patients with BD type 1 and their healthy and normal counterpart. The frequency of the G and A alleles of rs534654 polymorphism was 53% and 47%, respectively in patients. Genotype frequency in patients in comparison with control subjects was 5.4% vs 2.5% for the AA homozygous; 11.3% vs 80.8% for the GG homozygous; and 83.3% vs 16.7% for the heterozygous AG. Statistical analysis showed a significant diﬀerence in frequencies between the control and patient groups (P = 0.001). Based on this finding, it is possible to conclude that the impairment in the rs534654 single nucleotide polymorphism in TMEM165 gene is associated with the risk of BD development.Bipolar disorder (BD) is a major health care concern worldwide. There are some reports showing an association between genes and their variants involved in circadian rhythm; clock and clock related genes function and development of BD in patients. Therefore, the aim of this study was to investigate the possible association of rs534654 variant on Bipolar disorder (BD) is one of the most significant  disabling mental diseases affecting 1–4% of the population worldwide . It is a2+ and pH lysosomal homeostasis, and is mainly located in Golgi apparatus  . This siTMEM165 gene (rs534654) and elevated risk of BD.The rs534654 polymorphism is an intron variant of TMEM165 gene with reference allele A, C, G and T. Based on the results of previous studies, the present study attempted to explore the relationship between the single nucleotide polymorphism (SNP) of Study subjectsIn the present study, 203 individuals who were admitted to the Shahid Beheshti’s Imam hossein Teaching Hospital in Tehran-Iran by the psychiatrists and clinical staff in psychiatry wards were selected. All patients’ selection was based on the criteria mentioned in Manual of Mental Disorder; Fourth Edition-Text Revised (DSM IV-TR) and DSM-5 diagnosis of BD version . The samGenotyping methodsTMEM165 gene was carried out using the tetra primers-amplification refractory mutation system-PCR (4P-ARMS-PCR) method in Applied Biosystems™ Veriti™ thermal cycler . The sequences of inner and outer primers, their annealing temperature and the expected amplicon sizes for G and A alleles are shown in Three milliliters of peripheral blood were obtained from all individuals in EDTA-contained tubes, and genomic DNA was extracted from each sample by means of salting out method. Genotyping of the rs534654 of the Amplification of rs534654 alleles generated 104, 160, and 210 bp bands for A allele, Gallele, and outer primers, respectively on gel electrophoresis. The PCR products were further approved by random sequencing of 10% of the obtained genotypes using the ABI 3730 DNA analyzer Statistical analysisThe Microsoft Excel 2019 and SPSS 24.0 statistical software  were applied for statistical analysis of this case–control study. Both patients and control groups were analyzed using Chi-square (χ2) test to determine the fitness to the Hardy– Weinberg equilibrium. The χ2 test was also used for comparing genotype and allelic frequencies between the BD subjects and controls. The P-values were two-sided and a P < 0.05 was considered as statistically significant differences in all analyses.The subjects in the control and patient groups were compared for demographic features such as sex and age. The mean age of the patients and controls were 43.23±11.2 years and 36.63 ± 9.42 years respectively. The demographic data of the selected patients showed that more than 53.2 percent of the cases were males.Evaluation of demographic indicatorsDifferences between groups were assessed by t-test with Mann-Whitney formula (MS). There was no significant difference between the patient and control groups in terms of age index (P = 0.10). There was no significant difference between men and women .In addition, there was a significant difference between affected patients based on the social background such as being single, married or divorced, their education level, age at illness onset, family history of psychiatric disorder  28)..28).The specific band related to each genotype of the rs543654 SNP is shown in The frequency of the G and A alleles of rs534654 polymorphism was 53% and 47%, respectively in the patients. Genotype frequency of the rs534654 polymorphism in patients in comparison with control subjects was 5.4% vs 2.5% for the AA homozygous; 11.3% vs 80.8% for the GG homozygous, and 83.3% vs 16.7% for the heterozygous AG. This statistical analysis shows a significant diﬀerence in frequencies between the control patient groups (P = 0.001). A positive association between SNP rs534654 and BD in the genotypic distributions (P = 0.001),  was obseBD has a complex genetic background. In the present study, it was found that more than 51.2% of patients had related history in their family, supporting the fact that a significant relationship may exist between heredity and BD , 29. It TMEM165 and the risk of BD type I. Results showed a significant association between this SNP and BD development. SNP rs534654 in TMEM165 gene is near the CLOCK gene which is a part of circadian genes. Several studies have demonstrated association between the role of circadian genes and the risk of MD. Indeed, the rs534654 polymorphism is part of a three-way interaction associated with BD  gene and rs1534891 at the CSNK1E gene. Similarly, rs534654 at the 3’ end of the clock gene (TMEM165 gene) is significantly associated with BD in these studies (TMEM165 gene is one of the genes located near the