Periprosthetic joint infection (PJI) is the most serious complication of joint replacement surgery. Further comorbidities include bedsore, deep vein thrombosis, reinfection, or even death. An increasing number of researchers are focusing on this challenging complication. The aim of the present study was to estimate global PJI research based on bibliometrics from meta-analysis studies.A database search was performed in PubMed, Scopus, and Web of Science. Relevant studies were assessed using the bibliometric analysis.A total of 117 articles were included. The most relevant literature on PJI was found on Scopus. China made the highest contributions to global research, followed by the USA and the UK. The institution with the most contributions was the University of Bristol. The journal with the highest number of publications was The Journal of Arthroplasty, whereas the Journal of Clinical Medicine had the shortest acceptance time. Furthermore, the top three frequently used databases were Embase, MEDLINE, and Cochrane. The most frequent number of authors in meta-analysis studies was four. Most studies focused on the periprosthetic hip and knee. The alpha-defensin diagnostic test, preventive measures on antibiotics use, and risk factors of intra-articular steroid injections were the most popular topic in recent years.Based on the results of the present study, we found that there was no single database that covered all relevant articles; the optimal method for bibliometric analysis is a combination of databases. The most popular research topics on PJI focused on alpha-defensin, antibiotic use, risk factors of intra-articular steroid injections, and the location of prosthetic hip and knee infection. Periprosthetic joint infection (PJI) is a serious and challenging complication after joint replacement. Due to the lack of consensus on the management of PJI, physicians often face uncertainty. However, errors in diagnosis and treatment result in increased healthcare costs, reinfection, or mortality . PublicaThe choice of database and the search strategy used are a crucial step in bibliometric studies and meta-analysis. Due to differences in exporting information between different databases, most bibliometric studies use a single database for statistics and data analysis , 10. SucWe systematically searched PubMed, Scopus, and Web of Science from inception to December 2019. The search algorithm used was the following medical subject headings (MeSH) or keywords: “arthroplasty”, “joint prosthesis”, “joint replacement”, “periprosthetic joint”, “prosthetic joint”, “infection”, “infectious”, “infected”, “meta analysis”, and “meta-analysis”. As this study was performed using global research, there were no language restrictions.Data were extracted independently by two reviewers (LC and COT). Discrepancies were adjudicated by the third author (XC). Information on all eligible publications including the title, author, year of publication, country, institution, journal, keywords, citations, state of the manuscript, language, number of studies, impact factor, software, database, search algorithm, and subject information were collected. The number of citations was based on the final result, in the case that no single database covered all citation information. Subsequently, citations were collected from Google scholar. Finally, two authors (LC and COT) manually screened and analyzed the publication information in Microsoft Excel  and EndNote X7 .Results from the search strategy demonstrated that the database with the most publications was Scopus (570), followed by Web of Science 341), and PubMed 243). The greatest number of identical articles was through the combined database of Web of Science and Scopus , followed by eight (9) as well as six and eleven studies (8 each).Among the 117 meta-analysis articles, the earliest publications were from 2007. The greatest number of articles were published in 2018 24), followed by 2017 and 2019 (21 each). The trend line indicates an annual increase in the number of articles . The Rothman Institute and General Hospital of the Chinese People’s Liberation Army were third, with each publishing five research articles. Fourteen institutions published more than one paper, with 50% originating from China Table .Table 2The number of authors of a single article ranged from 2 to 37. The largest number of collaborating authors was four (27), followed by six (25) and 5 authors , followed by the Journal of Hospital Infection (82 days), Journal of Clinical Microbiology (83 days), and Journal of Arthroplasty (86 days).The average number of days from acceptance to publication was 56.52 (66 papers). From receipt to online publication, the average number of days was 157.48 (69). There were six articles accepted in less than 30 days after submission. The journal with the shortest acceptance time was the Journal of Clinical Medicine (16 days), followed by the Journal of Computational and Theoretical Nanoscience (18 days), Journal of Clinical Medicine (22 days), Journal of Arthroplasty (23 days), Journal of Orthopaedic Surgery and Research as well as Medical Science Monitor (27 days each).From Google Scholar, citation information was available for 103 meta-analyses. Forty-one articles were cited more than 20 times, with the highest number in 2014 (9), followed by 2013, 2016, and 2017 (7 each). The most cited article was published by AlBuhairan et al.  (264), fOne hundred and two meta-analyses were retrieved from the search strategy, which were exported to Microsoft Excel. All keywords or MeSH were combined. PJI-related keywords were 196, followed by diagnosis (179), prevention 82), risk factor (74), and outcome (60). All keywords are presented in Supplementary 2, risk fAfter combining all databases from 116 articles, there were a total of 52 databases. Embase was the most described database (101), followed by MEDLINE (80), and Cochrane , followed by REVMAN (25), and Meta-Disc (21).Information on the site of prosthetic joint infection from the included meta-analysis were found in 112 papers. The location with the highest number was the knee (93), closely pursued by the hip (90), shoulder (23), elbow (16), and ankle (3).From 40 diagnosis-related meta-analyses, 72 tests were related to preoperative examination, followed by intraoperative methods (12), and test prior to reimplantation (14). Synovial fluid alpha-defensin had highest pooled sensitivities in the list of preoperative examinations, pursued by serum IL-6 and bone scintigraphy. From all intraoperative examinations, tissue polymerase chain reaction (PCR) was the most sensitive method, followed by sonicate fluid into blood culture bottles (BCB) and PCR. Tissue culture was the most sensitive method before reimplantation, followed by the percentage of polymorphonucleocytes in synovial fluid (PMN%), and synovial fluid culture Table . The mosTwenty-three articles described 64 possible risk factors. The location of the risk factor was outlined in 20 studies, with the majority in the hip and knee Table . Nine prThere were 26 comparative analytic studies from all meta-analyses, with most related to the hip and knee (11), followed by the hip as well as the hip and knee (7 each). There was no statistical difference found in 13 comparison studies , with the greatest number of relevant papers in Scopus. Furthermore, we compared all databases with or without a search strategy, with PubMed demonstrating the greatest difference among the three databases. When combined with other databases, the missing information from the search strategy could be supplemented. All results could not be found with any of the databases, with or without a search strategy, whereas the combination of PubMed and Scopus enclosed all results without a search strategy. In addition, all available information from the database and search algorithm were collected and combined. Three to five database groups were found to comprise most options for meta-analysis. Embase, MEDLINE, and Cochrane were the top three most commonly used databases and were also mostly used for meta-analysis. The available search algorithm exported from 102 publications provided a reference for scholars for a further literature search and study design.Meta-analysis could offer a useful effective reference to support or refute controversial conclusions from multiple studies. The bibliometric analysis showed that the first meta-analysis appeared in 2007, with an increasing trend in the ensuing years. The growth number likely reflects the development of the subject with an academic dispute, and the International Consensus Meeting on PJI also indicated the presence of disparate opinions on the management of PJI . The curIn all meta-analysis papers, the Journal of Arthroplasty had the most number of relevant papers. With more than 20 citations, PLoS ONE had the greatest number of publications from the most cited publication list. The Journal of Clinical Medicine had the minimum time from receipt to acceptance. In addition, the bibliometric method report showed most articles to be received and accepted on Wednesday.In the top 10 most popular keywords on PJI meta-analysis, two keywords were related to treatment and diagnosis, with two-stage exchange and alpha-defensin in the top 10. Three keywords were associated with the location of PJI, with the majority on the hip and knee. Identical results were also found in regard to the location, with the top three keywords knee, hip, and shoulder. The most frequently used software in the meta-analysis were STATA, REVMAN, and Meta-Disc.Among the diagnosis list in meta-analysis studies, the synovial fluid test was the most frequently used preoperative examination (64%). The most popular diagnostic test applied in recent years was synovial fluid alpha-defensin and has been incorporated in the 2018 Musculoskeletal Infection Society (MSIS) definition as one of the minor criteria . When coSonicate fluid and periprosthetic tissue were performed most intraoperatively, whereas tissue PCR and sonicate fluid BCB were the most sensitive tests in tissue and sonicate fluid, respectively. In 2013, Qu et al.  performeDiagnosis prior to reimplantation always posed difficulty. In the meta-analysis study by Lee and colleagues , tissue There were 40 meta-analyses related to risk factor and prevention, with the majority of articles on preventive measures focusing on systemic or location antibiotics use. In regard to the risk factor, most concerns focused on intra-articular steroid injections, followed by age, diabetes mellitus, and rheumatoid arthritis.The top three comparison studies focused on cemented vs. cementless total joint arthroplasty, the outcome of using different types of spacers, and the outcome of one-stage vs. two-stage exchange. Cemented fixations were revealed to increase the overall PJI risk in comparison to uncemented fixations –68. InteThere are several limitations to the present study. First, the database of present bibliometric analyses was collected from three databases. Compared with results from without the search strategy, several articles were missed when using the search strategy, especially in PubMed. However, working with multiple databases could reduce this problem. In addition, we also collected database information from all meta-analyses. Embase, MEDLINE, and Cochrane were the most widely used databases. However, whether these databases were appropriate for bibliometric analysis remains unclear and requires further investigation. Second, due to the export of all meta-analysis information between different databases with disparate formats, a visualized analysis could not be performed. Third, although meta-analysis results on diagnosis, risk factors, prevention, and comparative studies were shown, the heterogeneity and quality of included meta-analysis studies were not considered. In the subgroup diagnosis, since there is no gold standard for the diagnosis of PJI, different culture results are obtained from the various diagnostics tests. The pooled sensitivity and specificity of meta-analysis are then further affected by potential false positive or negative results. Fourth, the current study only presented meta-analysis results and did not reflect the complete perspective of PJI research. The overall trends in this field are required to further confirm.The bibliometric analysis that presented global PJI research of meta-analysis studies showed an increasing trend between 2007 and 2019. The Embase database and STATA software were most frequently used for meta-analysis. Most studies focused on the periprosthetic hip and knee. The diagnostic alpha-defensin test, preventive measures on antibiotics use, and risk factors associated with intra-articular steroid injections were the most popular topics in recent years.Additional file 1:. Supplementary S1.


