Autoimmunity has been implicated in some patients with idiopathic chronic urticaria (CU). Because of the frequency of autoimmune thyroid diseases, their association with CU deserves special attention. We tested both the existence and the extent of an association between thyroid autoimmunity and CU.I2 tests, and the odds ratio (OR) for TPOAbs positivity was combined using random-effects models.A thorough search of PubMed, Scopus, Web of Science, and Cochrane databases was performed. Studies reporting the positivity rate for anti-thyroperoxidase antibodies (TPOAbs) in people with (cases) and without CU (controls) were included. Quality of the studies was assessed by the Newcastle–Ottawa Scale. Between-study heterogeneity was assessed by Cochrane Q and P < 0.00001). Correction for publication bias had a negligible effect on the overall estimate . Between‑study heterogeneity was established  and when, according to meta‑regression models, a sensitivity analysis was restricted to the 16 studies with the highest quality scores, the OR for TPOAbs positivity rose to 6.72  with no significant heterogeneity .Nineteen studies provided information about TPOAbs positivity on 14,351 patients with CU and 12,404 controls. The pooled estimate indicated a more than fivefold increased risk of exhibiting TPOAbs positivity in the group with CU (pooled OR 5.18, 95% CI 3.27, 8.22; Patients with CU have a five-to-nearly sevenfold higher risk of displaying TPOAbs positivity. All patients with CU may well be offered a screening for thyroid autoimmunity.The online version contains supplementary material available at 10.1007/s40618-022-01761-2. The term “urticaria” is widely used to define a skin manifestation characterized by the onset of itchy, fleeting wheals of variable size, shape, and distribution. These features arise from a series of pathophysiological events, including vasodilation, increased blood flow, and vascular permeability related to the activation and degranulation of mast cells, a process that can reflect both immunological and non-immunological mechanisms. Using a temporal criterion, urticaria can be classified into acute and chronic: in chronic urticaria (CU), manifestations occur daily or nearly daily and last for more than 6 weeks , 2. In aThe association between CU and Hashimoto’s thyroiditis was first described in 1983 by Leznoff and colleagues , who demOn this basis, we carried out a systematic review and meta-analysis of the available case–control studies to comprehensively assess the overall risk of thyroid autoimmunity in people with diagnosis of CU.The meta-analysis was conducted according to the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement ; it alsoThe study protocol was registered in the international prospective registry for systematic reviews (PROSPERO) with registration number: CRD42021274422.A systematic search was performed in PubMed, SCOPUS, Web of Science, and Cochrane Library, including the following free and vocabulary terms: “thyroid autoimmunit*”, “autoimmune thyroid disease*”, “TPOAb*”, “anti-thyroperoxidase antibod*”, “urticaria”, using the Boolean functions AND/OR. The search was restricted to English language, published up to December 2021. If it was not clear from the abstract whether the study contained relevant data, the full text was retrieved. The reference lists of the identified papers were also scrutinized to find possible additional pertinent studies.The outcome of interest was the relationship between CU and positivity for TPOAbs. The eligibility criteria were the following: (1) observational case–control studies, enrolling patients with (cases) and without CU (controls); (2) availability of odds ratio (OR) for having TPOAbs positivity or data for its calculation in both groups. Duplicates were rigorously checked and removed. Studies with missing/incomplete or unsuitable data or lacking to assess the outcome of interest were excluded. Three independent reviewers  assessed the eligibility of each selected paper; any disagreement was resolved via discussion involving a fourth reviewer (A.B.).Data were extracted from the selected articles by including the first author, publication year, geographic region, mean age of participants, the number of events (TPOAbs positivity), and the total number of participants in cases and controls. Additional information, such as TPOAbs assay methods and positivity cut-offs, male-to-female ratio, levels of thyroid stimulating hormone (TSH), percentages of patients with thyroid dysfunction (hypo- and hyperthyroidism), and/or severe urticaria (angioedema), was also extracted when available. Where data were missing or inconsistent, the authors were contacted to obtain the necessary information.The quality of the studies was assessed using the Newcastle–Ottawa Scale (NOS) . The scoχ2 (Cochran’s Q) and I2 tests were carried out to analyze statistical heterogeneity between the results of different studies. I2 > 50% and/or P < 0.05 indicated substantial heterogeneity.The relationship between thyroid autoimmunity and CU was assessed by calculating the aggregate OR (95% CI) for TPOAbs positivity comparing cases and controls. Mantel–Haenszel estimates were combined in a random-effects model , which iPublication bias was explored through the funnel plot  and the To detect possible sources of the between-study heterogeneity, available covariates that could affect the estimates were included in linear meta-regression models.Data were analyzed using the R statistical software , using the “metafor” package, and the Review Manager (RevMan) of the Cochrane Library .The electronic search yielded a total of 684 articles. After removal of duplicates, 389 articles were obtained, of which 361 were excluded, because they were deemed irrelevant based on title and/or abstract reading. Thus, as shown in Fig. Details of the main characteristics of the papers included in the quantitative analysis are shown in Table The quality rating of the studies, based on the NOS, is presented in Table P < 0.00001; Fig. I2 = 62%, Pfor heterogeneity = 0.0002).Overall, the 19 studies included in the meta-analysis provided information on 14,351 patients with CU (cases) and 12,404 subjects without CU (controls), resulting in an overall crude rate of TPOAbs positivity of 3.8%. The pooled OR indicated a more than fivefold increased risk of exhibiting TPOAbs positivity in the group with CU , the trim-and-fill test identified three putative missing studies on the left side of the distribution .The asymmetrical shape of the funnel plot Fig.  suggesteP = 0.001).As between-study heterogeneity in the pooled analysis was found Fig. , linear P < 0.00001) with decrease of heterogeneity to a no longer significant degree .As shown in Fig. The genesis of spontaneous CU has been considered idiopathic for many years, but the identification of autoantibodies in some patients has given rise to the new concept of “autoimmune urticaria” . In thisIn the present meta-analysis of 19 rigorously selected case–control studies, the diagnosis of CU was associated with an approximately fivefold higher risk of exhibiting positivity for TPOAbs, a marker of chronic autoimmune thyroiditis. In the analysis restricted to studies with higher quality scores, the OR of the association increased to 6.72  with a not significant heterogeneity.The mechanisms underlying the association between CU and thyroid autoimmunity are not fully elucidated. An immune-regulatory role of TSH would be supported by some evidence on the effect of levothyroxine treatment that, in some studies, led to improvements of urticaria clinical features , 42, 43,One of the pieces of evidence that mostly supports the autoimmune genesis of CU is based on the observation that 45% and 55% of patients with CU display anti-IgE and anti-FcεRI antibodies, respectively, whose titre exhibits a well-documented correlation with the positivity of the autologous serum skin test . The eviThis meta-analysis has some limitations. First, some potentially relevant studies were not included because of incomplete or unsuitable data. In this regard, only articles published in English language retrievable from well-recognized electronic databases were screened for eligibility. Nevertheless, when the analysis was restricted to TPOAbs, we included more studies than in the only other previously published meta-analysis on the topic . Second,In conclusion, people with CU have a five-to-nearly sevenfold higher odd of exhibiting TPOAbs positivity. From a clinical point of view, independently of the pathogenesis underlying such an association, this finding points to the opportunity to perform a screening for thyroid autoimmunity in the presence of CU. This approach could allow identification of patients with chronic autoimmune thyroiditis still in euthyroidism who could benefit from monitoring of TSH levels over time.Supplementary file1 (DOC 86 KB)Supplementary file2 (DOC 72 KB)Supplementary file3 (TIF 10368 KB) Supplementary Figure 1. Meta-regression bubble plot: odds ratio for having thyroid autoimmunity as a function of the quality score of the studies at the Newcastle-Ottawa Scale (NOS). The predicted effects (solid line) with corresponding confidence intervals (dashed lines) are also shown. Odds ratio values below 1 indicate a lower risk of thyroid autoimmunity in people with chronic urticaria; Odds ratio values above 1 indicate a higher risk of thyroid autoimmunity in people with chronic urticaria.Below is the link to the electronic supplementary material.


