The role of RAD51 gene polymorphisms with the development of head and neck cancer (HNC) and esophageal cancer (EC) remains controversial. This meta-analysis was conducted to evaluate the correlation between the RAD51 polymorphisms and these two cancers quantitatively.  Databases of PubMed, Web of Science, and Embase were used to search relevant papers prior to August 17, 2019. STATA 11.0 was performed to observe the correlation.  Ten relevant papers were enrolled in our analysis. Overall, a significant correlation was observed between the rs1801320 polymorphism and the increased risk of these two cancers . In subgroup analyses, an increased risk was found for EC , but not for HNC. Moreover, our analysis revealed that no statistical evidence of correlation was discovered between the polymorphism of rs1801321 and the increased risk of HNC. However, stratified analysis based on ethnicity suggested that rs1801321 polymorphism was related to the decreased risk of HNC among Caucasians .  rs1801320 polymorphism was strongly associated with the risk of these two associated cancers, especially with esophageal cancer. Moreover, our results revealed that rs1801321 polymorphism was correlated to the decreased risk of HNC among Caucasians. Head and neck cancer (HNC) is the sixth most common cancer , which iThe strong correlation between the incidence of HNC and the incidence of EC might be because these two cancers share some same factors. Although the primary risk factors for HNC and EC are smoking and heavy alcohol intake , 17, onlRAD51 gene, mapped to chromosome 15q15.1 in people, belongs to the system of DNA repair gene . RAD51 pTo date, a variety of articles have been conducted to assess the correlation between the RAD51 gene polymorphisms and the risk of HNC and EC –39. HoweRelevant papers were searched in databases of PubMed, Web of Science, and Embase prior to August 17, 2019. Selection strategy was carried out by combination of the following terms: “RAD51”, “135G/C”, “rs1801320”, “172G/T”, “rs1801321”, “polymorphism”, “polymorphisms”, “variant”, “mutation”, “SNP”, “HNC”, “head and neck”, “oral”, “oral cavity”, “pharyngeal”, “laryngeal”, “nasopharyngeal”, “oropharyngeal”, “laryngopharyngeal”, “hypopharyngeal”, “esophageal”, “oesophageal”, “cancer”, “carcinoma”, “tumor”, “tumour”, “malignancy”, and “neoplasm”. Furthermore, references cited by all the retrieved papers were checked to identify potentially relevant articles.Our meta-analysis was performed follow the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement .Papers which met all the following criteria were enrolled in the present meta-analysis: (1) associated with the correlation between the RAD51 SNP and the EC or HNC, (2) case-control studies, and (3) sufficiency of the data provided by the paper for estimating the correlation. Publications satisfying one of the following criteria were excluded: (1) unavailability of full text, (2) no sufficient information on data reported, and (3) duplicated papers, reviews, editorials, case reports, commentaries, and case-only studies.P value of the Hardy-Weinberg equilibrium (HWE) in controls. Cases of disagreement were resolved by two writers. Quality assessment of each paper enrolled in the analysis was performed by the Newcastle-Ottawa Scale (NOS) criteria [The following information on data were fetched by two writers, respectively, from each enrolled study: name of primary author, publication year, country where paper was performed, ethnicity of the study subjects, counts of case groups and control groups, source of the control groups, genotyping methods, genotype and allele for case and control frequencies, type of tumor, and criteria .The significant results were also assessed by the false-positive report probability (FPRP) . We set P < 0.05 in Z-test was regarded as statistically significant.STATA 11.0  was used to calculate the pooled ORs along with corresponding 95% confidence intervals (95% CIs), in order to examine the correlation between RAD51 SNPs and the risk of these two cancers. The allelic, homozygous, heterozygous, dominant, and recessive genetic models were examined in our meta-analysis. Subgroup analyses based on genotyping method, ethnicity, sample size , and tumor type were conducted. The value of Q-statistic and I2 test. If P value in Q‐test < 0.10 or I2 > 50%, the DerSimonian and Laird random-effects model was used to count the ORs. Otherwise, the Mantel-Haenszel fixed-effects model was conducted to assess the correlation between RAD51 SNPs and these two cancers. Sensitivity analysis was performed by deleting an article at a time in order to evaluate the reliability and stability of the pooled results. Publication bias was evaluated by Begg's funnel plots and Egger's tests. If the P value < 0.05, the publication bias was considered significant.Heterogeneity was evaluated by Cochran's According to the inclusion and exclusion criteria, ten papers involving a total of 2484 controls and 2377 cases were enrolled in our analysis after selection , 31–39. All the enrolled papers were related to RAD51 G135C rs1801320) polymorphism. Among ten articles, four were correlated with RAD51 G172T (rs1801321) polymorphism. There are seven articles for HNC and three articles for EC. Five articles were conducted in Caucasians; four articles were performed on Asians. All papers showed that the genotype distribution in the controls was consistent with HWE, except 2 papers , 39. The0 polymorThe correlation between the RAD51 polymorphisms and these two cancers is displayed in Tables P in Q‐test < 0.10 or I2 > 50%). We discovered a significant relationship between the rs1801320 polymorphism and the increased risk of these two cancers under all genetic models except homozygous and recessive models  =  for C vs. G, P) =  for CC vs. GG; OR = 1.50,  =  for CG vs. GG; OR = 1.44,  =  for CC+CG vs. GG; and OR = 1.15,  =  for CC vs. CG+GG). In our subgroup analyses, a statistically significant correlation was observed for PCR-RFLP genotyping method subgroup , Asians , large sample subgroup , and EC .With respect to RAD51 G135C (rs1801320) polymorphism, the random-effects model was performed under all genetic models because the statistical heterogeneity between articles was substantial . Significant correlation was not observed between rs1801321 polymorphism and susceptibility to HNC. In our subgroup analyses by genotyping method, ethnicity, and sample size, a significant correlation could be observed between the rs1801321 polymorphism and the decreased risk of HNC for Caucasians only (OR (95%CI) = 0.82 (0.72‐0.95) for T vs. G).As for RAD51 G172T (rs1801321) polymorphism, four papers enrolled were all related to HNC instead of EC. The random-effects model was performed under all genetic models, because the statistical heterogeneity between articles was substantial  and Begg's funnel plot  might influence mRNA stability and relate to the expression level of RAD51 protein.In recent years, a number of papers have focused on the correlation between HNC, EC, and RAD51 gene polymorphisms. However, the observed correlations of these papers between two cancers and RAD51 SNPs were inconclusive. Therefore, we conducted a meta-analysis to assess the correlation between RAD51 SNPs and the risk of HNC and EC. Our results revealed that rs1801320 polymorphism was significantly correlated to the risk of these two cancers under the allelic, heterozygous, and dominant genetic models. Nevertheless, no association between the rs1801321 polymorphism and the development of HNC was found.In the subgroup analyses of rs1801320 polymorphism according to a genotyping method, a statistically significant relationship was found in the PCR-RFLP genotyping method subgroup under allelic, heterozygous, and dominant genetic models, but not in the PCR genotyping method subgroup. This might be because different genotyping method would influence the association, indicating that a genotyping method with high sensitivity and specificity is required to increase the accuracy of results. In the subgroup analyses based on ethnicity, we discovered rs1801320 polymorphism increased the risk of HNC and EC in Asian populations, but not in Caucasian populations. This might be due to the following reasons. Firstly, it might be because the genetic trait was considerably different in various ethnicities. Secondly, it could be because the individuals' genetic susceptibility and environmental factors are diverse in different ethnic groups. When stratified by sample size, the rs1801320 polymorphism was related to the increased risk of HNC and EC in a large sample subgroup under the allelic, heterozygous, and dominant genetic models, which was the same as the overall results. Nevertheless, no marked association was discovered in a small sample subgroup. This might suggest that more studies with a large sample size are required to assess the correlation between RAD51 SNPs and the susceptibility to HNC and EC. Stratified analysis according to tumor type indicated that a marked correlation could be found between rs1801320 polymorphism and EC under the allelic, homozygous, and recessive genetic models, but not found between the SNP and the HNC. This indicated that rs1801320 polymorphism would contribute to the development of EC.In the subgroup analyses of rs1801321 polymorphism by a genotyping method and sample size, no statistical evidence of correlation was observed between rs1801321 SNP and HNC. Stratified analysis based on ethnicity, our results revealed that rs1801321 SNP was related to the decreased risk of HNC among Caucasian populations under an allelic genetic model.To the best of our knowledge, our study is proposed as the first one to observe the correlation between the RAD51 gene polymorphisms and the susceptibility to these two associated cancers. It is particularly worth mentioning here that rs1801320 polymorphism could increase the risk of EC, which had not been shown before. A previous meta-analysis carried out by Kong et al.  was perfHowever, some limitations exited in our analysis. First, the subgroup analyses could not have sufficient statistical power to identify the association because of the limited studies. Second, some eligible studies that have not published were not included in the present analysis, so publication bias could potentially exist. Third, subgroup analyses based on gender, smoking, or alcohol consumption were not performed since relevant data could not be obtained from most of the enrolled studies. Finally, the FPRP analysis results showed that the significant relationships of three subgroup analysis were not noteworthy . So further analyses are required to investigate the effects on the gene-environment interaction.The present meta-analysis explored that rs1801320 SNP was significantly correlated with the risk of these two associated cancers. Moreover, the correlation between the rs1801320 SNP and the susceptibility to EC was pointed out at the first time. However, more high-quality papers with a large sample size should be addressed to assess the correlation between RAD51 polymorphisms and cancer susceptibility.


