Objective: Osteoarthritis (OA) and age-related degeneration (ARD) are stimulants for the development of the fabella in the knee joint. This meta-analysis updates previous studies and reviews on the prevalence of the fabella in OA or ARD knee joints. In addition, it provides a quantitative estimation of the fabellar prevalence in knees having OA and ARD.Methodology: Twenty studies containing data from 11,056 knee joints were utilized in the investigation, consisting of 6,819 knees of individuals with OA (including those with age greater than 40 years) and 4,237 knees of individuals without OA (including less than 40 years of age), respectively. Totally, 2,434 knees of the OA subjects had fabellae (including more than 40 years), while in the non-OA subjects, 844 had fabellae (including less than 40years). The odds ratio (OR) and relative risk (RR) were calculated.Results: The fabellar prevalence was observed to be higher in OA knees, where the risk ratio of developing fabella was 2.55 (2.15-3.02). Compared with this, the risk ratio for the incidence of fabella in ARD knee was 1.71 (1.59-1.85). The bilateral occurrence of fabella was more common than unilateral. The risk of developing fabella in individuals aged less than 40-year was 0.59 which was 41% less than individuals aged more than 40 years. The risk ratio of developing fabella in co-exposure of ARD and OA was 1.84 .Conclusion: OA and ARD would increase the prevalence of ossified fabella by 84%, thus acting as stimulants or associations and risk factors for ossified fabella. The term fabella is Latin, meaning little bean. This sesamoid bone is embedded in the lateral head of the gastrocnemius in the posterior aspect of the femur . It presThe knee joint is most commonly affected by osteoarthritis (OA). In severe OA, knee arthroplasty is a usual procedure these days. Fracture dislocation of fabella was uncommon before the era of knee arthroplasty . The impLiterature reviewAvailable literature was explored from the electronic database of PubMed/Medline, European PMC, CINAHL, Embase, EBSCO, Scielo, Clinical Key, Up To Date, OVID search, Google Scholar, AUSPORT, and Cochrane library from June 2019 to November 2019. The search included Medical Subject Heading (MeSH) terms such as prevalence, incidence, fabella, sesamoid bone, osteoarthritis, OA, arthritis, aging, ARD, knee pain, and knee degeneration in different strings of combinations. The string of terms was included in Boolean search with ‘OR, AND, or NOT’, and speech marks such as ‘Fabella or Knee Sesamoid or Popliteal sesamoid’ and ‘Fabella or Prevalence or Osteoarthritis’ or ‘Fabella or Prevalence or Knee pain’, to acquire maximum relevant articles. The delimiter ‘NOT’ was used to obtain appropriate studies. The strategy used for the PubMed database is mentioned at the end of the manuscript. Appropriate published articles were collected from the journals of subjects like Anatomy, Anthropology, Orthopaedics, Sports Injuries, Biomechanics, Morphological Science, and Radiology from websites or library archives. These search strategies yielded 119 works.Literature selectionThese works were shortlisted based on titles and abstracts by Rayyan QCRI App for a systematic review. Case reports and case series were excluded because they did not provide sample sizes, making risk estimation impossible. The publications without useable data, or where data did not exhibit 95% confidence intervals, were also excluded from the analysis. Studies providing risk estimates of OA or ARD were included. Further, to ensure an unbiased approach in selecting the studies, a summary of conferences, preprint articles, and published articles were also included. In addition, email correspondences were performed to gather unpublished figures of published manuscripts. Case reports accompanied with literature review were included for references, but their data were excluded from the analysis. The average prevalence from course-books or published manuscript without sample references were neglected. No restriction was applied based on the year of publication, language, or ethnicity. Studies reporting fabella before 12 years of age in a population sample were not considered because the development of fabella in this age group could not be confirmed. In addition, if an author confused popliteal artery calcification with fabella in radiographic findings, the results were excluded as they were not appropriate for analysis. The radiological studies incorporated the data of radiographs, CT, and MRI scans. The figures of USG and PET scans were omitted from the analysis because of their low detection rates. Anatomical studies reporting the age of cadavers and OA changes were included in the analysis.The prevalence of fabella was measured in knees of OA subjects, non-OA subjects, subjects aged less than 40 years, and subjects aged more than 40 years. The Osteoarthritis Initiative  recommended the lowest age of 45 years for the OA cohort study, with a baseline of five years of exposure. Consequently, 40 years of exposure was considered as a baseline for ARD in this analysis. The prevalence of fabella was measured separately in males and females. In addition, the incidences of unilateral or bilateral fabella, and right or left were noted. The data on the size of fabella were not used because of insufficient sample size and variable methods of measurement.The primary outcome was to measure the risk estimates of fabella in ARD and OA knee based on radiological and anatomical assessment. The assessment of the prevalence of fabella based on sex, laterality, and ancestry were secondary outcomes.Assessment of risk of biasEvaluation and analysis for the risk of bias in all selected articles were performed by using the Anatomical Quality Assurance (AQUA) tool of the International Evidence-Based Anatomy (iEBA-WG) working group. Two authors assessed the risk of bias independently. Any disagreement was resolved by a third author. The risk of bias was evaluated in all five domains - objective and subject characteristics, study design, methodology characteristics, descriptive anatomy, and reporting of results. Additionally, ROBINS I was utilized to assess the integrity or quality of these observational studies because the AQUA tool was inadequate to evaluate the exposure (intervention) in them.Data extraction and statistical analysis Authors independently extracted the data and information relevant to the study using a standard data extraction form. The form included the following details: the number of participants, age, sex, inclusion, and exclusion criteria. Also, the statistics recorded were the publishing year, geographical area or population, the modality of study , the number of individual knees appraised, and the number of fabellae detected (events). The contingency tables were prepared, and the odds ratio (OR), as well as 95% confidence interval, were computed. The risk estimations for age, gender, and laterality were investigated individually. No prior data were accessible to adjust these confounding factors. The Kellgren-Lawrence radiological grade was used to assess the OA in two radiological studies. Mean K-L score were computed in knees having fabella and without fabella. Fabella degeneration grade (FDG) was examined: grade 0 for normal fabella which having a triangular or oval shape and smooth articulating surface, grade 1 articular surface subchondral sclerosis; grade 2 sclerotic fabella with osteophyte formation at the fabellar margins; and grade 3, enlarged fabella (over 2 cm) with large osteophyte formation [The unit of analysis was the prevalence of fabella in 100 knees examined. ProMeta v3 - Idostatistics and Revman 5.3 were used to analyze the pooled data. The OR and effect size were measured for each included study. The heterogeneity value was measured as i2. If i2 was <50%, then the fixed effect model was implemented; else, the random effect model was utilized. The Cochrane Q statistics was investigated. The OR, RR, and risk difference (RD) were measured with a 95% confidence interval. Sensitivity and cumulative analysis were performed to test the consistency of the findings. Publication bias was measured by the funnel plot. For the funnel plot, the logarithmically transformed OR against the standard error was utilized. Regression analysis was also performed to investigate the correlation between outcome and moderators . The publication bias was visually examined in the funnel plot along with Egger’s linear regression test and Begg and Mazumdar’s rank correlation test. The file drawer effect was investigated by generating Rosenthal Fail-Safe Number (FSN). Subgroup analysis was done to measure the risk estimates related to intervention if heterogeneity was above 50% because of the distribution of ethnicity or population and mode of study. The extracted data were not suitable to study the dose-response and dose-time effects. Finally, the OR, RR, and RD were computed based on data in the random-effect model.Description of studies The publications included were cross-sectional observational studies as case-controlled or cohort studies were unavailable despite extensive searches. One hundred seventeen relevant works were found as a result of electronic surveys, and two studies retrieved from conference proceedings. Five duplicated searched items were omitted. Another 37 studies were excluded because of non-human reports or case reports and series, review-based abstract, and title evaluation. Seventy-seven studies qualified after the title and abstract evaluation and three authors studied full texts of each work individually. A study was included based on the consensus of at least two authors. The interrater agreement was 0.87. For the meta-analysis, 22 studies from the years 1875 to 2019 were selected, which dealt with the prevalence of fabella associated with OA or ARD changes based on their abstract and full-text analysis. Of these, two studies  were excRisk of bias in the included studiesThe AQUA tool probed for potential risk of bias in five study domains, as previously mentioned. The risk of bias within each domain was categorized in percentage. A bias of less than 20% was considered low risk, 20-40% was categorized as moderate risk and >40% was high risk. The majority of the works included in this meta-analysis had a low to moderate risk of bias in domain 1 (objectives and subject characteristics) and domain 3 (methodology characterization) because of missing baseline demographic data of the study population and lack of information regarding the experience of the researchers. Almost all studies revealed a low risk of bias in the remaining domains . The agreement varied from average to excellent. ROBINS I risk of bias was found as low to moderate in the 20 studies (Table Effect of exposures2) was 81%, while the Cochrane Q value was 96.38 for df = 19 (P = 0.0001). It was unacceptable (i2 acceptable up to < 50%) to combine the risk estimate, and needed subgroup analysis to deal with heterogeneity.Eleven thousand fifty-six knees were evaluated for risk estimates in co-exposures of OA and the ARD processes. The risk estimate for the prevalence of fabella in combined exposure had an OR of 2.16 , and a RR of 1.71 . The risk estimate of prevalence of fabella in persons <40 years of age had an OR of 0.54  and RR of 0.59 . All studies revealed a serious heterogeneity, and the heterogeneity statistics  of the prevalence of fabella in comparison with males (P = 0.13). Laterality analysis did not show any RD of fabellar prevalence, and fabella was distributed equally on both sides (the diamond of risk estimate located on ‘no effect line’). The prevalence of bilateral fabella was higher than unilateral fabella, but estimation was done based on seven studies, and the estimated RR was 2.56  in OA and ARD  presented significant heterogeneity compared with European studies. Data from the USA and the Middle East could not be compared due to insufficient studies for comparison. There was no significant difference between the OR of studies from journal articles and conference presentations. The meta-regression of the effect size of fabellar prevalence with the year of publication had an insignificant association. Sensitivity and cumulative