clock gene and possibly involved in the circadian cycle, and encodes a calcium / proton transporter protein that is involved in calcium homeostasis and lysosomal pH (TMEM165 gene due to impairment of galactosylation and sialylation of N-glycoproteins are related to CDG (The present study assessed the association between the rs534654 in  with BD . There i studies . As mentsomal pH , 21. Calsomal pH . Mutatiod to CDG . Most CDd to CDG .N-glycosylation is a post-translational change for many proteins and lipids with an oligosaccharide. This function regulates many biological processes, including intercellular communication, cell adhesion, protein folding, protein placement, and protein activity . AnotherTMEM165 gene has significant expression in different parts of the brain with very high expression in the spinal cord of the brain (Evidence suggests that dysfunction of immune system and inflammation are associated with depressive disorder. A meta-analysis study found that patients with depressive disorder had fewer immune cells than healthy people. Elevated pro-inflammatory cytokines, including interleukin-1, interleukin-6, and tumor necrosis factor, have been associated with depression ,35 and hhe brain . In the present study, the rs534654 variant of this gene, which has previously been shown to be associated with circadian rhythm disorders, was shown to be associated with an increased risk of BD.TMEM165 in a calcium/proton transporter protein, importance of calcium ions in nerve conduction and the immune modulation, and the relation of immune system dysfunction with depressive disorder, as well as the relation between N-glycosylation and mental and neurological disorder, it is not unexpected that rs534654 variant of this gene is associated with risk of BD, and impairment in this gene may increase the risk of BD.Based on pivotal role of TMEM165 could be considered as a potential risk factor of BD. Additional studies are also necessary to find other associated variants of TMEM165 gene and understanding the underlying mechanism by which the rs534654 SNP influences the susceptibility to BD. According to the results of this study, rs534654 variant of Authors declare no conflict of interest.


CTLA-4) +49 adenine (A)/guanine (G) polymorphism and susceptibility of lung cancer, but the results remain controversial. Thus, we performed this meta-analysis to derive a more comprehensive estimation of the relationship.Lung cancer is one of the malignant tumors. Gene mutations associated with cellular immune function and regulating the activation and proliferation of immune cells. Several publications have explored the relationship between cytotoxic T lymphocyte antigen-4  with 95% confidence intervals (CIs) were used to assess the strength of association. Publication bias of relevant studies was examined via Begg's test and funnel plots.All articles addressed lung cancer and polymorphisms of meta-analysis included 8 case-control studies covering 4, 430 lung cancer patients and 5, 198 healthy controls from September 2008 to April 2020. The overall eligible data indicated that CTLA-4 +49A/G polymorphisms did not correlate with the elevated lung cancer risk in all genetic comparison models . In further stratified analyses, CTLA-4 +49A/G polymorphism was found to be significantly associated with susceptibility to NSCLC in these models .The CTLA-4 +49A/G polymorphism were not associated with the risk of lung cancer but might be a risk factor only in NSCLC. Current studies suggest that complex interactions between genetic anomalies and environmental factors are associated with cancer pathogenesis. It is a multi-factor, multi-stage and multi-gene process, 3. Thus, searching for susceptible genes to establish high-risk population and achieve early prevention and treatment is one of the focuses of lung cancer research.Lung cancer is one of the malignant tumors that seriously threaten human health and the incidence of lung cancer is increasing year by year worldwide. Tumor cells can escape the attack of the epidemic system through immunosuppressive checkpoints, 6. T lymphocyte and nature killer (NK) cells play a key role in tumor immune surveillance and are regulated by some immune suppressive or stimulus-related molecules. Thus, gene mutations associated with cellular immune function and regulating the activation and proliferation of T lymphocytes and NK cells may be involved in cancer susceptibility, 9.A considerable number of studies have showed that immune system plays a vital role in cancer development and progression. The key function of CTLA-4 is to control CD4+, CD8+ T cells and regulatory T cells (Treg). CTLA-4 has high homology with the co-stimulatory molecule receptor (CD28) on the surface of T cells. It shares B7 ligand with CD28. The binding of CTLA-4 and B7 can inhibit the binding of B7 and CD28, interrupt the activation of T cells and participate in the negative regulation of immune response. Many studies have shown that CTLA-4 inhibits T cell proliferation, induces activated T cell apoptosis and controls Treg. In addition, inhibitors targeting CTLA-4 can block the binding of CTLA-4 to B7, inhibit the production of T cell suppression signals and enhance specific anti-tumor immune response. Therefore, the gene status of CTLA-4 may be related to the occurrence of cancer which is a combination of genetic susceptibility and external factors.Cytotoxic T lymphocyte associated antigen 4 (CTLA-4), also known as CD152, is a member of the