The purpose of this study is to evaluate the role of pre-miR34a rs72631823 as potential risk factor and/or prognostic marker in patients with triple negative breast cancer.114 samples of DNA from paraffin embedded breast normal tissues of patients with triple negative breast cancer and 124 samples of healthy controls were collected and analyzed for pre-miR34a rs72631823 polymorphism.p = 0.176, Fisher’s exact test). The examined polymorphism was not associated with overall survival at the univariate or multivariate Cox regression analysis .Pre-miR34a rs72631823 A allele was associated with increased TNBC risk both in univariate and multivariate analysis. The number of pre-miR34a rs72631823 AA subjects was very small and the association did not reach significance (Our case-control study suggests that pre-miR34a rs72631823 A allele is associated with increased triple negative breast cancer risk. Triple negative breast cancer (TNBC) represents 15–20% of all invasive breast cancers and is characterized by high biological heterogeneity with increased levels of distal recurrence and poor survival, besides high response rate to chemotherapy that constitutes the only standard of treatment . Single MicroRNAs are small, endogenous, non-coding RNAs of approximately 22 nucleotides that could regulate gene expression at post-transcriptional level by binding with mRNAs. Depending on the complementarity between the seed sequence of a microRNA (region of 6-8 nucleotides in the 5’ end of microRNA) and mainly the 3’untranslated region of the target mRNA molecule, microRNAs could induce degradation or translational repression of their targets , 12. ThrSequence alterations in pre-miRNA molecules seem to affect the levels of the mature microRNA . Pre-miRThis study was designed in order to investigate the role of pre-miR-34a rs72631823 polymorphism as a potential risk factor and/or a prognostic marker in patients with TNBC who have received chemotherapy, via a case-control study of 114 patients with triple negative breast cancer and 124 controls.p = 0.023, MWW) and consumed alcohol more frequently , compared to controls. No significant differences were documented in education, menopausal status, smoking rates between cases and controls. The majority of TNBC cases were T2 (61.4%), node-negative (63.2%), grade 3 (86.9%) carcinomas.Table p = 0.176, Fisher’s exact test). The multivariate analysis, adjusting for age, smoking, alcohol consumption, menopausal status, age at menarche and education, confirmed that Pre-miR34a rs72631823 A allele was associated with increased TNBC risk .Genotype frequencies, unadjusted and adjusted ORs for the examined polymorphisms are provided in Table Subgroup analyses by menopausal status reproduced the findings of the overall analysis. In premenopausal women, the adjusted OR for the allele dose-response model was 5.15 (95%CI: 1.22–21.68). Accordingly, in postmenopausal women the adjusted OR for the allele dose-response model was 2.49 (95%CI: 1.20–5.16).p = 0.413).No significant deviation from HWE was documented for the examined polymorphism (Pearson’s chi2(1) = 0.67, The results of the nested prospective study in cases are shown in Table This study is the first to highlight that pre-miR34a rs72631823 A allele is associated with nearly 3-fold increased risk of TNBC. The association was evident in premenopausal as well as postmenopausal women and persisted after adjustment for various potential confounders, including age, smoking, alcohol consumption, age at menarche and education. On the other hand, pre-miR34a rs72631823 A allele did not seem to alter the overall survival of TNBC.This is the first study that evaluates the role of pre-mir34a rs72631823 polymorphism as a potential risk factor or/and prognostic factor in TNBC. Since the examined polymorphism has been previously investigated only once in a line of pancreatic beta cells, and not in cancer, based on current knowledge our results cannot be compared to other studies. However, these findings seem to agree with previous studies stating that alterations in pre-miRNAs could affect the expression levels of genes involved in oncogenesis. The association trend between pre-mir34a rs72631823 and TNBC is in accordance with the studies of Morales S et al  and Li MSince 2005, when Iorio et al  presenteAn important element of validity of the present study is the absence of deviation of allele frequencies in controls for pre-mir34a rs72631823 concerning HWE. Discrepancies on HWE might indicate incorrect or guided sample selection by the research team, genotyping errors or incongruity of mating. Despite the originality, limitations of this case-control study should be reported. First, more studies with increased sample size should be performed to overcome the obstacle of the small number of homozygous pre-mir34a rs72631823 AA subjects. Additionally, in our study, the investigated polymorphism was evaluated in paraffin embedded normal breast tissue, which however is a very common source for DNA extraction in the studies regarding microRNAs.In conclusion, according to our data it seems that pre-mir34a rs72631823 A allele is associated with increased TNBC risk. Future well designed studies should be performed to elucidate the mechanisms underlying the effect of this SNP in TNBC, across different races.Paraffin embedded breast normal tissues were collected from 114 patients with histologically confirmed TNBC during the period 2000-2014. Operations were conducted at the Gynecology Department, “Alexandra” Hospital, Medical School, University of Athens, Greece and patients received chemotherapy at the Oncology Department, “Alexandra” Hospital, Medical School, University of Athens, Greece. The exclusion criteria were as follows: metastatic disease at diagnosis, no invasive disease, family history of breast cancer , history of prior malignancy and no signed informed consent form. Additional information regarding the histology, tumor size, grade, histological stage, lymph node infiltration, the expression levels of ki67 and p53, disease free survival (DFS) and overall survival (OS) were registered in an electronic database according to the patients’ medical records. Concerning controls, women with negative results for breast cancer on routine mammography test were selected. Controls were matched on age (+– 2 years) with patients and had no history of other malignancy. Cases and controls were Caucasian and lived in the same geographical region . Informed consent was obtained from all individual participants included in the study. This case-control study has been approved by the local Institutional Review Board.DNA from paraffin embedded normal breast tissues of patients and DNA from the blood of healthy controls was isolated using the Nucleopsin Tissue kit . Amplification of the selected sequences was performed with allele-specific PCR (polymerase chain reaction), using two allele-specific reverse primers: RG, 5′ CTTGCTGATTGCTTCCTTAC 3′ for the wild type allele and RA: 5′ CTTGCTGATTGCTTCCTTAT 3′ for the mutant allele, in combination with a common forward primer F: 5′ CACATTTCCTTCTTATCAACAG 3′ in two separate PCR reactions. The 3′-ends of the reverse primers were able to anneal to the regions that differed between the two alleles. The endogenous levels of the corresponding gene products were quantified by ELISA.Data were cross-tabulated by case-control status; Mann-Whitney Wilcoxon test (MWW) and Chi-square test were used for the comparison of demographic, lifestyle and reproductive factors in cases and controls, as appropriate. To analyze the associations between the examined polymorphisms and the risk of TNBC, three separate logistic regression models were evaluated: heterozygous vs. wild type (the most frequent homozygous genotype was set as “wild type”), homozygous vs. wild type and dose-response allele model . Unconditional logistic regression analysis was performed to estimate univariate and multivariate odds ratios (ORs) with 95% confidence intervals (CIs). The multivariate ORs were adjusted for age, smoking, alcohol, menopausal status age at menarche and education. In addition, subgroup analyses for premenopausal and postmenopausal women were conducted. The deviation of allele frequencies in controls from the Hardy-Weinberg Equilibrium (HWE) was examined with the appropriate goodness-of-fit Chi-square test, given that the deviation may denote bias . Univari


Chili peppers have properties that plausibly could either increase or decrease a person’s risk of developing colorectal cancer, but their consumption in relation to disease risk has not been well studied. We sought to explore the association between chili peppers intake and the risk of colorectal cancer.Eight hundred subjects  were enrolled in this study. Cases were primarily colorectal cancer patients diagnosed by histopathology at the Department of Intestinal Surgery, Sichuan Cancer Hospital from July 2010 to May 2012. Controls were people receiving routine medical examinations from the Zhonghe Community Health Service Center during the same period of time. An in-person interview was used to collect demographic characteristics, lifestyle, and dietary habits of the subjects in reference to the 10 years prior to disease diagnosis. Conditional logistic regression was conducted to examine the possible association between the risk of colorectal cancer and chili peppers consumption.P = 0.413) and > 7 times per week  were not at an increased risk of colorectal cancer.Compared with persons who consumed chili peppers ≤ 2 times per week, those who consumed chili peppers 3–7 times per week (OR = 1.2, 95% CI 0.75–2.0, The results suggest that the consumption of chili peppers does not increase or decrease the risk of colorectal cancer. This question warrants being re-addressed in a study in which there is prospective ascertainment of dietary characteristics. Colorectal cancer(CRC)is at present the third most common malignancy in the world . HistoriThe chili pepper has been a part of the human diet for thousands of years . It was We made the matching principle before participants recruiting. Controls were matched 1:1 to cases by gender and age (± 3 years). Eight hundred subjects (400 cases with CRC and 400 controls) were enrolled who were (1) Han Chinese and (2) had lived in the province of Sichuan for more than 10 years. We excluded persons with (1) a history of other cancers; (2) a history of digestive system diseases; and (3) several other conditions . Cases were primarily CRC patients diagnosed by histopathology at the Department of Intestinal Surgery, Sichuan Cancer Hospital  from July 2010 to May 2012. The age of cases was no limit. Controls were people from the Zhonghe Community Health Service Center  seen during the same period of time who had no earlier history of cancer. We obtained written informed consent from all subjects. The study protocol was approved by the West China Fourth Hospital of Sichuan University .A face-to-face interview was conducted with subjects. If the patient could not answer the questions, family members were asked to serve as proxy respondents. The interview sought information on demographic characteristics, family history of CRC, and dietary habits and lifestyle characteristics during the 10 years before diagnosis.Specifically, we asked about