analysis were done to detect RR variation after adding and removing each study, respectively. The variation in RR was constant with minimum variation (0-0.05) after 4,768 knees were included in the studies. The authors examined approximately 11,000 knees, and RR will not vary beyond this range. Hence, it was determined that any further study would not impact the RR.Publication biasThe publication bias was guessed to be present, as exhibited in the funnel plot, but that might be due to sample variations Figure . Egger’sThis meta-analysis summarizes the finding of 20 observational studies, encompassing a total of 10,890 knees, investigating the association of prevalence of fabella and OA along with ARD. This analysis presented the increased risk of developing fabella in an OA knee. The ARD process has an additional impact on the prevalence of fabella. This analysis measured the risk estimates of the cumulative as well as individual effects of OA and ARD. Sufficient data were unavailable to find age-adjusted risk estimates of fabellar prevalence in OA. The fabellar prevalence was higher bilaterally and on the right side in case of unilateral prevalence. A similar distribution was found in the literature for OA. OA has bilateral with asymmetrical presentation and farther on the right side in terms of severity, which mimics the distribution of fabella in OA . In thisPotential biases in the study Because only 19 studies were included for the risk estimate without adjustment of age and sex, the analysis was not free of possible confounding factors. ARD and OA are inter-related to each other, and their relationship is a major hurdle to get the pooled estimates of effect size. The size of fabella and its degeneration could not be considered because of variable methods of measurement of dimensions . Apart from OA and ARD, traumatic injury, chondromalacia, bony stress, physical habits, or occupational need may affect the fabellar prevalence in these studies. But studies included in this meta-analysis did not have sufficient information to stratify for the above factors.This meta-analysis confirms the role of mechanical stimulus due to knee degeneration and ARD in the prevalence of fabella. The sesamoid bone appears as a cartilaginous nodule, and it is under the regulation of genetic and environmental factors. But, the ossification of fabella in a later stage needs a mechanical stimulus, especially in the form of traction . SesamoiThere were five case reports of fabella syndrome after total knee arthroplasty ,29. The The relationship between aging or ARD with fabellar prevalence is controversial. This meta-analysis showed that a moderate relationship existed between both variables. OA was another influencing component and the co-existence of ARD and OA made them covariance for fabellar prevalence. OA was a strong determinant of fabellar prevalence. Hou et al. suggested the fabellar degeneration was correlated with Knee OA . They clLimitations of the studyThis meta-analysis offers vital information about the fabellar prevalence in OA and ARD with some limitations. The studies included in this meta-analysis did not disclose physical habitus or occupation; hence, the pooled estimates were not free of possible variance. The unequal sample variance (the number of knees per study) may impact the final estimate of the outcome. The small amount of heterogeneity and risk estimates without age-adjustment are some minor limitations due to the unavailability of appropriate data.The prevalence of fabella is higher in OA than non-OA subjects and lesser prevalence of fabella in subjects under 40 years. It assists to appreciate the variation of fabellar prevalence in old and young subjects. Coherent with earlier results, the fabellar prevalence is insignificantly higher in the female. The bilateral occurrence of fabella is much higher than the unilateral occurrence. These are related to the distribution of OA, which is bilateral, asymmetrical, and common on the right side. The evaluation of the fabellar prevalence in players, security personnel, and the population residing near the mountains will facilitate understanding of biomechanical stress or load on the fabellar prevalence and the role of fabella in knee kinematics. The stratification of the recommended study will furnish the final estimate of the fabellar prevalence according to physical activity or biomechanical load on the knee.


In this study, we evaluated the association of modified Glasgow Prognostic Score (mGPS) with prognosis in pancreatic cancer (PC) by performing a meta-analysis. Potentially eligible studies were shortlisted by searching PubMed, Embase, Web of Science, Scopus, and the Cochrane Library. A total of 4,629 patients with PC from 25 studies were finally included in this meta-analysis. Meta-analyses were performed using a random-effects model or fixed-effect model according to heterogeneity. We pooled the hazard ratios (HRs) with 95% confidence intervals (CIs) to estimate the association between mGPS and overall survival (OS). The results showed that elevated mGPS correlated with poor OS in patients with PC . In addition, subgroup analysis indicated that increased mGPS remained a significant prognostic factor irrespective of the study design, region, disease status, treatment, survival analysis, cancer type, study center, or the Newcastle-Ottawa Scale (NOS) score . There was a significant correlation between higher mGPS and male gender . Elevated pretreatment mGPS is a marker of poor prognosis in patients with PC. As an easily available and cost-effective inflammatory parameter, mGPS can serve as a promising tool for prognostication in PC. Pancreatic cancer (PC) is one of the most aggressive malignant tumors with a very poor prognosis . PC is cCancer cells activate systemic inflammatory pathways that aid cancer progression by facilitating tumor cell proliferation, immune envision, and dissemination. A variety of inflammatory markers have attracted much attention as potential prognostic markers including C-reactive protein (CRP), neutrophil to lymphocyte ratio, and the modified Glasgow Prognostic Score (mGPS). The mGPS was established combining the levels of CRP and serum albumin. Some studies –15 have As shown in The basic characteristics of the 25 included studies are summarized in I2=65%, P<0.001), a random-effects model (REM) was used. It was shown that elevated mGPS is associated with poor OS  and tumor location (head vs. body/tail) was analyzed based on data from 4 , 21, 30 A sensitivity analysis was carried out by calculating the combined HR and 95% CI after omitting one study each time. As shown in As shown in In the present meta-analysis, we showed that a high mGPS was a prognostic indicator for poor survival in patients with PC. Moreover, the prognostic efficiency of mGPS was consistent and was not influenced by the study design, region, disease status, treatment, survival analysis, cancer type, study center, and NOS scores. In addition, the results suggested that male PC patients tend to have higher mGPSs, and therefore, have worse prognosis. Therefore, our meta-analysis indicates that mGPS could be applied as a reliable and cost-effective prognostic marker for PC.Inflammatory responses play pivotal roles in tumor microenvironment, which can educate cancer cells to evade immune surveillance . The mGPPrevious studies have explored the prognostic role of mGPS in various cancers using meta-analysis –39. Nie Some limitations of the current meta-analysis require acknowledgment. First, most of the included studies were of retrospective design and the results were easily influenced by confounding factors. However, in the subgroup analysis stratified by survival analysis , the resIn conclusion, elevated pretreatment mGPS is a marker of poor prognosis in patients with PC. The prognostic efficiency was reliable across different subgroups. As an easily obtainable and cost-effective inflammatory parameter, mGPS can serve as a promising indicator for prognostication in PC.The current meta-analysis was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement . The ethWe retrieved potentially eligible studies by searching PubMed, Embase, Web of Science, Scopus, and the Cochrane Library. The search period was from inception to June 17 2020. Search terms used were the following free text words and medical subject heading (MeSH) terms:  AND  AND . Reference lists of literature were also manually examined for eligible studies. Two reviewers (D Wu and X Wang) searched the database independently, and all disagreements were resolved by discussion.The following inclusion criteria were applied: (1) prospective and retrospective studies exploring the association between mGPS and OS in PC, with OS being calculated from the date of diagnosis to the last date of follow-up or death from any cause ; (2) mGPhttp://www.ohri.ca/programs/clinical_epidemiology/oxford.asp). The NOS consists of 3 sections: selection (0–4 points), comparability (0–2 points), and clinical outcomes (0–3 points). The maximum score of NOS is 9 and studies scoring 6–9 are regarded as high-quality studies.Two authors (G Shi and H Sun) independently extracted data from the included studies, and all discrepancies were resolved by discussions with a senior investigator (G Ge). Data extracted from the literature included the first author’s name, publication year, geographical region, histological type, study design, sample size, endpoint, age, disease status, survival analysis, treatment, study center, TNM stage, source of HRs, and HRs and 95% CIs. The HRs and 95% CIs of mGPS 1–2 vs. 0 were extracted. If studies provided the HRs and 95% CIs of mGPS 1 and mGPS 2 as two groups, the two groups were combined and the HR of mGPS 1–2 vs. 0 was computed as previously described , 43. TheI2) statistics. Either p<0.1 or I2 > 50% indicated the existence of significant heterogeneity, and the REM was applied for analysis. Otherwise, a fixed-effects model (FEM) was adopted. Subgroup analysis stratified by study design, region, disease status, treatment, survival analysis, cancer type, study center, NOS score, and TNM stage were performed to detect the source of heterogeneity. We also performed a sensitivity analysis to evaluate the validity of the combined results. Moreover, we used the Begg’s funnel plot and Egger’s test to evaluate publication bias. A p-value of less than 0.05 was considered statistically significant.All statistical analyses were performed using Stata software version 12.0 . For every study, HR and 95% CI were used to assess the relationship between mGPS and the prognosis of PC patients. The association between mGPS and clinical factors was analyzed using ORs and 95% CIs. HRs and 95% CIs were directly extracted from the articles or calculated from the Kaplan–Meier (K–M) curves according to Parmar’s method . HeterogSupplementary Table 1


