Dietary inflammatory index (DII) has been suggested to be associated with oral cancer risk. However, a quantitative comprehensive assessment of the dose–response relationship has not been reported. We performed a meta-analysis to clarify the risk of oral cancer with DII.We searched PubMed, Embase, Cochrane Library, and Web of Science databases for relevant articles published up to 1 March 2022. Fixed- or random-effects models were utilized to estimate the pooled odds ratio (OR) of oral cancer with DII, as appropriate. Restricted cubic splines were used to model the dose–response relationship.non-linearityp = 0.752), and the risk was increased by 17%  with 1 unit increment in DII score.We included five case–control studies involving 1,278 cases and 5,137 controls in the meta-analysis. Risk of oral cancer was increased by 135% with the highest versus lowest DII level , and 79% with higher versus lower DII level . We found no evidence of a nonlinear dose–response association of DII with oral cancer (This meta-analysis suggested that a higher DII score was associated with increased risk of oral cancer. Therefore, reducing pro-inflammatory components and promoting anti-inflammatory components of diet may be effective in the prevention of oral cancer. Oral cancer is the most prevalent subtype of head and neck cancers, and has become a major public health problem. It has long occupied one of the top 20 leading causes of morbidity and mortality worldwide , 2. Acco12, have pro-inflammatory features (>0), and another 36 food components have anti-inflammatory properties (<0). In terms of dietary intake data, it was linked to the regionally representative world database to obtain a Z-score and corresponding centered percentile value for each food parameter. Finally, the centered percentile of each food parameter was multiplied by its respective inflammatory effect score, and then all 45 scores were summed to create an overall DII score for each participant. Sometimes, the DII score was further adjusted for total energy intake to control for its potential effects. In practice, the total DII score has been proven to be positively correlated with the concentrations of several common inflammatory biomarkers, such as CRP, interleukin-2 (IL-2), and TNF-α , which was derived from a literature review of 1,943 articles . The orind TNF-α . In summIn recent years, DII has been implicated in the occurrence and development of several types of cancer, such as breast cancer, colorectal cancer, and gastric cancer –17. TherThe systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) . To defiIn the form of PICOS , the study was described as follows:Population: not specified;Exposure: participants at the highest or higher DII level;Comparator: participants at the lowest or lower level of DII level;Outcome: occurrence of oral cancer;Study design: observational studies including prospective cohort, case–control, or cross-sectional studies.We systematically searched PubMed, Embase, Cochrane Library, and Web of Knowledge database for literatures reporting the association of DII with oral cancer that were published up to 1 March 2022. The search strategy was designed by combining the following MeSH terms with free words: dietary inflammatory index; dietary inflammatory score; dietary score; inflammatory diet; inflammatory potential of diet; dietary inflammation potential; inflammatory potential intake; anti-inflammatory diet; pro-inflammatory diet; dietary pattern; diet-related inflammation; index-based dietary patterns; DII; mouth neoplasms; mouth neoplasm; oral neoplasms; oral neoplasm; mouth cancers; mouth cancer; oral cancers; oral cancer; cancer of mouth; cancer of the mouth; oral squamous cell carcinoma; oral squamous cell cancer. The details of the search strategy are shown in Studies were included if they (1) were prospective cohort, case–control, or cross-sectional studies; (2) investigated the association between DII and risk of oral cancer; (3) reported estimates of the hazard ratio (HR), relative risk (RR), or odds ratio (OR) with their 95% confidence intervals (Cis) or sufficient information to calculate these; and (4) provided quantitative data of DII as well as number of cases and participants, or exposed person-years for the dose–response analysis.Two investigators (Luo and Zhu) independently extracted data using a designed extraction form, and any disagreements were resolved by discussion. The collected information was as follows: name of the first author, publication year, country where the study was conducted, study design, study duration, participants characteristics (sex and age), DII assessment and measures, DII ranges or median or mean for each category, risk estimates with corresponding 95% CIs of oral cancer, and covariates adjusted in each included study.The Newcastle–Ottawa scale (NOS) was used to assess the quality of the included studies by two authors (Luo and Zhu) . The scaIn this meta-analysis, the term “odds ratio (OR)” was regarded as the unified effect size for all studies . To estiWe also investigated possible linear or non-linear associations of DII with oral cancer risk by using the method of Greenland and Longnecker . This meI2) and Cochran Q test , and the covariates adjusted in the analysis . For analysis, we considered SES adjustment as adjusting for one or more of the following factors: occupation, income level, and educational level. In addition, sensitivity analysis was conducted to examine the potential impact of each study on pooled risk estimations through omitting one study at a time. Potential publication bias was evaluated by the Begg’s and Egger’s tests, and p-value at < 0.05 was considered to indicate publication bias  and evaluating the abstracts and titles of the articles , we obtained 20 full-text articles. Next, we further excluded 15 articles for the following reasons: irrelevant exposure or outcome (n = 11), duplicate study (n = 1), and review or discussion paper (n = 3). Finally, five studies were included in this meta-analysis. The detailed literature screening process is shown in We initially identified 4,324 articles from PubMed, Embase, Cochrane Library, and Web of Science databases and two from other sources. After excluding duplicates   , with low heterogeneity . We applied RCS with three knots to analyze the dose–response relationship between elevated DII and oral cancer risk (non-linearityp = 0.752), and meanwhile indicated that risk of oral cancer increased linearly along with increments in DII score (linearityp < 0.001).The pooled OR for a 1-unit increment in DII was 1.17 (95% CI: 1.05–1.30) Figure 3heterogeneity among subgroupsp > 0.05) (heterogeneity among subgroupsp = 0.039) and family history of cancer . With sensitivity analysis omitting one study at each time, none of the individual studies had a substantial change on the pooled results . For the highest DII versus the lowest DII and higher DII versus lower DII, the associations between DII and oral cancer risk were consistent across strata of all the analyzed factors  vs. 1.19 ,  history . Guo et  history . The inc+ T cells and CD4+ T cells, and upregulated expression of inflammatory mediators such as COX-2, MMP-7, TNF-α, and IL-6  and the National Natural Science Foundation Program of China (grant nos. 81973137 and 82173608).We would like to thank all the authors of the included studies.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.


RIT2) polymorphism is a susceptible factor for Parkinson's disease (PD) and autism spectrum disorder (ASD). SNP rs12456492 and rs16976358 show the emerging evidence of increased risk of PD and ASD, respectively. A meta-analysis examining the relationship between rs12456492 and PD was reported, but the association between rs16976358 and ASD has not been investigated.  Recent studies have shown that Ras-like without CAAX2 . The results of sensitivity analysis and publication bias of Begg's and Egger's tests were stable in the models of allele (C vs. T), codominant (CC vs. TT), dominant (CC+CT vs. TT), and recessive (CC vs. CT+TT).  All genetics models indicate a significant association between rs16976358 polymorphism and ASD susceptibility (C vs. T:  Our meta-analysis exhibits that the allele C, CC, and CT genotyping of rs16976358 suggest the risk for ASD, but additional studies using a large sample size and ethnically diverse populations need to be included in the future. MARK1), oxytocin receptor (OXTR), SH3 and multiple ankyrin repeat domains 3 (SHANK3), and gamma-aminobutyric acid type A receptor subunit beta3 (GABRB3) [Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by global developmental delay, speech and language impairment, intellectual disability, restricted interests, and social communication deficits. It affects approximately 1-2% of the population worldwide with a ratio of 3 : 1 in males compared with females [(GABRB3) . HoweverRIT2) has been introduced as a genetic risk gene for neurological and psychiatric disorders such as Parkinson's disease (PD), schizophrenia, and ASD. RIT2, as a member of the Ras superfamily, is highly expressed in the brain, in particular the retinal ganglion cells and dopaminergic neurons [RIT2 rs12456492, was identified as a risk factor for PD patients in the white population by conducting a meta-analysis of genome-wide association study (GWAS) [RIT2 rs16976358 polymorphism had the strongest association with ASD [Recently, Ras-like without CAAX2  . In 2016with ASD , suggestThe databases PubMed, Embase, Google Scholar, ScienceDirect, EBSCOhost, OVID, Web of Science, and Wiley were used for the literature search. The searching strategy was applied by the following terms: “Autism spectrum disorder or autism or ASD” and “Ras-like without CAAX 2 or RIT2 or Rin or rs16976358” and “polymorphism or SNP”, with the last report up to February 26th, 2021. In addition, we also examined the references in the retrieved papers to identify extra studies.The inclusion criteria are listed as follows: (1) association between rs16976358 and ASD risk; (2) case-control studies; (3) those providing sufficient genotyping data to calculate the odds ratio (OR) and 95% confidence interval (CI); and (4) patients with ASD were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (5th edition) or the Autism Diagnostic Inventory-Revised (ADI-R) criteria. Studies were excluded for the following reasons: (1) republished or duplicated studies; (2) animal tests or reviews or nonrelated; and (3) insufficient genotyping data.Data were collected independently by two investigators according to the inclusion and exclusion criteria described above. In each study, the following information was extracted from the eligible studies: first author, year of publication, study type, region, ethnicity of the sample population, genotyping method, sample size of case, and control groups. Genotyping distributions and minor allele frequency (MAF) were separately listed to facilitate analysis. For the data which are not provided in published papers or the supplementary materials, the relevant information was obtained by direct communications with the corresponding authors.Z-test, in which p < 0.05 was considered as statistically significant. We examined the heterogeneity with the Q-test and I2 statistics using the fixed- and random-effect model. If PQ > 0.10, the fixed-effect model was adopted to calculate the pooled ORs; if PQ < 0.10, the random-effect model was applied instead. Sensitivity analysis was carried out by sequentially omitting one study at a time to estimate the stability of the results. Publication bias among studies was determined using funnel plot and Begg's and Egger's tests. A meta-regression analysis was used to assess the impact on moderator covariables on the heterogeneity of results.Statistical analyses were performed by STATA software, version 15.0 . The association between rs16976358 and risk of ASD was evaluated by pooled OR and 95% CI. Six genetic models were established for analysis, including allele (C vs. T), codominant (CC vs. TT), codominant (CT vs. TT), dominant (CC+CT vs. TT), recessive (CC vs. CT+TT), and over dominant (TT+CC vs. CT). The significance of OR was determined by the Sixty-four initial studies were retrieved from the databases . Thirty-four studies were remained by removing duplicates. After browsing through the titles and abstracts, we excluded 5 reviews, 3 animal tests, 22 irrelevant studies, and 1 research article because of sufficient genotyping information. Finally, three studies published between 2016 and 2017 were selected with a collection of 1160 ASD cases and 1367 controls . All of p values from these models in the studies were, respectively, shown in PQ < 0.05). I2 statistics showed that all the genetic models had high heterogeneity (I2 > 50%)  , codominant (CC vs. TT), codominant (CT vs. TT), dominant (CC+CT vs. TT), recessive (CC vs. CT+TT), and over dominant (TT+CC vs. CT). Odds ratio (OR), 95% confidence interval (CI), and 2 > 50%) . In over= 0.013) . Thus, tp = 0.097) and Hamedani et al.' s studies . In the model of over dominant (TT+CC vs. CT), sensitivity was also unstable after deleting Liu et al.  and Hamedani et al.'s studies . But there was high sensitivity in the remained models of allele (C vs. T), codominant (CC vs. TT), dominant (CC+CT vs. TT), and recessive (CC vs. CT+TT) (p < 0.05) (Metaregression was performed to explore the effect of covariables on the heterogeneity caused in our study. Different publication years and regions had no impacts on the heterogeneity found in any genetic models . Unfortu < 0.05) .Funnel plot and Begg's and Egger's tests were carried out to evaluate the publication bias in our study. A publication bias was found in codominant (CT vs. TT) and dominant (CC+CT vs. TT) models in funnel plot. One paper  was slightly apart from the symmetrical shape in these 2 models . HoweverRIT2 gene was identified as a new locus for both Parkinson's disease (PD) and autism spectrum disorder (ASD) [In two distinct GWAS reports, er (ASD) , 11, 12.er (ASD) , 14. Recer (ASD) –17. The I2 tests, which could be caused by the heterogeneity of clinical information, methods, and statistics. Moreover, an increasing number of publications could be a possibility to reduce the heterogeneity. To uncover the reason of heterogeneity, the sensitive analyses were further performed in all the 6 models. Results showed the estimated OR in the models of allele (C vs. T), codominant (CC vs. TT), dominant (CC+CT vs. TT), and recessive (CC vs. CT+TT) stayed steadily between the lower and upper CI limits after omitting any of one study, suggesting that the data in most models show stable and reliable results. Collecting numerous of literature may increase the sensitivity in models of codominant (CT vs. TT) and over dominant (TT+CC vs. CT).For this reason, we carried out a meta-analysis on six genetic models , codominant (CC vs. TT), codominant (CT vs. TT), dominant (CC+CT vs. TT), recessive (CC vs. CT+TT), and over dominant (TT+CC vs. CT)). We found that CC and CT genotyping of rs16976358 might also underlie the ASD susceptibility in Asian populations. A high heterogeneity was found in all the genetic models in Publication bias was not detected in Begg's and Egger's tests but slightly found in the funnel plot when analyzing the genetic models of codominant (CT vs. TT) and dominant (CC+CT vs. TT). This bias could be due to the fact that researchers in Emamalizadeh et al. did not find significant results in the dominant model (CC+CT vs. TT). In addition, it may suggest that the number of studies included in the meta-analysis was not sufficient. Our meta-analysis suggests that the C allele and CC and CT genotyping of rs16976358 polymorphism might be associated with ASD risk, but this results should be verified in the future with a large number of studies and an increasing sample size.RIT2 rs16976358 and susceptibility to ASD is not well understood. Since SNP rs16976358 is located in the far downstream region of RIT2 gene, one possibility is that SNP rs16976358 may affect gene and protein expression by altering the distant elements [RIT2, as a functional GDP/GTP regulator switch, plays an important role in various signaling pathways within the nervous system. It is involved in EGF receptor- and mSos-mediated signaling pathways and in calcium/calmodulin-mediated cellular processes [2+-dependent enzymes and modulates neuronal functions including synaptic development and plasticity, learning, and memory formation [RIT2 rs16976358 may disrupt the central dopaminergic system, which is closely related to the ASD pathogenesis [The mechanism of the correlation between elements . RIT2, arocesses . Calmoduormation , 20. RITormation . In thisormation . Thus, Rogenesis . In addiogenesis . HoweverOur meta-analysis has some limitations. Firstly, the publications in English were included in our studies. Secondly, the number of literature and sample size was not large. Thirdly, only Asian populations were analyzed in the current meta-analysis, as the RIT2 rs16976358 polymorphism has not been reported in Caucasian populations. Lastly, despite publication of year and region of patients, we could not analyze the other potential influencing factors due to the insufficiency of data. All these limitations could cause bias in the results, though we try to eliminate the bias.RIT2 rs16976358 polymorphism is significantly associated with ASD in Asian populations. The allele C, CC, and CT genotyping of rs16976358 suggest the risk of ASD. However, more additional studies from different countries and ethnic populations may be helpful to supply a more reliable estimation of the association between rs16976358 and ASD susceptibility.In conclusion, our meta-analysis indicates that


Although several studies have reviewed the suicidal risk of antidepressants, the conclusions remain inconsistent. We, therefore, performed a meta-analysis of observational studies to address the association between exposure to antidepressants, especially selective serotonin reuptake inhibitors (SSRIs) and the risk of suicide and suicide attempt in children and adolescents.MEDLINE and Embase were searched from January 1990 to April 2021. Seventeen cohort and case-control studies were identified that reported suicide or suicide attempt in children and young adults (aged 5–25 years) who were exposed to any antidepressants. We extracted the estimates and corresponding 95% confidence intervals (CIs) from each publication.I2 = 83.1%). Among the antidepressants, SSRI use was associated with an increased risk of suicide and suicide attempt, and the pooled RR was 1.28 . In subgroup analysis, the attempted suicidal risk of antidepressant and SSRI was significantly increased , while the completed suicidal risk of antidepressant and SSRI was not statistically significant . In addition, the risk of suicide and suicide attempt between SSRIs and other antidepressants was similar .The results showed that antidepressant exposure significantly increased the risk of suicide and suicide attempt when compared with no antidepressant usage among children and adolescents. The pooled relative risk (RR) was 1.38  when prescribing antidepressants to children and young patients. Accumulating evidence suggests that antidepressant use in children and adolescents is substantially increased in recent years , though Suicidal ideation and behavior developed during depression treatment are called treatment emergence or worsening of suicidal ideation (TESI/TWOSI). The incidence of TESI varies from 3.2 to 17% among different studies, depending on the studied population and the threshold used for TESI . PredictMeta-analysis of the randomized controlled trials (RCTs), the highest level of evidence, produced inconsistent findings. Unlike the meta-analysis  conducteA recent umbrella review  of obserWe followed the checklist of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for background, design, analysis, and interpretation. We conducted a literature search of MEDLINE/PubMed, Embase, and Cochrane Library from January 1990 to April 2021 for relevant studies assessing the association between antidepressants and the risk of suicide. Various combinations of keywords were utilized, including but not limited to  and . We also scrutinized the reference lists of relevant major reviews. No language restrictions