consumption of (1) chili peppers; (2) red meat . According to the Dietary Guideline and Balance Diet Pagoda for Chinese Residents, the recommended daily consumption for red meat is 50–75 g . This stWe also asked study participants about smoking regularly (smoking more than one cigarette per day for at least 6 months ), drinkiP value (P < 0.05). Other factors were identified as the adjustments because they were mostly thought to be related to CRC in other studies. The significance level was P < 0.05.EpiData 3.1 software and SPSS 22.0 software were used for statistical analysis. Referring to the classification of dietary factors in other studies , Chili pP > 0.05). Demographic characteristics of cases and controls are presented in Table For the cases and controls, 233 (58.2%) were males and 167 (41.8%) were females. The mean ages were 55.73 ± 11.08 years old in the cases and 55.74 ± 11.19 years old in the controls. There were no significant differences in education, profession, and household per capita annual income between cases and controls (P < 0.05).In Table P < 0.05). However, there were no significant differences among chili peppers, fruit, vegetables, high-fat food, sweetmeats, smoking regularly, and drinking regularly (P > 0.05). We observed that weekly consumption of chili peppers 3 to 7 times (OR = 1.2 95% CI 0.75–2.0) and > 7 times (OR = 1.4 95 %CI 0.84–2.2) were not associated with the risk of CRC. (Table Table P > 0.05). There was one possible exception; among persons with a relatively low consumption of cured meat, we observed an increased risk associated with weekly consumption of chili peppers 3–7 times (OR = 1.2 95% CI 0.78–2.0) and > 7 times (OR = 1.6 95% CI 1.1–2.5), whereas no such increases were seen among persons with a relatively high consumption of cured meat.Table Capsaicin concentration is related to the variety and maturity of chili peppers and its concentration can change. E-capsaicin is the major capsaicin in chili peppers. A study shows a greater than 25-fold variation in E-capsaicin levels among individual peppers, ranging from about 0.04 μg/mL to 1 μg/mL . In geneThe results of some studies suggested that intake of capsaicin may predispose to one or more forms of gastrointestinal cancer. Dietary administration of capsaicin produced duodenal tumors in Swiss albino mice . An epid1 and the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone anthracene led to no significant enhancement of papilloma formation in the skin, compared with the control animals that received the carcinogen alone. Summarizing the relevant studies, Surh and Lee suggested that although a minute amount of capsaicin displays few or no deleterious effects, heavy ingestion of the compound has been associated with necrosis, ulceration, and even carcinogenesis [Initial work by Hoch-Ligeti showed that rats fed diets containing 10% chili pepper developed liver tumors . The valogenesis . AccordiIn our study, we did not observe a significant difference in chili peppers: compared to persons consuming chili peppers no more than twice each week, the relative risk in those whose weekly intake was 3–7 times and > 7 times was 1.2 (95% CI 0.75–2.0) and 1.4 (95% CI 0.84–2.2), respectively. In fact, the relationship between chili peppers and CRC was indeed complex. The chili pepper is a spicy food, and excess consumption may damage to colonic mucosa. The long-term damage is related to the occurrence of CRC. In addition, capsaicin may play the weak carcinogenesis role in causing CRC. In another context, chili peppers are beneficial. Capsaicin also has an anticancer effect. Besides, ingestion of chili peppers can promote digestive juice to secrete and accelerate bowel movements , which mGenerally, there was little difference in the size of the OR associated with consumption of chili peppers across different subgroups, though we did observe an increased risk associated with weekly consumption of chili peppers 3–7 times (OR = 1.2 95% CI 0.78–2.0) and > 7 times (OR = 1.6 95% CI 1.1–2.5) among persons with a relatively low consumption of cured meat. With our existing knowledge, we considered it suggested a link or an interaction between chili pepper and cured meat. Lots of capsaicin may weakly suppress the chemical carcinogens, such as PAH found in cured meat. It needs further study to elucidate the mechanism associated with this observation.Interpretation of the results must take into account some limitations of our study. First, family members responding to proxy respondents about diet habits over the past 10 years is a limitation. And the study collected dietary information only for the past 10 years, which may be less relevant to risk than intake earlier in life. Second, even for intake during the past 10 years, there can be non-differential misclassification of exposure status when interviews are used to obtain the information on frequency of intake. Third, the study measured only the times of chili peppers intake, not the quantity consumed. Finally, the referent category used in our analysis included some persons who did consume chili peppers, just at a lower frequency than 3 times per week. However, an analysis in which the referent category has no chili pepper intake could not be done, due to the fact that among the study participants, there was virtually no one who did not consume chili peppers.In summary, the results suggest that the consumption of chili peppers does not increase or decrease the risk of CRC. The results of studies with prospective and more detailed ascertainment of diet, in populations (such as this one) in which a high intake of chili peppers is present, are needed to clarify.


I2 = 80%, P<0.00001] and PLT . While PDW exhibited significant difference . Subgroup analysis about geographical area suggested PLT have obvious evidence for SSHL in Eastern country . Our study did not support a correlation between MPV and SSHL, while PLT may have clinical significance for SSHL in Eastern country. With insufficient data to explore the resource of heterogeneity for PDW, there is no decisive conclusion reached.Recent years, the discussion about whether platelets participant in the development of sudden sensorineural hearing loss (SSHL) continues and many studies on the relationship between them have come to our attention. Some studies believe that platelet parameters have significantly changed in patients with SSHL, while some not, controversially. Therefore, to investigate the association between platelet parameters, including mean platelet volume (MPV), platelet distribution width (PDW) and platelet count (PLT), and SSHL, expecting to resolve controversy and provide clinical evidence for diagnosis and monitoring of SSHL. Basic methods: Literature was retrieved searching electronic databases  and searching references of related articles by hand. A total of 18 case–control studies involving 1837/1734 subjects (SSHL/control) were included. Meta-analysis showed there was no difference between the patients who suffered SSHL and healthy controls in MPV level [standard mean difference (SMD) ) = 0.16 ,  Sudden sensorineural hearing loss (SSHL) or sudden deafness, is typically defined as a hearing loss of at least 30 decibels occurring over at least three consecutive frequencies and lasting at least 3 days . The estThis systematic review and meta-analysis is reported in accordance with the Preferred Items for Systematic Reviews and Meta-analysis (PRISMA) Statement. Studies were retrieved by searching electronic databases  and searching references of related articles by hand. These computer searches were from the creation of the databases up to December 2017. Retrieval strategy of PubMed as follows: )) OR “Hearing Loss, Sudden” [Mesh])) AND (((((platelet count) OR platelet)) OR ((platelet distribution width) OR PDW)) OR ((“Mean Platelet Volume” [Mesh]) OR mean platelet volume)).The inclusion criteria were as follows: (1) Participants: SSHL patients without other illness related to platelet activity, such as venous thrombosis, cardiovascular disease; (2) Exposures: platelet parameters level; (3) Comparatives: healthy controls; (4) Type of studies: independent case–controlled studies using either a hospital-based or population-based design; (5) Publications with English or Chinese, the latter must be on Medline.Exclusion criteria included the following: (1) Duplicated data; (2) Case reports and studies where the original data could not be extracted; (3) Animal experiments and basic research; (4) Reviews and letters.Two authors (S.F. Ji and X.M. Chen) independently extracted the original data. Disagreement was resolved by discussion. If the two authors could not reach a consensus, the result was reviewed by a third author (H. Shi). The extracted data consisted of the following items: the first author’s name, publication year, population (ethnicity), methods, study design, matching criteria, sex, total number of cases and controls, and age (years).The Newcastle-Ottawa Scale (NOS) was used to assess the methodological quality of the individual studies. Each study was evaluated and scored based on three criteria: selection (4 stars), comparability (2 stars), and exposure (3 stars). The NOS point scale ranged from 0 to 9 stars, the researches with NOS ≥7 stars were considered high quality.I2 statistic, and P<0.10 and I2 > 50% indicated evidence of heterogeneity. If heterogeneity existed among the studies, a random-effects model was used to estimate the pooled standard mean difference (SMD). Otherwise, a fixed-effects model was adopted. The SMD and corresponding 95% confidence interval (CI) were utilized to assess the associations. Subgroups analysis regarding geographical area, median of detection of patients, sample size, with EDTA anticoagulation treatment and NOS quality, were also performed to explore source of heterogeneity. Egger’s and Begg’s tests (P<0.05) can demonstrate a statistically significant publication bias and were conducted with the Stata 14.0 software, if there was any publication bias, trim, and fill method was implemented. Sensitive analysis was also conducted by changing effect model.We utilized Review manager 5.3 and Stata 14.0 software to perform the meta-analysis in the present study. Heterogeneity among studies was assessed by the We retrieved a total of 152 studies in the literature search . After dI2 test indicated that the heterogeneity was significant , therefore, a random-effects model was applied to perform the meta-analysis. The results showed that MPV level in the SSHL group was not different from that in the control group [SMD (95% CI) = 0.16 ]. The weights were evenly distributed, and sensitive analysis showed that re-synthesized result was similar to previous one after fixed-effects model conducted [SMD (95% CI) = 0.09 ], which suggested the result is reliable. In addition, Egger’s test (P=0.097) and Begg’s test (P=0.193) showed that there was no publication bias ; therefore, a random-effects model was applied to perform the meta-analysis. The results showed that there was statistical significance in the comparison of SSHL and control group [SMD (95% CI) = 0.85 ]. The weights were evenly distributed, and sensitive analysis showed that re-synthesized result did not change obviously after fixed-effects model conducted [SMD (95% CI) = 0.85 ], which