Background and Purpose: The lifetime prevalence of benign paroxysmal positional vertigo (BPPV) is high, especially in the elderly. Patients with BPPV are more susceptible to ischemic stroke, dementia, and fractures, severely reducing quality of life of patients. Many studies have analyzed risk factors for the occurrence of BPPV. However, the results of these studies are not identical. We performed this meta-analysis to determine potential risk factors associated with the occurrence of BPPV.Methods: PubMed, EMBASE, and the Cochrane Library (January 2000 through March 2020) were systematically searched for eligible studies analyzing risk factors for the occurrence of BPPV. Reference lists of eligible studies were also reviewed. We selected observational studies in English with a control group and sufficient data. Pooled odds ratios (ORs) or the mean differences (MDs) and 95% confidence intervals (CIs) were calculated to measure the impacts of all potential risk factors. Heterogeneity among studies was evaluated using the Q-test and I2 statistics. We used the random-effect model or the fixed-effect model according to the heterogeneity among the included studies.Results: We eventually included 19 studies published between 2006 and 2019, including 2,618 patients with BPPV and 11,668 participants without BPPV in total. In this meta-analysis, the occurrence of BPPV was significantly associated with female gender , serum vitamin D level , osteoporosis , migraine , head trauma , and total cholesterol level .Conclusion: Female gender, vitamin D deficiency, osteoporosis, migraine, head trauma, and high TC level were risk factors for the occurrence of BPPV. However, the effects of other risk factors on BPPV occurrence need further investigations. Benign paroxysmal positional vertigo (BPPV) is one of the most common types of vestibular vertigo, accounting for ~17–42% of patients with vertigo . The lifAlthough canalith repositioning maneuver is an effective treatment for BPPV, nearly 50% of patients experienced at least one recurrence in 2 years after treatment . Many ofHowever, the underlying causes of BPPV remain unclear. In recent decades, many studies have investigated risk factors for the occurrence of BPPV, including female gender, serum vitamin D deficiency, osteoporosis, vascular risk factors, head trauma, and other potential risk factors –26. HoweThe electronic databases PubMed, EMBASE, and the Cochrane Library (January 2000 through March 2020) were systematically searched by two researchers (JB Chen and WS Zhao) for eligible observational studies analyzing risk factors for the occurrence of BPPV. The MeSH terms “Risk Factors,” “Benign Paroxysmal positional vertigo,” and all related free words were combined to search relevant literature as comprehensively as possible. Reference lists of all eligible studies were also reviewed to identify other potentially relevant studies.Articles included in this meta-analysis must meet the following criteria: (1) clearly define the experimental group (patients diagnosed with BPPV) and the control group (participants or patients without any history of vertigo); (2) all BPPV patients included in studies were diagnosed by a characteristic history of recurrent positional vertigo or a typical nystagmus during Dix-Hallpike tests or Roll test; (3) reported sufficient data on risk factors investigated in our meta-analysis; (4) the outcome was BPPV; (5) case–control studies, cohort studies, or other observational English studies analyzing relevant risk factors for occurrence of BPPV. The following studies were excluded from this meta-analysis: (1) sufficient information could not be obtained; (2) the outcome was the recurrence of BPPV, not the occurrence of BPPV.Two reviewers (JB Chen and WS Zhao) independently assessed the quality of each study included in this meta-analysis using the Newcastle Ottawa Scale . StudiesA standardized pre-extraction form was used to extract available data, including study characteristics, sample demographic information, medical comorbidities, and serum indicators. For each risk factor, we performed a detailed analysis and compared their definitions in the original literature. Data extraction was independently completed by the same two reviewers according to the revised extraction form from January 2020 to February 2020. All disagreements between the two reviewers were fully discussed, and furthermore a third reviewer (XJ Yue) was consulted for unresolved discrepancies to reach a consensus. The following data were extracted for each included study: (1) Study characteristics: fist author, study region, sample size, publication year, and study design ; (2) sample demographic information: gender, age (mean ± SD), body mass index (BMI), smoking, drinking, and regular exercise; (3) medical comorbidities of participants: osteoporosis, osteopenia, migraine, stroke, head trauma, hypertension (HTN), diabetes mellitus (DM), and hyperlipidemia; (4) serum indicators: total cholesterol level (TC) (mmol/L) and serum vitamin D level (ng/ml).Q-test and I2 statistics. A fixed-effect model was used when heterogeneity was not significant (I2 < 50%) and a random-effect model was used when heterogeneity was significant (I2 > 50%)  or mean differences (MDs) and 95% confidence intervals (CIs). ORs were calculated for categorical variables including female gender, osteoporosis, osteopenia, migraine, stroke, head trauma, hypertension, DM, hyperlipidemia, smoking, drinking, and regular exercise. MDs were calculated for continuous variables including age, serum vitamin D level, and TC level. Heterogeneity among studies was tested and quantified using the Cochrane 2 > 50%) . In addiThe literature search produced a total of 256 records. Six additional records were identified through screening the reference lists of each study included in this meta-analysis. After 49 duplicates were removed, we further excluded 158 records through screening the titles/abstracts. The remaining 55 studies were assessed by reviewing the full text in detail. Finally, 19 studies published between 2006 and 2019 were included in our meta-analysis. A flow diagram of the literature selection was present in P = 0.004) .Fifteen studies involving 13,819 participants analyzed the relationship between female gender and the occurrence of BPPV. Four studies were not included in this risk factor analysis, because the participants in these studies were all male or female. The pooled results showed that female had a slightly higher risk of BPPV compared with male  . We usedP = 0.13) .Thirteen studies including 7,056 participants reported sufficient data between age and the occurrence of BPPV. The pooled results showed that age was not associated with BPPV occurrence  . These rP = 0.02) . As shown in P < 0.00001; I2 = 22%; P = 0.27).Seven studies including 1,254 participants measured serum vitamin D level to investigate the relationship between serum vitamin D level and BPPV occurrence. Significant relationship was found between serum vitamin D level and BPPV in our analysis. The vitamin D level was lower in patients with BPPV than in controls  . StatistT scores and we specifically analyzed the effects of osteoporosis and osteopenia on BPPV. Osteopenia was defined as −2.5 < T score < -1.0, and osteoporosis was defined as T score ≤ -2.5. Eight studies including 3,944 participants investigated the effects of osteoporosis on the occurrence of BPPV. Our analysis indicated that osteoporosis was a risk factor for BPPV occurrence    . The I2- = 0.59) . The I2-P < 0.00001) .Two studies including 8,493 participants investigated the relationship between migraine and BPPV occurrence. Our analysis indicated that migraine was a risk factor for BPPV occurrence  . No heteP = 0.24) .The same two studies also analyzed the correlation between stroke and the occurrence of BPPV. The pooled results showed no significant correlation between BPPV and stroke  , with siP = 0.02)  . The I2-P = 0.08) . Significant heterogeneity between studies limited the accuracy of the results.Twelve studies including 10,869 participants evaluated the effects of hypertension on the onset of BPPV. The pooled results suggested no significant association between BPPV and hypertension  . This riI2 = 18%; P = 0.27).Twelve studies including 10,869 participants reported the relationship between DM and BPPV occurrence. The pooled evidence showed that DM was not associated with BPPV occurrence  . No signP = 0.13)  . The I2-P = 0.03)  . The I2-P = 0.07) .Seven studies including 8,019 participants were conducted on the relationship between smoking and BPPV. The pooled results indicated that smoking was not associated with BPPV occurrence  . StatistP = 0.28)  . The I2-P = 0.63) .Five studies including 1,428 participants evaluated the effects of regular exercise on BPPV. Our analysis suggested that physical inactivity was not associated with BPPV occurrence  . There wThis systematic review and meta-analysis indicated that female gender, vitamin D deficiency, osteoporosis, migraine, head trauma, and high TC level were risk factors for the occurrence of BPPV. There was no sufficient evidence to suggest that age, osteopenia, stroke, HTN, DM, hyperlipidemia, smoking, drinking, and physical inactivity were associated with BPPV occurrence. The accuracy of some of our results may be limited to significant heterogeneity or the limited number of included studies, so further research was needed to confirm some of our results.Although many included studies controlled the sex ratio between the experimental and control groups, our analysis showed that women were more likely to develop BPPV than men. Previous studies have also suggested that women had a higher incidence of BPPV than in men, especially in the elderly women . This reOur analysis of serum vitamin D level suggested that vitamin D deficiency appeared to be a risk factor for the occurrence of BPPV. This result was consistent with a previous meta-analysis . BPPV siOur analysis results indicated that osteoporosis was a risk factor for BPPV occurrence, but osteopenia was not. A previous systematic review also showed that BPPV may be associated with osteoporosis or osteopenia . Many stThe pooled results showed that BPPV has no significant relationship with hyperlipidemia, but BPPV patients have a higher TC level. An increased TC level was a risk factor for BPPV occurrence. A higher TC level or hyperlipidemia can cause vascular damage in the inner ear, which may lead to BPPV occurrence . In addiBPPV was frequently induced by secondary factors such as head trauma, migraine, or other inner ear diseases. Recent studies showed that migraine  and headSome studies have investigated associations between vascular risk factors and BPPV, such as hypertension, DM, and hyperlipidemia, but the results were controversial , 19. In Previous studies suggested that smoking has adverse effects on middle ear diseases and hearing loss  and evenOur analysis showed no significant association between BPPV and physical inactivity. However, previous studies showed that moderate physical exercise can prevent the occurrence of BPPV and decrease the risk of falls and fractures, especially in the elderly . IntenseInevitably, there were several limitations in this meta-analysis. First, searches were restricted