immunoglobulin superfamily and an important immune checkpoint gene, which is mainly expressed in Treg and activated T cellsCTLA-4 gene, such as + 49 adenine (A)/guanine (G), -318 cytosine (C)/thymine (T), -1611 G/A, -1722 T/C, 10223 G/T polymorphisms, etc, 15, 16. Among the cancer susceptibility studies, CTLA-4 +49 A/G polymorphism is the most widely studied mutation point. Some studies have shown that CTLA-4 +49 A/G polymorphism is associated with the risk of various cancers, such as breast cancer, 18 and cervical cancer. However, the relationship between CTLA-4+49 A/G polymorphism and lung cancer is still unclear. Several studies have drawn contradictory conclusions, 20-26. Considering the importance of CTLA-4 in tumorigenesis and the limitations of single study, we conducted a comprehensive meta-analysis of published studies to derive a more precise and objective estimation of the relationship between CTLA-4 +49A/G polymorphism and the risk lung cancer.There are more than 100 single nucleotide polymorphisms in meta-analysis.A systematic literature search was conducted on PubMed, Embase, Wanfang, China National Knowledge Infrastructure (CNKI) and Web of Science databases until June 29, 2019, using the following key words and search strategies: ("CTLA-4" or "cytotoxic T-lymphocyte-associated antigen 4" or "+49 A/G" or "rs231775") and ("polymorphisms" or "mutation" or "variants") and " or "NSCLC"). These terms were arranged into different combinations used for search. Only published studies written in English with available full-text were included in this CTLA-4 +49 A/G polymorphism and the risk of lung cancer; (2) studies designed as a case-controlled study; (3) contained available data on the frequency of genotypes including odds ratios (ORs) and 95% confidence intervals (CIs). In addition, the studies that did not meet the inclusion criteria were excluded. Data for the meta-analysis were available from 8 articles including 9 case-controlled studies (The selection criteria were as follows: (1) studies involved the association between  studies .Hardy-Weinberg equilibrium (HWE) test. Ethnicities were categorized as Asians or Caucasians.Two investigators extracted data from the eligible studies independently according to the inclusion criteria. When confronted with conflict, an agreement was settled by discussion with the third reviewer. For each study, the extracted information included: the first author's surname, year of publication, country of origin, ethnicity, sample size of case and control groups, source of controls, histological types, genotyping methods, genotype distributions and CTLA-4 gene polymorphisms and the risk of lung cancer under five genetic models: allele model, homozygous model, heterozygous model, dominant model and recessive model. The pooled ORs were calculated using the fixed-effects model or the random-effects model and a P < 0.05 was considered to indicate statistically significant heterogeneity. When the P > 0.05, the pooled ORs were calculated using the fixed effects model based on the Mantel-Haenszel method. Otherwise, the random-effects model with the DerSimonian-Laird method was chosen in this meta-analysis. Stratification analyses were performed according to ethnicity (divided into Asians and Caucasians), histological type, source of controls and sample size. In addition, Funnel plots and Begg's test were used to evaluate publication bias. All the statistical tests were performed using Stata 11.0 software . A P < 0.05 was considered statistical significance.The pooled ORs and its 95%CIs were calculated to evaluate the strength of association between meta-analysis for further evaluation, which were accrued between September 2008 and April 2020. Besides, the distribution of genotypes among the controls was consistent under HWE. The flowchart of literature search and selection procedure is shown in Following the selected criteria, a total of 105 studies were initially identified through a primary search of PubMed, Embase, Wanfang, CNKI and Web of Science databases and reference lists. Among the studies, 8 full-text articles, including 9 case-control studies harbouring a total of 4, 430 cases with lung cancer and 5, 198 controls met the inclusion criteria and were included in the CTLA-4 +49 A/G genetic polymorphism and lung cancer risk was evaluated using the pooled ORs and 95%CIs based on five genetic comparison models. A summary of the meta-analysis results for the 9 studied CTLA-4 polymorphism and lung cancer susceptibility is provided in Overall, the strength of association between meta-analysis, the combined results of all analyses showed that the pooled OR of nine studies was 1.037  for the dominant model, 0.968  for the recessive model, 0.992  for the allele model, 0.980  for the homozygote model and 1.023  for the heterozygote model, indicating no significant association between CTLA-4 +49 A/G mutation and lung cancer susceptibility -2 and IL-2 receptor productions, 28. Targeting CTLA-4 with a type of monoclonal antibodies in immunotherapy was a prospective therapeutic approach in many types of tumor by enhancing the activation and expansion of antitumor T cell, 30. Thus, CTLA-4 may involve in cancer development and progression and exerted an important function in cancer immunosurveillance. The current meta-analysis results showed an increased risk of NSCLC for carriers of the A allele. The +49 A/G polymorphism of CTLA-4 refers to a threonine (Thr) to alanine (Ala) substitution in the