In most African countries, cervical cancer is the most common cancer among women, both in terms of incidence and fatality. In the existing literature, age is risk factor for developing cervical cancer since it occurs mainly after the middle life of women. However, there have been contradictory findings in the literature on whether early sexual intercourse is linked to cervical cancer, with some studies indicating no relationship and others reporting an increased risk. Hence, this review analyzed data from recently published studies on cervical cancer.2). The publication bias was checked by a funnel plot and Egger’s test. The pooled estimates of odds ratios were calculated by a random-effects model.Seven databases  were searched for papers published from January 2000 to March 2022 in English. Ten studies were included in analysis. The statistical analysis was performed using STATA 11. Heterogeneity between-study was explored by forest plot and inconsistency index , indicating that women who began sexual intercourse before the age of 18 had a higher risk of getting cervical cancer than adult women.In this analysis, women who began having early sexual debut had a greater risk of developing cervical cancer than those who initiated sexual intercourse later in life. Delaying the age of first sexual activity among adolescents could help prevent the occurrence of cervical cancer. Cervical cancer is the second most common cancer in women, and it is a major public health concern worldwide, accounting for 16% of all female cancers . Every ySeveral risk factors for cervical cancer have been identified as of yet. Cigarette smoking has long been recognized as the main risk factor for cervical cancer through genotoxic and immunosuppressive mechanisms ,12. InfeInterestingly, the available literature consistently showed age is another risk factor for developing cervical cancer since cervical cancer occurs mainly after the middle life of women ,25,26. HAs such, these individual studies have limited statistical power and are relatively unreliable because they have small sample sizes or scope limitations, have been reported using similar procedures, and, in some cases, lack adjustment for confounding factors. Therefore, the association between early sexual activity and development of cervical cancer is yet unclear. To provide strong evidence of whether the early onset of sexual activity is a risk of cervical cancer, we decided to analyze data from recently published literature of risk factors for cervical cancer. This systematic review can add to the existing body of knowledge by providing a comprehensive estimate of early sexual activity as a risk factor for cervical cancer. The pooled estimations could contribute to identify sexually active adolescents for the purpose of delaying the age of first intercourse and initiating routine Pap tests so that early prevention can be effective.The overarching research hypothesis was; “early-onset of sexual activity is a risk for developing cervical cancer. The chance of developing cervical cancer is higher among women who had started sex before the age of 18 years”.Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) flow diagram  was follThe following search terms were employed to search for articles from major databases mentioned above: (early OR adolescent OR less than 18 years old) AND  AND  AND  AND . These key terms were combined using Boolean operators “AND” and “OR” to narrow the search. We also limited our search to peer-review literature as it guarantees quality checks.To meet the inclusion criteria, titles and abstracts of studies were examined, and the following study selection criteria were applied for considering studies for this review.Full-text case-control, cross-sectional cohort studies were included.This study included studies conducted among African women populations. This study was restricted to African countries because the sexual behavior of this population was varied from developed regions and other parts of the world  and their 95% confidence intervals (CI) were excluded. Studies involving women over the age of 18 were excluded because early sexual activity is defined as having sexual intercourse at the age of 18 or younger. Moreover, studies published other than the English language were excluded from the study.The authors screened all identified titles/abstracts. Articles found relevant by title and abstract were undergone for full-text review for eligibility. For eligible studies, two authors extracted the data using the pre-determined inclusion criteria. All steps of the data extraction process were carried out blindly. The review authors recorded the data on Microsoft excel and extracted the following data for each study: the authors, year of publication, study setting, study design, sample size, and quality of publication . The stuWe used the Newcastle-Ottawa Scale  ,39 for q2) . The I2 provides the percentage of variability due to heterogeneity rather than the chance difference or sampling error. The I2 greater than 75% and Chi2 test (P<0.10) was considered statistically significant heterogeneity. Pooled estimates of odds ratios were calculated by a random-effects model with a 95% confidence interval. The random-effects model which assesses the variability within and between studies was applied to estimate odds of developing cervical cancer among females who had started the early sexual activity. Besides, random effect minimizes heterogeneity of the various included studies than the fixed effect model [The statistical analysis was performed using STATA 11 . Heterogeneity between-study was explored by forest plot  and inconsistency index  and Egger’s test. In the presence of a cloud of data points that is symmetric around the population effect size and has the shape of a funnel, one can conclude as no publication bias . StatistIn this search for published studies, 967 records were identified through the database search and cross-referencing. From these studies, 481 articles were removed using their title review and 179 were removed using abstract review. Following title and abstract review, 307 studies were potentially eligible for full-text review, and 289 research articles were excluded after the full-text review, with the majority not meeting the inclusion criteria. Finally, 10 studies ,42–49 coOf the included articles, 7 studies were case-control studies –44,46,472 = 98.9%, p = 000). Besides, the visual inspection of the funnel plots suggested that the potential sources of the heterogeneity could be attributed to the study by Cooper D et al [The included studies were assessed for heterogeneity. Accordingly, the studies were significantly heterogeneous and the true variability among the 10 studies other than chance was 98.9% . As shown in 2 = 87.1%, P = 000), and early sexual activity was not associated with cervical cancer . However, the overall pooled analysis of these ten studies showed that there is an association between early sexual intercourse and having cervical cancer. We found a pooled odds ratio of 2.95  in the random effect model, indicating that women who began sexual intercourse before the age of 18 had a greater risk of getting cervical cancer   to 6.70 l cancer . This reThis systematic review and meta-analysis, to the best of our knowledge, is the first comprehensive meta-analysis conducted in the African population to determine the association between the early sexual activity and its risk of cervical cancer. Our findings contribute to the growing body of evidence by indicating that early sexual engagement is associated with an increased risk of cervical cancer. Additionally, the findings can be used to support intervention strategies that focus on delaying the age of first sexual intercourse and instituting routine Pap testing in order to achieve effective cervical cancer prevention.Cervical cancer is becoming more common in resource-limited countries, which also account for the majority of cervical cancer deaths ,10. ThisIn this systematic review and meta-analysis, women who began sexual intercourse before the age of 18 years had a greater chance of having cervical cancer than women who initiated sexual intercourse after the age of 18 years. The pooled estimate showed that women who had sexual intercourse before the age of 18 years had 2.95 times higher risk of acquiring cervical cancer than women who began sexual intercourse later in life. This finding is in agreement with a study conducted among Chinese women . The assAnother possibility is that HPV infection among adolescents is high because their sexual partners are more likely to be adult men who have had multiple sexual partners and have been exposed to HPV infections . As evidIn subgroup analyses stratified by regions, however, there was no association between early sexual intercourse and the risks of having cervical cancer. Remarkably, we found no evidence of significant association between early sexual activity and cervical cancer in studies conducted in East and West African countries. Even though individual studies lacked statistical power and were relatively heterogeneous, majority of them reported the relationship between early sexual intercourse and having cervical cancer. In contrast to our findings, for example, a study published in 2009 reported evidence of a relationship between cervical cancer and sexual intercourse before the age of 16 years . The relEven though we pooled the adjusted estimates of individual studies and retrieved studies that adjusted for HPV negative results to minimize confounding by HPV infection, this meta-analysis may have some other limitations. We were unable to determine whether the included studies had been adjusted for the independent risk of cervical cancer since the specific adjustment factors vary from study to study. Since the included studies were restricted in reports published in English, important data sources might be missed. The authors also acknowledge the methodological limitation of the included studies and unknown biases.In this analysis, women who began having early sexual debut had a greater risk of developing cervical cancer than those who initiated sexual intercourse later in life. Delaying the age of first sexual activity among adolescents could help prevent the occurrence of cervical cancer.