suggested it is reliable. Likewise, there was no significant publication bias according to Egger’s test (P=0.993) and Begg’s test (P=0.806) (There were five studies reporting the association between PDW level and SSHL compared with control groups . An I2 tP=0.806) . With inI2 test indicated that the heterogeneity was significant ; therefore, a random-effects model was applied to perform the meta-analysis. The results showed that there was no statistical significance in the comparison of SSHL and control group [SMD (95% CI) = −0.03 ]. Likewise, sensitive analysis with fixed-model [SMD (95% CI) = 0.07 (−0.00 0.14)] showed our result was reliable. Although there was publication bias according to Egger’s test (P=0.037) and Begg’s test (P=0.043) (There were 15 studies reporting the association between PLT level and SSHL compared with control groups . An I2 tP=0.043) , the triP=0.043) . SimilarP=0.043)  showed tAlthough platelet parameters, such as MPV, PDW, and PLT, have exhibited diagnostic significance in various diseases and conditions ,26, it iSSHL is a clinical condition characterized by the acute onset of unilateral or bilateral hearing loss greater than 30 dB over three consecutive frequencies in less than 72 h. Different theories about the pathogenesis of SSHL have been proposed, including vascular incidents, vascular occlusions, viral, bacterial, and protozoan infections, intracochlear membrane rupture, autoimmune disorders, and side effects from ototoxic medications . There aPlatelets are the smallest cells of the peripheral blood, and they are involved in hemostasis and the formation of thrombosis in blood vessels. Mediators and substances released by platelets play a significant role in the progress of coagulation, inflammation, thrombosis, and atherosclerosis. MPV is a commonly used parameter to indicate the volume, function, and activity of platelets. It has been proven that MPV levels increase in vascular events such as atherosclerosis, acute syndromes, venous and arterial thrombosis, or thromboembolism . The incIn recent years, a series of studies concerning the relationship between platelet parameters and the occurrence and severity of SSHL have been performed, but there was no consistent conclusion. Ulu et al.  and DurmMPV, PDW, and PLT are susceptible to many vascular risk factors including age, smoking, diabetes mellitus, hypertension, hyperlipidemia, and obesity . It is aIn the methods section, in order to measure MPV, venous blood samples were collected into tubes containing EDTA. However, in an earlier study, Bath et al.  found thIn respect of MPV in SSHL, pooled results did not support there exit the association, but quality of included studies may be main resource of heterogeneity. Although we discover PDW exhibit difference between SSHL group and control group, there was no enough data to explore resources of heterogeneity, in addition to considering small studies included, we could not reach a conclusion impetuously. A total of 16 studies included to study the relationship between PLT and SSHL, our result also did not uphold the relationship completely. However, subgroup analysis by geographical area showed that there was significant difference in Eastern country, while other subgroups not, which suggested geographical area may be the source of heterogeneity. Sensitive analysis revealed that our results were stable. And there was no publication bias, if any, it did not impact our results. All of them demonstrated our results were reliable.There were several limitations exiting in this analysis need to be carefully considered. First, all the including researches were case–control studies, and we could not ensure other factors matched completely. Second, in terms of PDW, too few articles included to find the source of heterogeneity, so we could not reach a conclusion. Third, although we have implemented full subgroups analysis, we failed to discover the other sources heterogeneity about MPV and PLT. Finally, with insufficient data, we did not explore the threshold.In summary, we concluded that MPV failed to apply to diagnosis and monitor of SSHL, while PLT might be a positive factor for SSHL in Eastern country. The clinical significance of PDW for SSHL is remaining to be confirmed with more well-designed and large-scale studies.


However, considerable heterogeneity among studies was verified . Periodontitis may represent a risk factor for RA by heredity, bacterial infection, and the pro-inflammatory profile shared between both diseases. Although most of the elective studies report an association between periodontitis and RA, the quantitative analysis showed a high heterogeneity, leading to the need for further studies.Periodontitis is an inflammatory disease of dental supporting tissues  and it has been suggested as a possible etiology for rheumatoid arthritis (RA). In this systematic review, we aim to verify if periodontitis represents a risk factor for RA. Electronic databases were consulted until March 2018 considering eligibility criteria focusing on:  adults;  with periodontitis;  without periodontitis; and  development of RA. Quality assessment of studies and risk-of-bias evaluation were also performed. To undertake a quantitative analysis, the number of persons with RA and a total number of participants for the case group (with periodontitis) and control group (without periodontitis) were used to calculate the odds ratio (OR) with a 95% confidence interval (CI). A total of 3888 articles were identified, and nine studies were considered eligible. Seven of 9 articles suggested an association among diseases by the common pro-inflammatory profiles. The pooled analysis of 3 articles showed a higher RA prevalence for persons with periodontitis ( This study was conducted following the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines  presenting with periodontitis  and the absence of periodontitis , in which the primary outcome (O) was the development of RA in this population, were considered eligible. The null hypothesis of the study was ‘there is no association between periodontitis and the development of RA.’Supplementary Table 2).The searches were conducted in the following electronic databases, without language restriction, until March 2018: PubMed, Scopus, Web of Science, The Cochrane Library, and LILACS. The gray literature was also searched through OpenGrey and Google Scholar. All publications presented in the databases and gray literature contained a combination of controlled predefined Medical Subjects Headings (MeSH) and free terms relating to periodontitis and RA. Boolean operators  were used to combine searches . Duplicated results were considered only once. Titles and abstracts were analyzed according to inclusion and exclusion criteria. Additional citations were sought from the analysis of the reference list of all articles previously selected. The selection process was conducted by two examiners (ROF and NCFF) and checked by a third examiner (RRL), in case of disagreements.After the duplicate removal, opinion articles, technical articles, guides, and animal studies were excluded. The titles and abstracts that did not adhere to the established eligibility criteria were excluded. The resulting articles were evaluated and judged by their full text.The extraction of data was conducted from the selected articles. A table was used to report year of publication, study design, participant characteristics (source and sample size), age, periodontitis assessment, RA assessment, statistical analysis, and results.In case of absence of information that makes data extraction or risk-of-bias evaluation impracticable, we attempted to contact the authors by email. The contact consisted of sending a weekly email, for up to 5 consecutive weeks.13 adapted by Almeida et al.12 was applied. The checklist has domains that assess study designs and study samples, control group characteristics, quality of measurements and results, completeness, and distortion influences.For assessment of methodologic quality and the risk of bias, the Fowkes and Fulton checklist,To provide valid information and feasibility of methods, the checklist was standardized by the examiners. The sign (++) was applied when the analyzed criteria had a major problem, and the sign (+) was used when the research had criteria with a minor problem. The number ‘zero’ (0) was applied when the analyzed criteria had no problems, and the sign NA was marked when the analysis of the topic was not applicable. The criteria used for quality assessment are listed in The Review Manager software, version 5.3  was used in the meta-analysis to evaluate the association between periodontitis and the risk of developing RA. The number of participants with RA, the total number of participants for the case group (with periodontitis) and control group (without periodontitis) were used to calculate the odds ratio (OR) with 95% confidence interval (CI).I2 index. Sensitivity analyses were conducted to estimate and verify the influence of studies, one by one, on the pooled result.14 Publication bias was not quantitatively evaluated by the Egger test or funnel plot, as there were not enough studies to be grouped in a funnel plot.15A fixed-effects model was applied, and heterogeneity was tested using the The original authors were contacted when further results were required. If, after contact attempts, there was no response from the authors, the study was not included in the meta-analysis.A total of 3888 articles were identified from the searches and 793 articles were excluded because of duplication. Titles and abstracts of 3095 potentially eligible manuscripts were verified following the entry criteria resulting from the exclusion of 3079 articles, and 14 articles were selected for full-text reading.1618 and due to the inclusion of patients with symptoms of arthralgia.19 The reasons for exclusion and citations are presented on Supplementary Table 3.After this step, four studies were excluded due to their evaluation of established cases of RANine articles were included in this review and their selection process is shown in 21 while seven were cross-sectional studies2228  as tooth loss and periodontal surgery were associated with studies with higher sample sizes.27 The other seven articles reported relationships between periodontitis and RA, which were grouped by:Among the nine articles included, two articles present a cohort design,dies2228 . The ass20(1) Associations provided by regression analysis, relative risk, and odds ratio (OR) of periodontitis diagnosis parameters and occurrence of RA;2226(2) Associations supplied by laboratory association of periodontitis pathogens and the pro-inflammatory profile of RA;27(3) Associations provided by periodontitis diagnosis parameters and pro-inflammatory profile of RA.28The periodontal parameters used by the selected studies were tooth loss/missing teeth (MT), probing depth, clinical attachment loss (CAL), bleeding on probing BOP, tooth mobility (TM), radiographic evaluation of periodontitis (PD), recent periodontal surgery, periodontal index (PEI), community periodontal index (CPI), and plaque index (PI). Between those parameters, only four of the selected studies described the evaluated parameters.P. gingivalis and deoxyribonucleic acid (DNA) assessment of periodontal