to English literature, which means that potentially high-quality literature may not be included in our analysis. Second, some potential risk factors were not analyzed in our analysis, because too few published studies were available, such as coronary heart disease, serum uric acid level, and albumin level. Third, subgroup analysis of each risk factor was not performed due to insufficient data. Furthermore, many included studies were retrospectively conducted in Asia and BPPV had many levels of its severity, which may limit the reliability of our results. In addition, for some risk factors, the limited number of included studies, significant heterogeneity, or ambiguous definition may limit the accuracy of these results. Large-scale randomized controlled trial (RCT) studies were necessary to confirm the reliability of our results.This meta-analysis was based on 19 studies involving a total of 14,286 participants, which provided strong evidence that female gender, vitamin D deficiency, osteoporosis, high TC level, migraine, and head trauma were risk factors for the occurrence of BPPV. However, the effects of other risk factors on BPPV occurrence needed further investigations. Further investigations should focus on exploring potential mechanisms, how to effectively intervene in high-risk populations, and preventing these risk factors as much as possible.All datasets presented in this study are included in the article/JC and WZ contributed to literature search, data analysis, and drafting and revision of the manuscript. JC and XY contributed to data collection and crafting and revision of the tables and figures. PZ given constructive suggestions for the revision of this manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


P < 0.001), perineural invasion , Breslow greater than 2 mm , diameter greater than 20 mm , and location on temple  were associated with an increased risk of recurrence, whereas immunosuppression status and location on cheek, ear, or lip were not associated with the risk of recurrence. Poor differentiation ; perineural invasion ; Breslow greater than 2 mm ; diameter greater than 20 mm ; and location on ear , lip , and temple  were associated with an increased risk of metastasis, whereas immunosuppression status and location on cheek did not affect the risk of metastasis. Finally, poor differentiation , perineural invasion , and Breslow greater than 2 mm  were associated with an increased risk of disease-specific death, whereas diameter; immunosuppression status; and location on ear, lip, and temple did not affect the risk of disease-specific death. We found that differentiation, perineural invasion, depth, diameter, and location could affect the prognosis of cSCC. The potential role of other patient characteristics on the prognosis of cSCC should be identified in further large-scale prospective studies.In this study, we sought to identify the potential impacts of disease characteristics on the prognosis of cutaneous squamous cell carcinoma (cSCC). We searched the PubMed, EmBase, and Cochrane Library databases from their inception until February 2020 to identify studies that investigated the prognosis of cSCC. The pooled effect estimates were applied using odds ratios (OR) and 95% confidence intervals (CI) and were calculated using the random-effects model. Forty-three studies including a total of 21,530 patients and reporting 28,627 cases of cSCC were selected for the final meta-analysis. Poor differentiation (OR, 3.54; 95% CI, 2.30–5.46;  Nonmelanoma skin cancer is the most common type of cancer, and the number of cases has increased to more than 1 million in the United States annually . CutaneoThe incidence of head and neck cSCC is increasing, and the specific anatomic subsites have been associated with an increased risk of regional metastatic involvement . The parThis study was performed and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Statement . StudiesTwo reviewers independently conducted the literature search and study selection. Any disagreements were resolved by discussion until a consensus was reached. A study was included if it met all of inclusion criteria: (1) all patients had cSCC; (2) the study reported at least 1 of the following: differentiation, perineural invasion, depth, diameter, immunosuppression status, and location; and (3) the study reported at least 1 of the following: recurrence, metastasis, and DSD. Furthermore, there were no restrictions placed on study design.The information of included studies were collected by 2 reviewers independently. The abstracted items included the first author’s name, publication year, study design, country, sample size, mean age, number of cSCCs, outcomes, risk factors, inclusion criteria, duration of follow-up, and investigated outcomes. The quality of included studies was assessed using the Newcastle-Ottawa Scale (NOS) according to selection , comparability , and outcome , and the “star system” for each individual study ranged from 0 to 9 . The quaI2 and the Q statistic were applied to assess the heterogeneity among the included studies. Significant heterogeneity was defined as I2 greater than 50.0% or a P value less than 0.10 .–62.20–62P < 0.001) (P = 0.001) (P < 0.001) (P < 0.001) (P = 0.030) (P = 0.050) (P = 0.924) (P = 0.668) (P = 0.686) , perineural invasion , diameter greater than 20 mm , and location on ear . No significant heterogeneity was detected for Breslow greater than 2 mm , immunosuppression status , and location on lip . Sensitivity analyses indicated that the pooled conclusions for poor differentiation, perineural invasion, diameter greater than 20 mm, and immunosuppression status were not altered by sequential exclusion of each individual study , perineural invasion , and diameter greater than 20 mm  on the risk of recurrence. However, we noted a potential significant publication bias for the role of immunosuppression status on the risk of recurrence   , perineu= 0.001) , Breslow< 0.001) , diamete< 0.001) , and loc= 0.030)  were ass= 0.050)  and loca= 0.924) , ear (OR= 0.668) , or lip = 0.686)  did not al study . Finally= 0.260) . HoweverP < 0.001) (P < 0.001) (P < 0.001) (P < 0.001) (P = 0.002) (P = 0.005) (P = 0.017) (P = 0.051) (P = 0.435) ; perineural invasion ; diameter greater than 20 mm ; and location on cheek , ear , and temple , but no significant heterogeneity for Breslow greater than 2 mm , immunosuppression status , and location on lip . The pooled conclusions were stable and not changed by sequential exclusion of individual studies , perineural invasion , Breslow greater than 2 mm , and immunosuppression status . The potential significant publication bias for diameter greater than 20 mm   , perineu< 0.001) , Breslow< 0.001) , diamete< 0.001) , locatio= 0.002) , locatio= 0.005) , and loc= 0.017)  were ass= 0.051)  and loca= 0.435)  were not studies . Finally= 0.640)  and the P = 0.003) (P < 0.001) (P < 0.001) (P = 0.095) (P = 0.161) (P = 0.137) (P = 0.490) (P = 0.584) , perineural invasion , Breslow greater than 2 mm , diameter greater than 20 mm , and immunosuppression status , but no significant heterogeneity for location on ear  or lip . Furthermore, the pooled conclusions for the role of poor differentiation and perineural invasion on the risk of DSD were robust and not altered by sequential exclusion of individual studies  or perineural invasion   , perineu< 0.001) , and Bre< 0.001)  were ass= 0.095) , immunos= 0.161) , locatio= 0.137) , locatio= 0.490) , and loc= 0.584)  did not  studies . Finally= 0.462) .The current study was based on observational studies and explored the role of clinicopathological characteristics on the risk of recurrence, metastasis, and DSD. This comprehensive quantitative study included 21,530 patients and 28,627 cSCC from 7 prospective and 36 retrospective studies with a wide range of patient characteristics. The findings of this study found that poor differentiation, perineural invasion, and Breslow greater than 2 mm were associated with an increased risk of recurrence, metastasis, and DSD. Moreover, diameter greater than 20 mm and location on the temple were associated with excess risk of recurrence and metastasis. Finally, location on the ear or lip was associated with an increased risk of metastasis.A previous systematic review and meta-analysis included 36 studies and reported that the risk of recurrence was significantly increased with Breslow greater than 2 mm, invasion beyond subcutaneous fat, Breslow greater than 6 mm, perineural invasion, and poor differentiation. Invasion beyond subcutaneous fat; Breslow greater than 2 mm; Breslow greater than 6 mm; diameter greater than 20 mm; poor differentiation; perineural invasion; location on temple, ear, and lip; and immunosuppression were associated with an increased risk of metastasis. Furthermore, diameter greater than 20 mm, poor differentiation, location on ear or lip, invasion beyond subcutaneous fat, and perineural invasion were associated with an excess risk of DSD . HoweverThe potential role of clinicopathological characteristics on the risk of recurrence was consistent with that reported in a previous meta-analysis . Nearly Several advantages of this study should be highlighted. First, most of the included studies were of relative high quality, and the pooled conclusions were robust. Second, the large sample size allowed us to quantitatively assess the role of clinicopathological characteristics on the prognosis of cSCC. Thus, our findings are potentially more robust than are those of any individual study. Third, the analysis of this study provides comprehensive results regarding the role of differentiation, perineural invasion, depth, diameter, immunosuppression status, and location on the risk of recurrence, metastasis, and DSD.Despite these advantages, however there are also limitations that should be acknowledged. Most of the included studies were retrospective in design, and selection or recall bias was inevitable. In addition, significant heterogeneity was detected for several of the investigated outcomes, which was not fully interpreted by sensitivity analyses. Third, most of the reported results were unadjusted data, and the results could be affected by the patient characteristics. Fourth, the role of clinicopathological characteristics on the risk of DSD was reported in a smaller number of studies, and the conclusions might vary. Also, publication bias was inevitable because of the analysis based on published articles. Finally, the analysis was based on the study level, and individual data were not available.In conclusion, this study indicated that the risk of recurrence, metastasis, and DSD among cSCC patients are significantly increased when patients are characterized by poor differentiation, perineural invasion, and Breslow greater than 2 mm. Moreover, we noted that diameter greater than 20 mm and location on the temple were associated with an increased risk of recurrence and metastasis. Furthermore, location on the ear or lip could result in an excess risk of metastasis in patients with cSCC. The results of this study should be verified by further prospective cohort studies.S1 Checklist(DOC)Click here for additional data file.S1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.S3 Appendix(DOCX)Click here for additional data file.