were imposed. The detailed search strategy and the PubMed search term are shown in Eligible studies were included in this meta-analysis if they satisfied the following criteria: (1) the study design was observational cohort or case-control studies, (2) the study population include children or young patients (age < 25 years), (3) the exposure of interest was antidepressant use, and (4) the outcomes were suicidal behaviors  or deliberate self-harm . One reviewer assessed the titles and abstracts of all studies identified through electronic searches. Potentially eligible studies were reviewed independently by a second reviewer, with discrepancies resolved by discussion.Two reviewers (ZGB and XY) independently extracted and collected the data. The following information was extracted from each eligible study: name of the first author, year of publication, study design, study location, mean follow-up time, participants’ characteristics, number of participants, outcomes, outcome assessment methods, and adjustment for potential confounders. We extracted crude and adjusted estimates and corresponding 95% confidence intervals (CIs). When studies had several adjustment models, we used the most comprehensively adjusted estimates in multivariable-adjusted models. Crude relative risks (RRs) or odds ratios (ORs) were calculated when the case numbers in the exposure group and comparison group were shown but the risk estimates remain unknown.Quality assessment was performed using the Newcastle-Ottawa Scale (NOS) . The maxI2 statistic  when heterogeneity was negligible, and a random effect model (DerSimonian and Laird method) when heterogeneity was significant , resulting in a common estimate of RR. Potential heterogeneity among studies was estimated using the Cochran Q test and tatistic . I2 can nificant . In addinificant  and the The characteristics of 17 identified studies are shown in I2 = 83.1%, P < 0.001). To explore the potential source of heterogeneity across studies, a sensitivity analysis was performed by removing one study at a time, and the corresponding pooled RR was not materially altered after the removal of any study (P = 0.026). Neither the Begg test nor the Egger regression test for publication bias reached significance (P > 0.05 for both tests).Among 11 studies that examined the association between any antidepressants (including SSRIs) use and completed or attempted suicide among adolescents (13 estimates), antidepressant exposure significantly increased the risk of completed or attempted suicide when compared with no antidepressant exposure , and theny study . We perfI2 = 86.2%, P < 0.001), with no significant effect on completed suicide . We also performed subgroup analyses according to the adjustment, and the pooled adjusted and crude RR showed similar results . The control group was no antidepressant use or any other antidepressant use. This result was robust in the sensitivity analysis (P > 0.05) and follow-up duration (P > 0.05) were not the sources of heterogeneity. We found no evidence of publication bias (P > 0.05 for Begg and Egger tests).Across 15 studies that examined the association between SSRIs and completed or attempted suicide among adolescents (18 estimates), SSRI exposure significantly increased the risk of completed and attempted suicide , and theanalysis . ResultsI2 = 73.8%, P < 0.001), with no significant effect on completed suicide . In the subgroup analysis of adjustment (I2 = 69.7%), similar to analysis that included all studies, while the pooled crude RR was 1.11 .In the subgroup analysis according to the outcomes , SSRI exjustment , the pooI2 = 73.8%, P < 0.001), but similar to other antidepressants . This subgroup analysis indicated that the increased risk of suicidal behavior for SSRIs and other antidepressants was similar among children and adolescents. Since the subgroup finding was based on a small number of studies, the results should be interpreted with caution.The comparisons of antidepressant exposure were no antidepressant exposure in all included studies, and the comparisons of SSRI exposure were any other antidepressant use or no antidepressant use. Thus, we performed the subgroup analysis based on the comparisons, and the results indicated that the risk of suicide/suicide attempt of SSRI use was significantly increased compared with no antidepressant use , and the adjustments of each study are listed in Several limitations of our study should also be acknowledged. First, a time-dependent decline in the suicidal rate for antidepressant recipients was identified ; howeverThe main findings of this meta-analysis provide some evidence that antidepressant exposure seems to have an increased suicidal risk among children and young adults. Since untreated depression remains one of the largest risk factors for suicide and the efficacy of antidepressants is proven, clinicians should evaluate carefully their patients and be cautious with patients at risk to have TESI and TWOSI when prescribing antidepressants to children and young patients . The mosThe original contributions presented in the study are included in the article/KL and JW conceived and designed this study. JG and QC conducted the databases search. GZ and YX selected the studies, extracted the data, and assessed the risk of bias. KL was in charge of writing-reviewing of the manuscript. SX and JW took supervision. All authors contributed to this study and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Acceptance and commitment therapy (ACT) is an empirically supported transdiagnostic approach that involves mindfulness processes and behavior change processes for valued living.This systematic review and meta-analysis of randomized controlled trials (RCTs) aimed to assess the efficacy of internet-based ACT (iACT) for depressive symptoms, anxiety, stress, psychological distress, and quality of life (QoL).PubMed, CINAHL, PsycINFO, and SCOPUS databases were searched to identify relevant RCTs published up to June 5, 2021. The included RCTs were assessed using the Cochrane Collaboration risk-of-bias tool. The use of either a random effects model or fixed effects model was determined using I2 statistic values for heterogeneity. Subgroup analyses were conducted according to the type of control group, the use of therapist guidance, delivery modes, and the use of targeted participants, when applicable.A total of 39 RCTs met the inclusion criteria. Meta-analyses found small effects of iACT on depressive symptoms, anxiety, stress, psychological distress, and QoL at the immediate posttest and follow-up. There was no significant effect of iACT on stress at follow-up. Subgroup analyses showed small to medium effects of iACT on all the outcomes at the immediate posttest and follow-up compared with the passive control groups. In contrast, subgroup analyses that compared iACT with active control groups found no differences between groups on stress, psychological distress, and QoL at the immediate posttest or on depressive symptoms, anxiety, and stress at follow-up. In addition, subgroup analyses conducted according to the use of therapist guidance, delivery modes, and the use of targeted participants found no statistically significant subgroup differences among studies in all the outcomes, except for the subgroup difference among studies according to the use of targeted participants for depressive symptoms at the immediate posttest . The overall risk of bias across the studies was unclear.The findings of this study contribute to the body of evidence regarding the effects of iACT on depressive symptoms, anxiety, stress, psychological distress, and QoL and may be applicable in any population, as ACT is a transdiagnostic approach. Few studies have compared iACT with active control conditions, especially for stress and psychological distress at the immediate posttest and follow-up. In addition, the active control conditions varied among the included studies. Further high-quality studies are needed to better understand whether iACT is comparable or superior to other evidence-based interventions, such as cognitive behavioral therapy, in decreasing depressive symptoms, anxiety, stress, and psychological distress and improving QoL. Acceptance and commitment therapy (ACT) is an empirically supported transdiagnostic approach that involves mindfulness and acceptance processes and behavior change processes for valued living ,2. ACT aA growing body of evidence shows that ACT can reduce depressive symptoms, anxiety, stress, and psychological distress and improve quality of life (QoL) in various populations ,4. For eInternet-based psychological interventions are easy to access and inexpensive; therefore, it is important to determine whether iACT is an effective alternative option for reducing depressive symptoms, anxiety, stress, and overall psychological distress and improving QoL . Brown eThis systematic review and meta-analysis aimed to assess the efficacy of iACT for depressive symptoms, anxiety, stress, overall psychological distress, and QoL in any population, with subgroup analyses according to the type of control group and other possible subgroup analyses depending on the characteristics of the included studies, when applicable.Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0)  OR “Acceptance and Commitment Therapy”[MeSH]) AND . The full search strategies for all databases can be found in low risk of bias, high risk of bias, or unclear risk of bias according to the criteria provided in the Cochrane Collaboration handbook [The characteristics of the included RCTs  were extracted into a table. Data regarding the means, SD, and sample sizes of each group were entered into an Excel (Microsoft) file. The risk of bias in the included RCTs was assessed using the Cochrane Collaboration risk-of-bias tool . The domhandbook . Summaryhandbook . One autI² statistic was used to measure the statistical heterogeneity across studies, and an 2I>60% was interpreted as substantial heterogeneity [2I statistic values for each outcome, that is, a random effects model was used when the 2I statistic for each variable was >60%; otherwise, a fixed effects model was used. A significance level  of .05 was used. The standardized mean difference (SMD) with 95% CIs was used as a summary statistic for the size of the intervention effect to account for outcomes measured using different assessment tools [Means, SDs, and sample sizes of the intervention and control groups in the included studies were entered into RevMan  for meta-analysis and pooled for each outcome at the immediate posttest and at follow-up. The ogeneity . The decnt tools . SMDs <0nt tools . SubgrouThe main characteristics of the included 39 RCTs are summarized in The average sample size of participants in the included RCTs was 139 (SD 185), ranging from 24 to 1162. The mean age of the participants was 40.1 (SD 13.3) years, ranging from 15.3 to 63.1 years, and the average percentage of female participants was 69.14% , ranging from 0% to 98.5%. The included RCTs were conducted in Sweden (10 studies), the United States (8 studies), the Netherlands (6 studies), Finland (5 studies), the United Kingdom (2 studies), Australia (2 studies), Canada (1 study), Belgium (1 study), Ireland (1 study), France (1 study), Denmark (1 study), and Germany (1 study). Of the 39 included studies, 30 (77%) were published between 2016 and 2021, and the remaining 9 (23%) were published between 2012 and 2015.The following section describes the results of the meta-analyses regarding the efficacy of iACT for depressive symptoms, anxiety, stress, psychological distress, and QoL at the immediate posttest and follow-up. Subgroup analyses for each outcome were performed according to the type of control groups  when applicable.χ21=0.8; P=.37), indicating that the effects of the 2 subgroups  at the immediate posttest were not statistically different from one another. Small effects of iACT on depressive symptoms were found at the immediate posttest regardless of the control group conditions in 8 studies (N=1155 participants) that compared iACT with active control groups  and 23 studies (N=2969) that compared iACT with passive control conditions .A meta-analysis of 31 RCTs (N=4124 participants) showed that iACT had a small effect on reducing depressive symptoms at the immediate posttest compared with control groups overall , indicating that the effects of the 2 subgroups  at follow-up were not statistically different from one another. The iACT had a medium effect compared with passive control groups at follow-up , but iACT was not significantly different from active control groups .A meta-analysis of 13 RCTs with follow-up data (N=1645 participants) revealed that iACT had a small effect on reducing depressive symptoms at follow-up compared with control groups overall , indicating that the effects of the 2 subgroups  at the immediate posttest were not statistically different from one another. Small effects of iACT on anxiety were found at the immediate posttest regardless of the control group conditions in 8 studies (N=1155 participants) that compared iACT with active control groups  and 14 studies (N=1251 participants) that compared iACT with passive control conditions .A meta-analysis of 22 RCTs (N=2407 participants) found that iACT had a small effect on reducing anxiety at the immediate posttest compared with control groups overall , indicating that the effects of the 2 subgroups  at follow-up were statistically different from one another. At follow-up, iACT had small effects compared with both passive control groups  and active control groups , but the effect size of iACT was larger compared with passive control groups.A meta-analysis of 10 RCTs with follow-up data (N=1483 participants) showed that iACT had a small effect on reducing anxiety at follow-up compared with control groups overall , indicating that the effects of the 2 subgroups  at the immediate posttest were not statistically different from one another. The iACT had a small effect on reducing stress compared with passive control groups at the immediate posttest , but iACT was not significantly different from active control groups .A meta-analysis of 12 RCTs (N=2260 participants) revealed that iACT had a small effect on reducing stress at the immediate posttest compared with control groups overall , indicating that the effects of the 2 subgroups  at follow-up were statistically different from one another. The iACT had a medium effect on reducing stress compared with passive control groups at follow-up , but iACT was not significantly different from active control groups .A meta-analysis of 5 RCTs with follow-up data (N=646 participants) found that iACT did not differ from control groups in reducing stress at follow-up overall , indicating that the effects of the 2 subgroups  at the immediate posttest were not statistically different from one another. The iACT had a small effect on reducing psychological distress compared with passive control groups at the immediate posttest , but iACT was not significantly different from active control groups .A meta-analysis of 12 RCTs (N=890 participants) found that iACT had a small effect on reducing psychological distress at the immediate posttest compared with control groups overall , indicating that the effects of the 2 subgroups  at follow-up were statistically different from one another. The iACT had a medium effect on psychological distress compared with an active control group at follow-up , whereas the iACT had a small effect compared with passive control groups at follow-up .A meta-analysis of 4 RCTs with follow-up data (N=314 participants) revealed that iACT had a small effect on reducing psychological distress at follow-up compared with control groups overall , indicating that the effects of the 2 subgroups  at the immediate posttest were not statistically different from one another. The iACT had a small effect on improving QoL compared with passive control groups at the immediate posttest , but iACT was not significantly different from active control groups .A meta-analysis of 14 RCTs (N=1232 participants) showed that iACT had a small effect on improving QoL at the immediate posttest compared with control groups overall  compared iACT with passive control groups only, so no subgroup analysis at follow-up was conducted. The iACT had a small effect on improving QoL compared with passive control groups at follow-up , anxiety at the immediate posttest  and at follow-up , stress at the immediate posttest  and at follow-up , and psychological distress at the immediate posttest  compared with control groups. A subgroup analysis found a medium effect of iACT with therapist guidance on depressive symptoms at follow-up . However, subgroup analyses revealed small effects of iACT without therapist guidance on depressive symptoms  and anxiety  at the immediate posttest only, with smaller effect sizes than those for iACT with therapist guidance. The iACT without therapist guidance was not significantly different from the control groups in depressive symptoms at follow-up , anxiety at follow-up , stress at the immediate posttest  and at follow-up , and psychological distress at the immediate posttest . There was no statistically significant subgroup difference in all the outcomes, indicating no statistically significant difference among studies according to the use of therapist guidance. Forest plots of these subgroup analyses are illustrated in Figures S1-S7 in P>.05), indicating no statistically significant difference among the studies according to delivery mode. Forest plots of these subgroup analyses are illustrated in Figures S8-S17 in Subgroup analyses showed small effects of web-based ACT on depressive symptoms at the immediate posttest  and at follow-up , anxiety at the immediate posttest  and at follow-up , stress at the immediate posttest , and QoL at the immediate posttest  and at follow-up  and medium effects of web-based ACT on psychological distress at the immediate posttest  and at follow-up  compared with control groups. Subgroup analyses revealed small effects of iACT accompanied by in-person ACT sessions on depressive symptoms  and QoL  at the immediate posttest only compared with control groups, findings that may be because of a smaller number of studies included for these subgroup analyses. Few studies compared videoconferencing ACT with control groups , and these subgroup analyses showed no statistically significant difference of videoconferencing ACT from control groups in these outcomes. There was no statistically significant subgroup difference in all the outcomes (P>.05), except for depressive symptoms at the immediate posttest (P=.007). These findings indicate that there was no statistically significant difference among studies according to the use of targeted participants in all the outcomes, except for depressive symptoms at the immediate posttest, for which a statistically significant, larger effect of iACT was found when studies targeted people with depressive symptoms . Forest plots of these subgroup analyses are illustrated in Figures S18-S24 in Subgroup analyses found medium effects of iACT on depressive symptoms  and anxiety  at the immediate posttest compared with control groups when studies directly targeted participants with depressive symptoms and anxiety, respectively. In contrast, subgroup analyses showed small effects of iACT on depressive symptoms  and anxiety  at the immediate posttest compared with control groups when studies did not involve targeted participants for each of the outcomes . Subgroup analyses found small effects of iACT on stress at the immediate posttest  and on depressive symptoms  and anxiety  at follow-up compared with control groups when studies did not involve targeted participants for each of the outcomes. However, there was no statistically significant difference of iACT from control groups in stress and psychological distress at the immediate posttest and in depressive symptoms and anxiety at follow-up when studies directly targeted participants for each of the outcomes, findings that may be because of a smaller number of studies included for these subgroup analyses . There was no statistically significant subgroup difference in all the outcomes  had an unclear risk of bias, 14 (36%) had a low risk of bias, and 5 13%) had a high risk of