There is increasing evidence that left atrial appendage flow velocity (LAAFV) is linked to the recurrence of atrial fibrillation (AF) after catheter ablation (CA), suggesting the potential predictable significance of LAAFV in this setting. We performed a systematic review and meta-analysis to assess whether LAAFV is association with AF recurrence after CA.2 statistics. The Newcastle-Ottawa Scale (NOS) was used to assess the methodological quality of each included study, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method was adopted to evaluate the quality of evidence.Up to May 1, 2022, six databases  were searched for literature reporting the association between LAAFV and AF recurrence after CA. All statistical analyses were carried out using STATA version 16 software. Heterogeneity was determined by the Cochrane’s Q test and IP < 0.01]. Moreover, we evaluated the association of LAAFV and the risk of AF recurrence after CA. Nine studies (11 data sets) defined LAAFV as continuous variables, and the pooled analysis suggested that for every 1 cm/s rise in LAAFV values, the risk of AF recurrence after CA decreased by 3% . Seven studies defined LAAFV as categorical variables, and the pooled analysis showed that lower LAAFV were associated with an increased risk of AF recurrence after CA . The subgroup analyses showed that the association between LAAFV and AF recurrence after CA was not significantly affected by the AF type and ablation procedure. The NOS indicated that included studies were moderate to high quality, while the GRADE assessment suggested a low certainty of the evidence.Sixteen studies with 5,006 AF patients after CA  were included in the meta-analysis. The meta-analysis of 15 studies (16 data sets) showed that patients with recurrence exhibited lower LAAFV values than those without recurrence , identifier [CRD42022333627].[ Atrial fibrillation (AF), affecting more than 46.3 million individuals worldwide, is the most common sustained arrhythmia . As one This systematic review and meta-analysis was reported followed the criteria outlined in the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) and the PRISMA 2020 . The sysA systematic literature search was conducted independently by two investigators (Peng-fei Chen and Yu-jiao Shi) in six databases . We searched for English-language literature published up to May 1, 2022. The following search MESH terms and keywords were used: “left atrial appendage flow velocity,” “atrial fibrillation,” “catheter ablation,” “radiofrequency ablation,” “cryoablation,” “recurrence.” Detailed search strategies were shown in the Two investigators (Peng-fei Chen and Yu-jiao Shi) independently screened titles, abstracts, and full-text material to select eligible studies. The criteria for inclusion in this meta-analysis were as follows: (1) observational studies with at least 6 months and completeness of follow-up period; (2) the target population was patients with AF  after CA ; (3) comparing means and standard deviations (SDs) of LAAFV values in individuals with AF recurrence after CA to those without recurrence; and (4) reporting odds ratios (ORs) or hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) for LAAFV as a predictor of AF recurrence after CA. The abstracts, editorial, animal experiment, or review were excluded.Pre-specified data variables were extracted independently by two investigators (Peng-fei Chen and Yu-jiao Shi) using a standard form. The following information was extracted from the eligible literature: the first author’s name, publication year, study location, study design, baseline characteristics of patients , numbers of patients , LAAFV measurement method, blanking period in months, and follow-up duration in months.The quality of the included research was assessed according to the Newcastle-Ottawa Scale (NOS), an assessment tool focused on three aspects: participant selection, comparability, and exposure. The NOS score ranged from 0 to 9, with more than or equal to 8 stars defined as high quality, 6–8 stars as moderate quality, and less than 6 stars as low quality . To asseP < 0.1 was considered statistical heterogeneity) and I2 Statistics . We adopted a random-effect model for the meta-analysis because it incorporates the potential effects of heterogeneity and therefore allows for the retrieval of more generalizable results. Subgroup analyses were stratified by study location (Europe or Asia), study design (prospective or retrospective), sample size (≤100 or >100), AF type , ablation procedure , follow-up time (≤12 or >12 months), and ablation type . The inverted funnel plot and Egger’s test were performed to assess publication bias. Sensitivity analyses by removing one individual study at a time to confirm the robustness of the results. All statistical analyses were carried out using STATA version 16 software.In the analysis of LAAFV values in AF patients with and without recurrence after CA, means and SDs of LAAFV values were extracted, and standardized mean difference (SMD) and 95% CI were calculated for each study. In analyzing the association between LAAFV and the risk of AF recurrence after CA, univariate or multivariate ORs for AF recurrence reported by logistic regression analysis were extracted. For the study that only reported HRs, HRs was adopted as the best estimate of ORs. Since the studies included in this meta-analysis used LAAFV values as either a categorical or continuous variable to evaluate ORs, two separate meta-analyses were conducted for both variables. Heterogeneity was assessed by the Cochrane’s Q test , indicating moderate to high quality. Detailed quality assessment is presented in According to the GRADE grade system, the evidence supporting the link between LAAFV and AF recurrence following CA was of low certainty. n = 1,349) and without  AF recurrence after CA. Patients with recurrence exhibited lower LAAFV values than those without recurrence [SMD:−0.65, 95% CI: −0.88 to −0.42, P < 0.01; 2I = 87.9% P-value of Egger’s test was 0.12 , and pulmonary vein isolation (PVI) is the cornerstone of CA. Although the surgical effect is satisfactory, the long-term recurrence rate post-operative remains high, because non-PV areas other than PVI may be the source of initiation and maintenance of AF –30. The Left atrial remodeling, including LA enlargement, hypertrophy, and/or fibrosis is the basis of AF recurrence . MoreoveAlthough there have been many studies on the relationship between LAAFV and AF recurrence after CA, how to determine the cut-off value of LAAFV is a crucial question to be answered. In our meta-analysis, the cut-off values of the seven studies that defined LAAFV as categorical variables were displayed in To our knowledge, this is the first meta-analysis to summarize the association between the LAAFV and AF recurrence after CA. The advantages of the meta-analysis may include the following. First, the results of this study were relatively stable and reliable because the meta-analysis covered studies from different countries and had a large sample size. Second, the finding that LAAFV is associated with the risk of AF recurrence after CA was based on most adequately adjusted ORs, suggesting that the finding may not be affected by potential confounding factors. Third, studies with LAAFV analyzed as categorized and continuous data were summarized separately and derived consistent results, which further verified the stability of the results. Fourth, the sensitivity analyses by removing one individual study at a time had no significant impact on the results, suggesting the outcomes were credible. Fifth, multiple subgroup analyses were conducted to assess the potential study characteristics of the relationship between LAAFV and AF recurrence after CA.However, this meta-analysis also had some limitations. First, as a meta-analysis of observational studies, it carries inherent limitations of the study design. Second, the heterogeneity of our study was significant. Even if sensitivity and subgroup analyses were adopted, the origin of heterogeneity could not be explored. Third, we cannot rule out that some residual factors may confuse the link between LAAFV and AF recurrence. Forth, studies that defined LAAFV as categorical variables have different cut-off values, which would impact our study result.Meta-analyses of observational studies show that patients with AF recurrence after CA have lower mean LAAFV values than patients without recurrence. Lower LAAFV was associated with an increased risk of AF recurrence after CA, and the assessment of LAAFV before CA could be used as a potential and feasible screening method to predict the risk of AF recurrence. Further studies with larger, well designed, and randomized studies with longer follow up periods for LAAFV should be conducted. In addition, the mechanism of LAAFV and AF recurrences remains to be further explored.The original contributions presented in this study are included in the article/JD and ZC were involved in conceptualization and supervision. PC, LM, and XG collected, analyzed, and interpreted the data. PC, YS, and DP drew pictures and wrote the original draft. JJ and JD edited and modified the final version. All authors contributed to the article and approved the submitted version.


The fixed-effects model revealed a significant pooled correlation coefficient  between seminal ORP and SDF. Furthermore, subgroup analyses indicated that the pooled correlation coefficient between ORP and sperm chromatin dispersion (SCD) assay was less than other SDF assays (0.23 vs. 0.29). There was a moderate level of heterogeneity (I2 = 42.27%) among the studies, indicating a lack of publication bias. This is the first meta-analysis to reveal a positive correlation between seminal ORP and SDF. Furthermore, this study indicates the role of oxidative stress in the development of sperm DNA damage and thus warrants prospectively exploring the clinical value of these sperm function tests.Seminal oxidative stress and sperm DNA damage are potential etiologies of male factor infertility. The present study aims to evaluate the relationship between oxidation-reduction potential (ORP), a measure of oxidative stress, and sperm DNA fragmentation (SDF) by conducting a systematic review and meta-analysis of relevant clinical data. A literature search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The COVIDENCE tool was used to screen and identify studies evaluating seminal ORP and SDF. Studies ( Infertility affects 8–12% of couples of reproductive age, with the male component being implicated as the causative factor in up to 50% of cases . About 3Sperm DNA integrity is vital for fertilization and embryo development . One of Suitable keywords were used to retrieve articles reporting both seminal oxidative stress and sperm DNA damage from databases such as PubMed, Web of Science, and Embase . In AuguA modified Newcastle-Ottawa Scale was used to assess the quality of studies included in this analysis . Two inv2 statistics were used to assess heterogeneity of effect sizes. A forest plot was produced to visually assess the correlation and corresponding 95% confidence intervals across studies. A subgroup analysis was conducted according to the SDF method to test whether the SDF method impacted the correlation between seminal ORP and sperm DNA damage. The SDF method was separated into two groups (a) sperm chromatin dispersion (SCD) and (b) other SDF methods that included terminal deoxynucleotidyl transferase (dUTP) nick end labelling (TUNEL) and sperm chromatin structure assay (SCSA). Possible publication bias was assessed by visual inspection of the funnel plot and the trim-and-fill method [Statistical analysis was conducted by using STATA statistical software version 12.0 . The Pearson correlation coefficient between seminal ORP and sperm DNA damage served as the effect size for synthesis. The correlation for each study was weighted by the inverse of its variance. Correlation coefficients and their standard errors were transformed to the Fisher’s z scale for meta-analysis. All results were converted back to correlations for reporting. Fisher’s z-transformed correlations were pooled by using the fixed-effects model, due to insignificant heterogeneity among effect sizes. Q and Il method .n = 119)  . Based on = 5) were of good quality according to the modified Newcastle-Ottawa Scale, although others (n = 2) showed some concerns and were of fair quality . The z value of the test ES = 0 was 14.18, p < 0.001. Therefore, the pooled effect size estimation was significant (p < 0.05).The fixed-effects model revealed that the pooled correlation coefficient between seminal ORP and SDF was 0.24 , as presented in b (1) = 1.19, p = 0.27). There was a moderate level of heterogeneity (I2 = 42.27%) among the studies; however, this was not significant (p = 0.10).Results of the subgroup analysis are presented in Visual inspection of the Funnel plot indicated a lack of publication bias, as there was symmetry . The disThe evaluation of male factor fertility potential is primarily based on physical examination and conventional semen analysis, as recommended by the World Health Organization (WHO) . However6 sperm/ ml has been established based on a multicenter study to differentiate men with normal and abnormal semen parameters [Oxidative stress plays a major role in the pathophysiology of male infertility caused by various clinical, environmental, and lifestyle factors ,26,27. Arameters ,30. Men ORP and sperm DNA damage were correlated with poor sperm parameters in men with infertility ,33,34,35The current meta-analysis has certain limitations. Some studies had low sample size (or) reported variation among the subjects (or) weak correlation between ORP and SDF (or) lack of uniformity among assays used for DNA damage detection. In addition, there is a lack of information in regard to infertility duration, treatment, hormonal levels, history of genitourinary inflammation (GUI), lifestyle factors, etc. All these are likely to affect the SDF and ORP values. Despite these limitations, our findings are conclusive due to the inclusion of >3000 patients with male factor infertility issues. Furthermore, a majority of the studies included are of good quality according to the modified Newcastle-Ottawa Scale. A major strength of our meta-analysis is that there is a moderate degree of heterogeneity among the studies with no publication bias.This study is the first meta-analysis to evaluate the relationship between the newer seminal oxidative stress markers, mainly ORP and sperm DNA damage. The analysis revealed a positive correlation between seminal ORP and SDF. Furthermore, this study indicates the role of oxidative stress in the development of sperm DNA damage and thus warrants prospectively exploring the clinical application of these tests as related to male infertility diagnosis and better treatment modalities.