The consumption of sweet beverages, including sugar-sweetened beverages (SSB), artificial-sweetened beverages (ASB) and fruit juices (FJ), is associated with the risk of different cardiometabolic diseases. It may also be linked to the development of certain types of tumors. We carried out a systematic review and meta-analysis of observational studies aimed at examining the association between sweet beverage intake and cancer risk. Suitable articles published up to June 2020 were sourced through PubMed, Web of Science and SCOPUS databases. Overall, 64 studies were identified, of which 27 were selected for the meta-analysis. This was performed by analyzing the multivariable-adjusted OR, RR or HR of the highest sweet beverage intake categories compared to the lowest one. Random effects showed significant positive association between SSB intake and breast  and prostate cancer risk  and also between FJs and prostate cancer risk . Although the statistically significant threshold was not reached, there tended to be positive associations for the following: SSBs and colorectal and pancreatic cancer risk; FJs and breast, colorectal and pancreatic cancer risk; and ASBs and pancreatic cancer risk. This study recommends limiting sweet beverage consumption. Furthermore, we propose to establish a homogeneous classification of beverages and investigate them separately, to better understand their role in carcinogenesis. The consumption of sweet beverages has increased in the last decades, with sugar-sweetened beverages (SSB) and artificially sweetened beverages (ASB) among the most widely consumed ,2. SSBs It has been demonstrated that obesity and type 2 diabetes are well-known risk factors for cancer ,8,9. DieHigh sugar intake impairs glucose and insulin tolerance and augments insulin and insulin-like growth factor (IGF) levels. Insulin and IGF are major determinants of proliferation and apoptosis, and may therefore influence carcinogenesis . BeveragIn light of all this evidence, the association between consumption of sweet beverages and cancer risk has been investigated and reviewed by different studies. A meta-analysis from 2014 studied the association between SSB/ASB consumption and overall and specific cancer but no links were found . LikewisEvidence suggests that the link between sweet beverages consumption and cancer onset is biologically plausible. However, each type of beverage may have different mechanisms of action and different roles in cancer onset. Therefore, our study aimed to investigate these associations, by conducting separate analyses for SSB, ASB and FJ intake and cancer incidence. We analyzed case-control and cohort studies and performed a meta-analysis when feasible. Through this study we intend to update and develop a better understanding of the association between the consumption of sweet beverages and cancer incidence, a disease that caused 9.6 million deaths in 2018, a figure projected to nearly double by 2040 .This study was conducted according to the Preferred Reporting Items for Systematic Reviews Meta-Analysis (PRISMA) guidelines. To identify the suitable articles, we searched in PubMed, Web of Science and SCOPUS databases up to 31 June 2020, using the following keywords: (((((“soft drinks”[All Fields] OR “sugary drinks”[All Fields]) OR “sugary beverages”[All Fields]) OR “fruit juice”[All Fields]) OR “sugar-sweetened beverages”[MeSH Terms]) OR “artificially sweetened beverages”[MeSH Terms]) AND ((((“neoplasms”[MeSH Terms] OR “neoplasm”[All Fields]) OR “cancer”[All Fields]) OR “cancers”[All Fields]) OR “tumor”[All Fields]). We also applied search filters by article type  and by species (including only humans). Moreover, reference lists of included manuscripts and relevant reviews were examined for any possible unidentified study. The search process was limited to English and Spanish languages.Eligible cohort and case-control studies were selected if they met the following criteria: (1) included adult participants free of cancer (if prospective) or with no history of previous cancer (if case-control) at recruitment, except for nonmelanoma skin cancer; (2) overall or site-specific cancer incidence as an outcome; and (3) estimated and reported hazard ratio (HR), risk ratio (RR) or odds ratio (OR) with 95% confidence interval (CI) for the link between any type of sweet beverages and any type of cancer incidence. The exclusion criteria were: (1) participants with previous cancer history or currently undergoing cancer treatment; (2) cancer survival and cancer mortality as an outcome; and (3) duplicated studies. The following data were extracted: first author’s name, publication year, study name, country, age and sex of the participants, study sample size, number of cases and controls, follow-up duration, cancer site, type of exposure and amount of intake, dietary assessment methods, confounders’ adjustment and HR/RR/OR with 95% CI for the larger degree of adjustment. When time-varying results were reported, those related to baseline data were extracted.Three review authors independently performed the literature search, study selection and data extraction . Disagreements were discussed between all authors until a consensus was reached.Two independent review authors (FL and MG-L) examined the methodological quality of the individual studies using the Risk Of Bias In Non-randomized Studies—of Exposures (ROBINS-E)  tool forThe first obstacle that we had to overcome was the lack of a unique definition for beverages and a variety of other terms. In this text, the following group terms are used to generalize these products: SSB for sugar-sweetened beverages , ASB for artificially sweetened beverages  and FJ for fruit juices. In addition, two other terms are used: SB for sweetened beverages that includes both SSBs and ASBs; SFJ for high-sugar  beverages that includes both SSBs and FJs. The quantity of each beverage was provided mostly as categories of frequency of consumption, either in amount (mL or g/day) or serving sizes . To unify the data, we converted the categories to mL/day, based on the study-specific serving size for each beverage. When the serving size was not reported, we referred the national data of each study. Thus, we considered one can equal to 330 mL and one glass equal to 200 mL for European countries , one can2 and Tau2 statistics to measure between-study heterogeneity. The statistical analysis was performed with the Metafor package [P values < 0.05 were considered statistically significant.Prior to the analysis, the selected studies were classified by outcome (cancer incidence by site) and exposure . Data were summarized in a narrative manner and a meta-analysis was performed only if at least three studies reported data for the same exposure and outcome. In the meta-analysis, results for the total number of participants were considered. Separate analyses were considered  when the article did not report indices for total population. In the same manner, if studies reported data for specific beverages , results for the total beverage group  were weighted up. Despite having extracted data on fruit and vegetables juices together, for the meta-analysis we considered the studies that indicated FJs as the predominant beverage consumed. The meta-analysis was performed by pooling the multivariable-adjusted RR/HR/OR of the highest category of the exposure versus the lowest one, and random effects models were assumed. If statistical outliers were identified, secondary analyses were performed (without outliers) to remove possible sources of heterogeneity. An outlier was considered when its 95% CI lied outside the 95% CI of the pooled effect. To further explain heterogeneity, we performed subgroup and sensitive analyses, dividing studies according to design (cohort/case-control), country , level of overall risk of bias (serious/low-moderate) and beverage intake category (high vs. non-consumer/high vs. low). We used Cochran’s Q, I package  of the RThe study selection process according to PRISMA guidelines is reported in Of the included studies, 29 were performed in the United States (US), 17 in Europe, 6 in Asia, 5 in Canada, 3 in Australia, 2 in Latin-America, 1 in Egypt and 1 was multinational . They usually included both male and female participants. Ages ranged from 18 to 97 years. The 27 cohort studies were published between 2003 and 2020 and enrolled 4,458,056 participants in total, of which 30,646 developed cancer. Mean duration of the follow-up in cohort studies varied from 2 to 20 years. The 37 case-control studies were published between 1985 and 2019. In total, they enrolled 20,827 cancer cases and 34,315 controls. Most of the controls were selected from the general population.Sweet beverage consumption in both cohort and case-control studies was expressed as categorical or continuous variables. Exposure assessment was collected using food frequency questionnaires (FFQ), 24-h dietary recalls (24-H DR), dietary questionnaires (DQ), interviews, or surveys. Among all the studies, 37 types of cancer were considered as an outcome and 4 cohorts reported data for overall cancer risk, including different types of cancer ,50,52,54Nine publications reported data on breast cancer, four case-control ,58,69,80Three cohort publications ,53,55 anA meta-analysis of four cohort studies ,53,54,55Eight publications reported data on colorectal cancer, four case control ,89,90,91Three publications, one cohort  and two One case-control  and two 2 = 58.6, p = 0.02) and ASBs   , after p = 0.13) . No asso2 = 83.4%, p = 0.0001). Although heterogeneity was reduced after excluding outliers and doing subgroup analyses, the associations were positive but non-significant , no outliers were found, and the number of studies was too low to perform subgroup analyses (n = 3). One case control study [Four publications, two case control ,70 and tol study ,54. No sol study  finding ol study  reportedTwo case-control studies ,72 invesTwo cohort studies ,49 reporOne cohort study  reportedFour studies ,82,83,84Single studies reported data on different types of cancer and their link with sweet beverages. No significant associations were reported for cutaneous melanoma , glioma An Australian cohort  investigAccording to the ROBINS-E tool , 13 of 2According to the NOS  most of The aim of this study was to assess the relationships between different groups of sweet beverages and site-specific or overall cancer risk. We conducted a meta-analysis when at least three studies reported data for the same exposure (sweet beverage type) and outcome (cancer site). We found several statistically significant and borderline positive associations between the consumption of SBs, especially SSBs, and in some cases ASBs or FJs, and several cancer risks.Regarding breast cancer, the meta-analysis showed a positive association using random effects, with a 14% higher risk for SSBs, but non-statistically significant results for pre- and post-menopausal breast cancer. However, after