bias overall . However, more studies are needed to confirm these findings, especially in subgroup analyses according to delivery modes and targeted participants, as there were only a few studies that involved delivery modes other than web-based ACT modules or that involved directly targeted participants .P value) after Bonferroni correction was .005 (0.05/10). With the adjusted level of significance, most results remained the same, except for psychological distress at posttest and follow-up and QoL at follow-up. As RevMan does not allow users to choose the levels of significance other than 0.1, 0.05, or 0.01, and the values in the forest plots, including CIs, cannot be changed accordingly, we could not use the adjusted level of significance  in this meta-analysis. A total of 4 electronic databases were searched; therefore, some relevant articles could have been missed if they were published only in other databases. Only studies written in English were searched and included in this review, which could create a publication bias. One author with extensive experience in comprehensive literature reviews and expertise in ACT searched the literature; therefore, this review did not include 2 independent reviewers in the search process. A recent methodological systematic review found that single screening for study selection in systematic reviews conducted by an experienced reviewer had no impact on the findings of the meta-analysis [This review had some limitations. The Bonferroni correction method might be needed to adjust the results of multiple comparisons to reduce the false positive error rate  in a meta-analysis . As 10 canalysis . The ove


ALOX) and cyclooxygenase (COX) genes in the association between CRC and dietary fat.Genetics and dietary factors play important roles in the development of colorectal cancer (CRC). However, the underlying mechanisms of the interactions between CRC, gene polymorphisms, and dietary fat are unclear. This review study investigated the effects of polymorphisms of arachidonate lipoxygenase  in the ALOX and COX genes, such as rs2228065, rs6413416, and rs4986832 in the ALOX gene, and rs689465 in the COX gene may play significant roles in the association between the risk of CRC and dietary fats. SNPs of ALOX and COX genes may influence the effects of dietary fatty acids on the risk of CRC.Some single-nucleotide polymorphisms (ALOX and COX genes may have important roles in the effects of dietary fat on the risk of CRC. If future studies confirm these results, dietary recommendations for preventing colorectal cancer may be personalized based on the genotype of the ALOX and COX genes.Some polymorphisms of the  Colorectal cancer (CRC) is the second leading cause of cancer death in women and the third in men worldwide  and causPUFAs) may affect colonic carcinogenesis is the formation of specific eicosanoids (oxygenated metabolites of PUFAs) such as prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs), and lipoxins (LXs) (ALOX) pathways and prostaglandin-endoperoxide synthase (PTGS), which are also known as cyclooxygenase (COX) pathways (COX and ALOX genes as single-nucleotide polymorphisms (SNPs) can influence the risk of CRC  checklist (PICOS) were collected.In this review study, the quality of the collected studies was assessed by four researchers . In the case of having opposing ideas, other researchers (MH and HS) would be involved in reaching an agreement. After collecting the papers, all unrelated studies were excluded from the review process according to their titles and abstracts. Then, the full texts of the relevant articles were studied precisely. The standard quality assessment method of the ‘EPOC Risk of Bias Tool’ was applied to assess the quality of the methodologies . The Prehecklist  was usedCRC, ALOX, and COX genes and fat intake. The main characteristics of the studies are presented in The process of including the appropriate studies is presented in ALOX is to convert arachidonic acid (AA) into hydroperoxyeicosatetraenoic acid (HPETE) and eventually leukotrienes, a class of paracrine hormones involved in the inflammatory response. For example, ALOX12 converts AA into 12-hydroperoxyeicosatetraenoic acid (12-HPETE), which is involved in the expression of pro-inflammatory cytokine genes such as tumor necrosis factor-α (TNF-α)  and 12-lipoxygenase (ALOX12) played pro-carcinogenic roles in colorectal cancer  . The roll cancer . Additiosurvival . Moreove factors . In anotarcinoma . Thus, At of CRC Figure 2ALOX gene can affect the susceptibility to CRC. For instance, Goodman et al. assessed the effects of ALOX5 and ALOX12 gene polymorphisms on CRC in African-Americans and Caucasian patients. They found that the rs6413416 and rs4986832 polymorphisms of ALOX5 were associated with a decreased risk of CRC in Caucasians. They hypothesized that these polymorphisms could improve binding to the promoter region, leading to downregulation of ALOX5. In this way, they can lower the cancer risk by reducing enzymatic activity , while the rs4796535 and rs2619112 polymorphisms of ALOX15 were associated with an increased risk of rectal cancer    . Moreove09–1.74) . HoweverPTGS), catalyzes the first step in the biosynthesis of all prostaglandins and prostacyclins by converting arachidonic acid to prostaglandin H , can be inhibited by non-steroidal anti-inflammatory drugs (NSAIDs). Also, the end products of COX are related to various biological pathways in stimulating tumor growth , and telomerase reverse transcriptase (TERT). They used bioinformatics analysis on the Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) and rectal adenocarcinoma (READ) datasets. The results showed an inverse relationship between COX2 expression and telomerase activity in CRC. In the end, they identified differentially methylated patterns within the promoter regions of COX2 and TERT   (COX2 rs4648298 polymorphism (AA genotype) and a reduced risk of CRC in the Iranian population . Interestingly, they found this significant association only in non-smokers       who had the rs689466 polymorphism GG genotype compared with AA genotype carriers    . The COX-smokers . This fi03–2.04) . Interes= 0.022) . In this04–2.38) . Anothert of CRC . In cont  0.011) . Some reCOX enzymes  are important factors in the biosynthetic pathway of PGs from AA. ALOX enzymes  convert PUFA to fatty acid hydroperoxides, which results in the production of LTs. Recent studies reported an association between the CRC risk with the amount of fatty acids intake and COX and ALOX polymorphisms (COX1 rs10306110 polymorphism and low intake of docosahexaenoic acid (DHA), a fatty acid with anti-inflammatory properties, with an increased risk of colon cancer  (2PGE (LC-PUFA) may lower cancer risk by suppressing oxidative stress, tumor apoptosis, and inflammatory pathways by modulation of COX activity and inhibition of arachidonic acid-derived eicosanoids . However, there was no association between this polymorphism and the risk of rectal cancer regardless of the dietary n−6 PUFA intake levels  with COX1 rs3842787 polymorphism, high fish consumption and regular use of NSAIDs were associated with a decreased risk of CRC. In comparison, an inverse association was observed in individuals with at least one risk allele  in the COX-1 rs3842787 polymorphism  . Notably)  in the prevention of various types of malignancy, such as CRC, has been frequently reported .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.


Several serum biomarkers, particularly hs-CRP and NT-proBNP, have the potential to improve primary CVD risk prevention among asymptomatic middle-aged adults.Cardiovascular disease (CVD) continues as the most important cause of mortality. Better risk screening and prediction are needed to reduce the cardiovascular disease burden. The aim of the study was to assess the role of serum biomarkers in the prediction of CVD among asymptomatic middle-aged adults with no prior CVD history. A systematic review and meta-analysis were carried out using literature from PubMed and following PRISMA reporting guidelines. Twenty-five studies met our inclusion criteria and were included in the systematic review. The most commonly studied biomarker was high-sensitivity C reactive protein (hs-CRP) (10 studies), which showed that higher hs-CRP levels are associated with an increased risk of subsequent CVD events and mortality. In addition, several less-studied biomarkers , fibrinogen, gamma-glutamyl transferase (GGT), and others) also showed significant associations with greater future risk of CVD. A meta-analysis was possible to perform for hs-CRP and NT-proBNP, which showed statistically significant results for the ability of hs-CRP (hazard ratio (HR) 1.19, (95% CI: 1.09–1.30),  Despite concerted efforts from clinicians, researchers and public health authorities to prevent and reduce the burden of cardiovascular disease (CVD), CVD remains a leading cause of morbidity and mortality worldwide .The evidence base for controlling traditional CVD risk factors, such as lipids, blood pressure and blood glucose along with smoking cessation, to prevent and reduce CVD events is well-established, and clinical and population health measures in this regard have improved over the last decades. However, given the ongoing and large burden of CVD morbidity and mortality, significant research has been directed to studying additional tools, such as novel biomarkers and imaging techniques, that may prove to be better predictors of disease outcomes or permit earlier detection of CVD. Assessment of cardiovascular disease risk using biomarker analysis holds promise as a more effective approach for stratifying those at high risk for CVD and for optimizing the prevention and treatment of those individuals. Such an approach may also be helpful in asymptomatic individuals who are otherwise not known or identified to be at high risk to better quantify risk and help promote the adoption of lifestyle measures earlier ,3.Atherosclerotic cardiovascular disease accounts for a large proportion of the CVD burden. Atherosclerosis is characterized by a complex interaction between different processes, such as lipid accumulation in the