Escherichia coli among healthy adult population.Antimicrobial resistance is a serious public health problem. Fecal carriage of drug-resistant bacteria has been suggested as an important source of antimicrobial resistant genes (ARGs). We aimed to identify risk factors associated with fecal carriage of drug-resistant commensal E. coli for healthy population aged 18-65. Data on risk factors assessed in three or more studies were extracted.We conducted a systematic review and meta-analysis following the PRISMA guideline. We identified observational studies published from 2014 to 2019 through PubMed, Embase, and Web of Science. Studies were eligible if they investigated and reported risk factors and accompanying measure of associations for fecal carriage of drug-resistant E. coli. Among travellers, antimicrobial use (OR 2.81 [95%CI 1.47-5.36]), diarrhea symptoms (OR 1.65 [95%CI 1.02-2.68]), travel to India (OR 3.80 [95%CI 2.23-6.47]), and vegetarian diet (OR 1.92 [95%CI 1.13-3.26]) were associated with increased risk. Among general adult population, antimicrobial use (OR 1.51 [95%CI 1.17-1.94]), diarrhea symptoms (OR 1.53 [95%CI 1.27-1.84]), and travel to Southeast Asia (OR 1.67 [95%CI 1.02-2.73]) were associated with the increased risk of drug-resistant E. coli carriage.Fifteen of 395 studies involving 11480 healthy individuals were included. The pooled prevalence of drug-resistant Enterobacteriaceae was 14% . Antimicrobial use within the 12 months prior to stool culture (odds ratio [OR] 1.84 [95%CI 1.35-2.51]), diarrhea symptoms (OR 1.56 [95%CI 1.09-2.25]), travel to India (OR 4.15 [95%CI 2.54-6.78]), and vegetarian diet (OR 1.60 [95%CI 1.00(1.0043)-2.56(2.5587)]) were associated with increased risk of fecal carriage of drug-resistant E. coli.The findings indicate that dietary habit as well as past antimicrobial use and travel to high-risk country are associated with the risk of fecal carriage of drug-resistant commensal  Escherichia coli (E. coli) is the most frequent cause of extraintestinal infections such as urinary tract infection and bloodstream infection  OR escherichia [Title/Abstract] OR “e.coli” [Title/Abstract])) AND  AND (questionnaire [Title/Abstract] OR surveillance [Title/Abstract] OR survey [Title/Abstract]).The protocol of this meta-analysis was not preregistered. We performed a systematic review and meta-analysis following the PRISMA [Preferred Reporting Items for Systematic Reviews and Meta Analyses] guidelines   examined bacteria must be isolated from human feces, stool, or rectal swab; (3) must report risk factors. Studies reporting risk factors for drug-resistant Enterobacteriaceae were considered eligible because E. coli is the most common Enterobacteriaceae. Studies that remained of interest were then screened based on their full text by two independent reviewers, YH and YM. Disagreements were resolved by consensus. Inclusion criteria were: (1) reported risk factor(s); (2) reported measure of associations and accompanying 95% confidence intervals (95% CI) or its equivalent; (3) study population aged 18-65; (4) healthy study population; (5) survey conducted after 2010.All abstracts were screened first by author YH and then by author YM to minimize omission of eligible studies. Screening criteria were as follows: (1) examined bacteria must include For the meta-analysis, we excluded studies that (1) did not report risk factors commonly assessed in 3 or more studies or (2) did not offer sufficient data to create a contingency table.Data were first extracted by YH and checked by YM. The assessment measures extracted from the included studies were as follows: (1) publication data: lead author names, year of publication; (2) demographic and epidemiological data: location of study, study population, study design, sample size, outcome, prevalence of drug-resistant bacteria, outcome measurement methods, statistical analysis methods; (3) risk-factor associated data: risk factor(s) investigated, measure of associations  and accompanying 95% CI.When enumerating risk factors from each eligible study, we did not limit the analysis to statistically significant factors to avoid publication bias and to identify as many factors studied to date as possible.For studies which provided enough data to allow for the creation of contingency tables, unless the authors reported an adjusted OR and corresponding 95% CI, we manually calculated the OR and 95% CI. If there were insufficient data to create a contingency table, we excluded the study to calculate pooled estimates.E. coli. Mantel-Haenszel random-effects model estimates the amount of between-study variation by comparing each study’s result with a fixed-effect meta-analysis result but avoids approximating Normal distributions ), and vegetarian diet (OR 1.60 [95% CI 1.00(1.0043)-2.56(2.5587)]). Six (46%) of 13 studies found antimicrobial use in the previous 12 months, 4 (57%) of 7 studies found diarrhea symptom, and 2 (40%) of 5 studies found vegetarian diet to be significantly associated with the carriage of drug-resistant bacteria.Traveling to India was the only risk factor that all studies reported to be significantly associated with fecal carriage of drug-resistant Smoking, living with pet(s), gender, education level, previous hospital admission, proton-pump inhibitor (PPI) use, chronic disease, international travel, travel to Southeast Asia and exposure to livestock were commonly assessed but no significant pooled OR was found in these studies. Of these commonly assessed risk factors, three factors  were reported as significant risks among half or more studies included in this review. Two (67%) of 3 studies found PPI use, 2 (67%) of 3 studies found chronic disease, and 4 (50%) of 8 studies found travel to Southeast Asia to be significantly associated with the carriage of drug-resistant bacteria.E. coli carriage suggested two distinct populations. We divided the population into travellers and other general population adults and replicated the analysis . As stated above, pooled OR showed significant association with being a vegetarian (OR 1.60 [95% CI 1.00-2.56]). Two studies reported significant association, one with unadjusted OR , and anoE.coli (OR 7.54 [95% CI 2.41-23.45]) [E. coli. One of them reported that raw vegetable consumption during a trip to Southeast Asia significantly increased the risk of intestinal carriage of drug-resistant Enterobacteriaceae (OR 2.18 [95% CI 1.29-3.68]), while exposure to raw vegetable in South Asia significantly decreased the risk (OR 0.34 [95% CI 0.12-0.93]) [Four studies reported potential food-associated risk factors other than being a vegetarian. One study reported exposure to raw milk as significant risk factor for acquiring multi-drug-resistant -23.45]) . Two stu-23.45]) . Another-23.45]) . Two stu2-0.93]) . The oth2-0.93]) .We evaluated heterogeneity among studies, and potential extent of publication bias in meta-analysis Table b, and c.chi2  and I2 value (53-94%) except for travel to India. This suggests that there was substantially high heterogeneity among studies that examined the effect of international travel, travel to Southeast Asia, and travel to Africa, respectively. Smoking, PPI use, and chronic disease status also showed moderate to high heterogeneity (I2 66-77%). For all other risk factors, no heterogeneity was observed, suggesting that the evidence was of high quality.For pooled estimates of all studies, risk factors related to travel showed high chi2 19.27 and 41.24, respectively, p<0.01, and I2 90%). Among general adults, travel abroad and travel to Southeast Asia showed moderate heterogeneity . The shapes of the funnel plots were approximately symmetrical for significant risk factors, and Egger’s test showed p=0.42 for antimicrobial use within the previous 12 months among all populations included in this study  has slightly increased from an earlier review (14% [95% CI 9-20%] for ESBL producing Enterobacteriaceae) published in 2016 . KaranikThe high variability could also be explained by the types of populations studied. In our study, the prevalence between travellers and general adult populations were significantly different , suggesting different mechanisms for acquiring drug-resistant gut Enterobacteriaceae organisms. It is possible that travel includes distinct behavioral activities that affect exposure to potential risk factors for acquiring ARGs. This assumption led us to examine the pooled estimates of OR for each risk factor stratified by travellers vs general adult population.E. coli, prior antimicrobial drug use within 12 months prior to stool culture, diarrhea symptoms, travel to India, travel to Southeast Asia, and vegetarian diet. Antimicrobial use, diarrhea symptoms, and travel to India were also identified in previous reports [E. coli for travellers. Travel to Southeast Asia was significantly associated with ARG carriage only among the general adult population. We should note that due to the limited number of studies, some risk factors commonly assessed for entire population could not be assessed for stratified populations. To the best of our knowledge, no previous review has found vegetarian diet to be significantly associated with intestinal carriage of drug-resistant E. coli. Butcher et al. (2019) reported that unwashed vegetables could be a source for ESBL-producing extraintestinal pathogenic E. coli [E. coli and fecal E. coli [E. coli. Although we should note that our pooled ORs for drug-resistant E. coli intestinal carriage were not controlled for potential confounding factors other than travel status, our findings suggest that certain type of dietary practice could be a risk factor for acquiring drug-resistant E. coli by the gut microbiota.In the general adult population, we found five risk factors significantly associated with intestinal carriage of drug-resistant  reports , 20. Whe E. coli . Multipl E. coli , 54, andE. coli. However, 50% or more of the studies reported significant associations for proton-pump inhibitor use, chronic disease, and travel to Southeast Asia. This suggests that these factors could serve as risks for drug-resistant E. coli colonization under certain situations. In fact, travel to Southeast Asia was a significant risk factor for general adult populations. Previous hospitalization and travel to Africa were also assessed in the review by Karanika et al. [In addition to the five significant risk factors, we identified ten other risk factors commonly assessed in 3 or more reviewed studies. These include gender, smoking, living with pet(s), education level, proton-pump inhibitor use, previous hospital admission, chronic disease, international travel, travel to Southeast Asia, and travel to Africa. None of these factors were significantly associated with risk of intestinal carriage of drug-resistant a et al. . In agreE. coli infections [E. coli. Being a vegetarian was significantly associated with the carriage of drug-resistant E. coli among overall population and travellers. Pooled estimate among general adult populations could not be obtained due to limited number of studies. Several recent studies have reported contamination of leafy green vegetables with saprophytic bacteria harboring ARGs that occur in human Gram-negative bacterial pathogens [E. coli, which supports our hypothesis that ARGs may be acquired via contaminated food in addition to healthcare-associated acquisition and person-to-person transmission.Multiple studies reported food as potential sources of fections –13, 52. athogens , 55, 56.athogens , 42, 43.athogens . GeograpE. coli alone. Still, the frequency of E. coli found among studies that examined Enterobacteriaceae was high (79-97%) for 9 of 10 studies. One study that had low frequency (29%) of E. coli was not eligible for meta-analysis. Therefore, we can assume that risk factors identified in this review would apply to E. coli. Also, we cannot determine whether the identified risk factors have causal effects on fecal carriage of drug-resistant E. coli. For example, an episode of diarrhea among participants could have prompted the use of antibiotics, which could have selected for drug-resistant E. coli in the host intestinal microbiota. Still, identification of factors significantly associated with the carriage of drug-resistant E. coli will be useful for identifying individuals with high risk and early focused interventions. Another limitation of our study is that there was no study from North America included in this review. Karanika et al. (2016) reported the same limitation [E. coli [There are limitations associated with this systematic literature review. First, 10 of 15 studies investigated Enterobacteriaceae instead of mitation . Since Nmitation , 45, 50.[E. coli , 50, 51,[E. coli . Since PE. coli, antimicrobial use, diarrhea, vegetarian diet, travel to India, and travel to Southeast Asia. Due to the high heterogeneity of the studies, other factors may indeed serve as risks under certain circumstances. Further studies, especially those that examine food and other environmental exposures will be essential for identifying public health interventions that can be devised to decrease human intestinal colonization with drug-resistant bacteria.In this review, we found five significant risk factors associated with intestinal carriage of drug-resistant Additional file 1 Forest plots of insignificant risk factors. Individuals and combined ORs of fecal carriage of drug-resistant E. coli. A: entire population; B: travellers; C: general adults.Additional file 2 PRISMA 2009 ChecklistAdditional file 3 Reference information for excluded articles and reasons for exclusion.