A growing body of research suggests that inflammation and maternal infections may lead to an increased risk of neurodevelopmental problems such as attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), cerebral palsy (CP), and epilepsy in offspring. The aim of this study was to observe the connection between prenatal antibiotic exposure and the risk of these neurodevelopmental disorders in offspring.A comprehensive search was conducted in the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Google Scholar, and Scopus databases for observational studies that looked into the link between prenatal exposure to antibiotics and the risk of neurodevelopmental problems in offspring, published from 1 January 1950 to 31 January 2022. The Newcastle–Ottawa Scale (NOS) was used to assess the quality of the included studies. Data were analyzed using the STATA version 12 software, and an odds ratio (OR) with a 95% confidence interval (CI) was reported.I2 = 0%) and epilepsy . The link between prenatal antibiotic exposure and the risk of ASD  and CP  was found to be non-significant. In all of the included prospective cohort studies, subgroup analysis suggested a significant association between prenatal antibiotic exposure and the incidence of ASD  and CP .A total of 15 studies were included in the meta-analysis. Prenatal antibiotic exposure was associated with the increased risk of ADHD (OR = 1.14; 95% CI = 1.13 to 1.15; Prenatal antibiotic exposure during pregnancy is linked to a higher incidence of ADHD and epilepsy in the offspring. Further prospective studies that compare prenatal antibiotic use and are adjusted for various confounders are needed to further assess the association of prenatal antibiotic exposure and neurological disorders in offspring.https://www.crd.york.ac.uk/prospero/, identifier: CRD42022306248. A higher risk of neurological disorders has been related to severe viral and bacterial infections, as well as infections caused by parasites, particularly in hospitalized patients –3. ContiNumerous studies demonstrated that maternal infections and inflammation influence the development of the fetal brain, raising the chance of mental disorders, with a focus on neurodevelopmental diseases , 12–14. Antibiotic exposure during pregnancy has been linked to the likelihood of ASD  and ADHDThis study involves a systematic review and meta-analysis for critical assessment and evaluation of all published reports that evaluate the association of prenatal antibiotic exposure with the risk of neurodevelopmental problems in offspring.No ethical approval is needed for this systematic review and meta-analysis, as it was based on already published data.We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement  to condu(a) Observational studies investigating the effect of prenatal antibiotic exposure and the risk of neurodevelopmental disorders in offspring. (b) Children diagnosed with any one of the neurodevelopmental disorders including ASD, ADHD, CP, and epilepsy based on prenatal antibiotic exposure. (c) The Control group defined as Offspring with no diagnosis of any neurodevelopmental or other psychiatric or genetic disorders.(a) Duplicate studies, systematic reviews, editorials, case series, case reports, conference abstracts, and preprints. (b) Studies that do not describe required outcomes. (c) Unavailability of full texts. (d) Animal studies. (e) Gray literature  and ongoing studies.This systematic review was performed following the guidelines of the PRISMA  and CochData were collected independently by two reviewers and included author name, country, study period, publication year, study design, diagnostic criteria, exposure assessment, sample size, age at the time of antibiotic exposure, outcomes, and crude or adjusted estimates for disease occurrence.Two authors independently assessed the risk of bias using the Newcastle Ottawa Scale (NOS) . This scI2 statistic was used to calculate heterogeneity  with a 95% confidence interval (CI) was generated. The ogeneity . This teAs seen in Fifteen observational studies , 27–34 iFour studies reported international disease classification (ICD)-10 criteria, one study used ICD-9, three studies used medical history, and two studies used American academy of pediatrics guidelines as the diagnostic criteria for defining neurodevelopmental disorders. The detailed classes for the antibiotic exposed in all the included studies are represented in I2 = 78.9%]. Only prospective cohort studies found a significant relationship with the pooled OR of 1.17  in the subgroup analysis based on the study design.Six studies, including three prospective cohort studies , 18, 29,I2 = 0%]. However, subgroup analysis showed a borderline risk of ASD in the prospective cohort  and a strong association for the risk of ASD in the retrospective cohort . Subgroup analysis suggested a significant association between prenatal antibiotic exposure and the risk of CP  in all three included prospective cohort studies but not in the retrospective studies . However, these associations were not significant in the subgroup analysis in both prospective  and retrospective studies [OR = 1.84, 95% CI = 0.70 to 2.97, Five studies including three prospective cohort studies , 31, 32 Egger test and Begg's funnel plot were used to analyzing publication bias for all 15 included studies in our meta-analysis. There was no discernible asymmetry in any included neurodevelopmental disorders based on the visual assessment of the funnel plot . We founSensitivity analyses were performed to see how each individual study of each neurodevelopmental disorder affected the pooled ORs by omitting individual included studies one at a time. Deleting any individual study did not significantly change the associated pooled ORs , furtherInfections have long been linked to aberrant prenatal brain development, and negative outcomes include cerebral palsy , developTo the best of our knowledge, this is the first systematic review and meta-analysis to examine the link between antibiotic exposure and the risk of neurodevelopmental disorders such as autism, ADHD, CP, and epilepsy. Our findings show a strong connection between prenatal antibiotic exposure and the risk of ADHD and epilepsy. However, we found no significant association between antibiotic exposure during pregnancy and the risk of ASD and CP. While further subgroup analysis based on the type of studies showed a significant correlation between prenatal antibiotic exposure and the risk of ASD and CP in the included prospective cohorts, no such association was found in retrospective studies.Our findings are consistent with the previously published meta-analysis by Lee et al.  for ASD Lee et al.  concludeIn the present meta-analysis, we found a substantial association between prenatal antibiotic exposure and the risk of CP and ASD, as well as an overall association with ADHD and epilepsy. Our results show a strong association between prenatal antibiotic exposure with the increased risk of ADHD and epilepsy development. While our combined results did not indicate that there is a substantial relationship between maternal antibiotic treatment and incidences of ASD and CP in offspring, this association was significant in prospective cohort studies. This could be because neurodevelopmental diseases have multiple causes. For example, non-genetic causes account for 70% of cerebral palsy cases, whereas genetic variables account for 60–70% of epilepsy, ADHD, and ASD cases –56.Our systematic review and meta-analysis have some limitations, and therefore, results must be interpreted with caution. Only a limited number of published studies investigated a high degree of heterogeneity between study outcomes. This may be due to the inclusion of studies with different study designs leading to recall bias for the observed findings. Variability in the available outcomes, such as the type, number, and timing of antibiotic exposures among the included studies, limited our ability to perform further subgroup analyses. Due to the lack of genetic predisposition data, we were not able to correlate our findings with antibiotic exposure.Our data show that prenatal antibiotic exposure during pregnancy is linked to a higher incidence of ADHD and epilepsy in children. Further prospective studies, comparing prenatal antibiotic use with adjustment for various confounders, are needed.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.QT and YS analyzed the data and contributed to the writing of the manuscript. YL, HL, and MY contributed to the data collection and analysis. JG contributed to the substantial review and editing of the manuscript. All authors read and approved the final manuscript.This study was funded by a grant from the National Natural Science Foundation of China (No. 82071686), the Science and Technology Bureau of Sichuan province (No. 2021YFS0093), and the Research Fund of West China Second University Hospital .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.