The African Esophageal Squamous Cell Carcinoma (ESCC) corridor, which spans from Ethiopia down to South Africa, is an esophageal cancer hotspot. Disproportionately high incidence and mortality rates of esophageal cancer have been reported from this region. The aim of this study was to systematically assess the evidence on environmental and life-style risk factors associated with ESCC in African populations.We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and carried out a comprehensive search of all African published studies up to March 2023 using PubMed, Embase, Scopus, and African Index Medicus databases.We identified 45 studies with measures of association , which reported on several environmental and lifestyle risk factors for ESCC in Africa. We performed a meta-analysis on 38 studies investigating tobacco, alcohol use, combined tobacco and alcohol use, polycyclic aromatic hydrocarbon exposure, hot food and beverages consumption , and poor oral health. We found significant associations between all the risk factors and ESCC development. Analysis of fruit and vegetable consumption showed a protective effect. Using population attributable fraction (PAF) analysis, we calculated the proportion of ESCC attributable to tobacco (18%), alcohol use (12%), combined tobacco and alcohol use (18%), polycyclic aromatic hydrocarbon exposure (12%), hot food and beverages intake (16%), poor oral health (37%), and fruit and vegetable consumption (-12%).Tobacco smoking and alcohol consumption were the most studied risk factors overall. Areas where there is an emerging body of evidence include hot food and beverages and oral health. Concurrently, new avenues of research are also emerging in PAH exposure, and diet as risk factors. Our results point to a multifactorial etiology of ESCC in African populations with further evidence on prevention potential.The online version contains supplementary material available at 10.1186/s12889-023-16629-0. In 2020orldwide . About 8orldwide , in contESCC has a peculiar geographical distribution with high incidence rates reported from China to Iran, parts of South America and from Eastern to Southern Africa , 5. The The African ESCC corridor, which spans from Kenya down to South Africa on the easterly side of Africa, is an ESCC hotspot region. This African corridor includes Burundi, Malawi, Kenya, Uganda, Tanzania, Zimbabwe, Madagascar, and South Africa , 7. HighEC has a multi-factorial etiology. The risk factors reported worldwide comprise lifestyle, environmental and genetic factors. The lifestyle and environmental factors include smoking, alcohol consumption, poor diet, micronutrient deficiency, exposure to polycyclic aromatic hydrocarbons (PAHs) through cooking and heating methods, esophageal thermal injury from consuming hot foods and beverages, obesity, infectious agents, low socioeconomic status (SES), and exposure to contaminants which have carcinogenic effects , 10, 11.Despite advances in the management and treatment, ESCC prognosis is still poor with a survival rate of < 5% in economically developing countries . The etiThe aim of this systematic review was to provide an in-depth analysis of key environmental and lifestyle factors associated with ESCC development in African populations, and perform a meta-analysis and population attributable fraction (PAF) analysis. Since the last systematic review on ESCC , new stuThe study assessed all environmental and lifestyle risk factors reported in relevant peer-reviewed African literature  and tested for an association with ESCC development or progression. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . To asseWe carried out a literature search on all published African ESCC studies up to March 2023. We developed a comprehensive set of search terms subjectively and iteratively to capture all EC studies carried out in African populations. The search and screening strategy was based on the following framework: population—African individuals, exposure- any factors studied for an association with EC, comparison: N/A, outcome—esophageal cancer, study design—observational studies . Our search did not include the term "risk factor(s)" or any or the individual risk factors named in the manuscript. The goal was to capture all African literature (excluding gray literature) on ESCC and then manually screen the studies to find those which assessed risk factors. Our rationale for doing it this way was to avoid missing any studies that investigated the role of previously unknown factors in ESCC. We excluded animal- and lab-based studies during the screening process. We searched the following electronic bibliographic databases without time or language limits: Medline (PubMed), Embase (OViD), Scopus, African index medicus, and Africa-wide information (EbsCOHost). We also checked the reference lists of potentially relevant articles for additional citations and used the "related citations" search key in PubMed to identify similar papers.We checked Medline (PubMed) to identify controlled vocabulary (MeSH) terms related to EC, and identified text keywords based on our knowledge of the field . MedlineTwo authors (HS and VS) carried out the screening for eligible studies. First, the two authors read the titles and abstracts independently and then met to finalise an initial list. Full articles of the studies selected based on the initial screening, were read and assessed for inclusion to the systematic review. Figure Data extraction was carried out by two authors (HS and VS) using data extraction forms in Microsoft Excel software.The quality of the methods and reporting used in the published studies was assessed using a quality assessment tool adapted from the JBI-MAStARI  of how an outcome can be influenced with the removal or reduction of that risk factor. The PAF was computed using the formula :\documen studies . The for1 is the PAF for tobacco smoking, PAF2 is the PAF for alcohol consumption, PAF3 is the PAF for hot food and beverages consumption, PAF4 is the PAF for PAH exposure, and PAF5 is the PAF for oral health. This equation assumes independence of exposure from the five sources.We calculated the combined PAF from exposure to tobacco smoking, alcohol consumption, hot food and beverages consumption, PAH, and oral health using the following equation :\documenThe initial search produced 2,411 articles, which were screened for duplicates and six duplicates were removed  reported association of a risk factor to ESCC using ORs or RRs and 95%CIs.Quality of methods and reporting assessment was done on the 45 articles that reported ORs or RRs and 95%CIs and hence qualified for quantitative assessment  of the studies were from South Africa, and the rest were from Ethiopia (n = 2), Malawi (n = 3), Tanzania (n = 2), Zambia (n = 