Objective: Cyclooxygenase-2 (COX-2) is a critical enzyme associated with inflammation and tumorigenesis. Although several studies have compared the expression of COX-2 in endometrial cancer tissues and normal tissues, the results have been inconsistent thus far. This study aims to conduct a meta-analysis to elucidate the role of COX-2 in the determination of the risk, prognosis, and clinical features of endometrial cancer.Methods: We retrieved the suitable studies on the association between COX-2 expression and endometrial cancer from PubMed, EMBASE, and Web of Science databases that were published between 1999 and September 31st, 2019. The hazard ratio (HR) and 95% confidence intervals (CIs) were retrieved to assess the relationship between COX-2 expression and the prognosis of endometrial cancer. The odds ratio (OR) and 95% CIs were calculated to evaluate the correlation between COX-2 expression and the risk and clinical features of endometrial cancer.Results: To investigate the association between COX-2 expression and the susceptibility, clinical features, and prognosis of endometrial cancer, we performed a meta-analysis on data from selected studies that collectively involved 273 normal individuals and 1,376 patients with endometrial cancer. Overall, the pooled analysis indicated that COX-2 expression was significantly associated with susceptibility , cancer stage , myometrial invasion , lymph node metastasis , and prognosis  in endometrial cancer.Conclusions: Our findings suggested that COX-2 overexpression is significantly associated with poor prognosis and advanced clinical features in endometrial cancer. Therefore, COX-2 may function as an effective prognostic biomarker and a potential therapeutic target for endometrial cancer. Endometrial cancer is the most common gynecological cancer in developed countries, and the estimated mortality in the United States in 2017 was 10,920 . mTOR activation promotes cell growth and inhibits apoptosis  from arachidonic acid. The findings of basic elopment , 12. COXelopment . COX2 ispatients . Moreovepatients . ImmunohThe eligible studies published between 1999 and September 31st, 2019 were retrieved from PubMed, EMBASE, and Web of Science databases following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines . The folThe inclusion criteria were as follows:1) studies that assessed the relationship between COX-2 expression and endometrial cancer;2) studies involving endometrial cancer patients who were diagnosed according to the relevant diagnostic criteria;3) studies that had adequate data  to estimate the pooled odds ratio (OR) and HR.The exclusion criteria were as follows:1) reviews, case reports, editorials, conference records, and comments;2) studies that were published in non-English languages.Since this was a meta-analysis, no ethical approval and patient consent were required.Two investigators independently scanned the full-text articles and extracted the available data. The first author name, number of patients, year of publication, country, cancer type, race, follow-up duration, clinicopathological features of endometrial cancer patients, HRs, and 95% CI were extracted from the eligible studies. Furthermore, each study was scored on a scale of 0 to 9 according to the Newcastle–Ottawa scale (NOS) to evaluate the methodological quality. A study with a score <6 was considered low-quality, while that with a score ≥ 6 was considered methodologically sound. If conflicting results were observed, the two authors would discuss and reach a consensus.I2 statistic were used to estimate the heterogeneity among studies  was used to analyze the extracted data. We used the ORs and 95% CI to evaluate the association between COX-2 expression and the susceptibility and clinical features of endometrial cancer. Moreover, the HRs and 95% CI were applied to assess the effect of COX-2 expression on the prognosis of endometrial cancer. Cochran's Q test and Higgins  studies , 18, andion bias , 20. In Three hundred and forty-four relevant articles were retrieved from the initial search of PubMed, Web of Science, and EMBASE databases. After the title and abstract screening step, 200 publications were excluded, while 144 were retained. Next, the articles were read, and 175 publications were excluded for unusable data. Eventually, 22 studies involving 273 controls and 1,376 endometrial cancer patients were included in the meta-analysis  21–42).–42.21–42P < 0.05). The association between COX-2 expression and endometrial cancer risk  was assessed in nine studies. Owing to the significant heterogeneity, a subgroup analysis was conducted based on race, which revealed a significant association both in Caucasians and Asians . In addition, a subgroup analysis based on the pathological types revealed that COX-2 expression was associated with tumor stage , tumor grade in Caucasians , and lymph node metastasis in Asians . However, the stratified analysis revealed that COX-2 expression was not related to the outer half myometrial invasion   .P < 0.05. To achieve more accurate results, a subgroup analysis based on race was conducted. Moreover, the results of the sensitivity analysis indicated that the overall ORs and HRs were stable (The results of Begg's test and Egger's test did not provide evidence of publication bias among studies, except in those on tumor stage analysis, in which the Egger's test e stable , 4.Several studies have been conducted over the past few decades to identify novel biomarkers for the early diagnosis and treatment of cancers. A wide variety of molecules, including proteins, metabolites, DNA, RNA, or cellular events, such as epigenetic alternations, could be used as biomarkers. These biomarkers might be used for risk assessment, screening, diagnosis, prognosis, treatment response prediction, and cancer monitoring in clinical practice . Cox-2 oTo determine the stability of overall results and to remove heterogeneity from the study, we conducted a sensitivity analysis. There was significant heterogeneity in the overall analysis of endometrial cancer risk; to eliminate the same, a subgroup analysis based on race was performed and no heterogeneity was observed. Therefore, the results of the subgroup analysis were stable. In addition, a similar observation was made in the analysis of tumor grade of endometrial cancer, and the results of the subgroup analysis were robust. A significant heterogeneity was also observed in the other analysis. We excluded certain studies, such as those by Cai et al.  tumor s tumor g, FerrandI2 test indicated the absence of significant heterogeneity among studies in the survival analysis. Moreover, the results of the Begg' test and Egger's test suggested the absence of significant publication bias. Four studies were included to investigate the association between COX-2 expression and the prognosis of endometrial cancer, in which two studies yielded significant results (Based on results from 22 studies, we concluded that COX-2 overexpression predicted poor prognosis in endometrial cancer patients. The results of the Quantified Q test and  results , 34, and results , 25. TheWe also extracted clinical data from the included studies to explore the correlation between COX-2 expression and the progression of endometrial cancer. COX-2 expression was significantly associated with late-stage endometrial cancer, as well as with lymph node involvement in Asian populations. In previous studies, Ferrandina et al. reported that the frequency of COX-2 overexpression in late FIGO stage patients was higher than that in patients with <50% myometrial invasion , 32. CaoThere were several limitations in this study. First, the cut-off value for COX-2 expression evaluation was inconsistent, and this might have introduced heterogeneity in the results. Second, we could not comprehensively analyze the role of COX-2 in endometrial cancer because the clinical information was considerably limited. Third, there was a limited number of patients with endometrial cancer in the eligible studies, which highlighted the importance of conducting more large-scale studies in future. Fourth, studies with positive results usually had higher chances of getting published than those with negative results, which might introduce a publication bias.In general, our meta-analysis revealed the significant association between COX-2 overexpression and the poor prognosis and development of endometrial cancer. The results indicated that COX-2 overexpression might promote malignancy in endometrial cancer, and also suggested its significant association with increased susceptibility to endometrial cancer. Hence, determining the levels of COX-2 expression would help improve the diagnosis, treatment, and prognosis of endometrial cancer.All datasets generated for this study are included in the article/All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.YW was employed by Cisen Pharmaceutical Co., Ltd. Drug Discovery. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Hypertensive disorder of pregnancy is the second commonest causes of maternal death globally. Different public health studies were conducted on hypertensive disorder of pregnancy which presented inconsistent result. Therefore, this systematic review and meta-analysis was commenced to summarize the findings conducted in several parts of the country and to generate the nationwide representative data on the prevalence and risk factors of hypertensive disorder of pregnancy in Ethiopia.Electronic databases such as PubMed, Scopus, Google Scholar, Hinari, and African Journals Online were searched for studies published in English up to March, 2020. Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument and Newcastle-Ottawa Scale were used for data extraction and quality assessment of the included studies. The meta- regression analysis was computed at 95% CI to present the pooled prevalence and risk factors of hypertensive disorder of pregnancy.Thirty four studies were included in this systematic review and meta-analysis. The pooled prevalence of hypertensive disorder of pregnancy and preeclampsia in Ethiopia were 6.82% ) and 4.74% ) respectively. Maternal age ≥35 years (Adjusted Odds Ratio (AOR): 2.91 ), twin pregnancy ), previous history of preeclampsia ), family history of hypertension ), family history of diabetes mellitus ), body mass index ≥25 ), alcohol consumption ), urinary tract infection ), lack of nutritional counseling during antenatal period ), lack of fruits ), and vegetables consumption ) were the risk factors of hypertensive disorder of pregnancy in Ethiopia.The pooled prevalence of hypertensive disorder of pregnancy is relatively higher compared with the previous reports. Maternal age ≥35 years, twin pregnancy, previous history of preeclampsia, family history of hypertension, family history of diabetes mellitus, body mass index ≥25, alcohol consumption, urinary tract infection, lack of fruits and vegetables during pregnancy were risk factors of hypertensive disorder of pregnancy. The governments and stakeholders should work to strengthen the antenatal care practice to include the possible risk factors of hypertensive disorders of pregnancy. Hypertensive disorders of pregnancy (HDP) include; preeclampsia, gestational hypertension, chronic hypertension, and chronic hypertension with superimposed preeclampsia . HDP affEthiopia is one of the highest estimated number of maternal deaths observed in the world that accounts about 4.8%  of the global share in 2017 . In EthiResearchers identified different risk factors for HDP , 10. FacA systematic review and Meta-analysis of published and unpublished studies were conducted to assess the prevalence and risk factors of HDP in Ethiopia. We searched the following databases: Scopus, PubMed, Hinari, Google Scholar and African Journals Online (AJOL). The search was done by using the following Medical Subject Headings (MeSH) search terms; "Prevalence", "Risk Factors", "Hypertension", "Pregnancy", "Pregnancy induced hypertension", "Pre-Eclampsia" AND "Ethiopia" through using string term "AND" and "OR". A combination of MeSH terms and free terms were used for the searching strategy to conduct this systematic review and meta-analysis . All pubInclusion and exclusion criteria;Studies with cross-sectional, case-control and cohort designs were included.Articles that