A systematic evaluation of the diagnostic value of Ring finger protein 180 (RNF180) gene methylation as a novel tumor marker for gastric cancer (GC) is required to improve the early diagnosis of gastric cancer patients.Computer searches of PubMed, Web of Science, Embase, The Cochrane Library, CNKI, CBM, WanFang Data, National Research Register, Cclinical Controlled Trials, Opengrey and VIP databases were conducted from the database’s inception to September 1, 2022. Two researchers independently screened the literature, extracted information, and assessed the risk of bias in studies that were included. The meta-analysis was carried out using RevMan 5.3 and Stata 16.0 software.A total of 9 studies with a total of 1531 subjects were included. A random-effects meta-analysis revealed that the combined sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) of plasma RNF180 gene methylation for the diagnosis of GC were: 0.54 [95% CI ], 0.80 [95% CI ], 2.73 [95% CI ], 0.58 [95% CI ], 4.74 [95% CI ], respectively.The detection of RNF180 gene methylation in plasma has a high diagnostic value for GC and is expected to be a potential biomarker for the diagnosis of gastric cancer, according to current evidence. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=370903, identifier CRD42022370903. In 2020, the number of new cases surpassed 1 million, and the number of deaths surpassed 760,000, placing it fifth and fourth among global cancers in terms of incidence and mortality rates, respectively . HematolDNA methylation is an epigenetic mechanism that occurs through the covalent addition of methyl groups to DNA . DNA metvia the ubiquitin-proteasome system (UPS), RNF180 participates in several biological processes including apoptosis, gene transcription, and DNA repair (Ring finger protein 180 (RNF180) is a tumor suppressor gene located on the long arm of chromosome 5. RINES is an E3 ring finger protein with ubiquitin ligase activity, produced by the gene encoding RNF180 . By mediA repair , 11, 12.A repair –17. ReceA repair . RNF180 A repair . AccordiThere is a paucity of evidence-based medical evidence about the diagnostic effectiveness of RNF180 gene methylation in the diagnosis of gastric cancer. To establish a reference basis for early clinical screening of gastric cancer, this study aims to comprehensively compile the current studies investigating the relationship between RNF180 gene methylation and gastric cancer diagnosis. This will allow for a systematic evaluation of the feasibility of the plasma RNF180 gene methylation test as a diagnostic biomarker for gastric cancer.2The Preferred Reporting Items for Systematic Reviews and Meta-Analyses on Diagnostic Test Accuracy (PRISMA-DTA) were used to conduct this systematic review and meta-analysis. Our study has been registered with PROSPERO (registration number: CRD42022370903).2.1The following were the inclusion criteria: 1) Diagnostic accuracy studies. 2) Patients diagnosed with GC by the gold standard, regardless of age, gender or race. 3) Studies analyzing the relationship between RNF180 gene methylation status and gastric cancer. 4) Studies providing sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the summary receiver operating characteristic curve (SROC) (AUC).The following were the exclusion criteria: 1) Repeatedly published research. 2) Unable to obtain the full text or extract the data of the four-cell 2.2Computer searches of PubMed, Embase, The Cochrane Library, Web of Science, CNKI, WanFang Data, VIP, National Research Register, Clinical Controlled Trials, Opengrey and CBM databases were searched to collect clinical studies on plasma RNF180 gene methylation for the diagnosis of gastric cancer. The search time frames ranged from the database’s inception to September 1, 2022. In addition, to supplement access to relevant literature, a combination of Google Scholar and references from the included literature was used. The searches used a combination of subject terms and free terms. Using PubMed as an example, the search strategy is as follows: (Stomach Neoplasms OR gastric cancer OR gastric carcinoma OR stomach cancer OR Stomach Neoplasm OR stomach carcinoma OR gastric adenocarcinoma) OR ((gastric OR stomach) AND )) AND (rnf180 OR rines OR ring finger protein 180)) AND (methylation).2.3Two researchers independently screened the literature, and extracted and cross-checked the data based on the inclusion/exclusion criteria. Disagreements were settled through discussion or consultation with a third party. The title and abstract of the text were read first, and after excluding irrelevant literature, the full text was read again to determine inclusion. If information is missing from the study and data cannot be extracted, we contact the author by email to obtain the relevant information based on the email address of the corresponding author indicated in the included literature. The following data were extracted: 1) basic characteristics of the study: first author, year of publication, country, study type, sample size, and methylation detection method; 2) subject characteristics: gender, age, race, the amount of RNF180 methylation occurring in case and control groups, and source of the control group; 3) diagnostic information: sensitivity, specificity, and area under the curve (AUC).2.4Two investigators independently assessed the risk of bias in the included studies, and the results were cross-checked. The Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool was used to assess the risk of bias . Each bi2.52. If there was no significant heterogeneity among the results, Meta-analysis was performed using a fixed-effects model. If the study results were heterogeneous, the sources of heterogeneity were investigated further using meta-regression and subgroup analysis. After excluding the effects of significant heterogeneity, Meta-analysis was performed using a random-effects model. Publication bias between the included studies was evaluated by drawing Deek’s funnel plot (with P > 0.05 indicating no publication bias).The combined sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were calculated using RevMan 5.3 and Stata 16.0 software, and the hierarchical summary receive operating characteristic was plotted (HSROC). The Fagan nomogram was used to calculate the positive post-test probability (PPP) and negative post-test probability (NPP). The χ2 test (α=0.05) was used to assess heterogeneity between the results of each study, and the magnitude of heterogeneity was quantified by combining I33.1For the initial review, 95 relevant pieces of literature were obtained. Following the layer-by-layer screening, 9 studies on diagnostic accuracy with 1531 subjects were finally included , 24–29. 3.23.3None of the included studies met all domain criteria of the QUADAS-2 methodological quality tool. On average, each study met two of the four risks of bias domains. The case-control design and inappropriate exclusions (for specific diagnoses) explain why almost no studies had low risk in the domains of patient selection and index testing. One study was rated as high risk in the area of patient selection because the exact time frame and continuity were not mentioned. All articles met the applicability criteria for all three domains of concern Figure 23.4The included studies showed relatively high heterogeneity in terms of sensitivity and specificity (I²=82.48 and I²=89.83) using a random effects model, and Meta-analysis showed that SEN=0. 54 [95% CI ], SPE=0.80 [95% CI ], PLR=2.73 [95% CI ], NLR=0.58 [95% CI ], DOR=4.74 [95% CI ] Figure 3When defining a pretest probability of 0.50 for RNF180 methylation to diagnose gastric cancer, the PPP and NPP were 73% and 37%, respectively , suggesting a small possibility of publication bias Figure 64Due to a lack of timely physical examinations and/or limitations in the level of early diagnosis, gastric cancer remains one of the major threats to human health. Although gastroscopic biopsy is currently an effective method for the early detection of gastric cancer, endoscopic clinicians must have a high level of operational and pathological experience to perform the test. Furthermore, the biopsy is difficult to detect subtle lesions, and there is a risk of internal bleeding and perforation due to irregular surgical procedures. To address these issues, an increasing number of diagnostic studies are focusing on the discovery of tumor biomarkers and the development of molecular biology instrumentation . BecauseP=0.194, indicating that the SROC was symmetric. In this study, Lambda, an effect index representing diagnostic test discriminatory capacity, was 1.38 , indicating that the RNF180 gene methylation test has a relatively high diagnostic accuracy in gastric cancer diagnosis. For clinical decision-making, likelihood ratios and posterior probability are preferable. Because of the heterogeneity among studies, we conducted Meta-regression and subgroup analysis to explore the sources of heterogeneity. When subgroup analysis was performed on study design, method of detecting methylation, sample size, and source of control group, the within-group heterogeneity was still large, and the above factors could not explain the heterogeneity among studies well. Combined with the full text, the possible sources of heterogeneity were considered to be the different RNF180 methylation cutoff values among the included studies. However, some studies did not report the selection method of cutoff values and explain its rationality, resulting in the inability to further identify the sources of heterogeneity. Although the funnel plot showed a low likelihood of publication bias, the accuracy of the study results may have been compromised because the gray literature was not retrieved.The RNF180 methylation test had a specificity of 0.80 (95% CI: 0.72 - 0.87) in distinguishing gastric cancer patients from controls in our meta-analysis of 1531 participants from 9 research. However, its sensitivity was only 0.54 (95% CI: 0.45 - 0.62), which could be attributed to the confinement of lesions to localized areas and the insufficient amount of circulating free DNA that undergoes methylation in plasma, limiting its diagnostic value in the screening of gastric cancer . DespiteIn conclusion, the results of this study showed that the plasma RNF180 gene methylation test is more realistic and reliable in assisting gastric cancer diagnosis, which fully demonstrated its important role in gastric cancer diagnosis. Therefore, the RNF180 gene methylation test is an effective predictive biomarker for gastric cancer. It can be used as a screening tool for gastric cancer, especially for subjects with poor physical conditions and unable to tolerate gastroscopy. This is the first systematic review and meta-analysis of plasma RNF180 gene methylation in gastric cancer diagnosis. The findings show that RNF180 gene methylation has a high specificity but a low sensitivity, which can lead to missed diagnoses and has limitations in clinical application and practice. To provide a better reference for clinical decision-making, clinical attention should be paid to the comprehensive analysis and judgment of plasma tumor markers, traditional imaging detection, and histopathological findings. Furthermore, the current clinical studies have a high quality of evidence, according to QUADAS-2, and thus the results of this study are reliable. Meanwhile, the consistency of the sensitivity analysis results, fully supported the reliability of our findings.Several shortcomings of this study are worth considering: 1) All samples and related statistics are from China, and regional bias may exist, so the influence of ethnic and geographical factors on the selection bias of the study population cannot be excluded; 2) gray literature and conference abstracts were not retrieved, which may be led to publication bias; 3) The number of included studies was small and their quality was average, which to some extent reduced the credibility of the Meta-analysis results.5The discovery of promising biomarkers is critical for early detection and diagnosis of gastric cancer. The methylation status of RNF180 gene has diagnostic value for gastric cancer and has the potential to be used as a new tumor marker for the diagnosis of gastric cancer in clinical practice, according to our meta-analysis results based on nine studies. However, due to the current studies’ quality and quantity limitations, the conclusions drawn from a systematic review should therefore be interpreted cautiously, more high-quality studies are required in the future to further investigate the relationship between RNF180 gene methylation and gastric cancer.The original contributions presented in the study are included in the article/TW contributed to the conception and design, acquired and interpreted the data, and critically revised the manuscript. YZ contributed to the conception, analysis, and drafting of the manuscript. JW contributed to the design, interpreted the data, and drafted the manuscript. YL critically revised the manuscript. All authors contributed to the article and approved the submitted version