performing subgroup analyses by study type, cohort studies showed significant positive results for pre-menopausal breast cancer and SSBs. Chazelas et al.  reportedFor colorectal cancer risk, our meta-analysis found no positive results using random effects for SB, SSB or FJ intake. Despite having performed secondary analyses excluding outliers and having explained between-studies heterogeneity, results for the random-effect model remained non-significant. This is in a way consistent with results from a previous meta-analysis, which found no association between SSBs and colon cancer risk using a random-effects model . On the In regard to esophageal cancers, publications included in this review were also part of a meta-analysis from 2014 . This meWith respect to pancreatic cancer, we performed a meta-analysis for SBs, SSBs and ASBs. These associations, especially for SBs, tended to be positive but did not reach statistically significant levels using random effect models. These results go along with a recent meta-analysis from 2019  found a For bladder cancer risk, 3 out of the 6 included case-control studies ,63,65 shWith reference to prostate cancer, our meta-analysis demonstrated an 18% higher risk for SSBs comparing the highest with the lowest intake. Similarly, we found a small positive association for FJs (a 3% higher risk). No associations were found for SBs, which may suggest that the role of ASBs might not be relevant. However, one study  reported2= 65.4%). However, not enough studies (n = 3) were included to perform subgroup analyses. Even so, Maclure and Willet [Renal cell cancer appeared to be unrelated to SB consumption according to the meta-analysis results. We observed a high between-study heterogeneity  . They reIn respect of hepatobiliary cancers, data from the included studies showed a positive association with SB consumption, especially for gallbladder cancer, where the risk was doubled . This miAs regards hematologic cancers, no associations were found either for sugary or for artificially sweetened beverages, except for leukemia risk, for which one study  reportedThe evidence is more limited regarding cancer of the oral cavity, pharynx, larynx, lung, thyroid, glioma and cutaneous myeloma. The available data mainly showed nonsignificant results for SB and FJ intake. Only one study from Montenegro indicated an inverse association between SB intake and laryngeal cancer risk . HoweverTo the best of our knowledge, this is the first systematic review to evaluate the isolated association between different groups of sweet beverages and cancer risk. Several limitations should be considered while interpreting our findings. Some studies included in this systematic review were difficult to compare due to their design (cohort and case-control studies), methodology, classification and categories of beverages intake. Therefore, it was a challenge to perform such comparisons. According to the ROBIN-E tool, cohort studies were at low-moderate risk of bias. As per the NOS, the case-control studies were at moderate risk of bias and 6 studies ,79,82,86The majority of the included participants were from the US or European countries. Hence, extrapolating our findings to other geographical areas may not be appropriate. We attempted to classify beverages into specific groups. However, some studies did not report precise information on this topic, which might have given rise to misclassifications. Similarly, we attempted to convert original exposure information into amounts of intake (mL/day) based on national data. Nevertheless, this was not possible in all studies which prohibited performance of a dose–response meta-analysis. Another limitation may be the measurement error in collecting dietary data since self-reported questionnaires were used. Moreover, in the longitudinal studies we were limited to the baseline estimation of beverages consumption, and there is a possibility that their consumption changed over time. It is suggested that the link between SSBs or FJs and cancer risk is possible due to their high glycemic indexes  and to oThe current meta-analysis of cohort and case-control studies indicated a statistically significant positive association between higher consumption of SSB and breast and prostate cancer incidence. As regard pre-menopausal breast cancer, results from cohort studies alone showed a significant association. Likewise, it showed a statistically significant positive link between high intakes of FJs and prostate cancer risk. Although the associations between other sweet beverages and other cancer types were also positive, they did not reach statistically significant levels. The small number of studies and cancer cases might have been a reason why we did not find statistically significant results for several cancer types. Study location  did not appear to influence the results. Current evidence indicates that higher incidence of some cancers is related to a high consumption of SSBs. However, the evidence is limited to make recommendations regarding ASBs and FJs. This subject requires further investigation.We encourage future research in this field to perform more separated analysis on SSB, ASB and FJ consumption. We believe it would be prudent to establish a homogeneous classification of beverages in order to better understand their role in carcinogenesis. We also recommend considering other obesity-related factors besides body mass index, such as waist circumference, glycemic index and quality of diet as confounders. We could not study the different roles of non-carbonated soft drinks , sometimes used as healthier alternatives to carbonated drinks . TherefoThis systematic review supports the WCRF/AICR recommendations to limit sugary drinks consumption for cancer prevention  and to r


Coronary artery diseases (CAD) are clinical cardiovascular events associated with dyslipidemia in common. The interaction between environmental and genetic factors can be responsible for CAD. The present paper aimed to examine the association between c.56C > G (rs3135506) APOA5 gene polymorphism and CAD in Moroccan individuals and to perform an association update meta-analysis. R statistical language. In addition, a comprehensive meta-analysis including eleven published studies in addition to our case-control study results was conducted using Review Manager 5.3. Publication bias was examined by Egger's test and funnel plot.  The c.56C > G variant was genotyped in 122 patients with CAD and 134 unrelated controls. Genetic association analysis and comparison of biochemical parameters were performed using P-value = 0.001), recessive  and log-additive  inheritance models. In addition, this polymorphism was significantly associated with increased levels of systolic and diastolic blood pressures, triglycerides, glycemia, and total cholesterol. Furthermore, meta-analysis showed a significant association between the c.56C > G gene polymorphism and increased risk of CAD under recessive  and homozygote codominant  models.  The case-control study data showed that the c.56C > G polymorphism was associated with CAD susceptibility under codominant ( Our case-control study revealed a significant association between c.56C > G polymorphism and CAD in the Moroccan population. In addition, meta-analysis data supported the implication of this polymorphism in CAD susceptibility. Coronary artery disease (CAD) is the most common cardiovascular disease. It is caused by ischemia and hypoxia  due to tIn order to evaluate the associations between APOA5 gene c.56C > G polymorphism and CAD, we performed a case-control study in a Moroccan population. In addition, we conducted a meta-analysis to confirm the contribution of this APOA5 polymorphism to CAD in various ethnic populations.Study participants were recruited in the Medical Biology Center of Pasteur Institute of Morocco and Ibn Rochd Hospital. The present study involved 122 patients  with coronary artery disease confirmed by coronary angiography, defined as the presence of at least one coronary artery with ≥50% organic stenosis. The study recruited also 134 unrelated non-CAD controls . All subjects were Moroccan adult volunteers and all provided their written informed consents. Participants completed a health and lifestyle questionnaire including sociodemographic characteristics, medical history, physical activity, medication intake, and alcohol and tobacco use. Clinical, biochemical, anthropometric parameters, and CAD risk factors (hypertension and diabetes mellitus) were assessed in both patients and controls. Hypertension was defined as systolic blood pressure >140 mmHg or/and diastolic blood pressure >90 mmHg or using antihypertensive drugs. Type 2 diabetes mellitus was diagnosed according to World Health Organization criteria. All women were nonpregnant and nonlactating. Healthy subjects had normal biochemical variables, were nonsmoking, and without history of CAD.Blood samples were collected in EDTA tubes after at least 12 hours of overnight fast, centrifuged, and stored until subsequent laboratory analysis. Fasting plasma glucose, total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C) levels were determined using the VITROS automate analyzer (5.1 FS Chemistry System). Low-density lipoprotein cholesterol (LDL-C) level was calculated according to the Friedewald formula.K digestion followed by phenol-chloroform extraction and ethanol precipitation. The c.56C > G polymorphism was genotyped by PCR-RFLP analysis. PCR reactions were performed in a Biometra thermal cycler, using Taq polymerase (Bioline), and restriction fragments were analyzed by agarose gel migration (3%). Primers, PCR conditions, and RFLP analysis were performed according to a previously published protocol [Genomic DNA was isolated from peripheral leukocytes using the standard proteinase protocol .PCR of 157 bp fragment of the 56C > G polymorphism was performed using the following oligonucleotides: Forward: 5′- GGC TCT TCT TTC AGG TGG GTCTCCG -3′ and reverse: 5′- GCC TTT CCG TGC CTG GGT GGT -3′. The PCR started with an initial denaturing at 96°C for 5 min, followed by 30 cycles of 96°C for 30 s, 64°C for 30 s, and 72°C for 45 s and then a final extension of 72°C for 10 min. The PCR products were digested for 2 hours at 65°C with TaqI restriction enzyme: the 56C allele presents a TaqI restriction site which is suppressed in the 56G allele . All molWe conducted a comprehensive literature search using PubMed. Articles published up to January 2020 were searched using the following key words:  AND (“APOA5” OR “apolipoprotein A5” OR “C56G” OR “S19W” OR “rs3135506”) AND (“polymorphism” OR “SNP” OR “variant”). References cited in the identified articles were also analyzed to avoid missing any potential articles from the initial search. Data from studies were included in our meta-analysis only if the study met the following criteria: (1) only CAD as the outcome and the investigated variant should be c.56C > G exclusively or in the same study with other