KCNQ1) gene polymorphisms on the risk of type 2 diabetes mellitus (T2DM), but the findings are inconclusive.  Previous studies have examined the role of the KQT-like subfamily Q member1  with their 95% confidence intervals (CIs) were applied to assess the strength of associations in the random-effects models. We used the trial sequential analysis (TSA) to measure the robustness of the evidence.  Five electronic databases, such as PubMed and Embase, were searched thoroughly for relevant studies on the associations between seven most studied  49 publications including 55 case-control studies  were finally enrolled. In overall analyses, generally, increased T2DM risk was detected for rs2237892, rs2237895, rs2283228, rs151290, and rs2074196, but not for rs231362 under all genetic models. The ORs and 95% CIs for allelic comparison were 1.23 (1.14-1.33) for rs2237892, 1.21 (1.16-1.27) for rs2237895, 1.27 (1.11-1.46) for rs2237897, 1.25 (1.09-1.42) for rs2283228, 1.14 (1.03-1.27) for rs151290, 1.31 (1.23-1.39) for rs2074196, and 1.16  for rs231362. Stratified analyses showed that associations for rs2237892, rs2237895, rs2283228, and rs151290 were more evident among Asians than Caucasians. TSA demonstrated that the evidence was sufficient for all polymorphisms in this study. The genotypes of the three SNPs  were significantly correlated with altered KCNQ1 gene expression. KCNQ1 gene polymorphisms  might be the susceptible factors for T2DM, especially among Asian population. This meta-analysis suggested that  The global epidemic of diabetes is a major public health problem, and the number of cases has increased four times in the past 30 years . IncrediKCNQ1) is a family of voltage-gated potassium channels, and the KCNQ1 gene located on 11p15.5 encoded the protein /polymorphism/variant/genotype without language restriction. Some references might be inevitably missing during the database searching. Therefore, the corresponding items generated by PubMed have been recovered. The reference lists of the main related studies and review studies were reviewed to identify potential missing articles which are related to this topic.Five electronic databases , and Wanfang databases) were systematically searched up to July 3, 2019, using combinations of the following keywords: Diabetes Mellitus[MESH]/diabetes and Two authors (X-XY and M-QL) independently reviewed and selected the studies. The following inclusion criteria were used to select studies for this meta-analysis: (1) case-control study as study design; (2) T2DM as outcome; (3) evaluation of at least one of the following seven polymorphisms: rs2237892, rs2237895, rs2237897, rs2283228, rs231362, rs151290, and rs2074196; and (4) enough genotype information for data analysis. Studies with gestational diabetes or postoperative diabetes as the endpoint were excluded. Only the studies with the largest sample size were included when there were duplicate studies with overlapping data.For the included studies, the data were abstracted by two authors (XY and ML) using the same data extraction form as follows: first author, year of publication, country of origin or ethnicity of study participants, source of control groups, sample size of cases and controls, mean age and percentage of male of cases and controls, genotyping method, T2DM diagnostic criteria used, matching variables, and genotype and allele distributions of cases and controls.The method, derived from a meta-analysis by Thakkinstian et al.  in 2011,KCNQ1  with the T2DM risk were evaluated by the collected odds ratios (ORs) and their 95% confidence intervals (95% CIs) according to the following five genetic models: (1) allele genetic model: M vs. W ; (2) homozygote genetic model: MM vs. WW; (3) heterozygote genetic model: WM vs. WW; (4) dominant genetic model: MM+WM vs. WW; and (5) recessive genetic model (MM vs. WM+WW). Heterogeneity between studies was assessed using Cochran'sQand theI2statistics. The random-effects model by the DerSimonian and Laird method was used in all analyses regardless of I2 values because it provides more conservative estimates [The chi-squared goodness-of-fit test was used to assess whether the gene frequency in controls was consistent with the Hardy-Weinberg equilibrium (HWE). The associations of seven polymorphisms of The stratified analyses and metaregression analyses were performed by races , HWE (yes or no), control sources , quality scores (<9 or ≥9 points), year of publication (<2015 or ≥2015), and number of participants (<500 or ≥500), respectively. Sensitivity analysis by sequentially removing each study was also applied to verify the robustness of our findings . The pubP < 0.05 on two sides.All analyses mentioned above were conducted using Stata 11.0 software, and the test level was a The TSA tool was used to evaluate whether the quantitative results are reliable, and the required information size (RIS) was calculated to reduce type I error , 46. TSAKCNQ1 mRNA expression data was retrieved for KCNQ1 SNPs from the GTEx Portal database . These data were used to evaluate the correlation between SNP genotypes and KCNQ1 mRNA expression level alteration.The In total, 942 articles were identified through the literature search . After tThe main characteristics for each included study are presented in Forty-two studies  were included in the meta-analysis for rs2237892, 23 studies  for rs2237895, 12 studies  for rs2237897, and 10 studies  for rs2283228. Besides, there are less than ten studies focused on rs231362, rs151290, and rs2074196, respectively.KCNQ1 polymorphisms and T2DM risk is provided in P ranges: 0.12-0.39). Moderate to significant heterogeneity was observed for most of these polymorphisms .The summary of pooled estimates for the association between KCNQ1 polymorphisms and T2DM has been demonstrated by metaregression analyses   might be significantly associated with increased T2DM risk. These significant associations are more pronounced among Asian populations and can be further confirmed by TSA.To our knowledge, this meta-analysis is the most comprehensive study of the association between the KCNQ1 polymorphisms and the risk of T2DM were published in 2013 and 2014, respectively. However, only the allele genetic model was analyzed in the meta-analysis by Liu et al. [KCNQ1 was studied in the meta-analysis by Li et al. [KCNQ1 according to not only the allele genetic model but also the genetic models of the homozygote, heterozygote, dominant, and recessive comparison were performed in this meta-analysis. In the meta-analysis by Liu et al. [P < 0.001), C allele of rs2237895 , C allele of rs2237897 , A allele of rs2283228 , and G allele of rs231362 . Compared to the study by Liu et al. [KCNQ1 polymorphisms  and did not conduct research on genotype distribution. Therefore, correspondingly, its literature selection criteria are more lenient. The inclusion of the literature not included in this article may lead to statistically significant results for the rs231362 allele. Finally, the results of the study by Liu et al. [KCNQ1 rs2237892 T polymorphism and T2DM in the Asian population under the allelic , recessive , dominant , and additive genetic models . The result of recessive genetic models contradicted with this meta-analysis . Similarly, compared to the study by Li et al. [Two previous meta-analyses , 64 focuu et al.  and onlyu et al. , signifiu et al.  have beei et al. , 62, 63 KCNQ1 might play a role in the susceptibility of T2DM. KCNQ1, encoding the alpha subunit of the IKsK+ channel, is mainly expressed in the tissues or cells of the heart [KCNQ1 are associated with impaired fasting glucose, beta-cell function, and impaired metabolic traits [KCNQ1, assembling with KCNE2 in insulin-secreting cells, could block the KCNQ1 K+ channel with the sulfonamide analogue 293B and reduce 60% of whole beta-cell outward currents and that the presence of both 293B and tolbutamide could significantly increase the insulin secretion [KCNQ1 protein expression could limit insulin secretion in pancreatic beta-cells through regulating potassium channel currents [KCNQ1 expression in pancreatic beta-cells, which increased the risk of T2DM [KCNQ1 impaired capacity to maintain glucose homeostasis in vivo. A previous population-based study has indicated that the three polymorphisms of KCNQ1  were significantly associated with the OGTT-derived insulin secretion index [KCNQ1 was associated with insulin sensitivity and that CpG site-specific genetic variation predicted the methylation difference [KCNQ1 is associated with the risk of T2DM may be explained by the reasons mentioned above. We also found that under different genotypes of rs2237892, rs2283228, or rs231362, the expression level of KCNQ1 gene was significantly different. However, more research studies should be conducted to test the association between other SNPs with KCNQ1 gene expression levels.There is biological evidence supporting the hypothesis that he heart , as wellhe heart , 66. Thec traits , 48. Stucurrents . The pre of T2DM . And the of T2DM  showed ton index . In addion index . It was fference . The molKCNQ1 polymorphisms was observed among Asians and Caucasians , which might have led to a difference in the results between the two ethnicities.After stratified by race, the estimated risks were more evident among Asians than among Caucasians for rs2237892, rs2237895, rs2283228, and rs151290. Metaregression analyses also confirmed these phenomena. According to our data, the significantly lower proportion in the frequency of minor alleles in controls for KCNQ1 and T2DM have been published. However, none of these meta-analyses has conducted the TSA, suggesting the lack of support from TSA. Accompanied with our results, the TSA in our study showed that the RIS had been achieved in each SNP. Thus, the findings of the present meta-analysis are suggested to be robust.Since 2008, many related original studies or meta-analyses on the association of Following the PRISMA guidelines, our meta-analysis was carried out through conducting a comprehensive literature search, using Egger's and Begg's regression asymmetry test and funnel plot to assess potential publication bias, and exploring the potential sources of heterogeneity by subgroup and sensitivity analyses. Our findings persisted after excluding studies that deviated from HWE. This meta-analysis had included the largest number of existing original studies in this area; therefore, the statistical testing power was relatively higher than before. In addition, a TSA method has been used to test the robustness of our findings, which might further ensure our results.n = 4), and it might have attenuated the statistical power and confined the conduction of subgroup analyses. Fourthly, all the included studies for rs2237897 are derived from Asians, and more studies with diverse race are needed to confirm its role on T2DM risk. Finally, due to the lack of information about the age of onset of a large number of studies, we cannot assess the effect of the KCNQ1 polymorphism on the T2DM according to the age at baseline, which may also affect the further interpretation of our study.The findings of the present study should be mentioned with some limitations. Firstly, we noted the heterogeneity in the overall effect estimated for most of the SNPs which have been quantitatively synthesized. However, we had tried to explore the potential sources of heterogeneity by subgroup or metaregression analyses, and we found that ethnicity might be the main potential source of between-study heterogeneity in rs2237892, rs2237895, rs2283228, and rs151290. Secondly, in the sensitivity analysis, we found that the results of two genetic models for rs231362 would reach significance after removing the study by Ohshige et al. . NeverthKCNQ1 gene, might play significant roles in the susceptibility of T2DM, especially among Asian population. Still, larger and well-designed studies including other risk factors are warranted to validate the findings from the present analysis.In conclusion, our results demonstrate that the C allele of rs2237892, rs2237895, and rs151290, the A allele of rs2283228, and the G allele of rs2074196, but not C allele of rs231362 of