The present study aimed to quantify the effects of fermented soybean meal (FSBM) on broiler chickens’ performance by employing a meta-analysis approach.g effect size was used to quantify pooled standardized mean difference (SMD) using random-effects models at 95% confidence intervals (95% CI). Publication bias among studies was computed with Egger’s test and visualized using funnel plots.A total of 16 studies were included in the database after being systematically selected using a PRISMA protocol. Hedges’ Aspergillus oryzae, mixed probiotics+bromelain protease, Bacillus subtilis, and Lactobacillus bacteria significantly increased ADG and FI (p<0.01). Additionally, either Bacillus subtilis+protease or Bacillus subtilis alone decreased FCR (p<0.001). However, meta-regression analysis showed that levels of FSBM inclusion had no effects on final BW (p = 0.502), ADG (p = 0.588), FI (p = 0.861), and FCR (p = 0.462).Results indicated that dietary FSBM inclusion increased final body weight (BW)  of broiler chickens, particularly in starter period  while in the finisher period, the effect was weaker . Average daily gain (ADG), feed intake (FI), and feed conversion ratio (FCR) were not affected with FSBM inclusion when compared to control. Subgroup analysis revealed that FI increased in starter period . When considering types of microorganism as moderating variables in the subgroup analysis, we found that Substituting SBM in broiler chickens’ diet with FSBM improved BW of broiler chickens, especially in the starter period whereas the effects on ADG, FI, and FCR were mostly dependent on microbial strains used for fermentation. Soybean meal (SBM) is a major contributor of protein and indispensable amino acids such as lysine, tryptophan, threonine, isoleucine, and valine in broiler diets . These nAspergillus niger, Aspergillus oryzae, Bacillus subtilis, and Lactobacillus group)  AND ("soybeans"[MeSH Terms] OR "soybeans"[All Fields] OR "soybean"[All Fields]) AND ) AND (broiler [All Fields] AND ("chickens"[MeSH Terms] OR "chickens"[All Fields])). All relevant titles of articles from the platforms were imported into the reference manager to easily select the papers.A literature search was performed on scientific digital platforms of Science Direct  protocol was employed to reduce publication bias and to ensure the quality of meta-analysis . AccordiIn total, 1,613 articles were detected by employing the above-mentioned strategy. A total of 365 papers were excluded because they were review articles (86), book chapters (147), Encyclopedia (23), and other non-relevant types of articles (109). Following this, 1,248 remaining papers were evaluated to meet the criteria. Two investigators (Niati Ningsih [NN] and Rahma Fitriastuti [RF]) reviewed the titles and abstracts of the papers and excluded non relevant publications from the imported database. Subsequently, two independent investigators (Agung Irawan [AI] and Adib Norma Respati [ANR]) reviewed the selected studies to assess the risk of publication bias among individual studies ,21. In thttps://apps.automeris.io/wpd/). The summary of the studies used for meta-analysis is presented in Information on the broiler chickens used , replication, study design, FSBM inclusion level including processing methods and microbes used for fermentation, country in which the experiment was carried out, and nutrient compositions of the diet in respective periods  such as metabolizable energy (ME), crude protein (CP), lysine, and methionine were retrieved from each paper into Microsoft Excel spreadsheet. The main outcomes used for meta-analysis were final BW (g), ADG (g/d), FI (g/bird/period), and FCR (g feed/g BW). Therefore, mean values including the corresponding variant (standard deviation [SD]) or standard error of the mean (SEM) of each unit of comparison were extracted. The SD value of each study was calculated from SEM using the formula: SD = SE×sqrt(n); where n = sample size or number of replicates, when the study only provided SE rather than SD value. When available, the values from graphical data were extracted by employing an extraction tool of WebPlotDigitizer ( meta and metafor packages [g and expressed as standardized mean differences (SMD) in a forest plot following a random-effects model at 95% confidence intervals (CIs). We considered Hedges’ g because it is easy to interpret and has strong statistical power which can control study bias that may occur in small sample sizes [g outcome estimates >0 with p≤0.05 show a significant higher on BW, ADG, FI, or FCR due to FSBM inclusion when compared to control. Heterogeneity index (I2) among studies was analyzed using the DerSimonian and the Laird test (Q-statistic) at a significance level p≤0.05. The degree of heterogeneity was categorized as no heterogeneity (0<I2≤25%), low (25%<I2≤50%), moderate (50%<I2≤75%), and high (I2>75%) [Meta-analysis was performed using the packages  availablle sizes . Hedges’(I2>75%) .g) of the outcome variables. In addition, subgroup analysis was also performed to quantify the effect sizes of several factors that may influence the magnitude of the effect size. In this study, rearing period (starter and finisher) and type of microbes used to ferment SBM were used in the subgroup meta-analysis using random effects models.Meta-regression was conducted to evaluate the relationship between FSBM inclusion levels with the effect size (Hedges’ I2) [In addition to the risk of bias from studies, publication bias was assessed by using funnel plots and the results are presented in I2)  and to dI2) .Bacillus subtilis was the most frequently used, corresponded to 57.14% of the studies, either in a single strain or mixed with other microorganisms. Other microorganisms applied for fermentation were fungi (Aspergillus niger and Aspergillus oryzae), yeast (Saccharomyces cerevisiae), and from lactic acid bacteria group such as Bacillus subtilis, Lactobacillus spp., Lactobacillus acidophilus, Lactobacillus plantarum, and Bacillus stearothermophilus. Information on the nutrient composition of each study was summarized and is presented in This study included 5,176 broiler chickens from various strains predominantly by Ross 308 (57.14%) while the rest were Arbor Acres (21.43%), Cobb 500 (14.29%), and Vencob (7.14%). A total of 35.71% of studies used either male or mixed sexes of broiler chickens while others were female (14.30%) and not given (14.30%). All studies used corn and soybean-based diet for their experiments. Inclusion levels of FSBM varied among studies, from 15 g/kg diet to 361 g/kg diet . In eachI2 statistic), subgroup analyzes were performed to indicate which factors mediating the effect sizes. Results from subgroup analysis based on rearing period showed that significant increase was more pronounced in the starter period (≤21 d)  compared to finisher period (>21)  with considerable between-study variations . In addition, most microbial fermentation resulted in a significant increase of final BW except for Aspergillus niger  and multiple strain microbes containing lactic acid bacteria and yeast .Summary of meta-analysis is presented in I2 = 66.3%, Q<0.001). Although there was no effect both in starter and finisher period, however, positive effects were detected corresponding to the FSBM with Aspergillus oryzae , Mixed probiotics+bromelain , Bacillus subtilis , and Lactobacillus microbes  . By contrast, SBM fermented with Bacillus stearothermophilus significantly decreased the ADG  with low level of heterogeneity .Results from the Egger’s test indicated that there was no publication bias (p>0.05) for BW, FI, and FCR among studies which was supported by symmetrical funnel plots . Howeverp<0.001)  in whichQ = 0.001) , but it did not affect FI in finisher period (p = 0.223). Subgroup analysis on microbes used in the fermentation process indicated that groups of Aspergillus oryzae, Bacillus subtilis +protease, and mixed of probiotics+bromelain were responsible for increasing the FI. Contrary effect was found on the use of Bacillus stearothermophilus which significantly reduced cumulative FI  with high heterogeneity .Of the 51 comparisons satisfying the inclusion criteria, treatment with FSBM did not alter FI  at the degree of heterogeneity of 85.9% (= 0.001) . HoweverBacillus subtilis+protease  or Bacillus subtilis alone  with no evidence of heterogeneity from these treatments . In contrast, treatment with probiotics containing LAB, yeast, and Bromelain protease significantly increased FCR of broiler chickens  with no heterogeneity .Grand estimates obtained from SMD suggested that SBM fermentation had no effect on FCR of broiler chickens . Restricted subgroup analysis on rearing periods also showed that FSBM did not influence FCR both in starter and finisher phase . Howeverg effect size from the outcome variables with the inclusion levels of FSBM in the diet as predictor variable considering there were wide ranges of inclusion rates of FSBM in the broiler diet . This is in line with the fact that in the starter period, FI substantially increased in broiler chickens fed a diet containing FSBM . More spB. subtilis, B. stearothermophilus, and Lactobacillus bacteria significantly reduced trypsin inhibitor by 33.6% to 100%, 74.0%, and >80%, respectively [B. subtilis+Enterococcus faecium and multiple strains of bacteria and yeast [Major explanations regarding beneficial effects of FSBM on broiler chickens were due to their effectiveness eliminating ANFs present in the SBM ,12,14,17ectively . In addiProteobacteria either with partial or total FSBM replacing SBM in broiler diets. In their study, Li et al [Firmicutes phylum was predominantly presented. Abundance of Firmicutes is a good indicator for increasing non-starch carbohydrates degrading enzymes activities and it was positively associated with improvement of animal performances [In addition, fermentation also significantly increased protein, peptide molecules, and AAs of SBM ,7,12,13.Li et al  also repormances ,40.Aspergillus oryzae consistently increased BW, ADG, and FI of broiler chickens but had no effect on FCR. Meanwhile, Bacillus subtilis and Bacillus subtilis+protease were effective to reduce FCR although the sample sizes with these groups were small. The main factors that cause these effects were due to an increase in DM, CP, and energy retention and a decreased of indigestible fractions (ANFs) after fermentation [In addition to our findings, we found that strains of microorganisms performed different effects on the outcome variables including BW, ADG, FI, and FCR. In case of fermented SBM in broiler chickens, there is no evidence comparing the efficacy of microbial strains on SBM fermented products in a single study so far. However, to our knowledge, there is evidence that microbial strains have specific activity in utilizing substrates . It can entation ,10.Interestingly, among the large variability of FSBM inclusion levels in the diet, there was no evidence of relationship with all the outcome variables. This finding was in agreement with previous studies either with minimum FSBM use of 30 g/kg diet or with maximum inclusion of 150 g/kg diet ,13. ThisThis study suggests that broiler feed containing fermented SBM is beneficial to improve growth performance of broiler chickens, especially when it is substituted in the diet of starter period. The effects of FSBM on ADG, FI, and FCR are apparently depended on microbial strains used for fermentation. The meta-regression suggests that increasing the inclusion of FSBM did not affect broiler chickens’ performance, thus it may be used either partially or entirely to substitute the conventional SBM.