polymorphisms; (2) only the case-control studies were considered; (3) the genotype distribution of CAD cases and controls can be obtained from articles directly or by calculation; (4) the methods of data collection and analysis should be statistically acceptable; and (5) publications that presented data allowing such outcome to be derived were also included.t-test was applied for comparison of quantitative traits that follow a normal distribution. Otherwise, we used the Mann–Whitney test. The Hardy–Weinberg equilibrium (HWE) analysis of the genotyped SNP was performed using an exact test, available in the R package “compareGroups.” The R package “SNPassoc” was used to examine the association between CAD and APOA5 genotypes. A P value less than 0.05 was considered statistically significant.Clinical and biochemical parameters normally distributed were expressed as means ± standard deviation (SD), and nonnormally distributed data were expressed as median (Interquartile range) while qualitative parameters were expressed as frequencies. Student's Q-test, and the significance was fixed to P < 0.10. The inconsistency index I [P values of Egger's test.Furthermore, Review Manager 5.3 (The Cochrane Collaboration) was used to elaborate meta-analysis results. Heterogeneity between studies was assessed using the chi-square-based  index I  was alsoP values <0.001). There were also significant differences in total cholesterol (TC) and diastolic blood pressure (DBP). No significant differences were found in body mass index (BMI) and HDL-C between both groups.Clinical characteristics and lipid parameters of patients with CAD and controls are presented in P value >0.05). Logistic regression analysis adjusted for sex, age, BMI, and smoking showed a significant association between the c.56C > G polymorphism and CAD susceptibility under co-dominant, recessive, and log-additive models.We performed a case-control-based association analysis of the c.56C > G polymorphism with CAD . The genWe compared biological and clinical traits between APOA5 genotypes under homozygote and heterozygote codominant, dominant, and recessive genetic models. The APOA5 c.56C > G polymorphism was significantly associated with increased levels of systolic and diastolic blood pressure, triglycerides, glycemia, and total cholesterol .The literature search identified 109 potentially relevant articles, the publication date of these studies ranged from 2004 to 2018, forty-six of which were excluded after initial screening of title and abstract. The full text of remaining 67 studies was reviewed, and 56 additional articles were excluded because they did not meet the inclusion criteria. Finally, 11 studies were included in our meta-analysis in addition to our case-control study, with a total of 5705 CAD patients and 7242 controls. A flow chart of study selection is shown in P value <0.001). Moreover, using the homozygote codominant model, the GG genotype was significantly associated with susceptibility to CAD compared to the CC genotype . A random-effect model was used to estimate pooled odds ratios if considerable heterogeneity was detected (Q-statistic: P < 0.10 or I2 > 50%). Otherwise, a fixed-effect model was used (Q-statistic: P > 0.10 and I2 < 50%). No significant publication bias was shown using both funnel plot analyses and Egger's test in all tested genetic models.Meta-analysis of the 12 genetic association studies and publication bias analyses are summarized in Coronary artery disease (CAD) is a multifactorial disease in which atherosclerotic plaque accumulates inside the coronary arteries resulting in myocardial infarction and mortality. Hypertriglyceridemia is significantly associated with the increased risk of CAD, as elevated levels of triglycerides (TG) may lead to plaque formation –41. The Logistic regression analysis adjusted for possibly confounding factors  showed a significant association between c.56C > G APOA5 variant and coronary artery disease. Various studies were performed in different populations in order to assess the association between this variant and CAD, but the results are conflicting. Consistent with our findings, the c.56C > G SNP was significantly associated with increased risk of CAD in a previous study on Chinese patients . SimilarCurrently, the biological mechanisms by which the c.56C > G (S19W) missense polymorphism regulates the plasma triglyceride levels are not sufficiently well elucidated and need further research. Talmud et al. suggested that the c.56C > G variant may have functional effects on the APOA5 protein . The subIn the present study, the c.56C > G variant showed significant association with plasma triglyceride levels. We observed elevated triglyceride levels in subjects carrying the GG genotype compared to noncarriers. Similarly, TG levels were also significantly higher in Turkish subjects carrying the GG genotype . The rarIn contrast, we did not find any relationship between HDL-C levels in subjects carrying the G allele compared to noncarriers, which is consistent with findings reported by other studies , 33, 36.The association between the c.56C > G polymorphism and susceptibility to CAD remains controversial. To elucidate this discrepancy, we performed a meta-analysis considering the data from all studies exploring the association between this APAO5 variant and increased risk of CAD in various ethnicities.Several studies were interested in gathering data on APOA5 polymorphisms implication in CAD susceptibility , 46–50. Our work may have some limitations. Firstly, CAD is a multifactorial and polygenic disorder involving complex genes and environmental interactions that were not evaluated. Secondly, articles in other languages than English were not included in this meta-analysis. That may result in a bias, although funnel plots and Egger's test showed no significant bias. Lastly, we performed a comprehensive literature research to collect all eligible studies; however, the number of included studies was not large. Thus, further genetic association studies are needed to evaluate the relationship between this APOA5 variant and CAD risk in different populations.In summary, the current case-control study showed that the 56C > G polymorphism is a CAD risk factor in the Moroccan population. In addition, our results clarify that the overall conclusion of the literature to data indicates a significant association between 56C > G polymorphism and CAD in different populations, supporting our case-control study results. An improved case-control investigation with larger sample sizes and a balanced gender structure could provide sufficient statistical power to obtain a clear conclusion on the contribution of the 56C > G APOA5 polymorphism in CAD susceptibility.


Previous studies have described sex-based differences in the epidemiological and clinical patterns of non-alcoholic fatty liver disease (NAFLD); however, we understand relatively little regarding the underlying molecular mechanisms. Herein, we present the first systematic review and meta-analysis of NAFLD transcriptomic studies to identify sex-based differences in the molecular mechanisms involved during the steatosis (NAFL) and steatohepatitis (NASH) stages of the disease.Transcriptomic studies in the Gene Expression Omnibus database were systematically reviewed following the PRISMA statement guidelines. For each study, NAFL and NASH in premenopausal women and men were compared using a dual strategy: gene-set analysis and pathway activity analysis. Finally, the functional results of all studies were integrated into a meta-analysis.We reviewed a total of 114 abstracts and analyzed seven studies that included 323 eligible patients. The meta-analyses identified significantly altered molecular mechanisms between premenopausal women and men, including the overrepresentation of genes associated with DNA regulation, vinculin binding, interleukin-2 responses, negative regulation of neuronal death, and the transport of ions and cations in premenopausal women. In men, we discovered the overrepresentation of genes associated with the negative regulation of interleukin-6 and the establishment of planar polarity involved in neural tube closure.Our meta-analysis of transcriptomic data provides a powerful approach to identify sex-based differences in NAFLD. We detected differences in relevant biological functions and molecular terms between premenopausal women and men. Differences in immune responsiveness between men and premenopausal women with NAFLD suggest that women possess a more immune tolerant milieu, while men display an impaired liver regenerative response.The online version contains supplementary material available at 10.1186/s13293-021-00368-1. Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver disorders—ranging from fat accumulation in hepatocytes (NAFL) to non-alcoholic steatohepatitis (NASH)—which can lead to the development of cirrhosis or liver cancer. While steatosis characterizes NAFL, NASH exhibits the additional histological features of inflammation, ballooning, and fibrosis. Awareness of NAFLD has recently increased due to its worldwide impact on health; indeed, NAFLD now represents the most common liver disease in developed countries . While tOf note, there exists significant interindividual heterogeneity regarding NAFLD progression, which has a considerable impact on the clinical consequences to the individual. Patients in the initial stage of the disease (NAFL) display a low risk of adverse outcomes ; howeverInterestingly, NAFLD has a higher prevalence in men and postmenopausal women than premenopausal women . Indeed,In this context, we carried out the first (to the best of our knowledge) systematic review and meta-analysis of transcriptomic studies in NAFLD. We selected studies that had deposited data in the Gene Expression Omnibus (GEO) datasets database  to guaraA review was conducted in June 2020 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines . The GEOThe following exclusion criteria were applied: (i) studies conducted in organisms other than humans, (ii) studies without information regarding the sex of participants or that did not include both sexes, (iii) studies without individuals from the NAFL and NASH stages of the disease, and (iv) studies in which the disease had not been diagnosed with a biopsy. In the latter case, the requirement for NAFL and NASH diagnoses by biopsy was added as less invasive methods  cannot accurately detect mild steatosis or differentiate NAFL from NASH . This stThe same three-step transcriptomic analysis strategy was applied to each separate study: (i) data acquisition and preprocessing, (ii) differential gene expression and functional enrichment analysis, and (iii) differential pathway activation and functional analysis. The functional results of all studies were integrated using meta-analytical techniques Fig. . BioinfoDuring data preprocessing, the nomenclature of the distinct disease stages  and the association of the probe