To test the hypothesis that aspirin, non-aspirin nonsteroidal anti-infammatory drugs (NA-NSAIDs), or acetaminophen can reduce the risk of ALS, we conducted a systematic review and meta-analysis of related previous studies. A comprehensive search was conducted on the PubMed, Embase, Cochrane Library and SCOPUS databases. It included studies published up to 29 February 2020 that fulfilled our inclusion criteria. Aspirin, acetaminophen and NA-NSAIDs use information, between the ALS and control groups, was collected for the meta-analysis. Rates of aspirin, NA-NSAID, and acetaminophen use in ALS group, compared with control group were investigated. In the results, only three studies that relate the risk of ALS to aspirin, NA-NSAIDs and acetaminophen use satisfied the inclusion criteria for the meta-analysis. Regarding aspirin, the studies did not show any statistically significant difference in aspirin use between the ALS and control groups . NA-NSAIDs and acetaminophen use, however, did show up statistically significant differences in between the ALS and control groups.  and . However, our study has some limitations. Firstly, we only included a small number of studies. Secondly, the included studies did not control for past medical history, which may have confounded their results, and in turn, could have caused bias in our study. Thirdly, in this meta-analysis, the ALS patients were not subdivided into sporadic or familial type. Lastly, the studies also did not consider the types of NSAIDs and dosages used of each drug. For more convincing evidence regarding the effectiveness of aspirin, NA-NSAIDs and acetaminophen to reduce the risk of ALS occurrence, more qualified prospective studies are required. In conclusion, the use of NA-NSAIDs and acetaminophen is associated with a decreased risk for the development of ALS. In contrast, aspirin did not have any effect on the reduction of the risk of ALS occurrence. Patients diagnosed with ALS show gradual-onset, progressive muscle weakness and atrophy3. As ALS progresses the respiratory muscles are eventually involved and this leads to respiratory failure and death5. Although the course of progression can vary, the prognosis for most patients with ALS is extremely poor. The median survival time from onset of clinical signs to death is only 20 to 48 months6. A small percentage, about 10% of patients, diagnosed with ALS survive for more than 10 years after the disease onset7. Bulbar onset and advanced age specifically are reported to have a very poor prognosis8. Researchers have attempted to develop disease-modifying medications, but to date the results have not been favorable. Only a few medications, such as riluzole and edaravone, are known to have the potential to improve the patient’s quality of life, as well as the survival rate for patients living with ALS12.Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that affects the motor neurons in the spinal cord, brainstem and cerebral cortex, and which eventually leads to fatality15. Cyclooxygenase (COX) is an enzyme that is responsible for the activation of inflammation by inducing factors such as prostaglandins, thromboxane and cytokines20. Therefore, it was proposed that non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit the action of COX and are typically used for reducing pain and fever, might reduce the occurrence rate of ALS and delay the progression of symptoms of ALS24. Furthermore, some studies have demonstrated that acetaminophen use also confers a neuroprotective effect26. So far, three previous studies have evaluated the effect of aspirin, non-aspirin nonsteroidal anti-inflammatory drugs (NA-NSAIDs) and acetaminophen use to the risk of developing ALS, but their results were inconsistent23.Evidence of inflammatory processes in the motor neurons and glial cells, resulting in neurotoxicity and associated with the development of ALS has been found in several previous studiesHere, we conducted a meta-analysis of these previous studies to further explore whether aspirin, NA-NSAIDs and acetaminophen can reduce the risk of ALS development.amyotrophic lateral sclerosis or ALS or motor neuron disease or MND) and . The filters were used to select studies with human participants. We only included articles published in English.This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. We systematically searched the relevant literature in PubMed, Embase, Cochrane Library, and SCOPUS for studies published up to 29 February 2020. The following keywords were used in the database search: . Additionally, research characteristics, study design, number of study and control groups, number of included participants, diagnostic criteria, number of participants using aspirin, NA-NSAIDs, or acetaminophen in the ALS and control groups, incidence rate of aspirin, NA-NSAIDs, or acetaminophen use between the ALS and control groups, and sex ratio in the study group were investigated.All the data was independently investigated by two researchers (D.P and M.C.C) using a standardized data collection form. Discrepancies were resolved through discussions with a third investigator (S.G.K), and by referring to the original articles. In the three included studies27. This scale criticizes case–control and cohort studies according to three domains, including the selection of study groups (4 items), comparability of study groups (2 items) and exposure and outcome measurement (3 items). Those with an NOS score of at least 6 were considered high-quality studies.Quality assessment was performed using the Newcastle–Ottawa Scale (NOS)https://tech.cochrane.org/revman) was used for statistical analysis of the pooled data. In each analysis, a heterogeneity test was performed using I2 statistics, which measures the extent of inconsistency among the results. If p-values < 0.05, it was considered as having substantial heterogeneity, and the random-effects model was used in the analysis of the data. In contrast, if p-values were ≥ 0.05, pooled data were considered homogenous, and the fixed effects model was applied. We analyzed the odds ratio (OR) for association measures in case–control studies. The fixed and random effects models were selected according to the different heterogeneity levels of the rate ratio outcomes. Furthermore, a 95% confidence interval (CI) was used in the analysis. A p-value < 0.05 was considered statistically significant.The RevMan 5.3 software program  were recruited. Regarding to aspirin, in a study by Tsai et al.23, 111 out of a total of 729 patients with ALS used aspirin. Out of a total of 7,290 patients without ALS, 1,369 patients used statins  . A study by Fondell et al.21, had 374 in a total of 708 patients with ALS use aspirin. Of a total of 784,492 patients without ALS, 405,806 used statins . However, data on the doses of aspirin administered to the ALS and control groups was incomplete.In the three studies22, out of a total of 111 patients with ALS, 39 used NA-NSAIDs. In the total of 258 patients without ALS, 89 used NA-NSAIDs . In a study by Fondell et al.21, 217 out of a total of 708 patients with ALS used NSAIDs and 288,313 out of a total of 785,566 patients without ALS used NA-NSAIDs . In a study by Tsai et al.23, 384 out of a total of 729 patients with ALS used NA-NSAIDs and 4,134 out of a total of 77,290 patients without ALS used NSAIDs . However, data on the different classes of NA-NSAIDs used by the ALS and control groups were not fully available, except in a study by Tsai et al.23 Additionally, data on the doses of NA-NSAIDs administered to the ALS and control groups were also not fully available.Regarding NA-NSAIDs, in a study by Popat et al.21, 85 out of a total of 375 patients with ALS used acetaminophen and 120,900 out of a total of 417,360 patients without ALS used acetaminophen  . Once again, data on the doses of acetaminophen administered to the ALS and control groups were not fully available.Regarding to acetaminophen, in a study by Fondell et al.The three studies were assessed using NOS and all were rated with 8 stars, which is considered as having a relatively high quality .In the meta-analysis of aspirin use, a fixed effects model was adopted. The OR of the three studies is presented in Fig. 28. The Egger`s test of aspirin and NA-NSAIDs were not significant . Moreover, funnel plots of aspirin, NA-NSAIDs, and acetaminophen meta-analysis were produced to investigate the risk of publication bias, as shown in Fig. 28.Based on a few distinct methods, two of the authors (DP and MCC) individually assessed the risk of bias. We determined the risk of publication bias using a funnel plot and Egger’s test29, these effect sizes indicate that NA-NSAIDs and acetaminophen have very positive effects for reducing the risk of ALS development.In our meta-analysis review we evaluated the association between the use of aspirin, NA-NSAIDs and acetaminophen and the occurrence of ALS. We found that NA-NSAIDs and acetaminophen significantly reduced the occurrence of ALS. The effect sizes were 0.82 and 0.80 for NA-NSAIDs and acetaminophen, respectively. Based on Cohen’s study31, and it includes two isoforms: COX-1 and COX-217. While COX-1 is constitutively expressed in most tissues and produces prostanoids which sustain homeostasis in several organs and cells, i.e. the gastrointestinal tract, kidneys, and platelets20; COX-2 on the other hand is responsible for the transcriptional control of pro- and anti-inflammatory cytokines20. COX-2 activates the synthesis of prostaglandin and thromboxane, which in turn stimulates the secretion of inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-1, and induces the inflammatory pathway cytokines20. Non-aspirin NSAIDs inhibit the activity of COX-2, consequently inhibiting the inflammatory process by inhibiting prostaglandin synthesis34. This explains why non-aspirin NSAIDs would confer neuroprotective effects which seem to suppress the development of ALS.COX plays a pivotal role in the neurotoxicity seen in ALS25. Due to its minor anti-inflammatory effect, acetaminophen is not classified as an NSAID25. In a previous study, however, acetaminophen reportedly has the potential of exerting anti-oxidant effects to protect neurons from oxidative stress, i.e. by reducing the release of cytokines and chemokines such as tumor necrosis factor alpha, interleukin-1, and macrophage inflammatory protein, from the neurons by a superoxide releasing oxidant stressor26. In that study, acetaminophen was shown to have pro-survival effects on neurons by increasing expression of the anti-apoptotic protein Bcl2 in brain neurons and by decreasing the superoxide-induced elevation of the pro-apoptotic protein, cleaved caspase 326. Considering that the ROS-related genes, such as SOD1  inhibits the COX-2 isozyme more strongly than COX-1; low doses of aspirin (≤ 100 mg per day) inhibits COX-1 more than it inhibits COX-239. Low-dose aspirin is used to prevent coronary syndromes and cerebral infarcts in patients who are at high risk of developing these disorders40. While high-dose aspirin use does confer anti-inflammatory effects, it is rarely used in clinical practice due to the high risk of adverse effects, which include gastric ulcers and hemorrhagic stroke41. Although the doses in the three included reports in our meta-analysis were not described, we suspect that low-dose aspirin was used by the subjects of these studies. Therefore, potential neuroprotective effects by blocking the action of COX-2 seem to have been insignificant.In contrast to NA-NSAIDs and acetaminophen, in our meta-analysis, aspirin was not found to have an effect on the development of ALS. Aspirin, or acetylsalicylic acid, belongs to NSAID family and inhibits the actions of both COX-1 and COX-2 irreversiblyIn conclusion, we found that the use of NA-NSAIDs and acetaminophen is associated with a decreased risk of development of ALS, and these medications seem to confer neuroprotective effects. In contrast, aspirin did not have any effect on the reduction of the risk of ALS occurrence. Our study is the first meta-analysis to evaluate the association between aspirin, NA-NSAID, and acetaminophen use and the risk of ALS. However, our study has some limitations. Firstly, we only included a small number of studies. Secondly, the included studies did not control for past medical history, which may have confounded their results, and in turn, could have caused bias in our study. Therefore, to confirm it, further studies using Mendelian randomization analysis may be necessary. Thirdly, in this meta-analysis, the ALS patients were not subdivided into sporadic or familial type. Lastly, the studies also did not consider the types of NSAIDs and dosages used of each drug. For more convincing evidence regarding the effectiveness of aspirin, NA-NSAIDs and acetaminophen to reduce the risk of ALS occurrence, more qualified prospective studies are required.