leading peptide of CTLA-4 receptor. The studies reported that the 49G allele reduced CTLA-4 production than the 49A allele because of its lower messenger ribonucleic acid (RNA) efficiency and this polymorphism enhances the combination between CTLA-4 protein and its ligand B7.1. Individuals with 49GG genotype may lead to greater T-cell proliferation and stronger binding to ligand B7.1 than that with 49 AA genotype. According to our current results, these findings revealed that the Thr-to-Ala change in CTLA-4 may be related with the risk of NSCLC.CTLA-4 acts as a negative regulator of T-cell proliferation and activation through inducing Fas-independent apoptosis of activated T cells, retarding T cells at Gmeta-analysis. Significant heterogeneity existed in overall comparisons in the dominant model. After subgroup analyses by ethnicity, histological type, source of controls and sample size, the heterogeneity effectively was decreased or almost removed in some subgroups, suggesting different gene-environment factors effect on different histological type or different population. In the meta-analysis, publication bias was analyzed by Begg's funnel plots and the Egger's test and no significant publication bias was detected, suggesting the reliability of our results.The heterogeneity and publication bias are of importance which may affect the results of In addition, some limitations should be considered. First, the number of studies was limited, which may affect the power to reveal a reliable association. In the future, large numbers of studies need to be conducted to validate these association. Second, all case-control studies were from Asia and Caucasians, thus our results may be only applicated to these ethnic groups. Third, only published studies were recruited and publication bias might have occurred ineluctably. Fourth, data were not performed to further stratified analysis by other factors, such as environmental and lifestyle factors, because the information extracted from the primary publication was finite.meta-analysis demonstrated that CTLA-4 +49 A/G polymorphism was a risk factor for NSCLC. Future more large-scale and well-designed studies with functional evaluations should be carried out to definite the results and investigate the molecular mechanisms of CTLA-4 modify cancer risk.In conclusion, the results from the


Objective: Birth weight, an important indicator of fetal nutrition and degree of development, may affect the risk of subsequent leukemia. At present, little is known about the effect of birth weight on acute myeloid leukemia (AML) and whether there is a dose-dependent relationship of birth weight with acute lymphoid leukemia (ALL) and AML. To address these questions, the present work aimed to systematically investigate the relationship between birth weight and the risk of subsequent leukemia based on the current epidemiological studiesMethods: Relevant studies were systematically retrieved from electronic databases PubMed, Embase, and Cochrane Library, from inception to May 15th, 2021. Finally, 28 studies (including 21 case-control studies and 7 cohort studies) were included for the final meta-analysis. Results in cohort studies were performed by risk ratios (RRs), while those in case-control studies by odds ratios (ORs), and all results were assessed by adopting the random-effect model. Besides, a dose-dependent analysis was conducted based on the cohort studies.Results: Compared with the population with normal birth weight (NBW), the population with high birth weight (HBW) might have an increased risk of leukemia . Meanwhile, low birth weight (LBW) was associated with a decreased risk of ALL, as evidenced from the pooled analysis of case-control studies . However, relative to NBW population, the HBW population might have an increased risk of ALL . There was no obvious evidence supporting the relationship between LBW and the risk of AML from the pooled analysis of case-control studies .Conclusions: Overall, in children and young adults, HBW population may be associated with the risks of subsequent leukemia and AML relative to NBW population, but the supporting dose-dependent evidence is lacking. In addition, compared with NBW population, there is stronger evidence supporting a significantly increased risk of subsequent ALL in HBW population, and a decreased risk in LBW population in a dose-dependent manner. More prospective studies with large samples are warranted in the future to validate and complement these findings. Leukemia is a malignant clonal disease of hematopoietic stem cells (HSCs). It is characterized by the uncontrolled proliferation and development of leukocytes in the bone marrow and peripheral blood, which in turn invade the internal organs, such as the liver and spleen –3. LeukeBirth weight, an important indicator of fetal nutrition and degree of development, may affect the risk of subsequent leukemia. Although several previous studies have suggested that high birth weight (HBW) increases the risk of subsequent ALL, the results are inconsistent –9. NeverThis meta-analysis was conducted according to the guidance of Meta-analyses of Observational Studies in Epidemiology (MOOSE) . Two invInclusion criteria were determined following the PICOS standards: (1) The study population did not have any family history of cancers, exposure to radiation and chemicals, or congenital disease (such as Down's syndrome), with birth weight being the interested exposure. (2) Different birth weight levels were