arterial wall, a chronic low-grade systemic and local inflammatory response, oxidative stress and endothelial dysfunction . Thus, lAdditional biomarkers have also been investigated to determine their ability to predict CVD events, including cardiac biomarkers that could suggest existing cardiac damage, such as high-sensitive troponin (hsTn)  or N-terMany studies have assessed the potential of various biomarkers to predict cardiovascular disease and mortality, but most have focused on individuals known to be at high risk. Attempts to understand the predictive ability of biomarkers must be attentive to the association between biomarkers and age and underlying cardiovascular disease state. Relatively little guidance exists as to whether biomarkers can predict CVD and mortality in asymptomatic, middle-aged individuals. Such information would improve the identification of those who are at elevated CVD risk but are currently undetected using traditional risk factor screening. Therefore, this systematic review and meta-analysis assesses and summarizes the current evidence on the ability of advanced or novel lipoproteins/biomarkers to predict incident CVD among middle-aged adults without a prior CVD history or symptoms.The review protocol was registered in PROSPERO, the International Prospective Register of Systematic Reviews . An advanced search in the PubMed/Medline database with specific keywords related to the topic of interest was conducted using MeSH terms to create a uniform search strategy using some biomarkers with previous evidence , apolipoproteins, lipoprotein-associated phospholipase A2, oxidized LDL or metabolomics) and cardiovascular outcomes . In addition to filters for language, the age or date of publication was used  independently screened article titles and abstracts and decided if each study was eligible for further review. Inter-rater agreement was assessed, and discrepancies between the two independent primary reviewers were resolved by one of the senior investigators (SNK or DS). The inclusion criteria were as above: age (between 18 and 65 years), no prior or current history of cardiovascular disease, types of studies (case-control and cohort studies), and emerging/novel/advanced biomarkers beyond glucose and classic lipid profiles. The exclusion criteria were age (participants older than 65 years), current or prior history of cardiovascular disease, or other types of studies such as clinical trials, case reports or meta-analyses. After the screening of article titles and abstracts, 2055 articles were removed because they did not meet the inclusion criteria.After reading the full text and To assess the validity of the studies, we reviewed and evaluated the quality of each study on the basis of the criteria created by the third USPSTF (US Preventive Services Task Force) .2 test with values 25%, 50%, and 75% representing low, moderate, and high heterogeneity, respectively [p > 0.10 considered no risk of bias.We carried out the meta-analysis using meta command in Stata 15.0  to compute summary results for incident CVD outcome risk from eligible studies for each biomarker with sufficient individual results (at least three studies) for middle-aged adults without a prior CVD history or symptoms. The primary study outcomes were incident CVD, defined as any of the following: myocardial infarction, coronary revascularization procedures, stroke, heart failure, cardiac arrest, peripheral artery disease, or death from CVD. We used adjusted HRs to pool results when at least three studies were found for a given variable with comparable methodologies and results. The heterogeneity between the results of the studies was examined, and the magnitude of heterogeneity was judged by combining the findings with the Cochran’s Q test and the Iectively . A fixedWe identified 2264 studies through our search strategy. Based on a review of the titles and abstracts, 2055 were removed. After reading the full text of all articles, 183 studies were removed because their participants were older than 65 years old or had a previous history of CVD. Ultimately, 25 studies met all inclusion criteria with a total sample size of 287,020 participants. These included 20 prospective cohort studies, 3 nested case-control studies and 2 retrospective case-control studies ,37,38,39A total of 231,393 participants were included in the 10 studies that assessed the association between hs-CRP and cardiovascular outcomes among middle-aged, asymptomatic individuals  16,17,1,35,38,39p < 0.01, Q = 47.59, I2 = 85.3%) necessitated the use of the random-effects model for meta-analysis. Despite high heterogenicity, statistically significant results for the ability of hs-CRP to predict incident CVD were found , p < 0.05). Egger’s test was performed to assess the publication bias and showed significant results (p = 0.03). Therefore, sensitivity analyses were performed. The study by Zöga Diederichsen et al. (2018) [p < 0.01, Q = 18.01, I2 = 66.7%) and similar results to predict incident CVD , p < 0.05), in addition, the Egger’s test performed was not significant (p = 0.37)  .Four studies, including a total of 24,055 participants, were assessed for NT-Pro-BNP and risk of CVD and mortality  19,20,2,39. Thesp = 0.052, Q = 9.4, I2 = 57.5%). Despite high heterogenicity, the results showed the statistically significant ability of NT-proBNP to predict incident CVD among middle-aged adults without a prior CVD history or symptoms , p < 0.05). Egger’s test was performed to assess the publication bias, and it was not significant (p = 0.38).For NT-proBNP, it was possible to perform a meta-analysis including the four studies with continuous analysis to assess the association of NT-proBNP level with CVD incidence, using an adjusted hazard ratio per increment of 1 SD unit of the continuous predictor variable . A randoThree prospective studies were identified that assessed the risk of elevated fibrinogen levels for CVD  20,31,3,331,37. Three prospective studies assessed the risk of higher GGT levels and incident CVD events ,27,31 S. GGT wasOnly two cohort prospective studies were found that assessed the association between hsTn levels and CVD among asymptomatic middle-aged individuals ,20. Eachp = 0.001) and MS subjects .Only one prospective study and one case-control study were identified that assessed the association of higher homocysteine levels with CVD incidents in middle-aged, asymptomatic individuals ,30. In tp < 0.0001; 51-year-old subjects: HR 1.44 (CI 95%: 1.24–1.68), p < 0.0001; 61-year-old subjects: HR 1.26 (CI 95%: 1.13–1.41), p < 0.0001; and 71-year-old subjects: HR 1.1 (CI 95%: 1.02–1.19), p < 0.01). Diederichsen et al. (2018) [Two prospective studies met the inclusion criteria for the current systematic review and assessed whether higher suPAR levels could predict CVD in middle-aged asymptomatic individuals ,35. Euge. (2018)  also fouMany studies examined other biomarkers or ratios and met the inclusion criteria based on age and absence of CVD, including articles on uric acid, endostatin, HOMA-IR, lipoprotein (a), cystatin C, AST, ALT, alkaline phosphatase, albumin/creatinine ratio, etc., and their results are shown in the summary table  as thereThe results of this systematic review and meta-analysis provide important evidence about the relationship between various biomarkers and the risk for CVD events and CVD mortality among middle-aged asymptomatic subjects, especially for hs-CRP and NT-proBNP. Our findings are consistent with previous reviews that investigated the associations between biomarkers and CVD risk in individuals with a previous history of CVD or symptomatic subjects  and suggAtherosclerosis is considered a chronic, systemic, low-grade inflammatory disease of the arterial walls driving a gradual accumulation of lipoproteins from an early age. Initially, atherosclerosis is subclinical and often goes undetected. However, advancing atherosclerosis can lead to unstable atherosclerosis plaque and fatal cardiovascular events in older age .Traditional risk factors, including a family history of premature ASCVD, smoking, age, primary hypercholesterolemia, blood glucose and high triglycerides, have been the foundation of risk identification for several decades. Currently, many CV risk assessment systems, including classical risk factors, are used to estimate the risk of a first fatal CV event in apparently healthy subjects, usually expressed as a 10-year. Examples include the Framingham CVD risk score , SCORE , using the English language exclusively, or specific terms because we could leave out other interesting biomarkers and important works. Methodological limitations include wide variability in study protocols among the studies reviewed and the failure of some of those studies to make appropriate adjustments in the statistical analysis for confounders such as statin use, body mass index, alcohol consumption or socioeconomic status. In addition, as our results showed, the length of follow-up of studies included in the meta-analysis varied, with the possibility of fewer events in shorter studies leading to an underestimation of the ability of these biomarkers to predict CVD compared with longer studies. On the other hand, the strength of the current work is that it has assessed the relation of potential biomarkers in a population that has not previously been well described but where disease prevention could potentially lessen cardiovascular diseases substantially. It is necessary to highlight the important gap in the role of biomarkers to predict CVD in this specific population despite better evidence for their use in secondary prevention and the elderly population.Atherosclerosis starts at an early age as a low-grade systematic chronic inflammatory disease. The disease progression leads to clinical CVD with an elevated risk of an acute coronary event. The current work suggests the possibly important role of several biomarkers in improving the risk prediction of CVD in middle-aged asymptomatic individuals, especially for hs-CRP and NT-proBNP. However, longer and more extensive studies are needed to provide convincing evidence before general recommendations for clinical use can be made.