Various techniques in assisted reproductive technology (ART) have been developed as solutions for specific infertility problems. It is important to gain consensual conclusions on the actual risks of neurodevelopmental disorders among children who are born from ART. This study aimed to quantify the relative risks of cerebral palsy, intellectual disability, autism spectrum disorder (ASD), and behavioral problems in children from different ART methods by using systematic review and meta-analysis. Healthcare providers could use the results of this study to suggest the suitable ART technique and plan optimum postnatal care.I2 value.Pubmed, Google Scholar, and Scopus databases were used to search for studies up to January 2020. Of the 181 screened full manuscripts, 17 studies (9.39%) fulfilled the selection criteria. Based on the Newcastle-Ottawa scale ratings, 7 studies were excluded, resulting in 10 studies that were eventually included in the meta-analyses. Mantel-Haenszel risk ratio model was used in the meta-analysis, and the results are described using forest plot with 95% confidence interval. Heterogeneity was assessed using the P = 0.00001). Risk of intellectual disability  and ASD  are higher in intracytoplasmic sperm injection (ICSI) children compared to conventional in vitro fertilization (IVF) children. The differences in the risk of neurodevelopmental disorders in children born after frozen and fresh embryo transfers are not significant. Analysis on potential cofounder effects, including multiple birth, preterm birth, and low birth body weight highlight possibilities of significant correlation to the risks of neurodevelopmental disorders.Pooled evaluation of 10 studies showed that the risk of cerebral palsy in children from assisted reproductive technology (ART) is higher than children from natural conceptions (risk ratio [RR] 1.82, ; Pooled estimates suggest that children born after ART are at higher risk of acquiring cerebral palsy. ICSI treatment causes higher risk of intellectual disability and ASD. These findings suggest the importance of the availability of intensive care unit at the time of delivery and long-term developmental evaluation particularly in children from ICSI.The online version contains supplementary material available at 10.1186/s11689-020-09347-w. The dreams of many infertile couples to have offspring(s) have been made possible by assisted reproductive technology (ART). Through its constant development, morbidity due to infertility has been massively decreased . Every tStudies on prenatal and postnatal outcomes in ART, such as the risks of multiple pregnancies and congenital malformations, have already been comprehensively reviewed and meta-analyzed on previous publications –10. ConvThis study aims to assess the risks of neurodevelopmental abnormalities in children from ART treatments, in comparison to naturally conceived children through meta-analysis. As different ART treatments may translate into different pathophysiology, the neurodevelopmental outcomes in children from different ART techniques are also compared.This systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)  reportinStudies were included if they (1) compared any neurodevelopment aspects in ART children to children from natural conceptions, and (2) described the neurodevelopment in children from common ART techniques, including conventional IVF, ICSI, cryopreserved, and fresh embryo transfers, then compared them to either children in general population or children conceived by different treatment modalities. Studies were excluded if (1) information were insufficient, particularly related to the subjects and parameters in the study, (2) not including original data, such as reviews, systematic reviews, comments, or editorial letters, (3) not including control group , or could not ascertain the used fertility treatment, and (4) not written in English.> 7) were included in the meta-analyses.The title and abstract of every article were independently reviewed by 3 authors . If the abstract met the inclusion criteria, the full-text article was thoroughly reviewed. Reference lists on the identified publications were screened for previously unidentified but relevant studies. The following information were retrieved: author, country, publication year, number of patients, criteria of neurodevelopmental disorders, and the patients’ neurodevelopmental outcomes. The quality of methodology was assessed using the risk of bias criteria that were specified in Newcastle-Ottawa Scale (NOS) . Based oI2) test, which ranges from 0 to 100%, was calculated to evaluate heterogeneity across studies. Values above 50% or p value < 0.10 indicate a significant heterogeneity. Regression-based Egger’s test was used to evaluate small study effect and the risk of publication bias. p values less than 0.05 were considered as significant bias. Cochrane Risk of Bias Assessment tool (Cochrane Collaboration) was used to assess the risk of bias. Certainty of the evidence quality was evaluated by using the Guideline Development Tool by GRADEpro.Meta-analysis was performed using Mantel-Haenszel risk ratio (RR) with 95% confidence interval for dichotomous data. Meta-analysis was performed on subgroup analysis based on the types of the acquired neurodevelopmental disorders, including cerebral palsy, intellectual disability, autism spectrum disorder, and behavioral problems. To describe the overall risk of neurodevelopmental disorders, a meta-analysis of the overall data was also conducted. The RevMan version 5.3 software (Cochrane Collaboration) was used for these purposes. Inconsistency index   and no small-study bias  were acknowledged   and small-study bias  were undetected   was repoz = 0.33, p = 0.74; I2 = 0%, p = 0.72)  and small-study bias  were unidentified  .Risk of behavioral problems was reported in 2 studies , 29, and29) Fig. . Risk ofz = 1.29, p = 0.20; I2 = 54%, p = 0.005). Heterogeneity was identified for the overall studies, and this might be due to cofounder effects. The overall studies showed no risk of publication bias (Egger’s p = 0.501) and no small-study bias    Fig. a, with a72) Fig. .Fig. 3Fz = 2.13, p = 0.03; I2 = 46%, p = 0.16)  and small-study bias  were detected   Fig. . The ris39) Fig. .z = 2.23, p = 0.03; I2 = 0%, p = 0.39).The overall evaluation showed higher prevalence of neurodevelopmental disorders in children from ICSI compared to children from conventional IVF  and small-study bias  were undetected   and small-study bias  were undetected   Fig. c, with a76) Fig. .z = 1.69, p = 0.09; I2 = 0%, p = 0.87). The risk of neurodevelopmental disorder in children from frozen embryos is at 14 per 1000 births while in fresh embryos was 16 per 1000 births    is also higher compared to children without any history of low birth body weight  Fig. b, with tz = 472.11, p < 0.0001; I2 = 100%, p < 0.0001), preterm birth , and low birth body weight  compared to non-ART procedure , with the absolute risk of 386 more multiple birth, 167 more preterm birth, and 219 more low birth body weight per 1000 births ; thus, treatment of potential cerebral insults after birth can be optimized. Furthermore, children from ICSI carry higher risks of intellectual disability and ASD than children from conventional IVF. These findings suggest the importance of long-term follow-up and preimplantation genetic screening, particularly in fertilizations by ICSI. Lastly, cryopreservation and thawing of embryos did not seem to cause increases in any risks of neurodevelopmental disorders; therefore, freeze-all strategy seemed plausible.Supplemental Table 1. Newcastle Ottawa Scale on Cohort Studies. Supplemental Table 2. Newcastle-Ottawa Scale on Case-Control Studies. Supplemental Table 3. Characteristics of the study. Supplemental Table 4. Statistical Summary of Meta-Analysis. Supplemental Table 5. Summary of findings and study quality assessment with GRADE approach of ART vs Non-ART studies. Supplemental Table 6. Summary of findings and study quality assessment with GRADE approach of ICSI vs IVF studies. Supplemental Table 7. Summary of findings and study quality assessment with GRADE approach of Frozen vs Fresh Embryo Transfer studies. Supplemental Table 8. Summary of findings and study quality assessment with GRADE approach of Confounder Effects studies. Supplemental Table 9. Summary of findings and study quality assessment with GRADE approach of Risk of Multiple Birth, Preterm Birth, Low birth body weight in ART and Non-ART children.