3), Zimbabwe (n = 1), Kenya (n = 2), Uganda (n = 3), Mozambique (n = 1), and one study reporting on a multicenter case–control study from Malawi, Kenya and Tanzania. The studies were published between 1985 and 2023. Most studies indicated an increased risk of ESCC in people who use tobacco, with ORs ranging from 1.05 to 11.24 [Tobacco use was the most commonly investigated risk factor, with 29 (64%) of the 45 included studies reporting quantifiable associations between smoking and EC  of 67% with p < 0.01 was recorded after removal of two studies. Egger’s test did not reveal any funnel plot asymmetry (p = 0.38). One of the studies included in this analysis [The pooled analysis for tobacco use showed an effect size of OR of 3.01 (2.37–3.83 95%CI)  of the studies performed in South Africa, and three each from Uganda, Zambia, and Malawi, two each from Ethiopia and Kenya, one each from Mozambique, and Zimbabwe, whilst one study reported on a multicenter case–control study in Malawi, Kenya and Tanzania. All studies combined included 8,516 cases and 12,041 controls. There was a significant overlap with the studies reporting the effects of tobacco smoking. The studies were published between 1988 and 2023.Alcohol consumption was investigated as a risk factor in 28 of the 45 (62%) studies with quantifiable associations to ESCC Fig. . All theThe highest risk was reported in a study done on a South African population with OR of 15.40 (5.48–43.26 95%CI) for men and 9.90 (3.41–28.71 95%CI) for women consuming commercial beer . Another2 of 82% (p < 0.01) after removal of two studies. Egger’s test did not reveal any funnel plot asymmetry (p = 0.60).The pooled analysis for alcohol consumption demonstrated an effect size of OR 1.79 (1.35–2.37 95%CI)  after removal of two studies. Egger’s test did not show the presence of funnel plot asymmetry (p = 0.74).The pooled analysis of combined alcohol and tobacco had an effect size of OR 3.85 (2.49–5.93 95%CI)  with statistically significant associations had ORs ranging from 1.40 (drinking hot tea in Kenya) [Consumption of hot food and beverages serves as a proxy for esophageal injury through exposure to high temperature and it is thus plausible to combine the consumption of hot food and the consumption of hot beverages into one entity providing an indirect measure of thermal injury to the esophagus. This risk factor was reported in eleven case–control studies    to 5.10 n Kenya) , 62. Hown Kenya) .Fig. 5Ef2 of 80% (p < 0.01) was obtained for the pooled analysis of hot food and beverages exposure, showing that consumption of hot food and beverages doubles the risk of developing ESCC .An overall effect size estimate of OR 1.68 (1.13–2.49 95%CI) and ITwelve case control studies reported PAH exposure as a risk factor for ESCC Fig. . They in2 of 48% (p = 0.04) after removal of one study. Egger’s test gave p = 0.57 and did not indicate the presence of funnel plot asymmetry.In the pooled analysis, a forest plot of PAH exposure showed an effect estimate of OR of 2.08 (1.27–3.42 95%CI) Fig. . Test foTwo Kenyan and two Tanzanian case–control studies explored oral health as a risk factor for ESCC Fig. . They in2 of 0% (p < 0.47) was recorded without removing any studies. Egger’s test did not indicate the presence of funnel plot asymmetry.Pooled analysis of the association between poor oral health and ESCC development showed an overall estimate of OR 3.52 (2.64–4.69 95%CI). An In = 2), South Africa (n = 1), Mozambique (n = 1), Tanzania (n = 2), and Zambia (n = 1).Fifteen studies investigated the effect of diet on ESCC. This included food groups, food items, beverages, vitamins and trace elements. A total of 1,767 cases and 2,183 controls were assessed for fruit and vegetable consumption. This included seven case–control studies from Ethiopia , imbikicane , and umsobo (Sofanum nigrum). One of the studies on South African women reported an increased risk of ESCC in consumers of wild imifino vegetables with OR of 1.84 (1.04–3.27 95%CI) [Three South African studies reported increased risk of ESCC in participants who consume wild vegetables , 25, 58.7 95%CI)  with a ROther food items that were reported to increase the risk of ESCC development, were: purchased maize, pumpkin, beans, sorghum and porridge reported in three South African and one Ethiopian study , 58, 64.2 of 0% (p = 0.42)  and I42) Fig. . One stuBelow we summarize the results on the seven other ESCC risk factors for which we identified published studies, but pooled analysis was not possible due to the small number of studies for each of them. We also excluded some risk factors from pooled analysis if they would not have provided informative or meaningful results due to differences in the measurement or assessment of the risk factors. The risk factors without pooled analyses were: esophageal injury, non-acid gastroesophageal reflux, SES, infectious agents, water source, family history of cancer, and geophagia.Esophageal inflammation and injury due to self-induced vomiting and caustic ingestion was reported as a risk factor in two South African studies and one Kenyan study. The case–control studies had a total of 661 cases and 266 controls. These studies were excluded from pooled analysis due to the differences in exposure assessments. In the South African study, induced vomiting was associated with ESCC, reporting OR of 1.83 (1.13–2.96 95%CI) . The KenNon-acid gastroesophageal reflux was reported to increase the risk of ESCC in a South African case–control study with OR of 8.80 (3.20–24.50 95%CI) . The autLow SES was assessed as a risk factor for ESCC development in eleven case–control studies. One study was from South Africa, one from Malawi, two from Tanzania, one from Uganda, one from Zambia, one from Mozambique, one from Zimbabwe, one from Ethiopia, and two were from Kenya. Pooled analysis was not performed because the method used to measure SES varied across studies. Additionally some measures were not considered suitable for capturing the multidimensional, cultural and contextual nature of SES. Overall low SES was associated with increased risk of ESCC. SES was measured using salaries/household income , 47, 49,Mycobacterium tuberculosis, Herpes zoster, Helicobacter pylori, Herpes simplex, cytomegalovirus, Epstein–Barr virus, and Varicella zoster, none of which showed an association with ESCC development.Human papillomavirus (HPV) and human immunodeficiency virus (HIV) infection were assessed as risk factors in six studies . Pooled analysis was not performed due to the significant diversity among the infectious agents studied, which made it inappropriate to group them into a single category for a pooled analysis. HPV was assessed in two studies, a South African study  which reWater source was assessed as a risk factor