report prevalence or risk factors of HDP in Ethiopia were included.Published and unpublished articles written in English were includedStudies reporting HDP as an outcome variable were included.Studies conducted in the community or in the health institution levels were included.Conference papers, editorial notes and systematic reviews and meta-analyses were excluded from the study.All citations identified by our search strategy were exported to EndNote -X9- and duplicate articles were removed. And then the titles and abstracts of the identified articles were screened by two independent reviewers, and eligible studies were included for further review. The full texts of selected articles were retrieved and read thoroughly to ascertain the suitability prior to data extraction. In case of disagreement between the two reviewers, discussion has been held to reach consensus and the third reviewer was consulted. The search process was presented in PRISMA flow chart that clearly shows the studies that were included and excluded with sound reasons of exclusion  17]..17].The primary outcome of this study was the prevalence of HDP. HDP includes; preeclampsia, gestational hypertension, chronic hypertension, chronic hypertension with superimposed preeclampsia and eclampsia.Hypertension: Systolic blood pressure ≥140mmHg and/or diastolic ≥90mmHg that is measured at least two times within four hours interval.Proteinuria: urinary protein excretion of ≥300mg /24-h urine sample or ≥1+ on qualitative dipstick examination or a total protein: creatinine ratio ≥30 mg/ mmol (or ≥0.3 when both are measured in mg/dL).Gestational hypertension: hypertension diagnosed after 20 weeks of gestation.Preeclampsia: gestational hypertension plus proteinuria.Chronic hypertension: hypertension occurs before pregnancy or diagnosed before 20 weeks of gestation for the first time.Chronic hypertension with superimposed preeclampsia: Occurrence of proteinuria in women with chronic hypertension before 20 weeks of gestation.Eclampsia: Seizures in women with hypertension that cannot be attributed to other causes .The secondary outcomes of the current review were risk factors of HDP in Ethiopia .For case-control and cohort studies, we used Newcastle-Ottawa Scale (NOS) to assess the quality of the included studies while for cross sectional studies the modified version of NOS was used to assess the quality of the studies for inclusion . The NOSThe data extraction was done using a tool developed by the 2014 Joanna Briggs Institute Reviewers’ Manual data extraction form [The data were entered into Microsoft Excel and the meta-analysis was conducted using Stata 14 software. Forest plots were used to show the prevalence and risk factors of HDP in Ethiopia at 95% CI. Subgroup analysis was done by the region  and year of study . Risk factors like; advanced maternal age, twin pregnancy, primigravidity, previous history of preeclampsia, family history of hypertension, family history of DM, BMI ≥25, alcohol consumption, UTI, eating of fruits and vegetables were assessed for their association with HDP at 95% CI.2 statistic and P-value. If I2 statistic value < 25%, 25–50%, and ≥50% was used to declare the heterogeneity test as low, medium and high heterogeneity. In this review, random effect model was used for analysis. To cope with the reasons of heterogeneity subgroup analysis and sensitivity test were performed .In this review a total of 34 studies were included. Twenty of them were cross-sectional, thirteen studies were case-control and one study was cohort. Published and unpublished studies done in Ethiopia up- to March, 2020 were included. Most regions of Ethiopia were represented in this systematic review and meta- analysis. Eleven studies were conducted in Amhara region, eight studies from Addis Ababa city, five studies from Oromia region, four studies were from Tigray region, four studies were from South Nations and Nationalities Peoples’ region (SNNPR), one study from Somali region and one was a nation based study. In the included studies the smallest sample size was 129  and the A wider difference in the prevalence of HDP was observed in the studies included in this systematic review and meta-analysis. A lower prevalence (1.2%) of HDP was reported in the nation based study  and the The subgroup analysis of HDP prevalence by region showed the highest pooled prevalence 9.88% ) at 95% CI in Amhara region followed by 9.29%  at 95% CI SNNPR region. The lowest prevalence 4.02%  at 95% CI of HDP was observed in Tigray region. The subgroup analysis of HDP by the year of study had shown the highest pooled prevalence 7.82  at 95% CI in the studies conducted from 2016 to 2020. This indicates that the current trend of HDP has increased compared with the studies conducted from 2006 to 2015 .In this systematic review and meta- analysis different risk factors like; age, gravidity, previous history of preeclampsia, twin pregnancy, family history of hypertension, family history of DM, BMI, alcohol consumption, urinary tract infection, obtaining nutritional counseling during antenatal care (ANC) period, fruits and vegetables consumption were evaluated for their association with hypertensive disorders of pregnancy.In this sub-categorical analysis, thirteen studies were included for the assessment of age as a risk factor for HDP , 48, 50.In this sub-categorical analysis, twelve studies were included for the assessment gravidity as a risk factor for HDP , 45–49. In this sub-categorical analysis, eleven studies were included for the assessment of twin pregnancy as a risk factor for HDP , 47, 49.In this sub-categorical analysis, fourteen studies were included for the assessment of previous history of preeclampsia as a risk factor for HDP , 45–48. In this sub-categorical analysis, fifteen studies were included for the assessment of family history of hypertension (HTN) as a risk factor for HDP –47, 49. In this sub-categorical analysis, eleven studies were included for the assessment of family history of diabetes mellitus as a risk factor for HDP –47, 49. 2, alcohol consumption and presence of UTI during pregnancy increased the risk of HDP with the odds of 3.92 , 1.77  and 4.57  times, respectively compared with the women whose BMI< 25, and women having no history of alcohol consumption and UTI during pregnancy , 3.49  and 2.94  time, respectively. Similarly, BMI of ≥25kg/mThe results of this systematic review and meta-analysis were heterogeneous. To understand the cause of heterogeneity publication bias was assessed. The funnel plot figure shows the presence of possible publication bias . This biThis review was conducted to determine the pooled prevalence and risk factors of hypertensive disorders of pregnancy in Ethiopia. In this meta- analysis the pooled prevalence of all forms of HDP and preeclampsia were 6.82% ) and 4.74% ) respectively. This is slightly higher to the previous meta- analysis report done by Berhe and his colleagues which was 6.07%  . This reIn this review, different risk factors were assessed with their association to HDP in Ethiopia. Age is an important predictor for HDP and assessed for its association with HDP by classifying maternal age ≥35 and maternal age <35 years. Maternal age of ≥35 years is almost three times more likely to develop HDP compared with the maternal age <35 years and the association were statistically significant. Similar findings were reported in the studies conducted in Kenya, Asian, China, Latin American and Caribbean women among older maternal age group with HDP compared with maternal age <35 years , 52–54.The frequency of gravidity as a risk factor for HDP was assessed in this systematic review and meta-analysis. The odds of developing HDP in primigravida were 1.27 times compared with multigravida pregnant women. There was not statistical significant difference in the occurrence of HDP between primigravida and multigravida pregnant women in Ethiopia, although studies conducted in Kenya, China and Latin America had shown than women in primigravida were 2.1, 1.5 and 2.38 times more likely of developing HDP compared to multigravida pregnant women, respectively , 53, 54.In this meta-analysis, twin pregnancy increased the risk of developing HDP three times more compared to singleton pregnancy and the association was statistically significant. This is similar with the studies conducted in China multiple pregnancy where they have shown a 3.68-fold higher risk of HDP compared with singleton pregnancy . SimilarPrevious history of preeclampsia is an important risk factor for HDP. In this meta-analysis, women having previous history of preeclampsia were shown to develop HDP and the likelihood of its occurrence could be increased by five times as compared with HDP in those women having no previous history of preeclampsia and the association was statistically significant. Supporting evidence of our current finding was reported in the study conducted in China . SimilarObesity is one of an important predictor for HDP or preeclampsia. In the current meta- analysis, women having BMI ≥25 had 3.9 times more risk of developing HDP compared with the women having BMI< 25 and the association was statistically significant. Supporting evidence has been found in the systematic review and meta- analysis conducted by Wang and his colleagues . The exaIn this review, women obtained nutritional counseling during antenatal period, women consuming fruits and vegetables had lower risk of developing HDP compared with their counter- parts and the association is statistically significant. Similar report was observed in the prospective cohort study done by Timmermans and his colleagues . ExperimDrinking of alcohol during the second and third trimesters of pregnancy increases the risk of preterm birth and results in different adverse consequences on the fetal development . In the This systematic review and meta-analysis showed the national pooled image on the risk factors of hypertensive disorders of pregnancy in Ethiopia. In addition, it produced an updated data on the prevalence of hypertensive disorders of pregnancy in Ethiopia via including more articles from the previously published reviews.The search strategy may miss unpublished articles; publication bias likely high. In addition, high statistical heterogeneity was observed in this review because the inclusion of articles with different methodology and different outcome of interest for the assessment of risk factors of HDP. The included studies lack consistency to include more articles for a particular variable of risk factor that leads to small study effect. These together reduce the quality of the generated evidence.The pooled prevalence of hypertensive disorders of pregnancy was found to relatively higher than what was reported previously in Ethiopia. In the subgroup analysis, the highest prevalence was observed in Amhara region and in the studies conducted between 2016 to 2020. Maternal age ≥35 years, twin pregnancy, previous history of preeclampsia, family history of hypertension, family history of diabetes mellitus, body mass index ≥25, alcohol consumption and urinary tract infection during pregnancy were significantly increased the risk of developing hypertensive disorders of pregnancy. Conversely, pregnant women obtaining nutritional counseling during antenatal period, fruit and vegetable consumption during pregnancy significantly reduce the risk of developing hypertensive disorders of pregnancy. During patient diagnosis and management clinicians will conduct detail patient evaluation to identify the risk factors of hypertensive disorders of pregnancy and to develop better treatment protocol. The governments and stakeholders should work to broaden and strengthen the antenatal care practice by involving all possible risk factors of hypertensive disorders of pregnancy in the ANC follow up guidelines. Additionally, large-scale prospective cohort studies should be needed to identify risk factors of hypertensive disorders of pregnancy in Ethiopia.S1 Checklist(DOC)Click here for additional data file.S1 File(XLSX)Click here for additional data file.S2 File(XLSX)Click here for additional data file.S3 File(DOCX)Click here for additional data file.S4 File(DOCX)Click here for additional data file.S5 File(DOCX)Click here for additional data file.S6 File(DOCX)Click here for additional data file.