Exposure to recurrent infections in childhood was linked to an increased risk of cancer in adulthood. There is also evidence that a history of tonsillectomy, a procedure often performed in children with recurrent infections, is linked to an increased risk of leukemia and Hodgkin lymphoma. Tonsillectomy could be directly associated with cancer risk, or it could be a proxy for another risk factor such as recurrent infections and chronic inflammation. Nevertheless, the role of recurrent childhood infections and tonsillectomy on the one hand, and the risk of breast cancer (BC) in adulthood remain understudied. Our study aims to verify whether a history of tonsillectomy increases the risk of BC in women.A systematic review was performed using PubMed, Google Scholar, Scopus, Embase, and Web of Science databases from inception to January 25, 2022, to identify the studies which assessed the association between the history of tonsillectomy and BC in females. Odds ratio (OR) was calculated using the random/fixed-effects models to synthesize the associations between tonsillectomy and BC risk based on heterogeneity.Eight studies included 2252 patients with breast cancer of which 1151 underwent tonsillectomy and 5314 controls of which 1725 had their tonsils removed. Patients with a history of tonsillectomy showed a higher subsequent risk of developing BC  as compared to patients without a history of tonsillectomy. Influence analyses showed that no single study had a significant effect on the overall estimate or the heterogeneity.Our study revealed that a history of tonsillectomy is associated with an increased risk of breast cancer. These findings underscore the need for frequent follow-ups and screening of tonsillectomy patients to assess for the risk of BC. Inflammatory processes can increase the risk of cancer development. Tonsillitis is one of the most common presentations of inflammatory diseases, especially in children. Its treatment strategy includes performing a tonsillectomy, which is a routine procedure. The acute complications of this surgery include hemorrhage and infection, but long term, it has also been correlated with a higher risk for neoplastic development . StudiesTwo theories have been proposed in the literature that might explain the risk between tonsillectomies and the development of cancer. The first is that the immune function of tonsils is greatest in childhood and that it drastically decreases after adolescence. Therefore, children with tonsillectomies are put at a greater risk for viral infections which subsequently aid in the development of cancer . HoweverThe main aim of our study was to conduct the first comprehensive critical review and meta-analysis of observational studies to ascertain the risk of cancer in people with a reported history of tonsillectomy.The study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines . The UniThree electronic databases  were searched from inception to January 25, 2022, for relevant studies. The details of the search strategy for each database are presented in All included studies had to meet the following eligibility criteria: cohort or case-control study design; at least 1 study group of patients with tonsillectomy; and a comparison group involving patients without tonsillectomy or the general population. Included studies were also required to investigate breast cancer occurrence, incidence, or prevalence of cancer within this group of patients. Studies investigating only a pediatric population were excluded to minimize age-related bias. For overlapping studies from the same cohort , the latest and most appropriate outcomes were selected by the consensus of all the investigators.Two investigators independently screened the titles and abstracts of all the articles using the predefined inclusion criteria. The full-text articles were examined independently by all investigators to determine whether they met the inclusion criteria. Furthermore, the same authors independently extracted data using a data extraction form. The final inclusion of each article was determined by all investigators’ evaluation discussions. References and data for each included study were carefully cross-checked to ensure that no overlapping data were present and to maintain the integrity of the meta-analysis.To assess the risk of bias in the included cohort and case-control studies, the Newcastle-Ottawa Scale tool was used. Using the tool, each study was judged on 8 items in 3 categories, including the selection of the study groups, the comparability of the groups, and the ascertainment of the exposure of interest for case-control studies or the outcome of interest for cohort studies. Studies that received 7, 8, or 9 of a possible 9 points were regarded as high quality, whereas studies that received 4, 5, or 7 were regarded as fair quality (high risk of bias), and those that received 3 or less were regarded as low quality (very high risk of bias)  analysis to show the effect of every single study on the overall effect and heterogeneity.The systematic search identified 2523 potentially relevant studies. After initial review by title and abstracts, 2450 articles were excluded, leaving 73 to be reviewed in full text. Eight studies ultimately met our prespecified criteria and were included in our analysis. The detailed study selection process is depicted in a PRISMA flowchart in Together, these eight studies included 2252 patients with breast cancer of which 1151 underwent tonsillectomy and 5314 controls of which 1725 had their tonsils removed. Seven were case-control studies –16 and oThree studies were of high quality –17 while2 = 33%; P = .17; 2 = 33%).Our meta-analysis included eight studies comprising 2876 participants with a history of tonsillectomy and 4690 without a history of tonsillectomy. It revealed a statistically significantly increased risk of breast cancer in the group with a history of tonsillectomy as compared to the group without a history of tonsillectomy . The heterogeneity among the studies was of an acceptable level . All analyses showed an increased risk of breast cancer in the group with a history of tonsillectomy as compared to the group without a history of tonsillectomy. However, the test for subgroup differences was not significant for any of the comparisons, as shown in 2= zero) , and women, in particular, were more prone to develop breast cancer later in their lives (n = 2200).Theories put forward to explain this association suggests viral infections as the key driver of mutations, leading up to cancers. Late age tonsillectomies have been proposed as a proxy for a delayed type of infection by the Epstein- Barr virus (EBV) . MoreoveQuite a few studies conducted previously have investigated the association of tonsillectomy with cancers at various locations. Vineis et al. in a case-control study depicted a two-fold risk of lymphocytic leukemia with a tonsillectomy performed at 10 years of age . Liaw etin-vitro setting (Lubin et al. showed an increased risk of breast cancer diagnosed after 65 years of age in women with a history of tonsillectomy . Yasui e setting . Finally setting .This study provides a deeper insight into the relationship between tonsillectomy and developing breast cancer; it extends and confirms previous results. Some other strengths of our study include precise results as a culmination of a comprehensive review that has not been done so far. Moreover, a comprehensive investigation of heterogeneity and use of sensitivity analyses to demonstrate the robustness of our results futher strengthen our meta-analysis.Our study is not without limitations. Some of the major limitations that need to be highlighted include the observational nature of the included studies and the risk of confounding bias. Moreover, adjustment was not available for all of the studies, and some individual studies carried a high risk of bias. Due to inadequate reporting by the studies, we were not able to assess the association between the average age at tonsillectomy and risk of BC. Finally, there was a lack of matching between cases and controls in some studies.Our study underscores the need for frequent follow-ups and screening of tonsillectomy patients to assess for the risk of BC. The indications for tonsillectomy may need to be reconsidered, especially in those patients with pre-existing risk factors for BC. Large-scale studies with a robust design to reduce confounding bias are needed to confirm our findings. Mechanistic research is also needed to fully understand the pathogenesis of BC in tonsillectomy patients.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.SK, AE, MO, HC, AK: Data collection, analysis, screening and scientific writing. AB, MA, KD, LS, OR, NS: Data collection, analysis, screening and scientific writing. AA, JS, SG: Study concept, design, and drafting of the manuscript. All authors contributed to the article and approved the submitted version. SK, AA, JS, SG: Study concept, design, and drafting of the manuscript.Author MO was employed by IQVIA.The remaining 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.


Preeclampsia is a life-threatening disorder during pregnancy and postpartum periods. Preeclampsia can affect the activity of many organs. It is very important because if this disorder is associated with changes in thyroid function, it can affect the results of maternal and fetal tests. Accordingly, the aim of this meta-analysis study was to assess the abnormalities in thyroid function tests in preeclampsia.Studies were selected through a systematic search of the MEDLINE/PubMed, Scopus, Web of Science Core Collection, and Google Scholar databases in 31st August 2021. Also, reference lists of review articles and relevant studies were manual-searched to identify other potentially eligible studies. English studies that compared TSH, T4 and T3 of normal pregnant with preeclamptic women  were screened. Data sets were screened for eligibility by two independent reviewers. Articles were assessed by the Newcastle–Ottawa Scale. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used for quality assessment of evidence on outcome levels.p < 0.001) was significantly higher in preeclamptic women. TT4 , TT3  and FT3  were less in preeclamptic women. There was no statistically significant difference in FT4 between two groups . The results of publication bias and sensitivity analysis confirmed the reliability and stability of this meta-analysis. The quality of evidence was regarded as moderate, low, and very low for these risk factors according to the GRADE approach.After reviewing 886 published studies, 63 observational studies were selected and used for this meta-analysis. The study population included 21,528 pregnant women. The findings revealed that TSH (SMD = 1.70, 95%CI: 1.39 to 2.02; Findings of this meta-analysis indicated preeclamptic women were more at risk of changes in thyroid function tests. In order to prevent thyroid disorders, it is recommended that thyroid function tests be performed in women with pre-eclampsia.The online version contains supplementary material available at 10.1186/s12902-022-01154-9. Preeclampsia complicates 2–8% of pregnancies and is one main cause of maternal and neonatal mortality and morbidity worldwide , 2. The During pregnancy, the physiological changes of the thyroid gland are completely normal and incompatibility with these changes leads to dysfunction of the thyroid gland . NaturalPreeclampsia affects the function of many organs in the body, including the thyroid gland . In geneSome studies have shown that 29.3% of pregnant women with preeclampsia had hypothyroidism, 71.42% had subclinical hypothyroidism and the rest had overt hypothyroidism. . AnotherThe mechanism of hypothyroidism in pre-eclamptic women was not well understood. However, according to various theories, this mechanism in preeclampsia may be related to a decrease in plasma protein concentration and an increase in endothelin levels . In addiDuring a normal pregnancy, changes in thyroid function are well documented, but information on thyroid function in complicated pregnancies is scant , 23. TheThe purpose of this systematic review and meta-analysis is to evaluate of thyroid function test abnormalities in preeclampsia.This study was reported based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist for systematic review and meta-analysis. The report was prepared in accordance with PRISMA 2020 guidelines , and theThe study protocol was registered in the PROSPERO (Registration number: CRD42020213560).A comprehensive electronic search in the databases PubMed/Medline (NLM), SCOPUS, and Web of Science Core Collection was carried