for ESCC development in case–control studies of a total of 1,032 cases and 1,146 controls from Kenya, Tanzania, and Zambia , 46, 59.Family history of cancer was analysed in five case–control studies with 1,329 cases and 1,508 controls. It was reported to increase the risk of ESCC in study participants in Kenya  . A Tanzanian study  investigPAF calculations were done for seven risk factors: tobacco smoking, alcohol consumption, combined tobacco and alcohol use, hot food and beverage consumption, oral health, fruit and vegetable consumption, and PAH exposure. The data were taken from the 38 studies selected for the meta-analysis. Seven studies were excluded from the analysis due to not having enough information on exposure. The PAF attributable to tobacco smoking was 18%, whilst for alcohol consumption it was 12%. According to our analysis, the combined exposure of tobacco and alcohol attributed 18% of the ECs. Consumption of hot food and beverages was responsible for 16% of ESCC cases. Exposure to PAHs contributed 12% of ESCC cases. Poor oral health attributed 37% of ESCC cases in our results. Fruit and vegetable consumption, due to its protective effect, showed a negative PAF of –12%. Our estimates show that 66% of ESCC cases are attributable to the combined effects of tobacco smoking, alcohol consumption, esophageal injury and PAH exposure.EC constitutes a major health burden in specific geographic regions of the African esophageal cancer corridor. We performed a systematic review that identified studies which reported tobacco use, alcohol consumption, SES, diet, PAH exposure, consumption of hot food and beverages, oral health, infectious agents, esophageal injury, family history of cancer, water source, geophagia, and non-acid gastro-esophageal reflux as environmental and life-style risk factors for ESCC in Africa using risk estimates. Our results point to a multifactorial etiology of ESCC which was also reported in two other previous systematic reviews , 11. MosData from western countries have conclusively implicated tobacco smoking and alcohol consumption as the main risk factors for ESCC . In our 2 = 55.3% [2 of 32%. The results support the synergistic effects of combined alcohol and tobacco exposure reported in literature, with a two-fold increase in risk compared to alcohol consumption alone. Regarding tobacco smoking alone, the combined effect of tobacco smoking and alcohol consumption increases ESCC risk by one factor.Some previous studies reported the interaction between tobacco and alcohol, with high risk estimates, indicative of synergistic effects of combined exposure to tobacco and alcohol. However, because none of these studies were originally designed as interaction studies, they may not have had enough statistical power to detect interactions. In a systematic review and meta-analyses by Prabhu et al.  pooled a = 55.3% . The aut = 55.3% . In our Poor oral health  emerged as an important risk factor for ESCC in our meta-analysis, with OR of 3.52 (2.64–4.69 95%CI). Our results corroborated a meta-analysis from Asia which reported that teeth loss was associated with an increased risk of EC (OR 1.52) and high frequency of teeth brushing was associated with a lower incidence of EC (OR 0.62) . In a ChOver the past few years, there has been an increase in the number of African studies assessing the role of hot food and beverages in the ESCC pathogenesis. It serves as a proxy for esophageal injury through exposure to high temperature and it is thus plausible to combine the consumption of hot food and the consumption of hot beverages into one entity providing an indirect measure of thermal injury to the esophagus. These studies reported an association, corroborated with other studies in China, Iran and South America which demonstrated the same effect . AdditioOur study assessed PAHs from different sources  and found that PAHs increase ESCC risk. In a systematic review on the role of biomass fuel  in ESCC development, the use of biomass fuel for heating and cooking was associated with ESCC development, due to the smoke exposure . The higConsumption of fruits and vegetables reduced the risk of ESCC in our study. This evidence is supported by a previous meta-analysis  on 32 stOur study provides evidence-based assessment of the proportion of ESCC cases attributable to certain risk factors. To quantify the contribution of a risk factor to the development of ESCC, PAF analysis was performed. Our analysis showed that tobacco smoking and alcohol consumption contributed to 18% and 12% of the ESCC cases, respectively, whilst their combined exposure contributed 18% of the ESCC cases. In a Chinese study, the contribution of alcohol consumption in EC cases was reported to have a PAF of 10.9% (15.2% for men and 1.3% for women) . AnotherPoor oral health emerged as an important risk factor, and interestingly, had the highest PAF of 37% among all the risk factors. This finding underscores the importance of more comprehensive studies investigating the role of poor oral health in the African Esophageal Cancer Corridor and the underlying mechanism to pathogenesis. Consumption of hot food and beverages had a PAF of 16%. In a 2003 study done in Paraguay, maté consumption, which is normally consumed at high temperatures, had a population-attributable risk of 53% . HoweverThe combined attributable risk of the five most significant risk factors  was estimated to be 66%. Assuming that each of these exposures are mutually exclusive, this suggests that 66% of ESCC cases would be prevented if these exposures were removed. However, it is likely that most of these factors are related and therefore the true combined PAH is likely smaller.The cumulative estimate is therefore an upper bound based on independence of individual factors. If there is an interaction, such as between smoking and alcohol, some or all of the effect of one of the factors can be subsumed by the other  For instThe strength of this study is that it provides the most comprehensive meta-analysis on environmental risk factors associated with ESCC in the African populations to date. It is also the first study to perform an aggregated PAF analysis of multiple risk factors which contribute to ESCC cases in the African populations and thus able to inform esophageal health policy and cancer control and planning in the region.One of the main limitations was the heterogeneity of the original studies. Studies assessing the same risk factor often had a different study design, geographical location, exposure measurement, exposure assessment category, exposure intensity, and confounding factors adjusted for, and variability in sample size , therefore caution is needed when interpreting the magnitude of the risk estimates. Similar limitations regarding differences