compared. (3) One birth weight group served as the control or reference group. (4) The study outcomes reported the incidence of leukemia. (5) The study types were restricted to case-controlled, cohort studies, or randomized controlled trials (RCTs). (6) The related odds ratios (ORs), risk ratios (RRs), or hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were available or might be calculated. Meanwhile, the exclusion criteria were as follows: (1) The study population had a family history of cancers, exposure to radiation and chemicals, or congenital disease like Down's syndrome, and birth weight was not the interested exposure. (2) The studies did not report the risk of leukemia or acute leukemia by comparing different birth weight levels. (3) Cross-sectional studies, pooled studies, case reports or series, conference abstracts should be excluded. (4) Related ORs, RRs, or HRs were not obtained or converted.An unified list was used to extract the following baseline data from the included studies, including first author, publication year, country, sample size, date of birth or diagnosis, BMI categories, types of leukemia, ascertainment of leukemia, and maximum adjusted variables. The maximum variables adjusted for ORs, RRs, or HRs were extracted. Any disagreements were solved by the opinion from a third investigator. The quality of included studies was evaluated by using the Newcastle-Ottawa Scale (NOS) items, with the total score of 9 stars . StudiesI2 statistics, with the I2 values of 25, 50, and 75% indicating low, moderate, and high inconsistency, respectively (n > 10). This study used a random-effects model to more conservatively estimate the pooled RRs and ORs, since more robust results were obtained after aggregating with this model. In addition, the risk of potential publication bias was assessed by funnel plots as well as Begg's and Egger's tests ,” “normal birth weight (NBW),” and “HBW,” respectively. When one study reported different LBWs or HBWs , it was analyzed separately. The primary endpoint of our study was to qualitatively analyze the relationship between birth weight and leukemia/acute leukemia . Generally speaking, HRs can be roughly considered to be equal to RRs in cohort studies . Therefoectively . If ther's tests , 15. TriThe secondary endpoint of this study was to quantitatively assess the effect of birth weight on leukemia. For this purpose, a dose-response meta-analysis was performed on the included cohort studies. To maximally include the available cohort studies, the robust error meta-regression method described by Xu and Doi  was utilp-values were calculated by testing the second spline coefficients to zero. The non-linear model was adopted when the non-linear p < 0.05; otherwise, the linear model was used. In general, the lowest-dose category should be used as a reference in the included studies; however, when the non-lowest-dose studies were used as reference, they were converted via an Excel macro file produced by Hamling et al. ; (2) no available information of birth weight (n = 16); (3) the study endpoints did not include the risk of leukemia (n = 8); (4) pooled studies, letters (n = 8); and (5) case reports, conference abstracts (n = 16).At first, a total of 4,024 studies were included. After removing 566 duplicated studies, 3,458 studies were retained. Then, the titles and abstracts of these 3,458 studies were read, and 3,370 unrelated studies were further excluded; as a result, only 88 studies were left for full-text review. Finally, only 28 studies (including 21 case-control and 7 cohort studies) were included, as shown in In the 28 studies, participants were children and young adults <29 years of age. Among the 21 case-control studies –9, 20–36I2 27.6%). Compared with the NBW population, the HBW population might have an increased risk of leukemia . The potential publication bias was evaluated by the funnel plot, as shown in p = 1.00) and Egger's (p = 0.881) tests did not reveal any evidence of publication bias. Moreover, sensitivity analysis was conducted by removing one study each time, and the pooled results showed little change, as shown in As presented in I2 0% for LBW; RR 1.27, 95% CI 0.89–1.83; I2 31% for HBW), respectively, as presented in Compared with the NBW population, no obvious evidence was detected between LBW/HBW and the risk of leukemia from the pooled analysis of 4 cohort studies . However, compared with the NBW population, the HBW population might have an increased risk of ALL . In addition, the publication bias was evaluated by the funnel plot, as presented in p = 0.203) and Egger's (p = 0.256) tests revealed no obvious evidence of publication bias. Also, sensitivity analysis was conducted by removing one study each time, and the pooled results showed slight change, as shown in It was demonstrated from I2 0%), and the HBW population had an increased risk of ALL , as observed from Similar results were obtained the pooled analysis of cohort studies, suggesting that the LBW population had a decreased risk of ALL compared with the NBW population . Similarly, compared with the NBW population, the HBW population was not associated with an increased risk of AML . Besides, the publication bias was assessed by the funnel plot, as displayed in p = 0.650) and Egger's (p = 0.434) tests did not indicate any evidence of publication bias. Also, sensitivity analysis was conducted by removing one study each time, and the pooled results showed little change, as shown in In I2 0%), as