identifiers with their corresponding genes were standardized. In those studies containing treated and untreated patients, treated patients were eliminated from further analysis. For studies that used microarrays, probe codes were transformed to their respective Entrez identifiers from the NCBI database. For repeated probes, the median of their expression values was calculated. When available, data normalized by the original authors of the studies were used. Otherwise (studies GSE61260 and GSE66676), raw data were normalized using the Robust Multichip Average (RMA) algorithm . The genWomen were separated into premenopausal and postmenopausal groups to meet the objective of this work. As selected studies failed to include this specific information, women aged under 50 years were assumed as premenopausal based on studies indicating an average age of menopause at around 48–52 years , 16.After data normalization, the detection of possible anomalous effects within the studies was carried out by completing an exploratory clustering and a principal component analysis (PCA).limma and edgeR packages [p values adjusted using the Benjamini & Hochberg (BH) method [Differential expression analyses of selected studies were carried out using the packages , 18 to d) method .p value and the sign of the contrast statistic. Next, GSA was performed using the logistic regression model implemented in the mdgsa R package [Based on the differential gene expression results, functional enrichment analysis was then performed using gene set analysis (GSA) . First,  package  along wi package  and Kyot package  databasemdgsa package were propagated to inherit the annotations of the ancestor terms. Excessively specific or generic annotations  were subsequently filtered out. Finally, functions with a BH-adjusted p value under 0.05 were considered significant.Due to their hierarchical structure, the gene annotations with GO terms applied in the For the two functional elements (GO terms and KEGG paths), the number of overrepresented elements shared by the studies were analyzed. These results were graphically represented as UpSet plots  to demonhipathia algorithm [hipathia R package was used to analyze 1654 GO terms and 142 UniProt functions [hipathia and the differential activation results were integrated using the GSA method to identify differences at the functional level (GO terms and UniProt functions) in relation to NAFLD stages.The lgorithm  was usedunctions  associatunctions . The actOnce the gene functional analysis was applied to each study, a functional meta-analysis was carried out to summarize the results. Similarly, once the pathway functional analysis was applied to each study, the results were summarized via a homologous functional meta-analysis.metafor R package [Both meta-analyses were performed following the methodology described in detail by García-García . Briefly package  was used package . Incorpop values (adjusted using the BH method), LORs, and 95% confidence intervals (CIs) were calculated. A term was considered significant when its adjusted p value was lower than 0.05; a positive LOR in significant functions indicated a greater overrepresentation in premenopausal women than in men. In contrast, a negative LOR indicated higher representation in men than in premenopausal women. Finally, funnel plots and forest plots were used to assess the variability and measure each study’s contribution to the meta-analysis.For each meta-analysis and function, A total of 8223 elements were analyzed in the gene functional meta-analysis (7994 GO terms and 229 KEGG pathways); 1654 GO terms and 142 UniProt functions  were asshttps://bioinfo.cipf.es/metafun-NAFLD. Access allows any user to analyze the results shown in this manuscript and review other results that may be of interest. The front-end was developed using the Bootstrap library. All graphics used in this tool were implemented with Plot.ly except for the exploratory analysis cluster plot, which was generated with the ggplot2 package.The large volume of data and results generated in this study is freely available through the metafun-NAFLD platform: Gene Expression Omnibus database with accession numbers GSE48452, GSE61260, GSE66676, GSE83452, GSE89632, GSE126848, and GSE130970 were analyzed.In this study, transcriptomic data from the n = 55), in vitro studies (n = 15), lack of information regarding sex or inclusion of only one sex (n = 24), no patients in NAFL and NASH disease stages (n = 12), and diagnosis not based on histology (n = 1). The strict nature of these inclusion and exclusion criteria allowed the selection of comparable studies to ensure the reliability of the subsequent analytical strategies.As shown in the PRISMA flow diagram Fig. , our sysThe seven selected studies –36 incluAs previously indicated, we only used data from non-treated individuals in study GSE83452. Table The functional analysis of individual genes highlighted significant results overrepresented in both the groups of premenopausal women and men  throughout all individual studies, i.e., the LOR and its confidence interval. This effect indicated the magnitude of the overexpression of each term  and its direction (the LOR sign). This sign also helped to identify the group in which the element is overrepresented. In our analysis, positive signs indicate overrepresentation in premenopausal women and negative signs as overrepresentation in men.p value (FDR) that indicates the significance of the results. As a result of our meta-analysis, we identified thirteen significant GO terms , which refer to the molecular mechanisms altered in our comparison , “RNA polymerase II regulatory region sequence-specific DNA binding” (GO:0000977), “Vinculin binding” (GO:0017166), “Cellular response to interleukin-2” (GO:0071352), “Negative regulation of neuron death” (GO:1901215), and “Response to interleukin-2” (GO:0070669). We identified three terms overrepresented in men: “Negative regulation of interleukin-6 secretion” (GO:1900165), “Establishment of planar polarity involved in neural tube closure” (GO:0090177), and “Regulation of establishment of planar polarity involved in neural tube closure” (GO:0090178).The functional meta-analyses of the individual gene differential expression pipeline results provided a total of nine significant GO terms Table  but no sCation transmembrane transport” (GO:0098655), “Metal ion transport” (GO:0030001), “Regulation of cation transmembrane transport” (GO:1904062), and “Inorganic cation transmembrane transport” (GO:0098662). The meta-analysis of the UniProt functions failed to provide significant results.The functional meta-analysis of the individual results in the pathway differential activation pipeline returned four significant GO terms. These terms were overrepresented in premenopausal women compared with men, with a LOR value lower than 0.25 Table . These thttps://bioinfo.cipf.es/metafun-NAFD). This web tool contains the detailed results of all the steps of the bioinformatics pipeline and allows simple interactive exploration by any interested party.To contribute to data sharing and support the development of subsequent related studies, we generated the Metafun-NAFLD platform  sexual differences in metabolic regulation, the impact of sex on NAFLD pathobiology remains incompletely defined. Epidemiological studies have reported a higher prevalence of NAFLD in men and postmenopausal women than premenopausal women . To bettDespite the limitations of our approach (presence of studies with different sample sizes and types of platforms), meta-analysis techniques can integrate the selected studies. The individual results of the seven selected studies failed to identify any consistently different GO or KEGG terms between groups across all studies, a finding perhaps related to small sample sizes, underlying genetic and environmental variance in the source population, and methodological heterogeneity. Surprisingly, as shown in Fig. Our functional meta-analysis identified a total of thirteen GO terms Table  that disVinculin binding” (GO:0017166) in premenopausal women compared with men. The vinculin cytoplasmic actin-binding protein is enriched in focal adhesions and adherens junctions to contribute to junction stability [ANXA2 and MAG) between NAFL and NASH patients [A functional meta-analysis of differentially expressed genes identified differences in nine significant GO terms. Among these, our results established the overrepresentation of the “tability  and playtability . Of notetability . Furtherpatients .Negative regulation of interleukin-6 secretion” (GO:1900165) overrepresented in men and “Cellular response to interleukin-2” (GO:0071352) and “Response to interleukin-2” (GO:0070669) overrepresented in premenopausal women. These terms relate to interleukin 2 (IL-2) and interleukin 6 (IL-6), which displayed LOR values close to or above 0.5, thereby indicating a substantial difference between the groups. IL-2 is a known regulator of T cell responses, with low IL-2 levels regulating T cell central tolerance via the formation of regulatory T cells [Our analysis also identified sex-based differences related to the inflammatory response, specifically the expression of cytokine-related terms. We found “ T cells . Higher  T cells . Interes T cells , and lev T cells . Our resIL-6 has been previously implicated in NASH, with increased hepatic expression correlating with disease severity and insulin resistance . IL-6 alThese results suggest that differences in immune mechanisms between men and women may represent one possible factor in the sex-differences observed in NAFLD. For example, the macrophage phenotype in male NAFLD mice presents as pro-inflammatory and pro-fibrotic, but pro-resolution and anti-fibrotic in female mice . We hypoCidec/Fsp27β gene in the liver, finding that gene expression correlated with the presence and density of liver lipid droplets in mice fed a high-fat diet [Cidec/Fsp27β as a neuronal activator in the steatotic liver [Negative regulation of neuron death” (GO:1901215) could relate to the differences detected in this previous study. Upon restricting the gene ontology analysis to Homo sapiens, we found the components of the “Negative regulation of neuron death” pathway (GO: 1901215) as broad regulators of apoptosis. This finding may suggest an increase in liver cell apoptosis in men who develop advanced NASH at a younger age than women, as premenopausal women possess a level of protection. The observation that hepatocyte apoptosis represents a prominent feature of progressive NASH agrees with this hypothesis [A recent study by Herrera-Marcos et al. detected sex-based differences in the control of the fat diet . Matsusuic liver ; therefopothesis .Establishment of planar polarity involved in neural tube closure” (GO:0090177) and “Regulation of establishment of planar polarity involved in neural tube closure” (GO:0090178) in men with a LOR exceeding 0.5 (-0.514 and -0.523). Restricting analyses to Homo