in exposure assessment quality were reported in a recent systematic review on the carcinogenicity opium consumption  None of Several studies did not report risk estimates, and hence could not be included in the meta-analyses. Most of these studies were published before 1990. There were some deficiencies in the quality of reporting and methods in some of the studies. About one third of the studies did not report on adjusting for confounding factors. Unmeasured and unadjusted confounders can result in a false association.There is a lack of interaction studies to investigate the multifactorial etiology of ESCC. There are a number of gene-environment interaction studies which have been published  assessinWhilst we reported on PAFs, there are potential biases in our estimates due to the uncertainty of the magnitude (RR) of the effect given the sparse literature and the lack of population-based estimates of exposure. Additionally, for risk factors such as alcohol consumption and tobacco smoking, sex-aggregated data would have given a clearer picture of the attributable risk as prevalence of exposure may differ according to sex. Both the meta-analysis and PAF analysis combined fruits and vegetables as one factor, however, the nutritional value of fruits and vegetables differs . The comWhile this study employed a comprehensive search strategy, it is important to note that gray literature was not included. This exclusion was a deliberate choice made to uphold methodological rigor and minimize potential bias. Although this decision ensures the reliability of the included studies from reputable, peer-reviewed sources, it may have limited the incorporation of additional perspectives and ongoing research.We also acknowledge the challenges that come with doing research in low-to-middle-income countries. These include the availability of resources and infrastructure to perform research, including time and expenses. There is also a lack of suitable methods and technologies, which results in the use of non-standardized assessment tools. Most data collection tools are based on self-reporting of lifestyle behaviors and environmental exposures via questionnaires which have a low precision of accuracy and can result in recall and misclassification bias . It is iOverall, our study showed that there is a relatively large body of evidence for smoking and alcohol being associated with ESCC in the African populations, compared to other risk factors. Areas where there is an emerging body of evidence include hot food and beverages, and oral health. Concurrently, new avenues of research are also emerging in PAH exposure, and diet as risk factors. However, studies investigating the etiology of ESCC in Africa are still very limited, therefore more research needs to be done to understand the high prevalence seen in the African Esophageal Cancer Corridor. A standardized way of measuring risk factors will allow for future systematic reviews to report with certainty pooled estimates which can be generalized to the region. The results of our study point to a multifactorial etiology, which includes multiple environmental and life-style risk factors, playing a role in the ESCC risk. Our results have important implication for ESCC control and prevention.Additional file 1. Search histories for systematic review and meta-analysis. List of all queries used for searching PubMed, Embase, Cinahl, Scopus, Web of Science, and African index medicus. PDF.Additional file 2. Quality assessment of included studies. This table summarizes how the quality of reporting and methods was assessed in the studies included in this systematic review and meta-analysis. PDF.Additional file 3. Effect of tobacco use on esophageal cancer in Africa. This diagram is a forest plot showing pooled analysis of all studies (no exclusion of outliers). Study ID gives the first author and the year of the publication. OR, odds ratio; CI, confidence interval. PDF.Additional file 4. Effect of alcohol consumption on ESCC in Africa. This diagram is a forest plot showing pooled analysis of all studies (no exclusion of outliers). Study ID gives the first author and the year of the publication. OR, odds ratio; CI, confidence interval. PDF.Additional file 5. Effect of combined tobacco and alcohol use on ESCC in Africa. This diagram is a forest plot showing pooled analysis of all studies (no exclusion of outliers). Study ID gives the first author and the year of the publication. OR, odds ratio; CI, confidence interval. PDF.Additional file 6. Effect of hot food and beverage on ESCC in Africa. This diagram is a forest plot showing pooled analysis of all studies (no exclusion of outliers). Study ID gives the first author and the year of the publication. OR, odds ratio; CI, confidence interval. PDF.Additional file 7. Effect of PAH on ESCC in Africa. This diagram is a forest plot showing pooled analysis of all studies (no exclusion of outliers). Study ID gives the first author and the year of the publication. OR, odds ratio; CI, confidence interval; PAH, polycyclic aromatic hydrocarbons. PDF.Additional file 8. Effect of fruit and vegetable consumption on ESCC in Africa. This diagram is a forest plot showing pooled analysis of all studies (no exclusion of outliers). Study ID gives the first author and the year of the publication. OR, odds ratio; CI, confidence interval. PDF.Additional file 9. Baujat plot for tobacco use from outlier and influence analysis. PDF.Additional file 10. Baujat plot for alcohol use from outlier and influence analysis. PDF.Additional file 11. Baujat plot for combined tobacco and alcohol use from outlier and influence analysis. PDF.Additional file 12. Baujat plot for hot food and beverage consumption from outlier and influence analysis. PDF.Additional file 13. Baujat plot for PAH exposure from outlier and influence analysis. PAH, polycyclic aromatic hydrocarbons. PDF.Additional file 14. Baujat plot for oral health from outlier and influence analysis. PDF.Additional file 15. Baujat plot for fruit and vegetable consumption from outlier and influence analysis. PDF.Additional file 16. Sensitivity plot for tobacco use. Sensitivity analysis was done using the "Leave-One-Out" influence analysis on studies included in the final meta-analysis. This was done to determine which study may have had an excessive influence on the overall effect size. PDF.Additional file 17. Sensitivity plot for alcohol use. PDF.Additional file 18. Sensitivity plot for combined alcohol and tobacco use. PDF.Additional file 19. Sensitivity plot for hot food and beverage consumption. PDF.Additional file 20. Sensitivity plot for combined PAH exposure. PDF.Additional file 21. Sensitivity plot for oral health. PDF.Additional file 22. Sensitivity plot for fruit and vegetable consumption. PDF.