observed from Results from the pooled analysis of cohort studies demonstrated that the HBW population had an increased risk of AML compared with the NBW population  and maternal characteristics  on our results remained to be further confirmed. Although all of the extracted ORs or RRs were adjusted by the maximum variables, the effects of residual confounding variables were still unknown. Third, the dose-response analyses on birth weight were conducted within the range of 1,750–5,000 g, and the results beyond this range were still unknown. Last but not least, all the populations included in the study were children and young adults (<29 years), and the effect of birth weight on the risk of leukemia beyond this range is still unknown.Overall, in children and young adults, HBW may be related to an increased risk of subsequent leukemia and AML in HBW population compared with the NBW population, but support from dose-dependent evidence is lacking. In addition, stronger evidence supports a significantly increased risk of subsequent ALL in the HBW population compared with the NBW population, whereas a decreased risk in the LBW population, and this association is also found in the dose-response. More prospective studies with large samples are still warranted in the future to validate and complement these findings.The original contributions presented in the study are included in the article/HC participated in the data collection, data review, relevant data extraction, data analysis, statistical analysis, and the writing of the manuscript. DL, QS, and YL participated in checking data extraction as well as in the data analysis, statistical analysis, and the writing of the manuscript. LW participated in checking data extraction as well as in the statistical analysis and the writing of the manuscript. All authors saw and approved the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Meta-analysis is a powerful and important tool to synthesize the literature about a research topic. Like other kinds of research, meta-analyses must be reproducible to be compliant with the principles of the scientific method. Furthermore, reproducible meta-analyses can be easily updated with new data and reanalysed applying new and more refined analysis techniques. We attempted to empirically assess the prevalence of transparency and reproducibility-related reporting practices in published meta-analyses from clinical psychology by examining a random sample of 100 meta-analyses. Our purpose was to identify the key points that could be improved, with the aim of providing some recommendations for carrying out reproducible meta-analyses. We conducted a meta-review of meta-analyses of psychological interventions published between 2000 and 2020. We searched PubMed, PsycInfo and Web of Science databases. A structured coding form to assess transparency indicators was created based on previous studies and existing meta-analysis guidelines. We found major issues concerning: completely reproducible search procedures report, specification of the exact method to compute effect sizes, choice of weighting factors and estimators, lack of availability of the raw statistics used to compute the effect size and of interoperability of available data, and practically total absence of analysis script code sharing. Based on our findings, we conclude with recommendations intended to improve the transparency, openness, and reproducibility-related reporting practices of meta-analyses in clinical psychology and related areas. Systematic reviews and meta-analyses are commonly ranked among the most relevant sources of scientific evidence on the effectiveness of healthcare interventions Evans, , and theThe past decade has revealed significant problems in terms of replicability and reproducibility in psychological research, leading to the so-called replication crisis McNutt, . In thisSeveral efforts have been made to evaluate the replicability of findings from psychology and related fields  at least one meta-analysis focused on the effectiveness of psychological intervention/s was reported; (b) publication year after 1999; (c) the effect size index was a mean difference or a standardized mean difference; and (d) written in English or Spanish. Individual participant data meta-analyses and network meta-analyses were excluded from this study.Published meta-analyses of clinical psychological interventions were identified conducting a systematic electronic search in PubMed, Scopus, and the core collection of Web of Science. The search was carried out on 22 January 2020. The full search strategies followed in each database are available in Supplementary file 1: revtools’ .A total of 664 meta-analyses were identified by the electronic search and screening process. Of these, 100 were randomly selected using a random number generator between 1 and the total number of meta-analyses included, setting up a certain seed to guarantee the reproducibility of the process. Supplementary file 1 available at: https://www.osf.io/2dzmk/.A structured coding form was created based on previous studies  study ID and study characteristics (items 1-7); (b) preregistration, protocol, and the statement of compliance with guidelines (items 7–13); (c) identification and selection of studies (items 14–23); (d) data collection process (items 24–29); (e) effect or summary measures (items 30–35); (f) statistical methods (items 36–46); (g) data and script analysis availability (items 47–59); (h) conflict of interest and