XRCC1, rs25487 (Arg399Gln) and rs1799782 (Arg194Trp), have been widely studied for the association with clinical outcomes of platinum-based chemotherapy in Asian patients with non-small-cell lung cancer (NSCLC), but the results remain inconclusive. Thus, we performed the present meta-analysis.  Platinum-based chemotherapy plays an antitumor role by damaging DNA. X-ray repair crosscomplementing protein 1 (XRCC1) participates in DNA repair and thus affects the sensitivity to platinum drugs. Two polymorphisms of XRCC1 polymorphisms and clinical outcomes. Comparisons were performed in homozygous, heterozygous, dominant, and recessive models.  Literature search was performed in PubMed, Web of Science, and EMBASE up to June 2019. Odds ratios (ORs) for objective response ratio (ORR), Cox proportional hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS), and the corresponding 95% confidence intervals (95% CIs) were calculated to assess the association strengths between p = .007, I2 = 56.8%) and GlnArg  were associated with higher ORR. Meanwhile, GlnGln indicated a favorable OS  and PFS . We also found positive associations between rs1799782 and ORR in all comparison models with low between-study heterogeneity. The association strength increased with the number of variant alleles , suggesting a gene dosage effect. In addition, TrpTrp predicted a longer OS.  Finally, a total of 23 studies involving 5567 patients were included in the meta-analysis. Compared to ArgArg of rs25487, GlnGln (OR = 1.71, 95% CI: 1.16-2.52, XRCC1 are potential markers to predict clinical outcomes of platinum-based chemotherapy in Asian patients with NSCLC. Our results showed that rs25487 and rs1799782 of  Lung cancer is the most prevalence malignant tumor and the leading cause of cancer deaths worldwide. It accounts for about 13% of newly diagnosed cancers and is responsible for 17.6% of cancer-related deaths each yearPlatinum-based chemotherapy has been the standard treatment of advanced NSCLC for decades,Platinum drugs, including cisplatin and carboplatin, exert the antitumor effect by binding to DNA, forming DNA adducts that lead to intrastrand or interstrand crosslink and finally inducing severe dislocation of DNA double helix8,There are four mainly different DNA repair mechanisms: nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), and double-strain break repair (DSB)11XRCC1, rs25487 (Arg399Gln) and rs1799782 (Arg194Trp), that are believed to change the DNA repair activity and affect the sensitivity of tumor cells to platinum drugs15–18–XRCC1 and clinical outcomes of NSCLC treated with platinum-based chemotherapy in Asian populations.There are two polymorphisms of XRCC1” or “rs25487” or “rs1799782”) AND (“platinum” or “cisplatin” or “carboplatin”) AND (“lung cancer” or “NSCLC”) prior to June 2019. Studies investigating the association between XRCC1 polymorphisms and chemotherapy efficacy of NSCLC were retrieved. The language was restricted to English. Additional articles from the reference lists of reviews and retrieved articles were manually searched to avoid missing eligible studies.This meta-analysis was in accordance with the PRISMA checklist. We performed literature search on electronic databases including PubMed, Web of Science, and EMBASE using the following keywords and their combinations: ; all patients received platinum-based chemotherapy (2); all patients were Asians (3); genotype data of rs25487 or rs1799782 were provided (4); and objective response rate (ORR), overall survival (OS), or progression-free survival (PFS) was reported as the outcomes of efficacy assessment, and adequate data were given for the present meat-analysis (5). Studies involving small-cell lung cancer (SCLC) patients or duplicated with other studies or performed in animals or cell lines were excluded. Reviews and case reports were discarded.The following information for each eligible study was extracted: first author, year of publication, country, tumor stage, chemotherapy regimens, genotyping method, sample size , age of participants, genotype distribution, and clinical outcomes. Literature search, filtering, and data extraction were performed by two independent researchers (NZ and YO), and any discrepancy was solved by further discussion with a third researcher.http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp). NOS contains 8 items from 3 domains  and has a total of 9 stars. Studies with 6 or more stars were considered of high quality.We assessed the quality of all eligible studies by using the Newcastle-Ottawa Scale XRCC1 polymorphisms and ORR of NSCLC receiving platinum-based chemotherapy. Hazard ratio (HR) with corresponding 95% CI was calculated to assess the association strength of polymorphisms with OS or PFS. I2 test and Q test were performed for the assessment of between-study heterogeneity. If no obvious heterogeneity existed , a fixed-effect model was applied; otherwise, a random-effect model was used. Meta-regression regarding year of publication, sample size, median age of participants, percent of male, smoking rate, percent of stage IV patients and histological types, and sensitivity analysis were performed to identify the potential source of heterogeneity. Publication bias was assessed by funnel plots and Egger's test. All of the above analyses were performed in the following genetic models of rs25487 or rs1799782: homozygous model (homozygous variant vs. wildtype), heterozygous model (heterozygous variant vs. wildtype), dominant model (homozygous+heterozygous variant vs. wildtype), and recessive model (homozygous variant vs. heterozygous variant+wildtype). STATA v11.0  was used for meta-analysis, and a p value<.05 was considered statistically significant.Odds ratio (OR) and its 95% confidence interval (95% CI) were calculated to assess the strength of association between –22,24–29,A total of 121 potentially relevant articles were retrieved from literature search, and finally, 23 studies18I2 = 56.8%, p = .003, I2 = 29.0%, p = .037, I2 = 54.2%).Twenty-one studies involving 4708 NSCLC patients were included in the association analysis between rs25487 (Arg399Gln) and ORR, of which 17, 17, 20, and 18 were for homozygous, heterozygous, dominant, and recessive models, respectively. There was high between-study heterogeneity in most of the comparisons . Comparep = .009, I2 = 63.2%, p = .010, I2 = 24.4%). However, no significant associations were found in the other comparisons  and ORR of platinum-based chemotherapy, were included. Low or no heterogeneity was found, and fixed-effect model was used. After meta-analysis of all comparisons, Trp194 was found to be significantly associated with higher ORR . Comparip = .013, I2 = 53.4%, p = .173, I2 = 0). Only a few studies reported the association of rs1799782 with PFS, and none of the genotypes indicated a favorable PFS in pooling analysis (p > .05).Compared to ArpArp, TrpTrp carriers had a favorable OS  and year of publication in the recessive model , with ORR increasing with age and time (p > .05).For 25487, meta-regression analysis revealed an influence of age of participants in the heterozygous model , except in the heterozygous model of 1799782 with ORR.The funnel plots in most of the meta-analyses were symmetric, and Egger's test indicated no evidence of publication bias  and rs1799782 (Arg194Trp), are both located in the exons and modify the DNA repair activity. The Arg399Gln polymorphism occurs in the PARP-binding domain and may affect complex assembly or repair efficiency. The 399Gln allele was associated with elevated levels of aflatoxin B1-DNA adducts and glycophorin A somatic mutationsβ domain and PARP domain and was reported to disrupt the functionality of XRCC1 in hamsters27,29,15,17,p < .01). Meanwhile, the homozygous variant had longer overall survival and progression-free survival . However, obvious heterogeneity was found in most of the comparisons, and thus the results should be interpreted in caution. For rs1799782, significant correlations with ORR were identified in homozygous, heterozygous, dominant, and recessive models , suggesting a gene dosage effect of positive association. Additionally, the homozygous 194Trp was associated with a favorable OS .The present meta-analysis pooled all studies performed in Asian populations to further assessing the associations of both polymorphisms with platinum-based chemotherapy efficacy. For rs25487, carrying one or two 399Gln alleles had better ORR compared with the homozygous wildtype  by pooling 3 studies and with a decreased ORR in the dominant model  by pooling 5 studies. However, there seems a contradictory role of rs25487 in clinical outcomes between different ethnicities since it predicted longer OS and increased ORR in Asians. This may be caused by various factors, such as genetic background, sample size, and dietary or living habits. This discrepancy needs further confirmation by including more investigations with larger sample size in Caucasians. Since only a few studies in Caucasians were available, we gave up the subanalysis of Caucasians in the present study. Compared with previous meta-analyses50–The present study mainly focused on the Asian populations. Several studies have reported controversial associations with ORR, OS, or PFS in the Caucasians15XRCC1 may have prognostic value of NSCLC patients under platinum-based chemotherapy, but they are still far away from clinical practice, since many genes in other pathways, apart from the BER pathway, also contribute to the sensitivity to platinum drugs ERCC147,ERCC2ERCC5XRCC3TP53MDM2AKT1SMAD3β pathway, and MTHFROur results revealed that two functional polymorphisms of There are several limitations in our mate-analysis. First, an ideal meta-analysis should be based on individual-level data, especially in the analysis of OS and PFS, although it is usually quite difficult to obtain these data. The interpretation of our results in terms of OS and PFS should be cautious. Secondly, we did not analyze the interaction of both polymorphisms in predicting the clinical outcomes because of a lack of sufficient data. Thirdly, there were substantial between-study heterogeneities in the pooling analysis of rs25487, and thus more studies are needed in the future.XRCC1, rs25487 and rs1799782, can be used as prognostic factors for platinum-based chemotherapy in Asian patients with NSCLC.In conclusion, our meta-analysis suggested that two functional polymorphisms of