We assessed the efficacies of various corticosteroid treatments for preventing postexubation stridor and reintubation in mechanically ventilated adults with planned extubation.ClinicalTrial.gov registration for articles published through September 29, 2022. Only randomized controlled trials (RCTs) that compared the clinical efficacies of systemic corticosteroids and other therapeutics for preventing postextubation stridor and reintubation were included. The primary outcome was postextubation stridor and the secondary outcome was reintubation.We searched the Pubmed, Embase, the Cochrane databases and The 11 assessed RCTs reported 4 nodes: methylprednisolone, dexamethasone, hydrocortisone, and placebo, which yielded 3 possible pairs for comparing the risks of post extubation stridor and 3 possible pairs for comparing the risks of reintubation. The risk of postextubation stridor was significantly lower in dexamethasone- and methylprednisolone-treated patients than in placebo-treated patients . The risk of postextubation stridor was significantly lower in methylprednisolone-treated patients than in hydrocortisone-treated: OR = 0.24; 95% CI = 0.08–0.67) and dexamethasone-treated patients: OR = 0.55; 95% CI = 0.24–1.26). The risk of reintubation was significantly lower in dexamethasone- and methylprednisolone-treated patients than in placebo-treated patients: . Cluster analysis showed that dexamethasone- and methylprednisolone-treated patients had the lowest risks of stridor and reintubation. Subgroup analyses of patients with positive cuff-leak tests showed similar results.Methylprednisolone and dexamethasone were the most effective agents against postextubation stridor and reintubation. Endotracheal intubation is a common procedure for critically ill patients with acute respiratory failure that requires mechanical ventilation (MV) in an intensive care unit (ICU) or for patients under general anesthesia undergoing surgery in the operating room. Although endotracheal intubation is usually uneventful, it can lead to tracheal rupture, pneumothorax or pneumomediastinum, tongue necrosis, or soft palate injury –5. LarynSeveral interventions—parenterally administering corticosteroids, nebulizing epinephrine, and administering an inhaled helium/oxygen mixture—have been developed to prevent postextubation stridor and reintubation . CorticoClinicalTrial.gov registration. We used the following search terms: “intubation,” “intratracheal,” “laryngeal edema,” “airway obstruction,” “stridor,” “post extubation larynx* edema*,” steroid*,” “corticosteroid*,” ‘glucocorticoid*,” “prednisone,” “prednisolone,” “methylprednisolone,” “dexamethasone,” “cortisone,” “hydrocortisone,” and “adult”  was based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) extension statement . The pro “adult” . Only raThe following data were extracted from every included study: year of publication, study design, sample size, gender ratio, treatment regimens of corticosteroids and other interventions, cumulative doses (mg), frequency of administration, and incidence rates of postextubation stridor and reintubation. For RCTs that used medians and interquartile ranges as measures of central tendency and dispersion, we estimated means and standard deviations (SDs) .The primary outcome was overall postextubation stridor and reintubation. Subgroup analyses of patients with positive cuff-leak tests were also performed.The quality of the analyzed RCTs and the risk of bias were assessed using the Cochrane Risk of Bias Assessment tool . We asse2 value. The required property of transitivity was also assumed.We used STATA 15.0 , R (version 4.2.1) and R package “netmeta” to do a frequentist network meta-analysis . BecauseWe used a design-by-treatment interaction model for global tests and side-splitting model for local tests to evaluate inconsistencies between direct and indirect evidence. Network plots show direct comparisons of investigated outcomes, and odds ratios (ORs) and 95% confidence intervals (95% CIs) show network effect-size estimates of pairwise comparisons.A surface under the cumulative ranking curve (SUCRA) presents the likely rank order of each investigated treatment. To evaluate the joint ranking of postextubation stridor and reintubation both clinical outcomes, cluster analysis was performed. The optimal number of resulting cluster was defined by having maximum intra-cluster similarity and minimize inter-cluster similarity . Finallyn = 135), non-RCT (n = 30), the 99 remaining articles underwent a full-text review to assess their eligibility. Finally, a total of eleven RCTs (n = 5), (n = 4), (n = 2) , , 25 then(n = 4), , 14, 15  (n = 2) , 17, 18. (n = 2) . Four st (n = 2) , 17–19 uAmong enrolled studies, four reported nodes were methylprednisolone, dexamethasone, hydrocortisone and placebo, resulting in 3 possible pairs for comparing the risks of post extubation stridor and 3 possible pairs for comparing the risks of reintubation. Most comparisons with direct evidence are from dexamethasone or methylprednisolone and placebo. Regarding the risk of postextubation stridor, five studies compared the effects between dexamethasone and placebo. Four and one studies used methylprednisolone and hydrocortisone as study agents, respectively . Regardip = 0.013). In contrast, there was no publication bias (Egger's test: p = 0.623) in the collected reintubation-related literature.The risk of bias in each domain of each study was low . ControlNMAs showed that the risk of postextubation stridor was significantly lower in dexamethasone- and methylprednisolone-treated patients than in placebo-treated patients  .Compared with placebo, both dexamethasone and methylprednisolone were found significantly associated with lower risk of reintubation  .For preventing postextubation stridor, methylprednisolone had the largest surface under the cumulative ranking curve (SUCRA) (97.6), followed by dexamethasone (66.9), hydrocortisone (21.6), and placebo (13.9). For reducing the risk of reintubation, dexamethasone had the largest SUCRA (80.7), followed by methylprednisolone (70.7), hydrocortisone (41.0), and placebo (7.6) . AccordiFor patients with positive CLTs, both dexamethasone and methylprednisolone were associated with a significantly lower risk of postextubation stridor than was placebo . Moreover, both corticosteroids were associated with a significantly lower risk of reintubation than was placebo  methylprednisolone, respectively.This is the first network meta-analysis of 11 RCTs with a total of 2,371 patients that compare the efficacies of three commonly used corticosteroids  against postextubation stridor and reintubation in patients with a scheduled extubation. This analysis provided useful information on the choice of appropriate corticosteroid formula for preventing postextubation stridor and reintubation in this population. Of three kinds of corticosteroid, dexamethasone and methylprednisolone were the most efficacious corticosteroids in this network meta-analysis. Methylprednisolone was ranked highest in the preventing postextubation stridor, and in contrast, hydrocortisone was ranked lowest. Regarding reintubation, dexamethasone and methylprednisolone was ranked much higher than hydrocortisone. A similar trend was observed in the subgroup analysis of high risk patients selected using cuff-leak test. Overall, this network meta-analysis also found that methylprednisolone and dexamethasone were associated with significantly