funding statement (items 60–61); and (i) access format of the paper (item 62).At a first stage, the coding form items were tested in a pilot coding. Four authors  independently applied the coding form to a random sample of five meta-analyses. Subsequently, in a series of meetings, disagreements between the coders were resolved by discussion until consensus was reached. During this process, items were modified or refined where necessary.https://osf.io/xg97b/. Inter-coder agreement was assessed with Cohen’s kappa coefficient, for close-ended items, using the R package ‘irr’ .Next, two authors (RLN and MRA) independently applied the coding form to the 100 meta-analyses randomly selected. The coding form was applied between 3 April and 29 May 2020. Discrepancies between the two coders were resolved by discussion and review of the relevant materials. The three data sets  are available at: , given the implications of this aspect for the efficient reusability of the data. Thus, six sub-items paired with items 50–55 were added. The formats were categorized as interoperable or not , preregistration (item 7), and use of reporting guidelines (item 12) as predictors, and the following dichotomous (or dichotomized by removing the ‘Other’ category) indicators as dependent variables: items 15 to 20, 22 to 32, 34, 36, 38 to 42, 44, and 50 to 55. We started fitting single predictor models to observe unadjusted associations, and then switched to multiple regression models introducing all three predictors to explore the associations for each predictor controlling for the others. We quantified the strength of the associations by calculating odds ratios and 95% confidence intervals based on profile likelihood. Despite the large number of contrasts performed, we did not introduce any corrections for multiple comparisons due to the exploratory nature of our analyses.‘tidyverse’ , whereas publication year for the selected random sample of 100 meta-analyses ranged between 2001 and 2020 (median = 2016).Of the 100 meta-analyses examined, 19 see Fig.  stated tWith regard to the statement of compliance to guidelines Fig. , 70 out Funding sources and competing interests could be a potential source of bias. Of the 100 meta-analyses reviewed, 13 see Fig.  stated oDetailed and complete reporting of the search and screening procedures allows the assessment of the quality of the procedure and facilitates replication. We excluded one meta-analysis because it consisted of a reanalysis of a previous meta-analysis. Thus, this meta-analysis was excluded from the analysis of the items concerning electronic search (items 14 to 20). All the remaining 99 meta-analyses specified the electronic databases consulted Fig. ; of thesAmong the 100 meta-analyses examined, 96 Fig.  specifieThe data collection process should be detailed, including the methods for dealing with missing data and for assessing risk of bias in the included studies, so that the accuracy of the extracted data and their validity can be evaluated. Of the 100 meta-analyses, 68 see Fig.  describeIdentifying the effect measure used and specifying the method to calculate it is crucial due to the existence of many different effect size measures as well as several approaches to calculate some of them  on the same participants, and ignoring it may result in underestimation of standard errors and erroneous statistical conclusions . Furthermore, of the total of 100 meta-analyses, only 30 stated the weighting factor used, whereas 85 mentioned methods to assess heterogeneity. Moreover, 65 meta-analyses described methods to assess the influence of possible moderator variables, but only 22 of these (34%) specified the statistical model assumed for the moderator analyses.The choice of statistical model and meta-analytic method may have an impact on the results and conclusions, hence the importance of reporting a detailed description of the statistical analysis approach ; of these, 61 (84%) reported a funnel plot, 34 (47%) applied the trim-and-fill method, 31 (42%) used the Egger test, 24 (33%) applied some form of the fail-safe-N method, 13 (18%) used the Begg and Mazumdar test, and only one used PET-PEESE and p-uniform methods.Most meta-analyses identified the software used to carry out the statistical analyses (89%); of these, 38 (43%) used Comprehensive Meta-Analysis, 24 (27%) used Review Manager, 20 (22%) used STATA, 12 (13%) used R, eight (9%) used SPSS, and six (7%) used other software.https://osf.io/.The unit of analysis of a meta-analysis is usually the primary study, so when we talk about data availability, we typically refer to the summary-level data  from each primary study included in each meta-analysis. In systematic reviews and meta-analyses, it is common to report the characteristics of the included studies, as well as through table or forest plots, the individual effects measures. The vast majority of the meta-analyses we examined . Availability of the analysis code, along with the data shared, enables to check computational reproducibility of the reported results. Unfortunately, only one of the meta-analyses we examined see Fig.  mentionehttps://osf.io/9xsg2/Several logistic regression models were fitted; for space-saving reasons only a selection of the results is presented in this section. The full results are available at: OR = 1.29 [95% CI: 1.12-1.54], the statistical model assumed (OR = 1.29 [95% CI: 1.08-1.60]), the methods to assess reporting biases (OR = 1.19 [95% CI: 1.06-1.35]), and the software