Background: The evidence for an association between the adiponectin gene (ADIPOQ) polymorphism rs182052 and cancer risk is inconsistent. We performed a meta-analysis to obtain more precise conclusions.Methods: The PubMed, Embase, and Web of Science databases were searched until July 11, 2019. And seven epidemiology studies were retrieved, including 4,929 cases and 5,625 controls. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated to evaluate the strength of the association.Results: The meta-analysis demonstrated that rs182052 significantly increased the risk of cancer under the allele, homozygote, dominant, and recessive models, based on an overall analysis . In the stratified analysis by ethnicity, rs182052 significantly increased the cancer risk in both Asian and Caucasian populations under one or several genetic models. In the stratified analysis by cancer type, rs182052 significantly increased the risk of renal cell carcinoma (RCC) under the five models.Conclusions: Meta-analysis based on present studies suggests that rs182052 can increase the cancer risk. Obesity has become a global public health issue, and the number of overweight and obese individuals has been increasing worldwide in recent years ,2. ObesiAdiponectin is an adipokine produced mainly by white adipose tissue, and circulating adiponectin levels are reduced in overweight or obese people . A low ladiponectin gene (ADIPOQ) promoter region, and is associated with adiponectin levels as well as risks of a variety of cancers [The rs182052 polymorphism is positioned at the  cancers , such as cancers . The aimThe Pubmed, Embase, and Web of Science databases were searched for the possible studies that investigated the relationship between rs182052 and cancer risk until July 11, 2019.adiponectin or ADIPOQ,” “mutation or variant or polymorphism or SNP,” and “cancer or carcinoma or tumor.” We also checked the references of selected studies for possible related studies.The key search words were: “The studies should be about the relationship between rs182052 and cancer;The studies should be case–control or cohort designed;The studies should contain sufficient genotype data for meta-analysis; andThe studies were published in English.The inclusion criteria were:We excluded reviews or meta-analyses and any studies not containing sufficient genotype data.The following data were extracted from the selected studies by two authors separately: name of first author, year published, country or region, ethnicities of the population, genotype method, control source, and genotype frequency.The quality of the included studies was scored according to the following factors : source P values <0.05 were considered statistically significant. Heterogeneity was assessed by the Chi-squared test and Higgins’s (I2) test [I2 < 50% or the P-value of heterogeneity was > 0.10, the fixed-effects model was used [We evaluated the strength of the associations by OR and 95% Cl under five genetic models: the allele, homozygote, heterozygote, dominant, and recessive models. I2) test . If I2 <was used ; otherwiwas used . We condwas used . The potwas used ,29. All Trial sequential analysis (TSA) and false-positive report probability (FPRP) analysis were performed as reported previously . BrieflyThe process of article screening is shown in P=0.003; AA vs. GG: OR, 1.20, 95% CI, 1.07–1.34, P=0.002; AA+GA vs. GG: OR, 1.12, 95% CI, 1.03–1.22, P=0.010, AA vs. GA+GG: OR, 1.12, 95% CI, 1.01–1.23, P=0.025).In total, the meta-analysis consisted of 4929 cases and 5625 controls. The synthesis results demonstrated that rs182052 increased the risk of cancer under the allele, homozygote, dominant, and recessive models in the overall analysis (P=0.041), and increased the risk of cancer in the Caucasian population under the allele, homozygote, and recessive models . In the stratified analysis based on cancer type, rs182052 increased the risk of renal cell carcinoma (RCC) under all five genetic models . We found no evidence to support a relationship between rs182052 and prostate cancer risk. The results of stratified analysis based on the quality score showed that rs182052 increased the risk of cancer under the allele, homozygote, and dominant models when the score was less than 10 .In the stratified analysis based on ethnicity, rs182052 increased the risk of cancer in the Asian population under the recessive model . When the prior probability was 0.1, these FPRP values were all <0.2, indicating that the associations were noteworthy.In recent years, obesity has become one of the major public health challenges in the world ,35. A stADIPOQ polymorphisms and cancer risk [ADIPOQ rs2241766 G allele and a significantly reduced cancer risk [ADIPOQ rs1501299 was a protective polymorphism from cancer [Several previous meta-analyses have focused on the associations between cer risk . For exacer risk . Similarm cancer . Ye et am cancer .ADIPOQ promoter region, with the minimum gene frequencies (MAFs) greater than 5% in most populations of the 1000 Genome Project (Supplementary Table S4). It has been reported that the rs182052 polymorphism A allele was associated with lower levels of adiponectin [The rs182052 polymorphism is located in intron 1 of the ponectin . One stuponectin . SeveralADIPOQ in cancer. Our findings may also be helpful in developing new molecular monitor indicators of cancer risk and in providing a new theoretical basis for the prevention of cancer for the risk genotype population.The results of our meta-analysis suggested that rs182052 significantly increased the risk of cancer in the overall analysis. The results of the stratified analysis by ethnicity showed that rs182052 significantly increased the cancer risk in both Asian and Caucasian populations. The results of the stratified analysis by cancer type showed that rs182052 significantly increased the risk of RCC. The presence of rs182052 was not related to prostate cancer risk according to the synthesis results of our meta-analysis. Our research provides clues for detecting the molecular mechanism of the function of adiponectin mRNA expression requires further research.Some limitations of the meta-analysis need to be considered and further explored. First, only five types of cancer were included in our meta-analysis, so, whether the conclusions drawn from these studies can represent the overall cancer risk need to be further explored; second, due to the limited number of subject, we did not consider other factors, such as BMI, and we did not conduct stratified analysis based on these factors. Third, Many SNPs have been reported to be related to cancer risk because the polymorphisms could affect the mRNA expression of the gene . The mecIn conclusion, the synthesis results based on current existing studies suggest that rs182052 can increase the risk of cancer.Click here for additional data file.


Hence, an exhaustive meta-analysis can solve the discrepancies and provide a hint for upcoming investigations. Herein, a meta-analysis was carried out to attain a conclusive estimate of the association between VDR gene single nucleotide polymorphisms (SNPs) and urolithiasis risk.The currently available data with respect to the association between VDR gene polymorphisms, including FokI (rs2228570), TaqI (rs731236), BsmI (rs1544410), and ApaI (rs7975232), and urolithiasis risk was evaluated using pooled odds ratio (OR) and their corresponding 95% confidence interval (CI). Additionally, to seek for the potential source of heterogeneity, meta-regression analyses were exerted.The major databases, including ISI Web of science, Scopus, and PubMed/MEDLINE were searched systematically from until June 2020 to retrieve all relevant studies. Association between VDR gene SNPs and urolithiasis risk. It was observed that none of the four SNPs were significantly associated with urolithiasis predisposition. However, subgroup analysis confirmed higher risk of urolithiasis in East-Asian and Caucasian population with ApaI and TaqI gene polymorphism. The analyses of sensitivity acknowledged the results stability.Literature search led to finally finding of 33 studies evaluating the FokI, TaqI, BsmI, and ApaI in the overall polled analysis, it suggests that ApaI and TaqI SNPs is associated with increased risk of urolithiasis in East-Asian and Caucasians populations.Although this meta-analysis did not support the association of  Urolithiasis is known as one of the prevalent diseases among urological disorders that has been associated with many complicated factors . UrolithCLDN14 in Europeans and Japanese , Fig. Twenty-two case-control studies with 4188 cases and 3955 controls met inclusion criteria for evaluating the association between TaqI SNP and urolithiasis risk. Among them, ten studies were performed in Asian population –63, 66 aBsmI SNP and urolithiasis risk under any genetic models in both the overall population and the subgroup analysis.Fourteen eligible publications with 3065 cases and 2915 controls were included and evaluated the association between BsmI polymorphism and urolithiasis risk. Among 14 studies, only five publications were carried out in Asia , 66, 68 ApaI SNP and urolithiasis risk under recessive model , allelic model , and aa vs. AA model . Additionally, the results of subgroup analysis indicated a positive significant association in East-Asians across recessive model , allelic model , and aa vs. AA model  but not Caucasians. The results of pooled ORs, heterogeneity tests, and publication bias tests for different analysis models are shown in Table A total of 16 publications containing 2950 cases and 3065 controls were recognized eligible for evaluating the association between ApaI SNP and urolithiasis risk. Of which, eight studies were performed in Asians , 66, 68 The results of publication bias test indicated that there was no evidence of publication bias for overall population and subgroup analysis of all FokI, TaqI, BsmI, and ApaI SNPs. Additionally, the shape of the funnel plot confirmed absence of publication bias. No heterogeneity in both the overall and subgroup analyses was detected except for FokI polymorphism Fig. , Table 3Sensitivity analysis is an effective test to evaluate the influence of individual study on the pooled results. In the sensitivity analysis, each eligible study was sequentially removed to assess whether the individual data influence the pooled ORs. In this meta-analysis, the pooled results did not significantly affect by any single study in the dominant model for FokI, TaqI, BsmI and ApaI SNPs Fig. , indicatPotential sources of heterogeneity among included studies was estimated by meta-regression analyses Table . AccordiVDR gene SNPs and urolithiasis risk were analyzed. The results of pooled analysis revealed that none of the four SNPs in VDR gene were in significant association with proneness to urolithiasis. That notwithstanding, subgroup analysis based on the population stratification demonstrated increased risk of urolithiasis in East-Asian  and Caucasian (heterozygous model) population with ApaI and TaqI gene polymorphism, respectively.In the current most recent meta-analysis, 33 case-control association studies evaluating the VDR gene SNPs have been contributing genetic factors in susceptibility to urolithiasis [VDR gene SNPs and urolithiasis risk; that notwithstanding, the findings still show discrepancies and a comprehensive meta-analysis seems to be required to shed insights on the unknown conundrums. As a result, we performed a meta-analysis to investigate the consequence of the common four SNPs in the VDR gene, namely FokI (rs2228570), TaqI (rs731236), BsmI (rs1544410), and ApaI (rs7975232) on the risk of urolithiasis. The discrepancies in outcome among the various ethnicities might be due to differences in geographic and ethnical diversity, and impression of ethnicity on the serum level of vitamin D as well as the VDR gene expression [Several investigations have noted that ithiasis , 34, 49.pression .VDR gene [VDR gene as well as serum levels of vitamin D and, hence, modify the risk of urolithiasis susceptibility, along with VDR genetic polymorphisms.Reports have shown the role of environmental factors on the risk of different diseases. For example, seasonal differences may impress the serum level of vitamin D . Among tVDR gene . AdditioVDR gene . As a reVDR gene have been shown to impress the interactions of the vitamin D/VDR, modulating the susceptibility risk for several pathologic conditions. FokI polymorphism can modulate the ATG start cordon in the VDR protein and BsmI SNP can modify the VDR protein expression [VDR gene and can modulate the stability of VDR mRNA [Vitamin D is a critical hormone and play a role in the metabolism of calcium. This vitamin implements its function by binding to the VDR. The genetic variations in the pression , 75. AddVDR mRNA . FokI SNVDR mRNA , 77.VDR gene polymorphisms mentioned above were associated significantly with nephrolithiasis risk in the overall analysis except ApaI SNP. However, our subgroup analysis according to population stratification revealed that ApaI gene polymorphism increased risk of urolithiasis in East-Asian patients by the recessive, allelic and homozygous model and TaqI gene SNP in Caucasians population through the heterozygous model. On the other hand, a meta-analysis in 2014 with respect to the study of the associations between VDR gene SNPs and urolithiasis risk included 20 studies in the analysis [A recent meta-analysis by González-Castro in 2019 , includianalysis . They foVDR gene TaqI SNP in Asians might be attributed to the partially higher amount of exposure to UVR [VDR gene polymorphisms and disorders. In patients with non-Hodgkin lymphoma, it was reported that patients with CC genotype for TaqI SNP who experienced sun exposure less than 7 h per week exhibited higher risk of the disease in comparison to patients with TT genotype with the similar duration of sun exposure [The subgroup analyses were conducted based