out in 31 August 2021. Google Scholar was also used to search for online research-related articles that may not be in the search databases to increase the comprehensiveness of the search. Medical Subject Headings (Mesh) and Embase Subject Headings (Emtree) were used to finding keywords. Keywords that were obtained from Emtree or Mesh were included in our search strategy without any changes. The search terms used were: “pregnancy toxemia”, “toxemia of pregnancy”, “preeclampsia”, “pre-eclampsia”, “preeclamptic women”, “pre-eclamptic women”, “TSH”, “thyroid stimulating hormone”, “thyrotropin”, “T3”, “triiodothyronine”, “T4”, “thyroxine”, “tetraiodothyronine”, “hypothyroidism”, “hypothyroidism” and “thyroid”. These keywords were combined with “AND” or “OR” browsers during the advanced search (see Appendix All searches were restricted to English language. References were managed with EndNote 8.0 software.Two independent reviewers (MF and SF) screened identified eligible studies based on their titles and abstracts. Then, all potentially relevant full texts were read to produce a final list of included studies for rejection recorded. The list of studies rejected at this stage and reasons for rejection can be found in supplemental appendix Any disagreements were resolved with discussion or through adjudication by a third review (SHT). The results of Cohen’s kappa indicated a perfect agreement between two authors (Kappa = 0.84).Studies were incorporated if they were: original and peer-reviewed researches; one author conducted the initial screening analysis. After removing duplicates and scanning the titles and abstracts of articles, those meeting the inclusion criteria were reviewed.Studies that met all of the following criteria in this review:Compared TSH, T4 and T3 of normal pregnant with preeclamptic women ;English studies;Published or in-press articles until August 31, 2021.Articles without appropriate case or control groupsAnimal studiesCase reportsLetter to the editor without quantitative dataQualitative studiesSystematic reviews and meta-analysesAbstract without sufficient data or full-text for quality assessment.For prevention misleading conclusions about excluding abstracts or full-texts without sufficient data, the first author sent five emails (every three days) to correspondence of studies. unfortunately, she did not receive any replies.- Research information ;- Characteristics of the participants ;- Comparison of the details ;First outcome measurement in this meta-analysis were TSH, TT3, TT4, FT3 and FT4. Additionally, age, gestational age, birth weight, BMI, SBP, DBP, and parity were considered secondary outcomes measurement. Data were carefully and independently extracted from all eligible studies by two reviewers (MF and SF according to the inclusion criteria mentioned above using a Microsoft Excel spreadsheet). The extracted data included study characteristics .In this study for evaluating the quality of studies, was used the Newcastle–Ottawa Scale (NOS) for case–control and clinical trial studies. The NOS is the most commonly tool for assessing the quality of observational cohort and cross-sectional studies , and eacThe Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was recommended by the Cochrane collaboration and can be used for assessing the quality of study outcome levels. There are four levels of certainty of evidence: high, moderate, low, and very low . For theIn this study, effect sizes were the difference between the mean of thyroid function indices  divided by their standard errors related. The effect size was calculated for each study that had the inclusion criteria and was eventually used for combination in the meta-analysis.The standardized mean difference (SMD) and 95% confidence interval (CI) were applied to compare TSH, TT3, TT4, FT3 and FT4 in two groups. For each variable, to test SMD = 0, we used this formula:2 measure the inconsistency across study and in general when 2 < 50%, a fixed effect model is suitable for pooling the effect size. Therefore, a random effects model (the DerSimonian and Laird method) was used to estimate the pooled effect size (EF) and each target variable. The results of meta-analysis were reported as a form of a forest plot which containing SMD and 95% CI.Prior to the meta-analysis of the studies, a sensitivity test was performed and studies that were not within the confidence interval were excluded from the meta-analysis. To evaluate the heterogeneity between the studies, Cochran's Q test (p < 0.10 indicated significance) with I2 . I2 index (I2 > 50% indicating heterogeneity between studies) were used. If significant heterogeneity was observed between studies, meta-analysis was performed in layers of variables such as age, gestational age, birth weight, BMI (Body Mass Index), SBP (Systolic Blood Pressure), DBP (Diastolic Blood Pressure), and parity. When heterogeneity was observed in the layers of each of the mentioned variables, we related the reasons for possible heterogeneity to the mentioned variables. We also performed meta-regression for variables whose results in the subgroup test are significant.To evaluate the degree of heterogeneity between the mean studies, Q-Cochran test (p < 0.1 as heterogeneity) and IEgger’s regression test was used to evaluate the publication bias between simultaneous studies. Hence, when the potential publication bias observed, the fill and trim method was performed. Also, all meta-analyzes were performed in STATA software version 14.We concluded that there is a potential bias among studies. Then we use the “trim and fill” method to consider the missing potential studies on both sides of the funnel piece and then recalculate the effect size considering the inclusion of the missing potential studies .Our search resulted in 886 articles. The article selection process was such that articles that did not qualify and did not meet the inclusion criteria were removed from the initial screening (based on the title or abstract of the article). Finally, we selected 63 articles for further reviewing Fig. .Fig. 1FlAll of the studies selected after the search process met the inclusion criteria and had high quality according to Newcastle checklist. Mean age was 26.59 years in preeclamptic group and 25.67 in normal pregnant women. Mean gestational age was 35.32 years in preeclampsia and 38.2 in normal pregnancy.The final study population comprised 21,528 pregnant women participants. Of whom 4765 (22.13%) of pregnant women were preeclamptic and 16,763 (77.87%) normotensives. Included study characteristics are summarized in Table Initially, we performed sensitivity analyses by consecutive removal of a study at a time to evaluate the change in the pooled SMD and 95% CI of each thyroid hormone. The results of sensitivity analysis showed that the pooled effect size of thyroid hormones is 95% confidence interval. In other words, when each study was removed, there was no significant change in the pooled SMD.Since there was a significant heterogeneity between studies, subgroup analysis was performed. The subgroup analysis was performed according to the age, gestational age, birth weight, BMI, SBP, DBP, parity Table . In ordeBased on the results of pooled SMD in 28 studies, FT3 was significantly lower in women with preeclampsia than in normal women Table .Fig. 5Fop = 0.022) and SBP  significantly FT3 was decreased. Also, FT4 increased significantly with increasing SBP . In the group of normal pregnant women, FT3 decreased significantly with age   and FT3  no observed publication bias among studies for other variables.Publication bias in meta-analysis was evaluated by performing Egger rank correlation test for statistical analysis of plots symmetry. The results showed that except for TSH , TT4 (t = -3.32, We are moderately confident in the effect estimate TT4, FT4 and FT3: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different For TT3, our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Also, for TSH, we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.According to results of GRADE assessment the risk of bias, inconsistency, indirectness and imprecision for all effect sizes were not serious. The detailed table is presented in Table In this meta-analysis study, for the first time, thyroid function tests in preeclampsia were compared with normal pregnant women. The results of this study showed that the mean TSH level is higher in preeclamptic women, but TT4, TT3 and FT3 are lower. Additionally, there was no statistically significant difference in FT4 between the two groups.The results of this study showed that the higher TSH mean level in preeclamptic patients, which is consistent with other studies , 64, 82.Consistent with our findings, several studies have observed lower TT4 and TT3 levels in preeclampsia , 16, 35.Our finding observed FT3 in preeclamptic women was significantly different from normal pregnant. Low FT3 levels were observed in preeclamptic patients in a few studies, too , 41, 58.In our study, results of meta-regression presented that in preeclamptic women with increasing SBP significantly FT3 was decreased. Also, FT4 increased significantly with increasing SBP. Maduka and et al. did not reported any correlation between FT3 or FT4 with systolic blood pressure in the preeclamptic women .In another study, TSH is correlated positively with systolic blood pressure in preeclampsia  but thisThe relation between changes in thyroid function and preeclampsia may be reciprocal . This meOn the other hands, preeclampsia can be a key cause in the pathogenesis of hypothyroidism. Effects of preeclampsia in thyroid function is not yet elucidated, but increased levels of endothelin as a vasoconstrictor produced by vascular endothelium are involved in the pathogenesis of subclinical hypothyroidism in preeclampsia . Out of Nowadays, some researchers have cited the relationship between maternal and fetal complications with thyroid dysfunction is a problem of concern , 23, 33.The results of this study showed that except for TSH, there was no diffusion bias between studies for other variables. These results could mean that only research that has published positive results and published negative or insignificant statistical studies will not be published because they see it as a failed researcher that is not true. .The quality of evidence for TSH was rated as very low by the GRADE that any effect of preeclampsia on TSH is very uncertain. The quality of evidence for TT4, FT4, and FT3 were rated as moderate. It shows in future studies, preeclampsia has likely an important effect on them and may change the estimate. For TT3, the quality of evidence was rated as low which present future studies, preeclampsia is very likely to have an important effect on TT3 and is likely to change the estimate.Researches showed drug therapy may reduce the complications of pregnancy in women with thyroid dysfunction and recommended thyroid function be checked in preeclamptic women , 86. FurPresent study has several strengths. This is the first systematic review and meta-analysis about the relationship between preeclampsia and the thyroid function tests. Accordingly, the finding of current study showed more reliable and evident results than the separate studies. Moreover, included studies were performed in four continents of Asia, Africa, America and Europe. Forth, the results of this meta-analysis have important implications for care from preeclamptic women and screening of thyroid hormone levels during pregnancy. We used the GRADE approach to appraise the quality of evidence and assessed the risk of bias of studies.The limitation of the current study is that the great majority of studies comprising the meta-analysis reported findings for mixed groups of mild and severe preeclampsia. However, few studies reported results separately for mild and severe. Accordingly, we could not find the relation between changes in thyroid function tests with the severity of preeclampsia.Findings of this meta-analysis indicated preeclamptic women were more at risk of changes in thyroid function tests. Therefore, thyroid function tests should be considered in preeclamptic women. Identification of changes in thyroid hormones in preeclampsia might be of help in preventing the thyroid disorders.These results provide insights into the optimizing clinical decision-making strategies that should provide thyroid screening in women with preeclampsia.Additional file 1: Supplemental appendix 1. PRISMA 2020 Checklist.Additional file 2: Supplemental appendix 2. Electronic database search strings.Additional file 3: Supplemental appendix 3. Studies rejected at full-text review stage.