used (OR = 1.19 [95% CI: 1.04-1.39]), with more recent studies providing a more detailed description of the methods used. Moreover, preregistered meta-analyses were more likely to specify the year for first date searched (OR = 13.27 [95% CI: 2.32-253.59]) and following reporting guidelines such as PRISMA was associated with a more complete report of the full search strategy (OR = 3.20 [95% CI: 1.07-11.08]) and the methods used for assessing risk of bias of the individual studies (OR = 6.50 [95% CI: 1.12-124.12]).Table The key points identified where a substantial lack of transparency was found concerning the potential reproducibility of the meta-analyses examined are summarized in Table The main aim of this study was to analyse the prevalence of transparency and reproducibility-related practices in meta-analyses on the effectiveness of clinical psychological interventions. A random sample of published meta-analyses on the effectiveness of clinical psychological interventions was reviewed. Additionally, the relationship between publication year, preregistration, and guidelines adherence and different indicators was assessed. A lack of transparency in key aspects for the reproducibility of meta-analyses was found.Regarding preregistration, the 19% of preregistered meta-analyses found in our meta-review is substantially higher than findings from previous studies mainly focused on primary research , more detailed information on this should be specified. Commonly, general references to handbooks have been found, but the specific computation method used should be specified with a mention to the page(s) where the calculation formula(e) can be found. Furthermore, multiplicity of results in primary studies is a common meta-analysis issue and the way to deal with it could have an impact on the meta-analytic model estimates (Maassen et al., Previous studies examined the reproducibility of primary effect sizes of a set of meta-analyses: Gøtzsche et al.  found prmetafor (Viechtbauer, reporter. This function generates a readable text format output with a draft analysis report based on a previously fitted rma.uni object. Such draft may be used as a starting point when writing up the meta-analytic report.Regarding synthesis methods, different analytic choices have to be made when a meta-analysis is carried out. As pointed in Table Along with a comprehensive description of the synthesis methods, the availability of open data is the next key aspect that enables the reproducibility of the results as well as checking their robustness. Previous studies found poor ratios of data sharing in primary research in different areas (Alsheikh-Ali et al., Previously, we discussed the relevance of a comprehensive description of synthesis methods to guarantee the reproducibility of the results. However, this form of verbal description is often lacking in detail or contains errors making reproducibility difficult (Hardwicke et al., metafor (Viechtbauer, https://osf.io/5nk92/.Nowadays, there are many options for analysis script sharing, allowing easy reproducibility and detection of potential errors. R (R Core Team, The prevalence of funding statements found in our meta-review of meta-analyses of psychological interventions was similar to those reported in the broader fields of psychology (Hardwicke, Thibault, et al., This study has some limitations. First, the time span covered is fairly wide. Thus, the obtained estimates may not capture the changes that have arisen in recent years. Due our focus on a highly specific area of research our primary goal was to capture general transparency and reproducibility-related practices over a wide time span, and then we subsequently attempted to assess possible variations over time using logistic regression models with publication year as a predictor. Therefore, additional research is needed to examine more specific changes over years. Second, our conclusions might not be generalizable beyond the area of clinical psychology. Additional research is needed to address these issues in different meta-analytic contexts. Third, this study was not preregistered. Although the nature of our analyses is strictly exploratory, there are several benefits of preregistration for all kinds of studies, regardless of their design or aims—mainly regarding transparency in workflow and decision-making processes. We have attempted to address this gap by openly sharing all relevant material at the different stages of the study. Last, our results do not provide findings on the reproducibility of the meta-analyses reviewed, but on the prevalence of transparency and reproducibility-related practices. The reports were reviewed to assess the availability of necessary information and data to be able to check the reproducibility of a meta-analysis. Further research is needed that specifically addresses the analytic reproducibility of published meta-analyses in different research areas.Our findings show a relatively better level of transparency and reproducibility-related practices across meta-analyses on the effectiveness of psychological interventions compared to more general fields or research areas. Nevertheless, some gaps were found in key aspects, including full reproducible search, level of detail on statistical methods, availability and interoperability of relevant raw data, and script analysis code sharing. Nowadays, meta-analysis is widely considered as the best source of scientific evidence (e. g., OCEBM Levels of Evidence Working Group,