lower risk of postextubation stridor and reintubation than placebo among overall population and the subgroups selected with cuff-leak test. In summary, we found that methylprednisolone and dexamethasone are the most potent kind of corticosteroids in the preventing postextubation stridor and reintubation and their prophylactic use can effectively reduce the risk of postextubation stridor and reintubation before elective extubation among patients with mechanical ventilation. In contrast, the usefulness of hydrocortisone was limited in this clinical condition. All these findings should suggest the better role of methylprednisolone and dexamethasone than hydrocortisone in this clinical entity.Our findings in this network meta-analysis can be explained by the different anti-inflammatory activities of three corticosteroids. Corticosteroids differ in their relative amount of anti-inflammatory potency. Dexamethasone and methylprednisolone have much higher anti-inflammatory potency than hydrocortisone. In general, 25 mg of hydrocortisone is equivalent to 5 mg of methylprednisolone, and 1 mg of dexamethasone according to their relative anti-inflammatory potency . TherefoOur study has some limitations. First, the regimens of the corticosteroid treatments are different in the selected RCTs, which might lead to different preventive effects. Second, the number of enrolled studies is small; thus, we cannot further assess the effects of the different regimens of corticosteroids. Additional studies are needed to investigate their confounding effects. Third, some mechanisms such as publication bias and other forms of reporting bias might have impact on our interpretation of the results. Several possible confounding factors, such as sex, duration of intubation, and the size of the endotracheal tube were not assessed in this meta-analysis. There are some potential biases, heterogeneity or generalizability in meta-analyses. The meta-analysis combines the results of various types of study design to generate an overall effect size. If there are significant heterogeneities in these studies, the focus should shift from the summary effect to the dispersion itself. In addition, meta-analysis focused on the main outcomes and its results can be generalizable to particular group of patients but not another.However, we could not do a subgroup analysis because so few trials reported separate results based on sex, duration of intubation, and the size of the endotracheal tube. We did not evaluate the risk of adverse effects caused by corticosteroids.Although the risk of corticosteroid-related complications, e.g., fluid retention, infection, gastrointestinal bleeding, and hyperglycemia are low in additional investigations are needed to assess the possibility of negative side effects. Finally, because studies were not administering equipotent doses of steroids, methylprednisolone and dexamethasone are more effective than hydrocortisone and this may be a significant confounder.The comparison between different corticosteroids are statistical rather than direct clinical comparisons. However, we clarify the selection of studies, pre-specification of the pooled analysis, the risk of bias in each domain of each study was low and the outcome of individual studies in relation to the pooled result. We believe the validity and interpretation of pooled analyses.Our findings indicate that methylprednisolone and dexamethasone are the most effective corticosteroids for preventing postextubation stridor and reintubation. Nevertheless, future large-scale clinical studies are needed to confirm our findings.The original contributions presented in the study are included in the article/C-CL, C-MChe, and I-JF: concepts and design. J-WL, K-CC, S-RC, and I-JF: analysis and interpretation of data. C-MCha and C-CL: drafting of the manuscript. C-MChe, K-ML, and Y-TW: critical revision of the manuscript. I-JF: statistical analysis. All authors contributed to the article and approved the submitted version.


Moreover, compared with the administration of a placebo, the administration of 50, 100, and 200 mg of canagliflozin was associated with lower serum creatinine levels. Furthermore, compared with the administration of a placebo, the administration of 100 mg canagliflozin, 2.5 mg dapagliflozin, and 25 mg empagliflozin was associated with a lower reduction in the estimated glomerular filtration rate. Except for 300 mg canagliflozin, all SGLT-2i were associated with greater increases in blood urea nitrogen levels . Finally, the administration of all SGLT-2i significantly increased the ratio of urinary glucose to creatinine compared with the ratio upon administration of placebo . Briefly, canagliflozin exerts the greatest therapeutic effect in terms of reducing the risk of renal impairment. Empagliflozin and canagliflozin may be more effective than other SGLT-2i in preventing renal impairment.In this study, the summarized WMDs and RRs were calculated using a pairwise analysis and a network meta-analysis with a random effects model, to compare and rank the efficacy and safety of SGLT-2i for renal outcomes in patients with T2DM. Among 1894 identified articles, 30 trials including 50,244 patients with T2DM were evaluated. Network analysis revealed that the administration of canagliflozin was associated with a reduced risk of renal impairment (surface under the cumulative ranking: 90.8%). Further, although the administration of SGLT-2i was not associated with the risk of renal impairment (RR = 0.88, 95%CI = 0.68–1.15,  Type 2 diabetes mellitus (T2DM) is a chronic disease caused by complex genetic and environmental factors in which blood glucose control is crucial for patient treatment and management . As the According to a previous study, the use of available drugs for diabetes enabled 53% of patients to achieve glycated hemoglobin (HbA1c) levels of <7.0% . NotablyAlthough several systematic reviews have examined the role of SGLT-2i in patients with T2DM , to the This meta-analysis included no patient or public involvement; hence, ethics approval and consent for participation were not required.Supplemental online material 1 [section 1]). Notably, clinicaltrials.gov was searched to identify completed studies with unpublished data. Reference lists of relevant original articles and reviews were manually checked to identify studies that met the inclusion criteria. When data were missing for studies that met the inclusion criteria, we contacted the corresponding author of the original article for additional information.This systematic review and NMA was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis . PlaceboTwo reviewers (MJ and LJ) performed the literature search and selected studies based on a standardized approach. Further, a third reviewer (ZH) resolved disagreements until a mutual consensus was reached among the three reviewers. Studies were included if they met the following patient, intervention, control, outcome, and study-design criteria: 1) studies in which all patients were diagnosed with T2DM; 2) studies involving administration of SGLT-2i, including canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, and tofogliflozin; 3) studies involving comparison with placebo or SGLT-2i; 4) studies in which the primary endpoint was mild renal impairment and the secondary endpoints were serum creatinine level, estimated glomerular filtration rate (GFR), serum blood urea nitrogen (BUN) level, and urinary glucose/creatinine ratio; and 