on the ethnicity to identify the potential impression of the genetic background on the association of VDR gene polymorphisms and urolithiasis. Our analysis resulted in identification of ApaI and TaqI polymorphism association with increased risk of urolithiasis in East-Asian and Caucasians populations. However, the previous meta-analysis identified the same association in only Asians . These de to UVR . Moreoveexposure . In addiexposure . Plus, iexposure . Other texposure . NonetheVDR gene polymorphisms play a role in altering the risk of urolithiasis development. Although our analysis did not endorse the association of VDR gene BsmI, ApaI, FokI, and TaqI SNPs with susceptibility to urolithiasis, the gene can be of beneficial applications in populations with significant associations. Generally, the concept of personalized medicine has been widely accepted, implying to the consideration of genetic makeup of each patient in approaching with optimized medication. As a consequence, clarification of VDR gene polymorphisms contribution to the urolithiasis predisposition could be advantageous in clinics with respect to better diagnosis of subjects at risk as well as treatment with maximum efficacy.Data from GWASs as well as association studies in different ethnic groups have revealed that VDR gene SNPs and urolithiasis risk. Hence, additional works with respect to the gene–gene and gene–environment interactions is needed to approach with a more comprehensive estimation. Third, we noticed a significant heterogeneity among the studies for various comparisons, which may impress the perception of findings. Although we conducted subgroup analysis and weighted meta-regression in order to attenuate its effects. Finally, there were a number of VDR gene SNPs in the context of urolithiasis risk that could not be included in the meta-analysis due to lack of sufficient amount of data. Hence, it could barely implied that VDR gene could not convey a genetic risk factor for urolithiasis, merely regarding our findings.Despite we tried to perform the possibly well-suited analysis of the available data, a number of caveats and confining factors are related to this meta-analysis. First, our literature search was limited to only English-written papers, raising the chance of excluding of potentially worthwhile findings. Second, we could not analyze the role of age, gender, lifestyle, and other genetic variations, on the adjusted association of TaqI gene polymorphism increased risk of urolithiasis in East-Asian and Caucasians population, respectively. Further genes should be evaluated to disclose the genetic mechanisms contributing to urolithiasis development. Moreover, the role of life style, age, and gender needs be considered in the stratification analyses for VDR gene SNPs and urolithiasis predisposition.In conclusion, the results of pooled analysis did not demonstrate any statistically significant association between all four SNPs and susceptibility to urolithiasis. However, subgroup analysis showed that the Recessive, allelic, and aa vs. AA model of ApaI and Tt vs. TT comparison of the


Background: T cell immunoglobulin and mucin-domain containing molecule-3 (TIM-3), a novel emerging immune checkpoint molecule, was reported to express both on various kinds of immune cells and tumor cells. Many previous studies have investigated the prognostic significance of TIM-3 in cancer. However, the sample number from single study was limited and results remained controversial.Methods: We searched PubMed, Web of Science, and Embase databases for publications concerning TIM-3 expression in solid cancers up to March 2020. The correlations between TIM-3 and survival as well as clinical-pathological features were analyzed. Pooled hazard ratios (HRs), odds ratios (ORs), and 95% confidence interval (CI) were estimated by either fixed or random effects models.Results: A total of 3,072 patients were included in our meta-analysis. The result suggested that TIM-3 protein overexpression was relevant to poor overall survival . Moreover, TIM-3 was shown to be connected with lymph node metastasis , tumor grade , as well as PD-1 expression . In database test, significant correlations between high TIM-3 mRNA expression and poor overall survival for patients with non-small cell lung cancer and gastric cancer were observed .Conclusion: Our meta-analysis highlights that TIM-3 has the potential to serve as a prognostic marker and a valuable therapeutic target in solid tumors. Cancer is the leading cause of death all over the world . AlthougT cell immunoglobulin and mucin-domain containing molecule-3 (TIM-3), also called hepatitis A virus cellular receptor 2 (HAVCR2), is a member of the TIM gene family .In addition to its well-known expression on T cells , 5, 6, TOur meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement . RelevanPublications were included in our meta-analysis if they met the following criteria: [1] A definite source of the study was reported; [2] The sample size was more than 30; [3] The expressions of TIM-3 in tumor cells and/or tumor infiltrating lymphocytes (TILs) were measured by immunohistochemical (IHC) staining; [4] The relationships between TIM-3 and overall survival (OS)/disease-free survival (DFS)/progression-free survival (PFS) were described; [5] Hazard ratio (HR) and 95% confidence interval (CI) were reported, or with essential data to calculate it; [6] Studies were published in English. Studies were excluded if they were: (a) duplicate studies; (b) case reports, review articles, letters, conference abstracts, animal studies, or meta-analysis; (c) unpublished data.The following information was recorded: first author, year of publication, patient source, sample size, cancer type, detection of method, expression location, cut-off value, median follow-up, outcome, method to estimate HR , and HR ratio. Multivariate Cox analysis should be given priority if available, or univariate hazard analysis was instead . For stuTo control the quality of each study, all included articles were scored according to the Newcastle-Ottawa Quality Assessment Scale (NOS) by two investigators independently . The NOShttp://kmplot.com/analysis/). The affymetrix probe ID for TIM-3 was 1554285_at. The follow-up time threshold was set as 120 months. The Kaplan-Meier survival curves downloaded from the website were resized in Adobe Illustrator CS6.An online analysis tool Kaplan-Meier plotter was used to evaluate the effect of TIM-3 mRNA expression levels on OS of NSCLC , GC 25)25), and I2 test. PH value < 0.05 or I2 > 50% was defined as a significant heterogeneity, then a random effects model was applied to calculate the pooled effect. Otherwise, a fixed effects model was applied. Subgroup analyses were conducted to explore the source of heterogeneity. Begg's and Egger's tests were used to depict the publication bias of all enrolled studies (P > 0.05 indicating no publication bias)  . Cut-off value of TIM-3 extracted from the articles has divided patients into high and low groups. HR and relative 95% CI obtained from the individual study were pooled into a summary HRs to assess the impact of TIM-3 on survival outcome . In addition, odds ratios (ORs) and corresponding 95% CIs were used to measure the relationship between TIM-3 expression and the clinicopathological features. HR or OR higher than 1 indicated a worse prognosis or a significant correlation between TIM-3 and clinical-pathological parameters, respectively. If 95% CI did not include the value 1, the pooled result was considered statistically significant. Heterogeneity among researches were tested using the chi-square-based Q-test and on bias) . AdditioA flow diagram showing the study selection was presented in n = 17), Japan (n = 1), Korea (n = 2), and Poland (n = 1). The type of carcinoma included HCC, CRC, BUC, esophageal squamous cell carcinoma (ESCC), NSCLC, GC, RCC, cervical cancer, breast cancer, pancreatic cancer, prostate cancer, osteosarcoma, and skull base chordoma. The cut-off value of each study was not exactly the same. Among all included studies, eight studies reported the HRs and 95% CIs directly. In the remaining 13 studies, HRs and 95% CIs were estimated from survival curves. OS was reported in all studies, while DFS and PFS were addressed in seven and one study, respectively. Additionally, 13 studies showed the association between TIM-3 and clinical-pathological characteristics. The details regarding the characteristics of the 21 eligible studies were listed in A total of 3,072 patients, ranging from 30 to 587 patients per study, were involved in our meta-analysis. Among all eligible studies, 13 studies focused on the TIM-3 expression on tumor cells , 36, 39,H <0.001 and I2 value of 60.5%, we used a random effects model to pool the HR. As shown in P < 0.001). In order to seek the source of inter-study heterogeneity, subgroup analysis was further performed based on the expression position, cancer type, sample size, and method to estimate HR (P < 0.001) (P = 0.105). Elevated TIM-3 as a negative predictor on OS was confirmed in patients with ESCC , NSCLC , GC  and other types of cancers , but not in patients with breast cancer .All included studies supplied suitable data to analyze the association between TIM-3 on tumor cells/TILs and OS. The main results of this meta-analysis were listed in imate HR . Overexp< 0.001) . The TIMI2 = 86.9%, PH <0.001). The result showed that TIM-3 expression was not associated with DFS  (P < 0.001) and high level of TIM-3 significantly correlated with short DFS in study where HR was extrapolated by univariate analysis . As PFS was reported in only one related study, it was insufficient to conduct a meta-analysis.Seven studies comprising 1,243 patients assessed the link between TIM-3 and DFS in cancer patients, among which one study presented the data about the TIM-3 on tumor cells and TILs separately. A random effects model was used on account of the obvious heterogeneity among these studies (= 0.297) . Subsequ= 0.297) . We obseP = 0.013), tumor grade , as well as PD-1 expression .Relevant data were utilized to extrapolate the relationship between TIM-3 and ten clinical-pathological features. These parameters included gender, age, T stage, lymph node metastasis, tumor grade, TNM stage, smoking history, distant metastasis, vascular invasion, and PD-1 expression. The overall results were showed in Sensitivity analysis was conducted to assess the influence of each study on the synthetic results of meta-analysis by omitting one study at a time. As shown in P = 0.536, P = 0.465, Both Begg's test and Egger's test were used to evaluate publication bias of OS and DFS analysis. The shape of funnel plot did not appear dissymmetric, and Egger's test also showed no publication bias among the studies analyzing the association of TIM-3 expression and OS . No signP < 0.001) (P = 0.0038) (P = 0.51)   and GC ( 0.0038) , but not = 0.51) . The resThe identification of TIM gene family was found in searching for asthma susceptibility genes . TIM genP < 0.001), which supported that high TIM-3 expression was correlated with poor OS. However, a significant heterogeneity in OS across the included studies was existed. Thus, we performed sensitivity analysis to ascertain the cause for heterogeneity. The result suggested that pooled HR was not clearly influenced by any single study. We further performed subgroup analysis. Interestingly, subgroup analysis showed that TIM-3 overexpression on tumor cells was associated with poor OS, but the association between TIM-3 expression on TILs and OS didn't reach a statistical significance. TIM-3 was mainly expressed on immune cells with lower expression in tumor cells , an immune checkpoint molecule belonging to the CD28 superfamily, suppresses the activation and function of T cells by binding with its ligands PD-L1 and PD-L2 , 53. ImmA meta-analysis of the association between TIM-3 expression and cancer prognosis had been previously reported by Zhang et al. . They coAlthough we have made every effort to conduct a comprehensive analysis, some limitations still exist in our meta-analysis inevitably. Firstly, most of the subjects were from East Asia, which could have resulted in selection bias. Thus, the conclusion should be reassessed in European patients. Secondly, the number of eligible studies included in PFS and DFS were relatively small, which may cause heterogeneity. More studies are needed to explore the relationship among TIM-3, DFS, and PFS. Thirdly, although all studies employed IHC, the antibodies they used were not exactly the same, and the threshold value was inconsistent among trials, which may contribute to the observed heterogeneity. Establishment of the unified cut-off value should be further explored. Finally, some studies didn't provide the HRs directly, so we extracted HRs and 95% CIs based on survival curves, which may influence the accuracy of data.In summary, our meta-analysis illustrated that TIM-3 expressions on tumor cells were significantly associated with poor OS but not DFS in most human solid cancers. TIM-3 expression was also positively connected with lymph node metastasis, tumor grade, and PD-1 expression. It seems that TIM-3 is not merely an indicator of tumor prognosis but also a promising therapeutic target for solid tumors. Due to the inevitable limitations, our results should be interpreted with caution and further prospective multicenter studies with larger sample size will be necessary to determine the role of TIM-3 in both the prognostic prediction and targeted therapy for various types of cancers.All datasets presented in this study are included in the article/supplementary material.SQ analyzed the data and wrote the manuscript. SQ and BD searched and collected the literatures. MY and QC contributed to statistical analysis. KW designed the study and revised the manuscript. All authors participated in the discussion, read, 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.