While the weight of epidemiological evidence does not support a causal link with influenza vaccination evaluated over the last 30 years, Guillain–Barré syndrome (GBS) has been considered a vaccine-associated adverse event of interest since 1976. To investigate the existence of GBS risk after vaccination against seasonal influenza, a systematic review and meta-analysis have been conducted based on 22 eligible epidemiological studies from 1981 to 2019 reporting 26 effect sizes (ESs) in different influenza seasons. The primary result of our meta-analysis pointed to no risk of vaccine-associated GBS, as documented by a pooled ES of 1.15 (95% CI: 0.97–1.35). Conversely, an obvious high risk of GBS was observed in patients with previous influenza-like illness (ILI), as demonstrated by a pooled ES of 9.6 (95% CI: 4.0–23.0) resulting from a supplementary analysis. While the meta-analysis did not confirm the putative risk of vaccine-associated GBS suggested by many epidemiological studies, vaccination against seasonal influenza reduced the risk of developing ILI-associated GBS by about 88%. However, to obtain strong evidence, more epidemiological studies are warranted to establish a possible coincidence between vaccination and ILI prior to GBS onset. Guillain–Barré syndrome (GBS) is a rare but serious cause of acute neuromuscular paralysis, resulting in muscle weakness and a loss of reflexes in about two cases per 100,000 people per year . The synThe initiative of rapid vaccination of the USA population against swine influenza in 1976 entailed an unexpected increase in GBS risk in adults, alerting researchers to a dangerous vaccine association with GBS ,9,10. SiTherefore, we conducted a meta-analysis in which all epidemiological studies available from our computerized search were entered to develop a risk estimate of influenza vaccine-associated GBS. We only focused on GBS occurrence after immunization against seasonal influenza carried out every year using a common inactivated trivalent vaccine, in order to exclude the effect of the extraordinary use of a monovalent pandemic influenza vaccine with or without adjuvants. We aimed to evaluate the effect size (ES) not affected by potential confounders resulting from the new pandemic strain of influenza A subtype H1N1, rapid manufacture and distribution of a pandemic influenza vaccine, etc.This systematic review was based on the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta- analyses (PRISMA) Statement , using tEligible studies had to meet the following selection criteria: (1) observational studies with controls such as case-control (C-C) and cohort (C) studies, including their modifications, i.e., self-controlled case-series (SCCS) or self-controlled risk interval (SCRI), as well as case cross-over (CCo) and case-centered (Cc) studies; (2) exposure to vaccination against seasonal influenza; (3) control group without vaccination; and (4) outcome of interest measured using the ES of vaccination on GBS occurrence, including the 95% confidence interval .Data were independently extracted by two reviewers from eligible publications using a predefined format. If consensus was not achieved, the discrepancy was resolved by discussions among all authors. Extracted data contained the authors’ names; year of publication; study period or influenza season; country; participants, interventions, comparisons, outcomes, and study design (PICOS); time window ; ES used; and GBS risk estimate with 95% CI, factors of adjustment, or assessment.The primary result of the pooled ES was obtained from the general population, irrespective of sex and age, where only study outcomes of the longest time windows were taken into account.The studies’ quality was assessed according to the Newcastle–Ottawa Scale (NOS) in three domains: selection of participants, comparability of vaccinated and unvaccinated participants, and outcome of interest . The totStudy-reported relative risks, incidence rate ratios, or odds ratios with or without adjustment were used for a pooled quantitative analysis, i.e., for pooled ESs. The risk of developing GBS associated with vaccination against seasonal influenza was estimated from the pooled ES with a 95% confidence interval CI pursuant to a random-effect model , because the heterogeneity of studies’ outcomes did not allow us to employ a fixed-effect model .2 < 75% [Furthermore, the results of primary analysis were tested against the strength of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system  with the2 < 75% ; (4) no 2 < 75% . MoreoveStatistical analyses were performed using STATA version 15.1 . A total of 421 publications were identified , of whicThe development of GBS was documented using the International Classification of Diseases, Ninth Revision, code 357.0 (n = 10) or confirmed according to the Brighton Collaboration definition of levels 1–3 and/or possibly 4 (n = 9). In two studies, GBS was diagnosed by neurologists of the Committee of the National Institute of Neurologic and Communicative Disorders and Stroke or using inclusion criteria similar to the Brighton Collaboration definition. One study failed to specify GBS ascertainment at all.A total of 17 studies evaluated the risk of GBS after immunization with an inactivated trivalent vaccine against seasonal influenza (iTIV). Two studies failed to provide a specification of the influenza vaccine, but use of the inactivated vaccine was highly likely in the studies’ geographic region (China). Although the live influenza vaccine has been used in the USA since 2003, only a negligible number of participants were immunized with it, as reported by three studies.The association between vaccination and GBS risk was investigated in six case-control studies and in five cohort, self-controlled case-series and self-controlled risk interval studies each, plus one case-centered study. A total of 11 studies were based on a time window. Twelve studies were performed in North America (10 in the USA and two in Canada) and five in Europe . The others were conducted in Asia (China and Taiwan) or Australia. The investigated association was most often observed during influenza seasons in the 2009-11 period (six studies). A total of 15 studies assessed this risk within 42 days (6 weeks) of vaccination. Eleven studies were designed with longer time windows. Only two studies ,34 evaluA total of 16 studies focused on GBS risk estimates in the general population, independent of age. An age-specific association was evaluated in 10 studies, but the non-uniform age distribution across them did not make it possible to quantitatively assess the pooled ES for age-specific groups, except for people ≥ 65 years of age investigated in four studies.To prevent a high risk of bias, the primary analysis was conducted on a set of high-quality studies, i.e., 18 of them met an NOS score ≥ 7 stars. Another three had a score of 6, while one achieved a score of 5 see .2 = 40.5%) and imprecision (SE = 0.08) were not serious. The pooled risk estimate of developing GBS obtained from our primary analysis did not show any significant increase after immunization against seasonal influenza, i.e., ES = 1.15 (95% CI: 0.97–1.35) see . The pooThe absence of an increased risk of developing GBS after iTIV immunization was also confirmed by a set of all studies, independent of their quality, i.e., ES = 1.15 (95% CI: 0.99–1.35), so the pooled GBS risk estimate could be considered robust. Additional tests did not find any effect of small studies, asymmetry of entries, or the absence of unpublished studies. However, the risk of publication bias did exist, since there were different associations determined by ESs of both fixed- and random-effect models that could eventually influence the pooled outcome. The mere presence of a bias risk did not permit us to achieve the required strength of evidence. The impact of specific conditions on the outcome of interest was tested using sensitive meta-analyses of subsets of studies with different time windows, age-specific groups, methodologies, and geographic regions or influenza seasons. The pooled outcomes were obtained from at least three studies and are displayed in Our sensitivity analysis tested the impact of shorter  and longer  post-vaccination time windows on the GBS risk estimate. The pooled outcomes for shorter and longer time windows did not demonstrate any association between GBS occurrence and iTIV vaccination, i.e., ES = 1.19 (95% CI: 0.99–1.44) and ES = 1.08 (95% CI: 0.77–1.52), respectively.The risk estimate in age-specific groups was only limited to a population over 65 years of age, where no increased risk of developing GBS was found, as documented by the ES value of 1.11 (95% CI: 0.88–1.39).p = 0.003.Except for cohort studies, all the methodologies used provided consistent outcomes showing no vaccine-associated GBS. The pooled outcome obtained from cohort studies only suggested an increase in GBS risk, i.e., ES = 1.56 (95% CI: 1.16–2.09), p = 0.026.While the pooled outcome of studies conducted in Europe confirmed no post-vaccination GBS risk, the pooled outcome of North American studies did exhibit an increased risk, i.e., ES = 1.24 (95% CI: 1.02–1.50), p = 0.032. Conversely, this association was not observed in the following season (2010–2011), i.e., ES = 1.35 (95% CI: 0.88–2.07), p = 0.179.The analysed results of studies focused on the influenza season of 2009–2010 , which provided an ES proving an association between GBS and vaccination, i.e., ES = 1.43 (95% CI: 1.03–1.97), The pooled risk estimates of post-vaccination GBS obtained from sensitivity analyses could not be generalized because all of them were burdened by an unacceptable imprecision (SE ≥ 0.10). In addition, the sample size of subsets was usually insufficient (n < 10). 