I2 = 71.9%, n = 7) and prognosis . No evidence of publication bias was observed in the current analysis. Positive associations were observed in most subgroup analyses stratified by predefined factors, including region, study design, study quality, study population, participants’ gender, age of participants, cancer type, DAL assessment indicator, and adjustment of potential confounding parameters. No evidence of heterogeneity between subgroups was indicated by meta-regression analyses. The high DAL might be associated with an increased risk of cancer, as well as a poor prognosis of cancer. More high-quality prospective studies are warranted to further determine the associations between DAL and risk and prognosis for specific cancers.Epidemiological studies have suggested that dietary acid load (DAL) might be related to the risk and prognosis of cancer, whereas the evidence is contentious. Several high-quality observational studies have been published following a prior systematic review with only one study included. Consequently, we conducted an updated systematic review and meta-analysis to comprehensively investigate the relationship between DAL and cancer risk and prognosis. A systematic literature search was conducted in the PubMed, Embase, and Web of Science databases from inception to 26 October 2021. Summary relative risks (RRs) with 95% CIs were calculated using a random-effects model. Publication bias, subgroup, meta-regression, and sensitivity analyses were also conducted. Ten observational studies (six cohorts and four case–control studies) with 227,253 participants were included in this systematic review and meta-analysis. The summary RRs revealed a statistically significant associations between DAL and cancer risk (RR = 1.58, 95% CI = 1.23–2.05,  Cancer is a leading cause of death and an important barrier to prolonging life . GloballDietary acid load (DAL) is one of the indexes to evaluate the quality of the whole diet, which provides more comprehensive information about the dietary intakes of subjects . It has Experimental evidence has indicated that an acidic environment had a benign effect on the survival of cancer cells and promoted the invasion and metastasis of tumors , 11. TheTo the best of our knowledge, there has been no updated systematic review and meta-analysis comprehensively verifying whether DAL plays a vital role in cancer risk and prognosis after the study of Fenton and Huang . TherefoThis systematic review and meta-analysis were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines  and the There were four ways to estimate DAL: (i) PRAL, which considered the absorption rates for dietary proteins and minerals, ionic dissociation, and sulfur metabolism ; (ii) NETo be included in this review, the following criteria were used for inclusion: (i) studies had an observational design, including cross-sectional, case–control, and cohort studies; (ii) studies assessing the relationship between DAL and cancer risk and prognosis; and (iii) studies recommending relative risk (RR), hazard ratio (HR), odds ratio (OR), or required data for an estimate. The studies were excluded for the following reasons: (i) studies that were not original research, including editors, case reports, and reviews; (ii) studies with randomized controlled or ecological design; and (iii) studies published in other languages instead of English.The studies that fulfilled all the inclusion criteria were qualitatively evaluated by two investigators (RW and ZYW), and any disagreements were settled by a discussion with a third investigator (QJW). The extracted data included the first author, the year of publication, country, design of studies included, number of cases, dietary assessment index, exposure categories, risk estimates, and adjusted variables. We assessed the quality of the articles according to the Newcastle–Ottawa Scale NOS; . The NOSIn the meta-analysis, effect sizes for DAL were extracted from original studies, including standardized incidence ratio, HR, and RRs. The OR estimate and HR estimate were considered an approximation of the RR estimate . We calcI2 statistics. Cutoff points of ≤25, ≤50, ≤75, and >75% were used to indicate no, small, moderate, and substantial levels of heterogeneity, respectively, (P) value of <0.05 was considered statistically significant. All the analyses were conducted using Stata version 11.2 software .Heterogeneity in the relationship between DAL and cancer risk and prognosis across studies was quantified using ctively, . To explctively, . Publicactively, , Egger’sctively, , and visThe search strategy retrieved 13,153 articles from databases, of which 5,605 articles remained after removing the 7,550 duplicate articles. After the initial screening based on titles or abstracts, 5,588 studies were excluded, leaving 17 studies included. Of these, 5 articles –42 were n = 6), energy intake (n = 6), family history of cancer (n = 6), smoking status (n = 6), and body mass index , smoking status (n = 3), physical activity (n = 3), and age at diagnosis .Higher DAL was associated with a 58% increased risk of cancer  after removing the study by Ronco et al. (I2 = 69.5%) after removing the study by Park et al. . In sensitivity analyses, we sequentially removed one study; in turn, the pooled RR did not change substantially. Our sensitivity analysis showed that the RR for cancer ranged from a low of 1.41  after removing the study by Wu et al. (I2 = 82.7%) after removing the study by Wu et al. (Higher DAL was associated with a poor prognosis of cancer (RR = 1.53, 95% CI = 1.10–2.13, u et al.  to a higu et al. .To the best of our knowledge, the present review is the most comprehensive study reporting the relationship between DAL and cancer risk and prognosis. Findings from this systematic review and meta-analysis indicated that higher DAL might be an unfavorable factor for cancer risk and prognosis. These findings were consistently detected in numerous subgroups and sensitivity analyses.Our findings are inconsistent with the previous systematic review, which included articles published before April 2015, and concluded that DAL was overall not significantly associated with an increased risk of cancer . Our sysIn the subgroup analysis stratified by region, we only observed positive associations in studies carried out in the non-Asia region. This phenomenon could partly be attributed to the different DAL scores in patients with cancer from diverse regions. For example, when investigating 1,882 patients with breast cancer in the United States, it was found that the mean value was 2.25 for the PRAL score , whereasThe subgroup analyses suggested that DAL was positively associated with the risk of cancer in participants of age ≥50 years. Indeed, Frassetto et al. found that increasing age was associated with indicative of a progressively worsening low-level metabolic acidosis, and the changes seemed to be the most striking starting at about age 50 years . In addir = 0.9; Compared to the results of PRAL, the risk of cancer was considered to be substantially higher in NEAP. Both the PRAL and NEAP are approximate to DAL and highly correlated r = 0.9; . HoweverResults of our subgroup analyses demonstrated that DAL increased the risk of breast and pancreatic cancers. PRAL is inversely correlated with the consumption of vegetables, while phytochemicals contained in vegetables may contribute to decreasing the level of the epidermal growth factor receptor , 49, whiSeveral studies have indicated that consumption of high DAL dietary might be linked with a worse prognosis among patients with cancer , 25. Wu Although there was no evident mechanism to explain the relationship between DAL and cancer risk, several consensuses have been proposed. First of all, metabolic acidosis caused by DAL could promote cancer. Acid-base imbalance had been shown to regulate molecular activities, including insulin growth factor-1 IGF-1; , 57 and Regarding cancer prognosis, several studies existed to interpret this phenomenon. Metabolic acidosis had been shown to stimulate cancer metastasis in cell and animal models –70. In aThe principal strengths were that the present study was the most comprehensive systematic review to estimate the relationship between DAL and the risk and prognosis of cancer. We conducted a rigorous literature search to include all the pertinent studies. In consideration of study features and main adjustments for confounding variables, subgroup, sensitivity, and meta-regression analyses were conducted to probe into possible sources of heterogeneity. In addition, most of the selected articles had a low risk after using the NOS to evaluate the quality of all the included literature. Nevertheless, some limitations of this study should be recognized. First of all, measurement and recall bias in the assessment of dietary intake were inevitable. The calculation of PRAL, NEAP, NAE, and Pro:K based on self-reported data was collected by FFQ, DHQ, and 24-h dietary recalls. However, the majority of the included studies used valid and reliable FFQ, and it had been proved that FFQ could be more precise in assessing the association between diet and diseases . Second,In summary, the current systematic review and meta-analysis revealed that a higher DAL was associated with an increased risk and poor prognosis for cancers. Further large-scale prospective studies were warranted to explore the role of DAL in different cancers.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.RW, H-HW, and Q-JW conceived the study. RW, F-HL, Y-HZ, T-TG, and Q-JW contributed to the design. RW, Z-YW, and Q-JW collected the data, cleaned the data and checked the discrepancy, and analyzed the data. RW, Z-YW, Y-FW, H-LX, M-LS, Y-HZ, T-TG, H-HW, and Q-JW interpreted the data. All the authors have interpreted the data, read the manuscript, and approved the final vision of the manuscript.