sapiens demonstrated that these GO terms relate to the Wnt and frizzled family of proteins. Wnt ligands and their cognate receptor frizzled represent critical determinants of liver development, zonation, regeneration, and responses to liver injury [Interestingly, we discovered other significant GO terms that had not previously been associated with NAFLD. For instance, we found the overrepresentation of “r injury . Their or injury , as obseCation transmembrane transport” (GO:0098655), “Metal ion transport” (GO:0030001), “Regulation of cation transmembrane transport” (GO:1904062), and “Inorganic cation transmembrane transport” (GO:0098662). Previous studies have associated the alteration of pathways and functions related to cation transport with NAFLD [Our functional pathway meta-analysis identified four significant GO terms involved in cation transport: “th NAFLD ; howeverOur results support the existence of differences between men and premenopausal women in specific biological processes and molecular functions relevant to NAFLD. Given the well-known heterogeneity of NAFLD progression between men and women, this transcriptomic meta-analysis suggests the use of sex-specific pathophysiologically informed disease biomarkers. These findings may also impact disease diagnosis and prognosis and the design of clinical trials. For example, biological sex-driven differences may allow the enhanced classification of individuals with NAFLD and alter their inclusion in specific clinical trials. Our meta-analysis underscores the importance of recognizing and accounting for sex-related differences in the study of NAFLD pathobiology.While differences in clinical characteristics and pathogenic mechanisms in male and female NAFLD patients had been explored previously, details remained scarce. To this end, we selected seven studies suitable for functional meta-analysis and identified thirteen significant GO terms from these data. Of note, specific GO terms were previously identified to have relevance to NAFLD, which supports the notion that sex represents an important variable in understanding NAFLD pathobiology and heterogeneity. We identified novel functional terms that had not been linked to NAFLD previously; therefore, our study may open new avenues for further research. In conclusion, the meta-analysis of transcriptomic data represents a useful tool for the identification of sex-related differences in NAFL and NASH.Additional file 1: Figure S1. UpSet plots of our gene functional analysis for each individual study for GO terms overexpressed in premenopausal women or in men and KEGG pathways upregulated in premenopausal women or in men.Additional file 2: Figure S2. Forest plots for significant GO terms from our functional gene meta-analysis.Additional file 3: Figure S3. Forest plots of significant GO terms from our functional pathways meta-analysis.Additional file 4: Figure S4. Funnel plots of the significant GO terms from our functional gene meta-analysis.Additional file 5: Figure S5. Funnel plots of significant GO terms from our functional pathway meta-analysis.Additional file 6:Supplementary table. Libraries version.Additional file 7:Supplementary file. GEO Data.


We performed an updated meta-analysis to clarify the relationship between the CEBPE rs2239633 polymorphism and the childhood acute lymphoblastic leukemia (CALL) susceptibility.Q test and I2, and then the random ratio or fixed effect was utilized to merge the odds ratios (OR) and 95% confidence interval (CI). We also performed sensitivity analysis to estimate the impact of individual studies on aggregate estimates. Publication bias was investigated by using funnel plot and Egger’s regression test. All statistical analyses were performed using Stata 12.0.All the case-control studies were updated on October 5, 2020, through Web of Science, PubMed, Cochrane Library, Embase, and China National Knowledge Infrastructure (CNKI) electronic database. The heterogeneity in the study was tested by the CEBPE rs2239633 polymorphism with CALL . In the subgroup analysis by ethnicity, there is no significant association of this polymorphism and CALL risks among Asian and Caucasian populations in the three genetic models .A total of 20 case-control studies were selected, including 7014 patients and 16,428 controls. There was no association of This meta-analysis found no significant association between the CEBPE rs2239633 polymorphism and susceptibility to CALL. Acute lymphoblastic leukemia (ALL) is a malignant disease of the blood system. It occurs mostly in children under 15 years of age. The peak age of onset was 2–5 years old . AlthougThe CEBPE gene was located on the human chromosome 14q11.2, which was a member of the CCAAT-enhancer-binding protein family, and its encoded protein belongs to the basic leucine transcription factor. The CEBPE gene-encoded protein was essential for terminal differentiation and functional maturation of myeloid committed progenitor cells, especially for the maturation of neutrophils and giant wah cells . MutatioCEBPE rs2239633 polymorphism with the risk of CALL, but the conclusions obtained from the two studies were reversed. In addition, since 2015, many studies had reported CEBPE rs2239633 polymorphisms and the risk of CALL [CEBPE rs2239633 polymorphism and the risk of CALL.Two meta-analysis studies in 2014  and 2015 of CALL , 15–19. CEBPE”) AND (“polymorphism” OR “variant” OR “mutation”) AND (“acute lymphoblastic leukemia” or “ALL”). The literature on relevant data was searched in English and Chinese, respectively. In addition, the retrieved articles and references were performed with manual searches. Referring to the Preferred Reporting Project (PRISMA) Guide for Systematic Evaluation and Meta-Analysis [We conducted a systematic online search of the literature in the Web of Science, PubMed, Cochrane Library, Embase, and China National Knowledge Infrastructure (CNKI) electronic database, covering relevant studies published until October 5, 2020. The keywords for the search were as follows: (“rs2239633” OR “CEBPE rs2239633 polymorphism and the risk of ALL is according to the following inclusion criteria: (1) the design of the study was case-control, (2) the full text can be found, (3) the genotype information of the CEBPE rs2239633 polymorphism was available, and (4) the relationship of the CEBPE rs2239633 polymorphism and the risk of ALL was evaluated. The major exclusion criteria were (1) not a case-control study; (2) repeating early publications ; (3) unpublished articles, conference papers, meta-analysis, and systematic reviews; and (4) family-based pedigree research. This meta-analysis strictly followed the requirements of the preferred reporting project for the systematic review and meta-analysis guidelines [Screening for the studies of the relationship between idelines .CEBPE rs2239633. If the same sample data appeared in multiple publications, only the publication with the largest sample size was included in the study. The differences between the two investigators were resolved through discussion. If the discussion could not resolve the objection between the two, the objection would be judged by the third investigator. All data were obtained from the full text of the published research, and the author was not contacted for further information.The analysis data of the selected studies were independently extracted by two researchers using standard data collection forms. Study-related information extracted from each literature was as follows: first author, year of publication, country of origin, mean age and gender in cases and controls, numbers of cases and controls, Hardy-Weinberg equilibrium, genotyping method, source of controls, and available genotype frequency information for Two evaluators evaluated the quality of the included studies according to the Newcastle-Ottawa Scale (NOS) , which wQ test and I2 [Z test . To estimate the impact of individual studies on aggregate estimates, we also performed sensitivity analysis [The heterogeneity in the study was tested by the t and I2 , 23, andt and I2 . The siganalysis . Using fanalysis , 27. AllThe flow chart of the literature search was shown in Fig. Q test and I2 statistics. As shown in Fig. P < 0.001, I2 = 63.6%; CC + CT vs TT: P = 0.002, I2 = 70.2%; C vs T: P < 0.001, I2 = 79.2%); thus, we used the random-effect model to analyze the three models. Our results did not find significant associations between CEBPE rs2239633 polymorphism and the risk of ALL under the three models, CC vs CT + TT , CC + CT vs TT , and C vs T . In the subgroup analysis by ethnicity, no significant association was found in three models in both Caucasian and Asian populations   played an important role in the proliferation, growth, differentiation, and apoptosis of myeloid cells and participates in the transcriptional regulation of a series of myeloid-specific genes. Loss of activity was an important factor leading to the onset of bone marrow disease . In receALL risk –37. It aCEBPE has a strong correlation with children’s ALL in the European population, however, this meta-analysis showed that no significant association was found in the three selected genetic models. In the subgroup analysis of ethnicity, no significant correlation was found under the three genetic models. On the one hand, this difference may be caused by the linkage imbalance between populations. There are also some differences between the population samples. On the other hand, the exact pathogenesis of CEBPE in the etiology of leukemia was still unclear. The CEBPE mutation may have different effects on the immune system of different children.Although the GWAS study by Papaemmanuil et al.  proved tCEBPE rs2239633 polymorphism and childhood ALL risk, and subgroup analysis stratified by ethnicity found a significant association of this polymorphism with childhood ALL in the Caucasian subgroup and Hispanic subgroup, but not in the Asian subgroup. Sun et al. [CEBPE rs2239633 variant was associated with decreased risk of childhood B cell ALL in Europeans, but not among T cell ALL, Asian, and mixed populations. The results of the two meta-analyses are diametrically opposed, and this difference may be due to the difference in the number of samples included and the sample size. This study combines the latest research literature with the first two meta-analyses to more fully describe the relationship between CEBPE rs2239633 and CALL. In terms of statistical power, it is significantly better than the previous meta-analysis of Sun et al. [Previously, a meta-analysis was performed for 11 case-control studies with 5639 cases and 10,036 controls by Wang et al. , the resn et al.  also conn et al.  and Wangn et al. .However, there are certain limitations in our research. First, databases that include only published research in both Chinese and English are selected for analysis, and other languages or unpublished potential researches may be missed. Second, due to the lack of raw data, we were unable to assess potential interactions of gene-genes and genes-environments. Third, the meta-analysis includes data from Europeans and Asians, so the results of this item apply only to these two ethnic groups. Fourth, among the three models, heterogeneity may greatly influence the conclusion of the meta-analysis. Lastly, maybe the results obtained from this study have limited clinic significance, but we think that the current study was needed and meaningful for understanding the relationship between the CEBPE rs2239633 polymorphism and the CALL susceptibility.CEBPE rs2239633 gene polymorphism did not increase or decrease the risk of susceptibility to CALL. Although the specific causes of childhood leukemia were still unclear, a large number of existing researches tended to suggest that the occurrence of childhood ALL was the result of a combination of factors, especially the genetic and environmental factors. Therefore, in the future, when studying the relationship between CEBPE rs2239633 polymorphism and childhood ALL, the influence of environmental factors on the relationship between the two should be removed.In summary, our study showed that the