Background: The combination of immune checkpoint inhibitors (ICIs) and chemotherapy can improve clinical outcomes in the treatment of various tumors, but may also be associated with more adverse events (AEs). We performed a systematic review and meta-analysis to characterize the risk of gastrointestinal AEs in cancer patients treated with ICI plus chemotherapy.Methods: This review was based on comprehensive search through PubMed, EMBASE, and the Cochrane Library for randomized controlled trials (RCTs) that reported gastrointestinal AEs following the use of ICI plus chemotherapy. Literature screening, data extraction, and quality evaluation were performed by two individual reviewers. Revman (version 5.3) was used for meta-analysis. Risk ratios (RR) with 95% confidence interval (CI) were calculated. Meta-analysis was conducted according to different types of ICIs .Results: After a full-text review, 10 trials involving 5,142 patients were included in the study. Compared with chemotherapy alone, PD-1 inhibitor plus chemotherapy significantly increased the risk of diarrhea  and colitis , PD-L1 inhibitor plus chemotherapy significantly increased the risk of nausea , while CTLA-4 inhibitor plus chemotherapy significantly increased the risk of decreased appetite , diarrhea , and colitis .Conclusions: This meta-analysis demonstrated that ICI plus chemotherapy is associated with a higher risk of gastrointestinal AEs. However, combining different ICIs may lead to diverse gastrointestinal toxicities. Clinicians should be aware of these AEs in the application of ICI plus chemotherapy. Cancer therapy has made great progress with the advance of immune checkpoint inhibitors (ICIs) including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD-1), and programmed death ligand 1 (PD-L1) inhibitors. So far, they have been approved for the treatment of melanoma, metastatic renal cell carcinoma (RCC), non–small-cell lung cancer (NSCLC), head and neck cancer, and hematological system diseases . The ICIDespite the effectiveness of ICI plus chemotherapy, it may also be associated with more adverse events (AEs) , 21. In The literature search was performed by two individual reviewers. PubMed, EMBASE, and the Cochrane Library were searched from the inception of the database to March 2019. Keywords were “ipilimumab,” “pembrolizumab,” “nivolumab,” “atezolizumab,” “tremelimumab,” “durvalumab,” “avelumab,” “CTLA-4,” “PD-1,” “PD-L1,” and “immune checkpoint inhibitor.” Reference lists in the retrieved articles and supplemental materials were also examined manually to further identify any potentially relevant trials. The eligibility criteria for the systematic review were in accordance with the PICO  approach. Furthermore, the drug manufacturers' websites were searched for any additional information.RCTs meeting the following criteria were considered for inclusion:Participants: patients with malignant tumors.Intervention: ICI combined with chemotherapy.Comparison: chemotherapy.Outcomes: nausea, constipation, diarrhea, decreased appetite, vomiting and colitis.If more than one publication reported a same study, only the most complete, updated data were included in this analysis. Two reviewers independently screened all titles, abstracts, and full texts for eligibility. Any discrepancy among investigators was resolved by consensus.The data extraction was performed by two individual reviewers. The following baseline characteristic items of the included studies were extracted from each study: the year of study, trial phase, treatment regimen, number of patients, median age, sex proportion of patients, and cancer types. The following clinical outcomes data were also extracted: the number of patients treated with ICI plus chemotherapy regimen, the number of patients treated with chemotherapy alone, and the number of patients with each gastrointestinal AE. Any discrepancy among investigators was resolved by consensus. Two reviewers also independently assessed the qualities of the included studies. Discrepancies were resolved by discussion or through consultation with a third reviewer. The potential risk of bias in these RCTs was assessed according to criteria developed with the Cochrane risk-of-bias tool .Q statistic and I2 statistics were used to examine heterogeneity. The random-effect model was chosen if significant heterogeneity existed (I2 > 50%); otherwise, the fixed-effect model was used. Meta-analysis was conducted according to the type of ICI medications . The funnel plots were used to examine the publication bias among studies.Revman (version 5.3) was used for meta-analysis. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated. The Cochran n = 2198)  (n = 902) (n = 502)  , 18, sma= 1,487) , 17, trin = 902) , and melThe results of quality assessment are presented in P = 0.020; I2 = 0%). For patients treated with PD-1 inhibitor plus chemotherapy, there was no significant difference in the risk of nausea . In addition, the difference between CTLA-4 inhibitor plus chemotherapy and chemotherapy alone was also not significant   . Accordi2 = 59%) .P = 0.100; I2 = 17%), PD-L1 inhibitor , or CTLA-4 inhibitor  plus chemotherapy, none of the comparisons showed significant increase of the vomiting risk . CTLA-4 inhibitor plus chemotherapy was also associated with a significant higher risk of diarrhea . However, for PD-L1 inhibitor plus chemotherapy, the risk of diarrhea was not significantly increased compared with chemotherapy alone   . AccordiI2 = 0%) .P = 0.260; I2 = 0%) or CTLA-4 inhibitor  plus chemotherapy, neither of the comparisons showed significant increase of the constipation risk . For patients treated with PD-1 inhibitor plus chemotherapy, the risk of decreased appetite was not significantly different compared with those who received chemotherapy alone . Furthermore, we also found that patients treated with PD-L1 inhibitor plus chemotherapy experienced no significantly more decreased appetite events compared with those with chemotherapy monotherapy   . AccordiI2 = 0%) .P = 0.050; I2 = 0%). Moreover, patients treated with CTLA-4 inhibitors plus chemotherapy significantly developed more colitis events   . AccordiI2 = 0%) .This is the first systematic review that characterizes the risk of gastrointestinal AEs associated with the use of ICI plus chemotherapy. All trials included in this meta-analysis were basically well designed. Gastrointestinal AEs are common in both chemotherapy and ICI therapy, which deserve to be highly valued in combination. Our study demonstrated that the gastrointestinal AE profile observed was as expected on the basis of the known events, such as nausea, vomiting, diarrhea, constipation, decreased appetite, and colitis. However, compared with chemotherapy alone, a higher risk of gastrointestinal AEs was found among patients following the combination therapy of ICI plus chemotherapy.+) and thus caused inflammation. PD-1 protein is another T cell co-inhibitory receptor with a structure similar to that of CTLA-4 but with a distinct biologic function and ligand specificity  not only is the first defense barrier against oral pathogens but also constitutes an important part of the body's entire immune network . ICIs exAlthough this study has answered some important questions, there are still several limitations we should state. Firstly, this study included different types of gastrointestinal adverse effects with an incidence of more than 15% other than immune-related AEs, while it did not include the adverse effect with a lower incidence such as gastrointestinal hemorrhage. Therefore, this might lead to the overestimation of the safety of ICI plus chemotherapy. In addition, significant publication bias was shown in the analysis of diarrhea, which might lead to unreliable and misleading information in this meta-analysis. Furthermore, whether the increased risk of gastrointestinal AEs was due to the addition of ICI or the possible synergy mechanisms between two treatments (ICI plus chemotherapy) remains unknown, which needs further investigation. Finally, data on the gastrointestinal event leading to discontinuation of treatment, which is also an important gastrointestinal safety outcome, was not reported. Further studies are warranted to analyze this issue.In conclusion, this meta-analysis demonstrates that ICI plus chemotherapy regimen is associated with a higher risk of gastrointestinal AEs such as nausea, diarrhea, vomiting, and colitis compared with chemotherapy alone, while the risk of constipation and decreased appetite were not increased. Moreover, combining different ICIs  might lead to different gastrointestinal toxicity. These increased gastrointestinal AEs may restrict the applications of ICI plus chemotherapy regimen, and the management is of great importance for clinicians.WY and PM contributed to study selection, data extraction, quality assessment, statistical analysis and drafting of the manuscript. HX contributed to data acquisition, data interpretation. MJ and QL contributed to the study design and revision of the manuscript. All the authors have final approval of the submitted manuscript and reached agreement to be accountable for all aspects of the work.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.