pathogens. To correlate pro-inflammatory parameters of RA with periodontitis, the studies evaluate the anticitrullinated autoantibodies  only for diagnosis, but description of values in text was absent. The other studies evaluated samples using biochemical analysis of rheumatoid factors,26 and genetic polymorphisms of cytokines associated with RA.25Five of nine studies evaluated subsamples of national cohorts.2426 the entry criteria/exclusion (participants with smoking habits or systemic diseases),2028 and small sample size.2226Most problems relating to the articles were lack of sampling methods,2227 The link was established by comparison of levels of antibodies to citrullinated protein antigens/protein peptides (ACPA)/rheumatoid factor between groups,2227 the presence of bacterial DNA on synovial joints,26 and the association of the prevalence of two diseases after regression analysis of public health data.20The association of periodontitis and RA was found in seven of nine articles.2227 and one study did not provide the total number of patients in case and control groups.21 Unfortunately, these authors have not returned the contact attempts and were excluded from the meta-analysis. Only three studies were included in quantitative synthesis.28 Two of these studies were classified as having a low risk of bias,25 and one as a high risk of bias.28Five studies presented their results only in graphics,28 indicated a considerable heterogeneity  than controls (n = 254), demonstrating positive association (p < 0.00001) between them .The first meta-analysis of the three studies,et al.20 was excluded, and the I2 = 69% was considered.In an attempt to reduce heterogeneity, a sensitivity analysis was performed. Removing studies, one by one, the heterogeneity ranges from 97% to 69%. Therefore, the study of Chou 28 The periodontitis group had 1874 participants, and the control group had 3596 participants. A result contrary to the first meta-analysis was observed. The results showed lower RA prevalence for person with periodontitis (n = 67) than for controls (n = 137), demonstrating negative association (p = 0.03) between these variables , but the methodological heterogeneity of our meta-analysis means there is inconclusivity about the association of RA and periodontitis.30Systematic reviews can synthesize and critically evaluate the primary outcomes of investigations through specific strategies to limit bias and random errors. Thus, those reviews can produce supporting information for clinical decisions based on research evidence. In addition to defining key interventions, systematic reviews can also demonstrate ways to achieve decision making where knowledge is lacking.31 Periodontitis cases have shown an elevated ratio/relative risk for RA development, as demonstrated in other studies.32According to the epidemiological aspects of the included studies, four of the chosen studies showed a comparable prevalence of RA in patients with periodontitis. About 3% incidence and a proportion of 3:1 women:men cases were shown.28 The evaluation parameters are related to tooth loss, the number of teeth, and recent periodontal surgery. It is well known that periodontitis diagnosis is a criterion correlated with related symptoms , natural heritage, medical history, and clinical signs .4 Tooth loss is one of the measurements that demonstrated sensitivity to show a periodontal compromising of dental tissue.33 Nevertheless, tooth loss can be associated with dental caries and other diseases. So, associations of tooth loss may generate false-negative errors, mainly when previous infections of periodontal tissue is not present in patients.28However, some of the selected studies found no correlation between periodontitis parameters and the occurrence of RA.35 in a full mouth examination is difficult to execute, time consuming, and unfeasible in larger-sample studies.36 Therefore, analyzing indices with low specificity may generate misclassifications and weak associations between periodontitis and arthritis.37Although, other studies promote synthesis of many related signs of periodontitis using few indices. Hence, the gold standard index, CAL,38 and (b) reduction of distortion influences. Matching/randomization and statistical reduction of distortions are essential tools that allow the assessment of study groups with equal probabilities.39 Mathematical models that simplify the analysis only for chosen evaluated outcomes may reduce other influences like personal habits, systemic diseases, and environmental impacts.Among the six articles classified as having low risk of bias, the critical aspects to qualify with low risk of bias were: (a) periodontal characterization of the patient’s condition; periodontal conditions are mainly verified through clinical examination, being CAL, BOP, and PD, the most sensitive indices to periodontal evaluation;I2 = 96%, p < 0.00001). One of the articles20 significantly demonstrates the association of periodontitis with RA development. The sensitivity analysis changed the results of the association between periodontitis and RA in the meta-analysis. This suggests that methodological inconsistencies  regarding definition of periodontitis, and fewer proportions of RA/periodontitis patients analyzed , are still present among the studies included in this meta-analysis.Our meta-analysis shows an important heterogeneity .9 The articles assessed in this review show a critical relationship relating to shared genetic risks involving the cytokine polymorphisms and the human leukocytes antigen–DRB1 allele28 as well as the activity of periodontal pathogens.In RA, a systemic increase of TNF-α and IL-1β on gingival crevicular fluid and injured joints was reported, as well as an increase in the periodontal pathogens.43 These macromolecules are the first epitopes that provoke autoimmune activity by macrophages on joints.44 The possible association between periodontitis and RA converges to the central hypothesis of the relationship, in which the citrullinated antigens can cause changes in synovial joints.45The HLA-DRB1 allele is responsible for 25–50% of vulnerability to RA and, more recently, authors identified this allele as a mass producer of cyclic citrullinated autoantibody peptides (anti-CCP).43 Moreover, further authors have associated the formation of immune complexes in synovial joints involving the P. gingivalis, and recently, the A. actinomycetecomitans,8 the leading Gram-negative periodontal pathogens.Recent studies have shown the presence of periodontal bacteria DNA in synovial joints of patients with established RA.23 cases of periodontitis and presence of HLA-DRB1 expression result in aggravation and a possible development of RA. So, the treatment of RA, a complex investigation of symptomatology,46 requires another health concern regarding oral pathology aspects. If the two-hit model theory becomes a plausible mechanism of RA development in cases of periodontitis (more studies needed), we suggest a combined treatment involving a careful periodontal evaluation considering different measures  to reduce the clinical signs and symptomatology of periodontitis.46 Hence, the chance of RA development may be reduced, and the comorbidity in establishing cases of RA can be decreased as well.As reported in one of the included studies,The limitations of our study were the absence of research data that share methodological parameters to depict associations between periodontitis and RA. Among the selected articles, two articles that did not find associations directed our finding to inconclusivity regarding our review objective.The evidence from the included articles suggests a link between RA and periodontitis genetic risks, bacterial infection, and the typical pro-inflammatory profile shared between RA and periodontitis are key to possible RA development. Our meta-analysis, due to high heterogeneity, showed inconclusive results in the association between these two pathologies. So, more studies with representative samples and defined periodontal evaluation are necessary to establish this possible association of clinical relevance of periodontal treatment in prevention of RA.Click here for additional data file.Supplemental material, Supplementary_file_1_Table for Does periodontitis represent a risk factor for rheumatoid arthritis? A systematic review and meta-analysis by Railson de Oliveira Ferreira, Raíra de Brito Silva, Marcela Baraúna Magno, Anna Paula Costa Ponte Sousa Carvalho Almeida, Nathália Carolina Fernandes Fagundes, Lucianne Cople Maia and Rafael Rodrigues Lima in Therapeutic Advances in Musculoskeletal DiseaseClick here for additional data file.Supplemental material, Supplementary_file_2_Table for Does periodontitis represent a risk factor for rheumatoid arthritis? A systematic review and meta-analysis by Railson de Oliveira Ferreira, Raíra de Brito Silva, Marcela Baraúna Magno, Anna Paula Costa Ponte Sousa Carvalho Almeida, Nathália Carolina Fernandes Fagundes, Lucianne Cople Maia and Rafael Rodrigues Lima in Therapeutic Advances in Musculoskeletal DiseaseClick here for additional data file.Supplemental material, Supplementary_file_3_Table for Does periodontitis represent a risk factor for rheumatoid arthritis? A systematic review and meta-analysis by Railson de Oliveira Ferreira, Raíra de Brito Silva, Marcela Baraúna Magno, Anna Paula Costa Ponte Sousa Carvalho Almeida, Nathália Carolina Fernandes Fagundes, Lucianne Cople Maia and Rafael Rodrigues Lima in Therapeutic Advances in Musculoskeletal Disease


Background: Intussusception is a common abdominal emergency in infancy and childhood, and the recurrence rate is reported to be up to 20%. Numerous potential risk factors for recurrence have been reported, although some of them are still controversial.Objective: The present study was conducted to identify the risk factors or predictive symptoms for recurrent intussusception in children who successfully recovered via enema reduction.Methods: The databases of PUBMED, EMBASE, and Cochrane were searched up to August 2018. The primary outcome was the odds ratio involving the following potential risk factors: sex, the presence of blood in stool, fever, abdominal pain, right abdominal mass, pathological lead point, and vomiting.Results: A total of 12,008 participants from 10 studies included in the abovementioned databases were enrolled in this meta-analysis. The correlation strength with each risk factor was as follows: Sex ; fever ; blood in stool ; abdominal pain ; vomiting ; pathological lead point (PLP) ; location of the mass . Besides, children who were relatively older (over 1–2 years of age) were seen to have a higher risk of recurrence.Conclusion: The main conclusion of this meta-analysis was that children with the presence of fever and PLP may have a higher risk of recurrence following enema reduction for intussusception. The prevalence of vomiting was found to be lower in RI (Recurrent Intussusception) patients than in the non-RI patients (control group). Intussusception is defined as the invagination of a portion of the intestine into itself and is one of the most common causes of abdominal emergencies in infancy and childhood , with anThe main methods of treatment for intussusception are enema reduction and operation . The surSeveral studies have reported on numerous potential risk factors, although some of them are still controversial –13. SympAs the risk factors for RI have not been clearly defined, most hospitals admit patients for 24–48 h of observation . HoweverThis meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) .The RI group included children who had been treated for intussusception successfully by enema reduction and then experienced recurrence. The control group included children who had been treated for intussusception successfully by enema reduction without any recurrence.