Rosacea is a common inflammatory skin disorder. Several studies, but not all, have suggested a high prevalence of cardiovascular diseases (CVDs) in rosacea patients. This study is aimed at investigating the association between rosacea and CVDs and related risk factors.  We performed a literature search through PubMed, Embase, and Web of Science databases, from their respective inception to December 21, 2019. Two reviewers independently screened the articles, extracted data, and performed analysis, following the PRISMA guidelines. Odds ratios (OR) or standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated for outcomes. The included studies' quality was evaluated using the Newcastle Ottawa Scale (NOS). p < 0.05), low-density lipoprotein cholesterol , and C-reactive protein (CRP) . We found no association between rosacea and high-density lipoprotein cholesterol  or triglycerides .  The final meta-analysis included ten studies. The pooled analysis found no association between rosacea prevalence and the incidence of CVDs . Rosacea was found to be significantly associated with several risk factors for CVDs , including hypertension , dyslipidemia , and metabolic syndrome . However, no association was found between rosacea and diabetes mellitus . Among the biological parameters, a significant association was found between rosacea and total cholesterol (SMD = 0.40; 95% CI = −0.00, 0.81;  Although no significant association was found between rosacea and CVDs, rosacea was found to be associated with several of related risk factors. Patients with rosacea should pay more attention to identifiable CVD risk factors, especially those related to inflammatory and metabolic disorders. Rosacea is a common, chronic inflammatory skin disease. It is characterized by flushing, persistent erythema, papules, pustules, telangiectasia, and phymatous changes affecting mainly the convexities of the face, with ocular involvement . AccordiCardiovascular diseases (CVDs), especially coronary heart disease and stroke, are together the number one global death cause . Risk asAccumulating evidence has shown that rosacea is a systemic disease. The association between rosacea and multiple comorbidities, including depression, migraines, gastrointestinal disorders, and autoimmune conditions, has been demonstrated . SeveralThis systematic review and meta-analysis was conducted in accordance with PRISMA guidelines.We searched PubMed, Embase, and Web of Science databases from their inception dates to December 21, 2019. Keywords for this search were as follows: (“rosacea”) and (“cardiovascular” or “metabolic syndrome” or “diabetes” or “hypertension” or “dyslipidemia” or “cholesterol” or “C-reactive protein”). In addition, we screened references in all retrieved articles to identify potentially eligible studies and evaluated them based on the inclusion and exclusion criteria. Only studies in English were included for assessment.Studies were selected for the final analysis according to the following inclusion criteria: (i) studies evaluating the association between rosacea and CVDs and risk factors, (ii) case-control studies, and (iii) studies directly providing odds ratios (OR) for major CVDs and risk factors, or mean and standard deviation (SD) for biochemical factors, or giving original and sufficient data to calculate OR. The exclusion criteria were (i) studies of reviews, abstracts, case reports, or conference publications; (ii) studies of the repeated report of same research subjects or repeated publications; and (iii) studies not reporting relevant data or data not available.Two investigators (Y.L. and L.G.) independently reviewed literature, extracted data from each eligible study, and cross-checked, with disagreements resolved by consensus discussion with the third investigator (D.H.). The missing data were obtained by contacting the study author. The following clinical and demographic characteristics of included studies were extracted: (i) study characteristics including lead author, year of publication, and country; (ii) participant characteristics encompassing age, sample size, and diagnostic criteria for rosacea; and (iii) main outcomes including OR and 95% confidence interval for CVDs, including cardiovascular death (CD), CVD, major adverse cardiovascular events (MACE), peripheral atherosclerotic occlusive disease (PAOD), ischemic heart disease (IHD), myocardial infarction (MI), stroke, coronary artery disease (CAD) and heart failure (HF), and CVD risk factors . Mean and SD for biochemical indicators include high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TG), and CRP. In this study, the primary outcome was the association between rosacea and overall cardiovascular disease, while the secondary outcome was the relationship between rosacea and CVD-related risk diseases and the association of rosacea with biochemical indicators related to cardiovascular diseases.The quality assessment was based on the Newcastle-Ottawa Quality Assessment Scale (NOS) for case-control studies . Each arQ statistic (significant at p < 0.10) and the I2 test (significant at I2 > 50%). All meta-analyses were performed using a random effects model. To assess the impact of individual studies and to explain heterogeneity, we conducted a one-study removed sensitivity analysis. The risk of publication was assessed using Egger's test. p value of less than 0.05 was considered statistically significant.Quantitative meta-analyses were performed using the software Stata 12.0 . OR and 95% CI were meta-analyzed to assess the strength of the association between rosacea and CVDs and susceptibility to major risk factors. For biochemical indicators, the mean and SD were pooled and analyzed for comparison. Heterogeneity was tested based on Cochrane's A total of 641 studies were identified after the initial search. After removing duplicates, 316 potentially eligible records remained. Titles and abstracts of these articles were further screened, resulting in the selection of 26 potential publications. After reviewing the full text of these 26 studies, we selected for the final analysis, ten case-control studies that met the inclusion criteria, with a combined sample size of 97,456 patients .The basic characteristics of the ten studies are shown in Five studies, with 97,054 rosacea and 1,546,111 control cases, were included to assess the association between rosacea and the susceptibility for CVDs. The pooled analysis found no association between rosacea prevalence and the susceptibility for overall CVDs  .Seven studies, with 95,160 rosacea and 1,542,042 control cases, were included to assess the association between rosacea and the susceptibility to present with risk factors for CVDs. The pooled analysis found a significant association between rosacea and diseases that increase the risk for CVDs . Our results show that for individual risk factors, the prevalence of hypertension , dyslipidemia , and MS  is higher in rosacea patients than in the control group. However, there was no association between rosacea and DM  .p < 0.05) and LDL-C  in rosacea patients were higher than those in the control group. However, no differences were found in HDL-C  and TG  between the two groups (p < 0.05), for CRP  and hs-CRP , respectively   .In this meta-analysis study, we found no significant association between rosacea prevalence and the incidence of CVDs . Similarly, a large Danish cohort study of 5,993 rosacea patients found no association between rosacea and CVDs  . SeveralWe found significantly higher prevalence rates of hypertension, dyslipidemia, and MS among patients with rosacea. It might be related to the chronic inflammation in rosacea. MS is a group of classical cardiovascular risk factors, including central obesity, hypertension, dyslipidemia, and glucose intolerance/type 2 diabetes. Systemic inflammation is assumed to promote the development of MS . Underlyp = 0.001) [Furthermore, we found a significant association between rosacea and both CPR and hs-CRP. A test for hs-CRP is usually used to measure low-grade inflammation. Such inflammation is a chronic, subclinical, and systemic condition that contributes to the pathogenesis of many noncommunicable diseases like atherosclerosis. Both clinical and experimental studies have confirmed the important role of inflammation in the pathogenesis of rosacea . A cross= 0.001) . All the= 0.001) , the lowRecently, much attention has been paid to studying the role of lipid metabolism in rosacea patients. Transcriptome analysis of rosacea patients demonstrated significant upregulation of genes related to alcohol and lipid metabolism and sebaceous gland regulation . We founOur study has some limitations. First, heterogeneity and other confounding factors might have affected our findings. The results should, therefore, be interpreted with caution. Second, it would have been interesting to evaluate the association between different severity levels of rosacea or its different phenotypes and CVDs and related risk factors. This, however, was not possible due to the limited data. Third, the case-control design of the included studies makes it impossible to fully evaluate the cause-effect relationships.The present meta-analysis indicates that although no significant association was found between rosacea and CVDs, rosacea was found to be associated with several CVD risk factors. Patients with rosacea need to pay more attention to identifiable risk factors, especially those related to inflammatory and metabolic disorders. A comprehensive understanding of the incidence of risk factors for CVDs in rosacea patients can inform future preventive practices and treatment recommendations. Therefore, it is necessary to conduct prospective studies to determine whether patients with rosacea should more closely monitor the known CVD risk factors.