In the subgroup analysis, NAFLD were found to be the independent risk factor of colorectal adenoma (CRA)  and colorectal cancer (CRC) . There is no close correlation between smoking status of NAFLD patients and CRN. Interestingly, bioinformatics analysis revealed that there were overlap of dysregulated gene sets among NAFLD, CRC, and two recently identified regulated cell death types, ferroptosis and cuproptosis, respectively. Our meta- and bioinformatics analysis shows that NAFLD increases the risk of CRN. Ferroptosis and cuproptosis may be the critical links between NAFLD and CRN, respectively. These findings here support that NAFLD is necessary to be considered as an emerging risk factor for CRN.This study aims at assessing the potential association between non-alcoholic fatty liver disease (NAFLD) and colorectal neoplasms (CRN). PubMed, Cochrane Library, and Embase were searched for cohort studies. 14 cohort studies with a total population of 38,761,773 were included for meta-analysis after selection. The results showed that NAFLD is related to an increased risk of CRN (OR = 1.23; 95% CI: 1.14–1.32; I Colorectal neoplasms (CRN) include colorectal adenoma (CRA) and colorectal cancer (CRC), with CRA transformation typically leading to CRC. CRC has been estimated the third common cancer type, and the second most common cause of cancer-associated mortality worldwide . In the As the economy develops, people have changed a lot in their living habits and diet structures, which partly lead to the higher and higher incidence of non-alcoholic fatty liver disease (NAFLD). NAFLD is among the most common chronic liver diseases worldwide, with an estimated prevalence of 25.2%, making it a severe public problem that endangers human health . NAFLD iFerroptosis and cuproptosis are two novel regulated cell death modalities identified recent years. Ferroptosis is caused by the imbalance of diverse cellular metabolic processes, while cuproptosis results from copper-induced proteotoxic stress . Since iHere we performed systematic analysis of the existing population-based studies to check the association between NAFLD and CRN. We revealed that NAFLD is a novel independent factor for CRN (particularly CRC). In addition, we identified that ferroptosis and cuproptosis may link NAFLD with CRC mechanistically and therapeutically, respectively.The meta-analysis section fulfills the standard in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) . The appWe searched the PubMed, Embase, and Cochrane Library databases by using Medical Subject Headings (MeSH) terms and keywords as follows:  AND . The detailed search strategy is described in Following criteria were used to incorporate studies: 1) cohort study; 2) population-based study; 3) patients in the exposed group are with NAFLD, but in the control group are not; and 4) the outcome is the risk of CRN (with an adjusted odds ratio (OR)).Exclusion criteria were as follows: 1) conference abstracts, meta-analysis, reviews, and study protocols; 2) duplicate publications; 3) not cohort studies; and 4) studies without OR estimate with corresponding 95% confidence interval (CI).Data were extracted by using predesigned forms according to the guideline for data extraction for systematic reviews and meta-analysis .The Newcastle-Ottawa scale (NOS) was used to assess the quality of cohort studies . Star ra2 value were used to evaluate the data heterogeneity from different studies. Stata statistical software version 16.0 was used throughout the meta-analysis.OR and 95% CI were used to measure the relationship between NAFLD and the risk of CRN. The chi-square test and Ip < 0.05, were considered statistically significant, while in TCGA-COAD dataset, log2 (fold change) > 1 or log2 (fold change) < −1, p < 0.05 was considered significant difference. R software was used to draw separate volcano plots. Venn diagram package was used for Venn diagram analysis.We downloaded the GSE89632 dataset for NAFLD and TCGA-COAD dataset for CRC from NCBI and TCGA, respectively. 564 ferroptosis-associated genes were got from the FerrDb. According to the previously study , 347 potAccording to the selection strategy, we obtained 563 literatures, among which 145 duplicate literatures were excluded. In addition, according to their titles and abstracts, 342 irrelevant articles were excluded, and 76 related articles were concluded to be thoroughly analyzed. After excluding reviews, meta-analysis, conference abstracts, and those that were not cohort studies, 14 papers  were incThis batch of 14 cohort studies cover a total population of 38,761,773, which were published from 2011 to 2022. Their sample sizes range from 380 to 21,592,374 individuals, the age of participants range from 18 to 84, and the follow-up period ranged from 3 to 10.1 years. Eight studies were conducted in Korea , three iWe used NOS scale to evaluate the quality of included studies . Each st2 = 70.7%, p < 0.001; p < 0.001). The results before and after the trim and filling method were compared. The correlation between NAFLD and CRN was slightly increased after this adjustment, which could be considered as stable results of the existing meta-analysis . 10 studies .We separately analyzed CRA and CRC in the subgroup study. Seven studies  explored studies  investig2 = 85.1%, p < 0.001), and that of female patients was 1.63  (Eight literatures  studied = 0.522) . The siz2 = 66.6%, p > 0.001). Two studies . Given this, there is no close correlation between smoking status of NAFLD patients and CRN risk  meta-analysis of existing literatures to explore the correlation between NAFLD and CRN; and 2) bioinformatics analysis to interrogate the role of ferroptosis and cuproptosis in NAFLD-related CRN. The meta-analysis incorporated 14 cohort studies, covering 38,761,773 individuals, to reveal the relationship between NAFLD and CRN in detail. Noteworthily, we included all high-quality cohort studies, complemented recent studies, and performed relevant subgroup studies. We found that NAFLD patients had an upregulated risk of getting CRN, with an average of 1.23-fold increase compared with patients without NAFLD. This suggests that NAFLD needs to be treated as a new risk factor for CRN.p = 0.522 > 0.01 can support this possibility. More samples and parameters are needed to get a reliable conclusion about this issue. In the smoking subgroup, the OR of CRN in NAFLD patients who smoked was 1.08, and that in those who did not smoke was 1.13, indicating that smoking status had no significant effect on whether NAFLD patients would have CRN.In CRN subgroup studies, the risk of CRA in patients with NAFLD was 1.29 times higher than that in patients without NAFLD, and this parameter for CRC was 1.13 times. Since CRA is a precursor of CRC, the role of NAFLD in both CRA and CRC cannot be ignored. In gender subgroup, the risk of CRN in male and female NAFLD patients was 1.14 and 1.63 times higher than that in non-NAFLD patients, respectively. Notably, previous studies have concluded that male patients with NAFLD are more likely to have CRN than female patients. This inconsistency may be due to the lack of female-based risk studies in our project, resulting in inaccurate results. The calculation result About the underlying causes that link NAFLD with CRN, researchers now hold several mechanisms in mind. First, NAFLD can change the systemic immune state and upregulate the level of various pro-tumor cytokines, which promotes the initiation and development of CRN . Second,Ferroptosis and cuproptosis are two newly identified cell death types. Ferroptosis (which is majorly modulated by p53 and GPX4) participates in many disorders, while the pathological relevance of cuproptosis has not be fully studied . To dateIt is recommended that people over 50 years old should undergo routine colonoscopy every year, which is an effective way to reduce the incidence and mortality of colorectal neoplasms . Based oThis study also has some limitations. Case-control and cross-sectional studies can be included in future studies to improve the conclusion. In addition, covariate analysis was not included in this current project. However, the studies included were controlled for adjusted confounding factors, making the conclusion in our study reliable and easy to be translated into clinical practice. Another issue is the heterogeneity existing in these studies, which was large and could not be decreased after removing each article and recalculating and subgroup analysis. Diagnostic criteria are not identical across regions and some studies relied primarily on electronic health record correlation for diagnosis, which may contribute to the high heterogeneity. Some literatures used global CRN as the outcome, while some used CRA or CRC alone as the outcome, which may also lead to the high heterogeneity. Moreover, confounders in each study could also result in heterogeneity. More systematic and standardized studies are needed to lessen the heterogeneity and consolidate our conclusion.To summarize, this meta- and bioinformatics analysis suggests that NAFLD increases the risk of CRN. For the first time we revealed that ferroptosis and cuproptosis may link NAFLD with CRN, respectively. The results in our study can be quite effective in developing CRN prevention, diagnosis, and treatment strategies.


Approximately 80% of children, adolescents and young adults (CAYA) cancer patients are expected to fully recover and survive for five years or more. The reproductive health is a particular area of their concern. Evidence demonstrates that previous therapeutic treatments for cancer and comorbidities may have harmful effects on female fertility and delivery outcomes, which will significantly affect patient quality of life. However, these reports are heterogeneous. Therefore, the purpose of this study is to provide the up-to-date evidence on the risk of adverse obstetric and perinatal outcomes in female survivors of childhood or adolescent cancer.This meta-analysis will be carried out and reported with adherence to the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines and the Cochrane Handbook. We will search online databases including PubMed, Cochrane Library, and Embase from inception to August, 2022 to identify all relevant cohort studies examining the relationship between cancer and subsequent obstetric and perinatal outcomes. Data extraction from eligible studies will be conducted and crosschecked separately by two investigators using pre-tested standardized data extraction forms. Discrepancies will be resolved via a third investigator. Methodological quality assessment for each study will be conducted using the Newcastle–Ottawa scale (NOS) tool. We will apply the DerSimonian-Laird random-effects model to calculate the pooled estimates. Further sources of heterogeneity will be explored by performing subgroup analysis based on multiple study characteristics. Potential publication bias will be assessed by inspection of a funnel plot, Begg’s and Egger’s regression tests of funnel plot asymmetry.Ethical approval will not be required as all data used for this pooled analysis will be obtained from published cohort studies. The results of this study will be disseminated in a peer-reviewed journal and conference presentation.10.17605/OSF.IO/K6QBG.DOI  The increase in the number of children, adolescents and young adults (CAYA) cancer patients is becoming a growing concern, and such patients are expected to fully recover and survive for a long time –3. The oPrevious studies have found that cancer survivors have a higher risk of preterm birth and postpartum hemorrhage than cancer-free women, and that these risks are further inflated in patients who receive pelvic or abdominal radiotherapy –14. KaidThese contradictory results prompt us to conduct a comprehensive and systematic review with meta-analysis on the risk of adverse obstetric and perinatal outcomes in female survivors of childhood or adolescent cancer based on published high-quality population-based cohort studies.http://handbook.cochrane.org) [https://osf.io/x2vra) with the registration number of DOI 10.17605/OSF.IO/K6QBG.This meta-analysis will be reported and conducted based on the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines and the Cochrane Handbook (ane.org) . Its proane.org)   from inception to August, 2022 using the specific search strategies as presented in Studies with all inclusion criteria satisfying the PECOS framework will be included in the qualitative and quantitative analyses.Are adverse obstetric and perinatal outcomes mostly due to cancer itself and cancer-related treatments for female survivors of childhood or adolescent cancer?Prospective or retrospective population-based cohort studies published in any languages will be considered eligible;This study will draw participants from female survivors of childhood or adolescent cancer diagnosed based on the International Classification of Diseases (ICD) criteria in the population-based cohort which reported one type of adverse obstetric and perinatal outcomes identified by ICD criteria;The primary exposure of interest was defined as cancer diagnosis and cancer-related treatment including chemotherapy, radiotherapy, or other related antitumor therapies.Studies will be included if they compared outcomes in the exposed group with those in a group of unexposed population .Studies will be included if one of the primary outcomes including any adverse obstetric outcomes, obstetric complications, perinatal outcomes and perinatal complications are reported and their risk estimates are provided.Data extraction from eligible studies will be conducted and crosschecked separately by two investigators using pre-tested standardized data extraction forms. Discrepancies will be resolved via a third investigator. The following variables will be extracted from the included studies by applying a structured template: author of the publication, publication year, study set and design, research country and time range, participant mean or median age at cancer diagnosis, comparison population, criteria for ascertainment of cancer diagnosis and obstetric or perinatal outcomes, study results and risk estimates of the association of obstetric or perinatal outcomes with cancer.Methodological quality assessment for each study will be conducted using the Newcastle–Ottawa scale (NOS) tool for cohort studies, with focus on the major aspects including participant selection, comparability of study groups, and ascertainment of exposure and outcomes . The ful2 statistic, where an I2 > 50% representing significant heterogeneity [We will carry out all statistical meta-analyses with the software Stata 15.0 . For each obstetric and perinatal outcome, the pooled relative risk (RR) in female cancer survivors compared with the RR in the cancer-free controls with its 95% CI will be estimated. To account for heterogeneity in the involved population, study setting or design, and outcome assessment, we will apply the DerSimonian-Laird random-effects model to calculate the pooled estimates . We willogeneity . We willogeneity , 27. Senogeneity .To the best of our knowledge, this will be the first and most comprehensive meta-analysis to investigate the risk of adverse obstetric and perinatal outcomes in female survivors of childhood or adolescent cancer. This study will provide female cancer survivors with counseling and surveillance before and during pregnancy, and early risk warning for high-risk pregnant women who may develop adverse maternal outcomes, and offer evidence-based recommendations for those female survivors of childhood or adolescent cancer.This study has several other strengths. Firstly, the Cochrane Handbook and PRISMA guideline will be strictly adhered to when conducting and reporting this meta-analysis and study quality of each included study will be assessed using NOS tool, which can objectively gain the quality of the pooled evidence. Secondly, by performing several subgroup analyses and sensitivity analyses, we can comprehensively explore the sources of between-study heterogeneity and confirm the robustness of the meta-analysis results. Finally, we will search the three major electronic databases and manually search other sources without language or date limitations to minimize the possibility of publication bias. Nevertheless, this study has a major limitation due to its anticipated significant between-study heterogeneity in that the included populations are female participants diagnosed with all types of cancer. However, this study is expected to reveal the relationship between cancer and obstetric and perinatal outcomes provide us a general risk estimate of obstetric and perinatal outcomes among female survivors of childhood or adolescent cancer.S1 Table(DOC)Click here for additional data file.