2 = 90.5%).A total of five studies also investigated the possibility of an association between Guillain–Barré syndrome onset within 30 to 180 days of influenza-like illness (ILI) or upper respiratory infection. The pooled ES from these studies—ES = 9.6 (95% CI: 4.0–23.0)—showed a highly increased risk of GBS . The samiTIV/ESILI = 0.12 (95% CI: 0.05–0.29). Compared to ILI, vaccination against seasonal influenza decreased the risk of GBS onset by about 88% (95% CI: 71–95%).The GBS risk was significantly lower in patients with previous immunization than in those with previous ILI, as confirmed by the ES ratio, i.e., ESThis meta-analysis did not reveal an increased risk of developing GBS any time after vaccination against seasonal influenza, but a secondary outcome pointed to an undisputable risk of GBS in patients with previous ILI. In spite of the incomplete strength of evidence, the pooled ES of 1.15 (95% CI: 0.97–1.35) was clearly very similar to the results of another meta-analysis published in 2015, i.e., a marginally vaccine-associated GBS risk of 1.22 (95% CI: 1.01–1.48) .Unlike a previous meta-analysis, ours included an additional four studies and evaluated a total of 26 study-entered ESs. A more accurate outcome was achieved using the following strategy: (1) bias risk was limited by a rigorous assessment of the study quality; (2) effect sizes of interest were derived from high-quality studies only; and (3) estimation of standard errors ensured an original association of published studies.The outcomes of sensitivity analyses confirmed GBS risk, independent of the short- or long-time post-vaccination interval. Even if some studies documented, in time windows of ≤42 days ,38 or ≤4It is not likely that the risk estimate of GBS is influenced by age-specific populations. Similarly, an increased risk was not documented by the pooled ES in people over 65 years, as well as by study-determined ESs in children and adolescents under 18 years ,38 or peThe pooled risk estimate in subgroups in various types of studies, except for cohort ones, did not reveal any association between GBS and vaccination. Although the ES reported by cohort studies did not demonstrate any causality, the pooled ES showed a potential vaccine-associated GBS onset. At the same time, this type of methodology did not seem to be more sensitive than the others. The explanation for this may lie in the insufficient number of required entries, intensified by the estimation approach of quantitative analyses.The causality found in the 2009–2010 season resulting from the pooled outcome could be explained in the same way, because no vaccine-associated GBS for that season was documented in several studies ,18,36,39While the studies conducted in European countries did not find any risk, a somewhat higher risk of developing GBS was documented by the pooled ES in North American studies. Two Canadian studies ,38 with Our review of publications has identified other factors that have an impact on the increased risk of GBS. A total of five studies showed a strong association of GBS with influenza, ILI, or upper respiratory infections, commonly referred to as influenza-like illness under the umbrella term ,16,37,38Furthermore, some studies have reported ILI in vaccinated patients within the GBS risk interval ,38. It iAdmittedly, not all published references were identified in this systematic review and meta-analysis, albeit no additional references being retrieved from the reference lists in the articles emerging from the literature search, which we accept as a limitation of our study.The outcome of the present study points to no increase in the risk of GBS onset in patients who have previously received an inactivated trivalent vaccine against seasonal influenza, irrespective of the post-vaccination time. While the weight of epidemiological evidence does not support a causal link, the absence of a vaccine-associated GBS risk resulting from this analysis must be considered with caution because the strength of evidence has not been achieved. The benefit of influenza vaccination was shown by the 88% decrease in Guillain–Barré syndrome occurrence compared to patients with previous ILI.Therefore, it would be desirable to conduct other studies where the coincidence of vaccination and respiratory infection diseases is separated. This could help to better investigate the real vaccine-related impact on Guillain–Barré syndrome and to dispel any potential doubts about vaccination against seasonal influenza.


P for nonlinearity = 0.11). As for salted fish intake, the pooled risk of gastric cancer incidence was 1.17  times higher, comparing the highest to the lowest intake. Our findings supported the evidence that high intake of pickled vegetable and salted fish is associated with elevated risk of gastric cancer incidence.An increased risk of gastric cancer for pickled vegetable and salted fish intake has been suggested, yet the lack of a dose-response association warrants a quantitative analysis. We conducted a meta-analysis, combining results from our analysis of two large Korean cohort studies and those from previous prospective cohort studies. We investigated the association of pickled vegetable and salted fish intake with gastric cancer in the Korean Genome Epidemiology Study and the Korean Multi-center Cancer Cohort Study using Cox proportional hazard models. We then searched for observational studies published until November 2019 and conducted both dose-response and categorical meta-analyses. The pooled relative risk (RR) of gastric cancer incidence was 1.15 , 1.07–1.23) for 40 g/day increment in pickled vegetable intake in a dose-response manner ( Helicobacter pylori (H. pylori) infection contributing to the carcinogenesis ; P for heterogeneity = 0.14). The test for non-linearity using restricted cubic splines presented a linear association (p for non-linearity = 0.11). We additionally examined the risk for overall gastric cancer  and found an increased overall gastric cancer risk for a 40 g/day increment . Decrease in heterogeneity was observed in a sensitivity analysis, where we excluded the KoGES, which reported gastric cancer mortality as outcome .From a dose-response meta-analysis, we observed an increased risk of gastric cancer incidence for a 40 g/day increment in pickled vegetable intake . The heterogeneity was reduced when we excluded one study with a deviating risk estimate  ; P for heterogeneity = 0.26). When we further examined the association for the overall gastric cancer risk, the pooled RR was 1.10, but the association was not significant .From the categorical meta-analysis, we found a marginally significant increase in the risk of gastric cancer incidence, comparing the highest to the lowest intake of salted fish (P for heterogeneity = 0.50). The result was similar for the analysis of overall gastric cancer risk .There were not enough studies to conduct a dose-response meta-analysis of the gastric cancer incidence risk per 60 g/day increment in the salted fish intake. Only two studies were available, and the association was not significant. (P for heterogeneity = 0.002). No significant heterogeneity was observed by sex, outcome, publication year, and follow-up time . Therefore, we did not observe any publication bias (The Egger’s funnel plot asymmetry test failed to detect any small studies effect among the prospective cohort studies included in the meta-analyses (all ion bias .In this systematic meta-analysis of prospective cohort studies, we found a significant association between increased gastric cancer incidence risk and high intake of pickled vegetables. The pooled risk of gastric cancer incidence was 1.15 times higher for a 40 g/day increment in pickled vegetable intake and 1.24 times higher, comparing the highest to the lowest intake. The result from our dose-response meta-analysis further strengthens previous meta-analyses, which showed an increased risk of gastric cancer, comparing the highest to the lowest intake of pickled vegetables and salted fish ,13. We aN-nitro compounds, known as chemical gastric carcinogens [H. pylori infection. Cell proliferation induced by a high-salt diet facilitates H. pylori colonization, which sequentially promotes gastric inflammation, hypochlorhydria, Th1 and Th17 inflammation, and carcinogenesis [H. pylori infection [H. pylori infection [Several mechanisms have been postulated in epidemiological studies regarding the association examined in our study. Pickled vegetables and salted fish are exogenous sources of sodium nitrates and nitrites, which react with amino acids in the stomach and form cinogens . Epithelcinogens ,50,51. Pcinogens ,53. Exceogenesis ,54,55. Infection ,56, a renfection .kimchi, a major Korean pickled vegetable dish prepared by salting and fermenting Napa cabbage. Although we adjusted for fresh vegetable intake in the sensitivity analysis, it is possible that high cabbage intake accompanied by high kimchi intake might have a mixed effect. Furthermore, salted fish intake in the Korean cohort studies might not have been sufficient enough to show a significant association with increased gastric cancer risk. The median values of each quantile of salted fish intake were smaller compared to those presented from a Japanese cohort study which showed a significant association [Our findings from the two Korean cohort studies showed no associations for pickled vegetable and salted fish intake in relation to gastric cancer risk. Such incongruence may be attributable to skewed distribution of intake among the study participants. The intake amount of pickled vegetables for the reference group in the two Korean cohort studies corresponded to that of the intermediate or highest intake group in the other studies included in the meta-analysis ,46,47. AThe major strength of our study is that, to our knowledge, we were the first to examine the risk of gastric cancer mortality among the two large-scale Korean prospective cohort studies and further conduct a meta-analysis with literature studies. In our study, we excluded participants who died within three years from the baseline, thereby reducing the possibility of any subclinical disease influencing the diet at baseline. We also conducted both dose-response and categorical meta-analyses, thereby compensating for the possible loss of power due to solely conducting a categorical meta-analysis. Comparing the RR of the highest to the lowest intake category might neglect information regarding the intermediate intake of dietary exposure and reduce the power of association . In addiH. pylori infection, a class I carcinogen of gastric cancer, affected the association of gastric cancer and the intake of pickled vegetables and salted fish due to insufficient information provided from the participants in both cohorts.Our study has several limitations. First, the inability to conduct a periodic evaluation of the dietary intake might not adequately reflect possible changes in diet over time . Second,Our meta-analysis results provided evidence that a high intake of pickled vegetables and salted fish is significantly associated with increased gastric cancer risk. Although further prospective cohort studies are warranted, reduction in pickled vegetable and salted fish may be an appropriate public health intervention aimed at reducing the risk of gastric cancer.