This meta-analysis provides new evidence for a potential relationship between residential radon and all histological types of lung cancer.Epidemiological studies on residential radon exposure and the risk of histological types of lung cancer have yielded inconsistent results. We conducted a meta-analysis on this topic and updated previous related meta-analyses. We searched the databases of Cochrane Library, Embase, PubMed, Web of Science and Chinese National Knowledge Infrastructure for papers published up to 13 November 2018. The pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using fixed and random effects models. Subgroup and dose‒response analyses were also conducted. This study was registered with PROSPERO (No. CRD42019127761). A total of 28 studies, which included 13,748 lung cancer cases and 23,112 controls, were used for this meta-analysis. The pooled OR indicated that the highest residential radon exposure was significantly associated with an increased risk of lung cancer . All histological types of lung cancer were associated with residential radon. Strongest association with small-cell lung carcinoma  was found, followed by adenocarcinoma , other histological types  and squamous cell carcinoma . With increasing residential radon levels per 100 Bq/m Lung cancer is the most commonly diagnosed cancer in the world and the leading cause of death from cancer . AccordiRadon is a naturally occurring radioactive noble gas that arises in the radioactive decay chain of uranium-238. This gas is the main source of natural radiation for human beings and widely exists in the daily environment, such as homes, workplaces and schools . The maiRadon is one of the 19 environmental carcinogens recognised by the World Health Organization (WHO). The International Agency for Research on Cancer includes radon and its progeny as carcinogenic factors. According to the U.S. Environmental Protection Agency (EPA), radon has been identified as the second leading cause of lung cancer, after cigarette smoking and the first risk factor for nonsmokers . Radon cTwo meta-analyses ,19 and tTherefore, we conducted a meta-analysis of case‒control studies for the general population to quantitatively assess the strength of the relationship between residential radon and the major histological types of lung cancer. We also updated the previous related meta-analyses. We believe that a new combined analysis is necessary and beneficial.The meta-analysis in this study was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement  and was We searched the databases of Cochrane Library, Embase, PubMed, Web of Science and Chinese National Knowledge Infrastructure (CNKI) to identify all case‒control studies related to residential radon and lung cancer published up to 13 November 2018. As detailed in We identified and defined the selection criteria. Two independent reviewers (C.L. and W.Z.) screened all titles and abstracts for inclusion and the full-text articles of all case‒control studies identified. Conflicts were resolved by consensus within the review team. The inclusion criteria were as follows. (a) The studies had a case‒control design with a hospital- or population-based design. (b) The exposure of interest was residential radon, which was determined by a radon detector by measurements over at least three months. (c) The outcome of interest was histologically confirmed lung cancer. (d) The subjects performed only in the general population. (e) Finally, odds ratios (ORs)/excess ORs (EORs) with their corresponding 95% confidence intervals (CIs) were reported .Two independent review authors (C.L. and J.Y.) extracted and recorded data from the included studies. All discrepancies were discussed to reach a consensus. A predefined form was then used to extract information from each study as follows: first author’s surname; year of publication; country of study; participant characteristics, including age range, sex and smoking situation; sample size (controls and cases); sources of controls ; histological types of lung cancer; radon dosimetry, including detector type, duration of measurements and place of measurements; and ORs, EORs with their corresponding 95% CIs and statistical adjustment for the main confounding factors of interest. The qualities of the included studies were assessed independently by two authors (Y.F. and D.L.) using the Newcastle–Ottawa quality assessment scale, which ranged from 0 to 9; we defined high-quality studies as scoring 6–9 points .2 statistics were used to evaluate the statistical heterogeneity among studies. We used fixed effects models in the absence of significant heterogeneity on the Q tests (p > 0.1) and I2 statistic value ≤50%; otherwise, we used random effects models. A funnel plot and Begg’s test were applied to assess potential publication bias [The primary outcomes of the meta-analysis were the ORs, EORs and their corresponding 95% CIs for lung cancer in patients with the highest radon exposure compared with the non/lowest radon-exposed population. Study-specific ORs, EORs and corresponding 95% CIs for highest versus non/lowest radon exposure levels were extracted; and log ORs and log EORs were then weighted by the inverse of their variances to obtain a pooled OR, EOR and their 95% CIs. Initially, all studies were pooled together, and a sensitivity analysis was performed to assess the influences of the methodological concerns by grouping them into different subgroups, including histological subtype, study population, study design, smoking status, sex and duration of radon measurements. In addition, we performed dose‒response analyses of radon on lung cancer and its histological types. Q tests and Iion bias ,28. We uWe retrieved 6117 citations , after removing 625 duplicates. A total of 196 were selected for full text review. The process of study selection and exclusion is shown in The main characteristics of the 28 studies are summarised in 2 = 67.5%, p-heterogeneity = 0.000). The pooled OR indicated a statistically significant association between the highest residential radon exposure and an increased risk of lung cancer .The multivariable adjusted ORs of lung cancer for the highest and non/lowest residential radon exposures are shown in 2 = 43.1%, p-heterogeneity = 0.010), whereas the summary estimate was substantially unchanged . For the overall pooled analysis, no significant evidence of publication bias, as shown by the funnel plot (p = 0.465). In the sensitivity analysis, removing one study at a time did not significantly affect the pooled OR, ranging from 1.52 (95% CI = 1.29–1.77) to 1.44 (95% CI = 1.23–1.68). However, the heterogeneity was primarily due to one study by Sandler et al. (2006). After excluding the study, the heterogeneity significantly declined (Inel plot  and Beggp = 0.112).2 = 0.0%, p-heterogeneity = 0.994; adenocarcinoma: I2 = 0.0%, p-heterogeneity = 0.604; SCLC: I2 = 0.0%, p-heterogeneity = 0.983; squamous cell carcinoma: I2 = 0.0%, p-heterogeneity = 0.490; and other histological types: I2 = 52.4%, p-heterogeneity = 0.122). All studies showed a positive dose‒response relationship between residential radon exposure and the risk of lung cancer. With the increase in residential radon exposure per 100 Bq/m3, the risk of lung cancer increased from 5% to 28%. The pooled EOR also indicated that the risk of lung cancer increased significantly by 11% with increasing residential radon levels per 100 Bq/m3 . Among the histological types, residential radon showed a significant dose‒response relationship with SCLC , followed by adenocarcinoma . However, no dose‒response relationship was found in squamous cell carcinoma  and other histological types .We performed dose‒response analyses of residential radon exposure on the risk of lung cancer and histological types in nine studies . Fixed e3, the risks of SCLC and adenocarcinoma increased by 19% and 13%, respectively. However, no significant association was found between residential radon and squamous cell carcinoma and other histological types. A previous pooled analysis [In this meta-analysis of 28 case‒control studies, residential radon exposure was significantly associated with the risk of lung cancer and its histological types. To the best of our knowledge, this meta-analysis is the first to quantitatively assess the strength of the relationship between residential radon and the major histological types of lung cancer. The most remarkable finding is that all histological types of lung cancer were associated with residential radon, with varying strengths of association among the major types. Previous pooled analysis  of Europanalysis  of NorthA meta-analysis  showed t3 [3 and 100 Bq/m3, respectively [Although radon and smoking have their own pathogenic mechanisms and characteristics as two independent lung cancer risk factors, increasing evidence shows that they are closely related. The occurrence and development of lung cancer is a complex biological process. In this process, many common mechanisms occur between radon and smoking, from the early stage of injury to all stages of carcinogenesis . Therefo3 . Howeverectively ,62. ThesWhen the subgroup analysis was conducted by study population, a statistically significant positive association was only observed in Europe, but not in North America and Asia. This phenomenon may be due to the different levels of radon concentration in each region and the insufficient number of studies included. Although 58.5% of lung cancer cases occurred in Asia in 2018  of theseOur meta-analysis has several advantages. First, ours is the first to focus exclusively on the effect of residential radon on the histological types of lung cancer. We also updated the previous related meta-analyses. Second, we searched five Chinese and English databases and conducted manual searches to ensure that relevant research would be included in this meta-analysis. Finally, insignificant heterogeneity was found in the histology subgroup and dose‒response analyses. Our meta-analysis also has several limitations. First, only case‒control studies were included. A case‒control study is a retrospective observational study that is prone to various biases. On the basis of the literature search results, some cohort studies have been conducted on radon occupational exposure; however, no cohort study has been conducted on radon exposure in the general population. Second, our results may be affected by the classification of radon exposure. Given the distinct radon concentrations in different regions, the radon exposure classifications designed for each study also vary. We can only extract the OR values of the highest versus non/lowest radon-exposed groups in each study. Third, publication bias may have occurred because only published studies were included in our meta-analysis.This meta-analysis of 28 case‒control studies, which included 13,748 lung cancer cases and 23,112 controls, suggests that residential radon is a risk factor in all histological types of all lung cancer. Stronger associations were found with SCLC and adenocarcinoma than with squamous cell carcinoma and other histological types. Residential radon exposure remains a major concern worldwide, and appropriate measures should be undertaken to reduce radon exposure to ensure the health of environmental conditions and residents.