*[Title/Abstract]).” It is of note that the reference list of each of the initially included studies was checked to avoid missing any data.The PUBMED, EMBASE, and Cochrane databases were searched for articles without restriction of language until January 2019. For extending the range of retrieve, we only set two keywords as the limitation in case of some unexpected missing of any qualified studies. The final strategy is “(intussusception[Title/Abstract]) AND recurrenThe included studies met the following criteria: (1) All participants enrolled were children below 14 years of age. (2) The study groups were clearly defined based on the presence or absence of RI in the participants. (3) Adequate information could be obtained either from full-text screening or was provided by the authors. (4) Participants who received enema reduction did not expose to surgical intervention before the recurrence.Data such as the first author's name, year of publication, region, potential risk factor assessed in the study, the number of participants, and other useful information were elicited from full-text screening and recorded in Excel tables.Literature quality evaluation was conducted by means of the Newcastle-Ottawa Quality Assessment Scale . Two revOdds ratio (OR) was calculated for the outcome involving sex, the presence of blood in stool, fever, abdominal pain, right abdomen mass, PLP, and vomiting. The reason for the choice of OR was the retrospective design of the meta-analysis based on published studies that varied in design, subjects' population, primary outcome measure, and research quality .I2 statistic. Due to the potential statistical heterogeneity, a random effect model was chosen to synthesize data instead of a fixed-effect model when assessing the role of sex, blood in stool, vomiting, PLP, and right abdominal mass in developing RI. Heterogeneity was considered significant if I2 value was over 25%. All reported test results were two-tailed and P-value < 0.05 was considered significant. Data analysis was performed with Revman 5.3.Forest plot was depicted to present the pooled OR value and heterogeneity was evaluated using The flow-chart of this meta-analysis is shown in P = 0.05 as the cut-off value for the significance test. Based on that, four studies did not find any significant determinants to predict the presence of RI. Five studies provided the information about how age influences the onset of RI and two reported that the absence of vomiting happens more frequently in RI. Both Guo et al.   .P = 0.0008)  .P = 0.25)  .P = 0.46)  .P = 0.002)  .P = 0.003)  .P = 0.64)  .Because of the heterogeneity of the data, age in each of the studies could not be statistically pooled; thus, qualitative evaluation based on six related studies was taken. Both Guo et al.  and WangThis meta-analysis included ten studies in which 1,273 children who recovered from intussusception with a recurrence and 10,685 without recurrence were enrolled. The following potential risk factors of RI were investigated: sex, fever, blood in stool, abdominal pain, vomiting, pathological lead point (PLP), and location of the mass. The predictive risk factors of RI identified were age and the prevalence of vomiting.Of the five studies reviewed to investigate the influence of age in RI, two studies , 6 reporP = 0.06).The prevalence of vomiting was found to be lower in RI patients compared with patients in the control group. The other potential risk factors, including sex, the presence of blood in stool, fever, abdominal pain, right abdominal mass, and PLP failed to show significant association with RI in this meta-analysis. However, PLP may still be one of the potential risk factors of RI as it shows a result very close to statistical point (P = 0.048), while Kim et al. (P = 0.07), number of entrapped lymph nodes ≥2 (P = 0.71), and size of entrapped lymph nodes ≥1 mm (P = 1.0). Besides, radiological risk factors were also proved to be irrelevant with RI in the study performed by Vo et al.  While the majority of the included studies are from Asia, ethnic confounding factors still exist because of the other American studies. (2) Certain factors such as body temperature were recorded in different formats, which hinders statistical analysis. (3) The cause of RI in some patients is still unknown. Although 12,008 participants were enrolled in the study, the number of overlapped risk factors or predictive symptoms in each of the studies were too less to be analyzed statistically in a comprehensive way. However, it is the first meta-analysis to investigate the risk factors of RI after successful enema reduction in children, to the best of our knowledge, which will certainly have some practical clinical implications.The main conclusion of this meta-analysis was that children with the presence of fever and PLP may have a higher risk of recurrence following enema reduction for intussusception and the prevalence of vomiting was found to be lower in RI patients than in the control group. Therefore, older age, absence of vomiting, the presence of fever and PLP may not be good factors, at least in terms of the probability for the occurrence of RI, a fact which deserves the attention of clinicians.XY, RT, SC, ZL, and JZ contributed to the study conception and design. XY, RT, SC, and ZL performed data acquisition. XY, RT, SC, ZL, and JZ performed analysis and data interpretation. XY and RT drafted the manuscript. JZ performed critical revision.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.


In light of new published studies, we perform a meta-analysis to further explore the roles of this polymorphism in PS performance among elite athletes.The special status accorded to elite athletes stems from their uncommon genetic potential to excel in world-class power sports (PS). Genetic polymorphisms have been reported to influence elite PS status. Reports of associations between the a ≤ 0.05) using the allele-genotype model . Outlier analysis was used to examine its impact on association and heterogeneity outcomes. Subgroup analysis was race (Western and Asian) and gender -based. Interaction tests were applied to differential outcomes between the subgroups, P-values of which were Bonferroni corrected (Pinteraction BC). Tests for sensitivity and publication bias were performed.Multi-database literature search yielded 44 studies from 38 articles. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used in estimating associations (significance threshold was set at Pa = 0.002) were confirmed in the Western subgroup  and with outlier treatment . This treatment resulted in acquired significance of the RX effect in Asian athletes . Gender analysis dichotomized the RX genotype and R allele effects as significantly higher in male  and female  athletes, respectively, when compared with controls. Significant R female association was improved with a test of interaction (Pinteraction BC = 0.03). The overall, Asian and female outcomes were robust. The R allele results were more robust than the RX genotype outcomes. No evidence of publication bias was found.Significant overall R allele effects  and RX genotype  were for the most part, results of outlier treatment. Interaction analysis improved the female outcome. These robust findings were free of publication bias.In this meta-analysis, we present clear associations between the R allele/RX genotype in the  ACTN3 (α-actinin-3) polymorphism into prominence regarding its association with PS performance [Exceptional performance during national/international-level competitions defines elite athletes . Among eformance ,8.ACTN3 is the gene that encodes for α-actinin-3, which is a sarcomeric protein expressed mainly in type II muscle fibers [ACTN3 R577X (rs1815739), where a cytosine-to-thymine base substitution transforms the arginine base (R) to a premature stop codon (X). The X allele is a loss-of-function variant wherein homozygosity results in a complete lack of expression of α-actinin-3, the deficiency of which occurs in ~20% of the world’s population [e fibers . Type-IIR577X rs115739, whpulation  where atpulation . In linepulation ,13.ACTN3 in sports performance is attested by its coverage in several reviews [ACTN3 R577X polymorphism with sports performance involves investigation of its polygenic nature and interactions [ACTN3 literature has focused on association analyses between several genes related to sports performance [ACTN3 is an emerging possibility in the genomics of sports science. More commonly in ACTN3 R577X research, however, is the study of the R and X alleles as well as RX genotype frequencies between athlete and control; between sport types, mainly power and endurance and comparisons between populations. Studies have found that the R allele is more frequent in power athletes than controls [The popularity of  reviews ,8,14,15.ractions –20. Thusformance ,22. Genocontrols  and in pcontrols . Howevercontrols ,26.ACTN3 R577X in PS performance which is facilitated by an arsenal of meta-analysis tools that can be used; (ii) primary study outcomes on this topic have been inconsistent with associations found in some reports [ACTN3 R577X in the PS phenotype among elite power athletes.Meta-analysis is a potent methodology that synthesizes the results of independent studies thus increasing statistical power and resolution. Our rationale for doing this meta-analysis rests on the following: (i) the synthetic approach gives a simultaneous overview and detailed profiles of the role of  reports ,26,27 an reports –30 and  review; (ii) subjects were non-human; (iii) non-English; (iv) studies did not involve PS performance (e.g. ACTN3 polymorphism effects in disease conditions or cases were non-athletes) and (v) not ACTN3 by title/abstract. Other exclusion criteria are listed in ACTN3 R577X polymorphism and elite power athletes; (ii) sufficient genotype frequency data to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) and (iii) controls in studies comply with the Hardy-Weinberg Equilibrium (HWE) which was assessed using the online application (https://ihg.gsf.de/cgi-bin/hw/hwa1.pl). We searched MEDLINE using PubMed, Science Direct and Google Scholar for association studies as of June 28, 2018. The terms used were 2 test.Two investigators (PT and NP) independently extracted data and arrived at a consensus. Authors were contacted in order to obtain more information on incomplete data. The following information was extracted from each article: first author’s name, published year, country of origin, race and gender of participants, those that addressed gene-gene, gene-environment interactions, those that used haplotype analysis, matching and sample source. Reference lists of screened full-text articles were scanned for additional studies. Where articles reported multiple