Albeit not significantly heterogeneous by variables tested, a significant inverse association was limited to cohort studies and supplement use during cancer treatment for overall survival, and to studies with ≤3 years of follow-up for progression-free survival. Post-diagnosis vitamin D supplement use was associated with improved overall survival, but not progression-free or cancer-specific survival or relapse. Our findings require confirmation, as randomized trial evidence was insufficient to establish cause-and-effect relationships.Vitamin D administered pre-diagnostically has been shown to reduce mortality. Emerging evidence suggests a role of post-diagnosis vitamin D supplement intake for survival among cancer patients. Thus, we conducted a meta-analysis to evaluate the relationship. PubMed and Embase were searched for relevant observational cohort studies and randomized trials published through April 2022. Summary relative risk (SRR) and 95% confidence interval (CI) were estimated using the DerSimonian–Laird random-effects model. The SRR for post-diagnosis vitamin D supplement use vs. non-use, pooling cohort studies and randomized trials, was 0.87 (95% CI, 0.78–0.98;  Cancer is a global public health concern and the leading cause of death in most developed countries . AccordiAccumulating evidence suggests that vitamin D supplements may confer protective effects against total cancer mortality in “usual risk” populations . In a reThis meta-analysis was performed and reported in accordance with the PRISMA guideline  8]..8].PubMed and Embase were searched for relevant articles through April 2022. The search was limited to human studies and the English language, but no other restrictions were imposed. The detailed search terms are provided in To be included in this meta-analysis, studies had to be a RCT or cohort study that examined the relationship between vitamin D supplement intake after cancer diagnosis and survival outcomes . Abstracts, unpublished results, and review articles were excluded. When there were multiple publications from the same trial ,10, we sFrom each article, the following information was extracted: name of the first author, publication year, study design, definitions  of vitamin D supplement use and control, cancer type, outcome definition , relative risk (RR), 95% confidence interval (CI), confounding factors adjusted for, and important characteristics of the study population , and exclusion criteria regarding vitamin D supplements intake .Two authors (QYC and SK) participated in the study search, study selection, and data abstraction independently, and any disagreement was resolved through discussion with NK.I2 statistic was calculated to assess the degree of heterogeneity in the relationship across the studies [The summary RR (SRR) and 95% CI were calculated using the DerSimonian–Laird random-effects model for the association between post-diagnosis vitamin D supplement use and survival outcomes . The I2  studies . Potenti studies . Of notePotential sources of heterogeneity in the relationship were explored by performing subgroup meta-analyses and meta-regression according to a priori selected variables related to methodological characteristics , etiologic heterogeneity (cancer type), and potential effect modifiers D: <20 ng/mL vs. ≥20 ng/mL). Notably, because results of a meta-analysis of a small number of studies are not informative, subgroup analyses were not conducted when the total number of studies was less than five.p values of <0.05 were considered statistically significant. Analyses were performed using STATA 17 .All the statistical tests were two-sided and After screening 1742 publications, a total of 11 publications , with no evidence of heterogeneity (I2 = 0%) (EggerP = 0.83).Based on a total of nine studies  A. Small heterogeneityP = 0.77), the cancer type , the timing of vitamin D supplement use (heterogeneityP = 0.20), and the follow-up period (heterogeneity =P 0.73)  but not among RCTs  , but not when the supplement was used after treatment , but not with other cancer types  A–D. NeveI2 = 0%) A; it wasreatment C. There er types B.p = 0.12), with moderate heterogeneity (I2 = 51%) (EggerP = 0.78). The aforementioned results remained unchanged in the sensitivity analysis, excluding a study [Based on a total of eight studies  B. There  a study  that tesheterogeneityP = 0.63), the cancer type (heterogeneityP = 0.75), the timing of vitamin D supplement use (heterogeneityP = 0.59), the follow-up period (heterogeneityP = 0.07), or the baseline level of circulating 25(OH)D (heterogeneityP = 0.61) , but not among studies > 3 years follow-up  A–E. Neveollow-up D.p = 0.10) with no evidence of heterogeneity (I2 = 0%) (EggerP = 0.22). Heterogeneity in the relationship was not explored due to the small number of studies.Based on three studies (one RCTs  and two I2 = 0%) C. Small p = 0.29) with no evidence of heterogeneity (I2 = 0%) (EggerP = 0.66). Due to the small number of studies, heterogeneity in the relationship was not explored for relapse.Based on three studies  D. Small In this meta-analysis of observational cohort studies and RCTs, post-diagnosis vitamin D supplement use compared to non-use was associated with an approximately 13% improved overall survival, but was not associated with progression-free survival, cancer-specific survival, and relapse. The relationships did not vary significantly by the study design, the cancer type, the timing of vitamin D supplement use, and the follow-up period. Nevertheless, a significant inverse association with overall survival was limited to cohort studies and studies that assessed supplement use during treatment, and was suggestive for breast cancer. In relation to progression-free survival, a significant inverse association emerged among studies with ≤3 years of follow-up, which were the majority of the studies.Despite a heightened interest in dietary supplements among cancer patients , previouIn light of our current study, which evaluated studies on the association between vitamin D supplement use after cancer diagnosis and outcomes, finding null associations with most of the endpoints, the benefit of vitamin D supplements may be occurring primarily during the pre-diagnostic period by decreasing tumor invasiveness and metastatic potential. Nevertheless, we cannot completely rule out the potential benefits of vitamin D supplement during the post-diagnosis period. Firstly, we observed a significant inverse association between post-diagnosis vitamin D use and overall survival. Beneficial effects of vitamin D, such as immune-boosting, anti-inflammatory and insulin-sensitizing effects against non-cancer outcomes, may still operate after cancer diagnosis ,27,28. SBy cancer type, evidence for a beneficial effect of post-diagnosis vitamin D supplement use was most suggestive for overall survival among breast cancer patients. This result may be in part attributable to methodological factors, because all studies included for this breast cancer meta-analysis were observational cohort studies, and active research in the field of breast cancer survivorship resulted in a large number of publications. Yet there are potential biological mechanisms, albeit not exclusively applicable to breast cancer, that might explain a role of vitamin D supplementation for breast cancer survivorship. Vitamin D receptor (VDR) is a nuclear receptor, which upon activation by 1,25-dihydroxyvitamin D inhibits cell proliferation and induces cell differentiation and apoptosis . The VDROur study is the first meta-analysis that analyzed the association between post-diagnosis vitamin D supplement intake and cancer outcomes, addressing important heterogeneity in the relationship by the timing of vitamin D supplement use, the cancer type, the baseline 25(OH)D levels, and others. Yet, there are several limitations to acknowledge. First, as an inherent limitation of the meta-analysis, any biases present within individual studies, which cannot be corrected by the meta-analysis, may compromise the validity of our results. In fact, due to the limited number of studies available, our meta-analyses pooled RCTs and observational cohort studies together, except for subgroup analysis by study design. While the relationships were not significantly heterogeneous by study design, causal interpretation of our findings should be avoided. Second, because all studies compared supplement use vs. non-use except for one study (high vs. standard dose) , our stuIn conclusion, post-diagnosis vitamin D supplement use among cancer patients was associated with an improved overall survival, but was not related to progression-free survival, cancer-specific survival, or relapse. RCT evidence was limited and insufficient to establish cause-and-effect relationships. Future studies are needed to confirm our findings as well as to identify the optimal supplementation strategy  and the subgroup of people who will benefit most from the supplementation.