genotypes under PS levels, we chose those that referred to “elite” or “international” or otherwise contextualized the status of elite athletes according to Lorenz et al . DepartuThe Clark-Baudouin (CB) scale was used to evaluate methodological quality of each included study . SuitabiData distribution was assessed with the Lilliefors corrected-Kolmogorov-Smirnov (KS) test  using SPACTN3 literature. Raw data for genotype frequencies, without adjustment, were used to calculate study-specific ORs. To assess the strength of evidence, we used the following indicators: (i) magnitudes of effects are stronger or weaker when the values are closer to or farther from the non-associative OR of 1.0, respectively; (ii) precision of effects was assessed with the confidence interval difference (CID = upper CI—lower CI). High and low CID values indicate low and high precision, respectively and (iii) P-values close to 0.05 and 0.0001 indicate moderate and high significance, respectively. Two-sided P-values of ≤ 0.05 were considered significant except in estimations of heterogeneity where the threshold was set at ≤ 0.10 on account of the low power of the χ2-based Q test [2-based Q test [2 statistic which measures degree of inconsistency among studies [BC < 0.05) from the z-test means improved power of association. Data were analyzed using Review Manager 5.3 , SIGMASTAT 2.03, SIGMAPLOT 11.0 .We estimated associations (OR) and 95% CI among elite athletes for each study. Where genotype values were zero, we applied the Laplace correction by adding a pseudo-count of one to all values of the data set  before cd Q test . Heterogd Q test , explored Q test  and quan studies . Sources studies . Outlier studies . Less va studies  of the c studies . This wa studies , otherwi studies . Sensiti studies . The conCB score distributions were non-normal (KS: P ≤ 0.002), where median for the 38 studies was 7.0 (IQR 6.0–7.0) indicating high methodological quality of the articles. Confined to the 16 new articles (42.1%), median CB was higher at 8.0 (IQR 7.0–8.0). However, the difference between CB scores in the 38 and 16 studies was marginal (Mann-Whitney U test: P = 0.06). Proportion of articles using blood (65.8%) was higher than those that used saliva or buccal (57.9%) as sources for genotyping. Of note, 9 articles (23.7%) used both sources. Multiple datasets from 5 publications placed the total number of studies to 44 . Of the Here, we emphasize on reporting pooled effects found more in power (MP) rather than in controls (MC). There are two reasons for this emphasis, first, is that power-leaning (MP) effects allow interpretation of results that quantify the magnitude of association. The second reason relates to de-emphasizing the X allele effects which a = 0.002), confirmed in the post-outlier (PSO) analysis  and in Westerns . Seven (33.3%) of the 21 comparisons in a < 0.05). Of the 5, pooled effects in Asians were the only subgroup to gain significance (GS) and its heterogeneity unaffected by outlier treatment. Initial homogeneity (I2 = 0%) of the African non-associative (null/MC) effects  from 4 studies precluded outlier treatment.a < 0.05), both of which were PSO, underpinning the impact of outlier treatment. Two features mark our core findings in gender analysis regarding associations: (i) the RX genotype in males  and (ii) the R allele in females , but not in males .a = 0.11) and heterogeneous . The sources of this heterogeneity were identified [a = 0.0009) and reduced heterogeneity  with pooled female effect of the R allele higher in MP compared to MC .Operation of outlier treatment is outlined in Figs entified ,51 with interaction BC = 0.03) suggesting improved association. This comparative outcome strengthens the statistical evidence favoring the MP female effect.Interaction tests were performed on the significant R allele and RX genotype subgroup outcomes. In this section, we focused only the significant MP pooled ORs. Study-specific ORs under each of R and RX genetic components showed the non-normal distribution of the operating data (KS test: P = 0.002–0.02). Given this data distribution, we used the Begg-Mazumdar correlation  to assesThis meta-analysis has two principal findings: (i) overall associations of the R allele and RX genotype with PS performance were validated with outlier and subgroup treatments and (ii) the R allele was associated with Westerns and females whereas the RX genotype was associated with Asians and males. Gender-wise, the R allele effects differed between males and females. The significant Asian and male/female outcomes were the results of outlier treatment. This treatment impacted on heterogeneity (reduced or eliminated) of the gender outcomes, but not the Asian outcomes. Thus, retention of heterogeneity in the PSO Asian pooled effects warrants caution in its interpretation.ACTN3 R577X with PS performance.A total sample size of 20,753 individuals for this meta-analysis seems large until this number is contextualized in terms of the controls  which is > 3X those of the athletes n = 4,850). In the Western subgroup of Wang et al , there w50. In thACTN3 R577X polymorphism has a repeated influence on elite athletic performance [ACTN3 R577X polymorphism on elite PS performance has been established across studies that have employed differing methodologies. Our findings of RR and RX associations with PS appear to agree with both human [ACTN3 in muscle structure and phenotype [The formance , 57. Thith human  and animth human . Compareth human ,62, fastth human  and a hith human ,64. Liketh human ,65–68. Nhenotype ,69 direchenotype .α-actinin-3 in fast-twitch skeletal muscle fibers (RR and RX genotypes at the gene level), was associated with PS performance in elite Japanese athletes [Differential findings delineated the associations between the races. Outcomes in Africans were marginalized in view of their non-associative (null/MC) effects across comparisons. Conversely, there were significant and associative effects in Westerners  and Asians (RX genotype in PSO) and these formed the core of our subgroup findings. The RR and RX associations found in our study seem to agree with studies of Japanese and Caucasian (Western) PS athletes with higher frequencies of RR and RX than controls ,23,53. Oathletes . Not onlathletes ,55,71.Gender analysis of the R allele shows significance in females but not in males indicating the lack of support for PS in men, but with validated outcome in women. This R allele gender difference seems at odds with the men’s outcome that did not show enrichment for the RR genotype but did for the RX. Our significant male RX finding appears to contrast with the primary study of Ruiz et al.  who repoACTN3 gene on skeletal muscle performance included a meta-analysis that evaluated gene dosage effects using the Bayesian random-effects model [2 = 62%). However, our outlier results yielded fixed-effects outcomes (PSO) for the R allele and RX genotype which addressed and resolved the heterogeneity issue. Garton et al [ACTN3 and PS [ACTN3 R allele and RX genotype associations with PS.A recent 2018 publication  on the effect of the ts model . Becauseon et al  found th3 and PS . In contACTN3 R577X genotype was associated with PS performance among Europeans (Westerns) in Alfred et al [Because similar methodologies were used in the 3 previous meta-analyses ,13,49, wed et al  and WeyeACTN3 R allele may confer some advantage in PS is supported by cross-sectional studies in elite athletes and non-athletes as well as mouse models of ACTN3 deficiency [ACTN3 knockout mice, the loss-of-function variant for the XX genotype resulted in eliminated expression of the α-actinin-3 protein [The hypothesis that the ficiency ,60,72,73 protein ,74. SuchACTN3 in separate sections exclusive of each other. Five years earlier (2014), a GWAS and meta-analysis study was performed on African-American and Asian (Japanese) sprint (power) athletes and identified two loci of putative interest [ACTN3 R577X polymorphism. The two PS GWAS in the literature examined grip strength and sprint but they did not include ACTN3 which suggests the nascent status of the GWAS approach. A literature search yielded no other GWAS undertakings related to ACTN3, attesting to the paucity of studies in this area. Nevertheless, whole genome analysis of elite athletes has been predicted to reshape the current understanding of the genetic basis of athletic performance [The polygenic nature of gene involvement in sports performance generated studies to investigate this aspect of sports genetics. Other than haplotype and interaction studies, examining several genes simultaneously using GWAS appears to be the current fashion in genomics. In 2019, Jacques et al  summarizinterest  but did formance ,77.ACTN3 R577X on elderly populations could potentially affect health care and treatment for this segment of society. The ACTN3 R577X genotype exhibits a potential modifying effect on muscle deterioration (sarcopenia), which is associated with aging [ACTN3 R577X genotype could modify resistance training adaptations [ACTN3-longevity issue, where they found no associations of the ACTN3 genotypes with muscle phenotypes in octogenarians [Beyond the prestige of elite sports performance in power rests the long term issue of skeletal muscle integrity, which is an overriding concern in a human’s lifetime, more so in the elderly. Knowledge of the genetic influence of th aging . Given tth aging , the ACTptations  and protptations . The conptations ,82. Moreptations . In addiptations  found thptations . The R aptations . Unlike ptations . The stuenarians . In viewThe interpretation of our findings is best contextualized in view of its limitations and strengths. The limitations include: (i) statistical heterogeneity; (ii) possible admixtures of the Western subgroup; (iii) dominating presence of Western studies under-represented the Asian and African populations; (iv) only 8 included articles (21.1%) matched their controls with athlete participants; (v) that some included studies contain elements of endurance and mixed sports in the performance (e.g. team sports) might dilute the impact of our PS findings. On the other hand, the strengths comprise of the following: (i) confining our analysis to HWE-compliant studies effectively screened for genotyping errors, thus minimizing methodological weaknesses to the summary outputs ; (ii) ovACTN3 gene to form part of the genetic repertoire for identifying elite athletes with PS potential. The future of genetic testing for talent identification of elite sprint and power athletes has been posited to include the ACTN3 R577X genotype [ACTN3) has been proposed to determine training response by predicting potential for athletic performance [Strengthened evidence from this meta-analysis could establish the genotype . In factformance . Howeverformance . At presformance .ACTN3 R577X) affecting PS performance [ACTN3 R577X associations with PS status. Varying depths of supporting evidence are important in replicating significant results [ACTN3 R577X may be modest, but its replicative behavior observed in the subgroups likely establishes its role in enhancing PS performance.Focusing on a single but notable polymorphism Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S6 Table(DOCX)Click here for additional data file.


This finding highlights the importance of the TGF-β signaling in this type of cancer. In this line, further studies are needed to explore more in depth this important molecular pathway, focusing also on potential therapeutic strategies based on its effectors or molecular targets.Aberrant function of Smad2, a crucial member of transforming growth factor beta (TGF-β) signaling, is associated with the development of malignancies, particularly in the gastrointestinal district. However, little is known about its possible prognostic role in such tumor types. With the first meta-analysis on this topic, we demonstrated that the lack of the activated form of Smad2 (phosphor-Smad2 or pSmad2), which was meant to be the C-terminally phosphorylated form, showed a statistically significant association with an increased risk of all-cause mortality in patients with gastrointestinal cancers (RR, 1.58; 95% CI, 1.05–2.37,  Transforming growth factor beta (TGF-β) signaling plays an essential role throughout development and later in adult homeostasis, interacting and coordinating different cell mechanisms. Notably, biological activities of TGF-β initiate with its binding to a heteromeric complex of two types of transmembrane receptors, namely type I and type II receptors; TGF-β occupancy induces an association between the type I and II receptors, causing the phosphorylation of the type I receptor by the constitutively active type II receptor ,3,4,5,6.www.genecards.org, last access 07/22/2019), appear very important in tumorigenesis [Aberrant function of members of the TGF-β superfamily is associated with a wide range of human diseases, including cancer. Particularly, alterations in the activation of the protein Smad2, which is the product of the homonymous gene located on the q21.1 of the chromosome 18 , neo-angiogenesis and immunosuppression with loss of immunosurveillance ,10,11,12However, to further complicate the TGF-β landscape, recent evidence has indicated that the activation of this signaling pathway via Smad2, above all in late stages tumors, may promote tumorigenesis activating the epithelial-to-mesenchymal transition . This duAltogether, 1197 non-duplicated articles were identified through the literature search. After excluding 1171 articles based on title/abstract review, 26 articles were retrieved for full text review and, following the application of the inclusion criteria, six unique articles were considered as eligible for the meta-analysis  18,19,2,21,22,23The studies included in this meta-analysis regarded patient-cohorts from Asia (four studies) ,19,20,22Altogether, the studies followed-up 890 patients, 393 (44.2%) of which were pSmad2-. The mean Newcastle-Ottawa Scale (NOS) score was 8.5 points (range: 8–9), with no manuscript considered as at high risk of bias . All stup = 0.029, I2 = 84%)  .This association has also been highlighted by a forest-plot .p < 0.001; I2 = 4%)  .p = 0.54) and adjusted estimates . There was no risk of publication bias for both analyzed indexes, i.e., unadjusted RR for survival  or grading, measured as the prevalence in G3 cancers , were moderators of the heterogeneity. There was high heterogeneity only for (unadjusted) RR of all-cause mortality and, therefore we investigated if differences in TNM III-IV or G3 prevalence between Smad2+ and Smad2- could be significant moderators of the heterogeneity found. Neither the difference in stage, as measured by TNM III-IV between the two groups  and an increased risk of mortality. This finding appears robust also considering that the association of pSmad2- and risk of mortality has been confirmed using data from multivariate analyses. The independent prognostic value of pSmad2- was confirmed also observing that both cohorts of patients, pSmad2- vs. pSmad2+, showed no significant differences either in terms of TNM stage or of tumor grading. To further reinforce the reliability of the present finding, the risk of publication bias was not detected.Smad2 is a specific intracellular mediator of TGF-β signaling and plays a pivotal role in the antiproliferative effects of this pathway . A seminSMAD2 driver gene mutation [SMAD4, which is one of the most important driver genes in gastroentero-pancreatic tumors [First, it is important to consider that, in the TGF-β signaling, Smad2 is activated by phosphorylation upon activation of the TGF-β receptor . Notablymutation ,27. Indec tumors ,29,30,31Another important aspect to be considered in interpreting the present results on the negative prognostic role of pSmad2- in gastrointestinal cancers regards the process of epithelial-to-mesenchymal transition (EMT). EMT is a cell mechanisms in which the epithelial elements lose their polarity and cell-to-cell contacts, undergo remodeling of the cytoskeleton with morphological modifications, acquiring also motility and migratory capacities . ParticuAlthough the finding of a correlation of the absence of pSmad2 expression with a worse prognosis seems to contradict the general assumption that enhanced TGF-beta signaling activity favors tumor progression in late tumor stages, one possible further explanation is that tumor progression is driven by pSmad3, rather than pSmad2, and that pSmad2 acts as an endogenous inhibitor of the tumor-promoting function of pSmad3.SNAIL gene and by increased SNAIL expression in the absence of Smad2, thus enhancing the progression of EMT [In this line, it is also of importance considering the role of Smad3 in the complex interaction of TGF-β pathway with EMT. Smad3 indeed has been demonstrated as an important mediator in such interaction. For example, renal tubular epithelial cells deficient in Smad3 fail to undergo EMT in response to TGF-β or mechanical stress, and keratinocytes from Smad3–/– mice demonstrate reduced migration in response to TGF-β . Comparen of EMT . In a sin of EMT .Although the results of this systematic review with meta-analysis appears reliable, we recognize in it also some limitations, which are largely reflected by those within the primary studies. First, the design of the studies included in the present review were retrospective; moreover, in these studies, data about other co-morbidities (like cardio-vascular diseases) were not specifically considered, but it is known that such comorbidities also play an important clinical role in patients with cancer. A final limitation includes the high heterogeneity found for the unadjusted relative risk for all-cause mortality. However, using data from multivariable models, the heterogeneity became low and at the same time the statistical significance of the present results was preserved, further corroborating the reliability of the finding.In conclusion, with this meta-analysis it has been demonstrated that lack of pSmad2 is strongly associated with an increased risk of mortality in gastrointestinal cancers. This finding highlights the importance of the TGF-β signaling in cancer. Further studies are now needed to explore more in depth this molecular pathway and also possible therapeutic strategies, taking into account its potential effectors or molecular targets.This systematic review adhered to the Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guidelines and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, following a predetermined protocol ,52. Studies were eligible for inclusion upon meeting the following criteria: (1) a prospective cohort or retrospective study design; (2) it contained a comparison of prognostic factors between positive vs. negative pSmad2 with immunohistochemistry; (3) it considered only C-terminally phosphorylated Smad2; (4) a diagnosis of conventional gastrointestinal cancers; (5) it contained data about mortality/recurrence of disease; (6) it was published in a peer review journal or published abstract. Articles in any language were considered. Exclusion criteria were: (1) no presence of specific data on pSma2, (2) no clear standards of immunohistochemical protocol and its interpretation, (3) no data about prognostic parameters in the title/abstract, (4) no comparison between positive vs. negative pSmad2 patients, and (5) in vitro or animal studies.SMAD2 mutations are very rare in gastrointestinal cancers and do not represent a reliable indicator of Smad2 activity.We selected research papers that investigated Smad2 with immunohistochemistry since this is the best method to study the effective Smad2 function, given that Two investigators  independently searched PubMed, Embase and SCOPUS until 05/31/2019. The search terms used in PubMed included combinations of the following keywords: (SMAD2 OR JV18 OR JV18-1 OR MADH2 OR MADR2 OR hMAD-2 OR hSMAD2) AND (cancer OR neoplasm OR neoplasia OR carcinoma OR adenocarcinoma) AND . A similar research was made in SCOPUS and Embase. We considered the reference lists of all included articles and of previous related reviews. Following the searches as outlined above, after removal of duplicates, two independent reviewers  screened titles and abstracts of all potentially eligible articles. The two authors applied the eligibility criteria, considered the full texts, and a final list of included articles was reached through consensus with a third author (A.N.).Two authors were involved in data extraction in a standardized Microsoft Excel database. Specifically, one author (N.V.) extracted data from the included articles and a second independent author (A.N.) validated the data. For each article, the following information was extracted: Authors, year of publication, country, exclusion criteria, other genes/proteins abnormalities that have been studied in the specific work, number of participants and gender, age, pathologic TNM stage, tumor grading, type of IHC analysis (whole section vs. tissue micro-array), number of adjustments in survival analyses and duration of follow-up. The primary outcome was the number of deaths after treatment during the follow-up period in patients with positive vs. negative pSmad2. The secondary outcome was the risk, adjusted for the maximum number of confounders available in each paper, regarding the same outcome, taking those with positive pSmad2 as reference.We used the Newcastle-Ottawa Scale (NOS) to evaluate study quality . The NOS2 metric and chi square statistics [p < 0.05) after removing outlier studies, a series of meta-regression analyses according to pSmad2 status and each of prognostic parameters were considered. Finally, publication bias was investigated for the primary meta-analysis with a visual inspection of funnel plots coupled with the Egger bias test [All analyses were performed using Comprehensive Meta-Analysis (CMA) 2 . In our primary analyses, pooled risk ratios (RRs) and 95% confidence intervals (CIs) of risk of mortality between positive pSmad2 vs. negative pSmad2 were calculated using DerSimonian-Laird random-effects models . In secoatistics . In the ias test .