5) RCTs.Two reviewers (MJ and SP) applied a standardized flow to extract all relevant information from the included studies. Data regarding the following items were collected: first author’s name, publication year, clinical trial registration number, country, sample size, mean age of participants, the proportion of male participants, baseline body mass index, T2DM duration, baseline HbA1c levels, intervention, control, renal impairment definition, and investigated outcomes. Notably, the quality of each trial was evaluated using version 2 of the Cochrane risk of bias tool in which the bias domains include biases caused by the randomization process (low risk/some concerns/high risk), deviations from the intended interventions (low risk/some concerns/high risk), and missing outcome data (low risk/some concerns/high risk) as well as biases in the measurement of the outcomes (low risk/some concerns/high risk), selection of the reported results (low risk/some concerns/high risk), and overall bias (low risk/some concerns/high risk). Furthermore, two reviewers (SP and ZX) independently assessed the quality of each trial, and a third reviewer resolved any conflicts between the two reviewers. Disagreements between the reviewers were resolved by discussion to reach a consensus.2I and Q statistics were used to assess heterogeneity for pairwise meta-analyses. An 2I value of >50% or a p-value of <0.10 indicated significant heterogeneity among the included trials ).The networks of eligible comparisons for the risk of renal impairment in NMA are summarized in p = 0.002) . The administration of 50 mg , 100 mg , and 200 mg  canagliflozin was associated with a greater reduction in serum creatinine levels than the administration of placebo. However, the administration of 2.5 mg dapagliflozin was associated with higher serum creatinine levels than the administration of placebo  . The results of the pairwise meta-analysis for the change in estimated GFR between SGLT-2i and placebo are shown in Supplemental online material 1 (section 5). Notably, the administration of 2.5 mg dapagliflozin  and 25 mg empagliflozin  was associated with a greater reduction in estimated GFR, whereas the administration of 100 mg canagliflozin was associated with significantly increased estimated GFR compared with the administration of placebo . The results of the pairwise meta-analysis for the change in BUN levels between SGLT-2i and placebo are shown in Supplemental online material 1 (section 6). Most SGLT-2i were associated with higher BUN levels than placebo, with WMDs ranging from 0.68 (95% CI: 0.54–0.82) for 200 mg canagliflozin to 2.28 (95% CI: 2.12–2.44) for 50 mg dapagliflozin; however, the BUN level associated with 300 mg canagliflozin was not statistically significant compared to that associated with placebo. Furthermore, all dapagliflozin doses were associated with a higher urinary glucose/creatinine ratio. The WMD values ranged from 28.20 (95% CI: 16.16–40.24) for 2.5 mg dapagliflozin to 42.71 (95% CI: 37.28–48.13) for 10 mg dapagliflozin .The administration of empagliflozin was associated with a lower risk of renal impairment than the administration of placebo (RR: 0.74; 95% CI: 0.62–0.90; This comprehensive quantitative systematic review and NMA was based on 30 RCTs including 50,244 patients with T2DM randomly assigned to receive treatment with six different SGLT-2i or placebo. The findings of this study expand the findings of previous systematic reviews that investigated the role of SGLT-2i in cardiovascular or specific adverse events . NotablySafety analyses revealed that canagliflozin and empagliflozin have the potential to provide protection against renal impairment. Moreover, we found that canagliflozin was associated with a lower risk of renal impairment than dapagliflozin and placebo. A previous NMA by Lin et al. found that SGLT-2i have favorable renal protective effects; however, their study did not find any significant differences in the effects between different SGLT-2i . This inWe found that 2.5 mg dapagliflozin and 25 mg empagliflozin were associated with a greater reduction in estimated GFR, whereas 100 mg canagliflozin was associated with significantly increased estimated GFR compared with placebo. These results are inconsistent with those of the DAPA-CKD and EMPA-KIDNEY trials, suggesting renal protective effects of dapagliflozin and empagliflozin ,73. The This study has some limitations. First, most of the identified studies investigated the effects of SGLT-2i on cardiovascular and metabolic factors, whereas only a few studies reported the incidence of renal impairment. Second, the definition of renal impairment varied among the included studies, which is possibly affected by WMDs from the overall analysis. Third, substantial heterogeneity was noted for continuous data, and further subgroup analyses based on countries or continents, race, or follow-up duration are needed. Fourth, although the results of NMA suggested the best treatment option for patients with T2DM, the efficacy of each treatment strategy was not balanced. Fifth, this study was not registered online, and the transparency of the study was limited. Finally, the inherent limitations for any meta-analysis related to published articles, including multiple comparisons according to patient characteristics, and publication bias should be noted.The results of this study provide comprehensive evidence for the optimal use of SGLT-2i in patients with T2DM to improve renal outcomes. Moreover, the study found that canagliflozin and empagliflozin may play protective roles against renal impairment in patients with T2DM.Click here for additional data file.


Previous observational studies have reported that lifestyle factors, metabolic factors and socioeconomic status are associated with the development of female pelvic organ prolapse (POP); however, whether these associations are causal remains unclear. The current study aimed to assess the causal effect of lifestyle factors, metabolic factors and socioeconomic status on POP risk.P < 5 × 10–8) as instrumental variables from genome-wide association studies. The method of random-effect inverse-variance weighting (IVW) was used as the primary analysis method, supplemented with the weighted median, MR-Egger and the MR pleiotropy residual sum and outlier applied to verify the MR assumptions. Two-step MR was conducted to investigate potential intermediate factors that are on the causal pathway from exposure to POP.We conducted a two-sample Mendelian randomization (MR) study based on summary-level data from the largest available genome-wide association studies (GWAS) to evaluate whether lifestyle factors, metabolic factors and socioeconomic status are causally related to POP. We used single nucleotide polymorphisms that are strongly associated with exposure at the genome-wide significance level (P < 0.001), WHR adjusted for body mass index (WHRadjBMI)  and education attainment  in the meta-analysis. Additionally, genetically predicted coffee consumption , vigorous physical activity  and high-density lipoprotein cholesterol (HDL-C)  were inversely associated with POP in the FinnGen Consortium. The mediation analysis showed that the indirect effects of education attainment on POP were partly mediated by WHR and WHRadjBMI, with a mediated proportion of 27% and 13% in the UK Biobank study, respectively.There were associations with POP for genetically predicted waist-to-hip ratio (WHR) (odds ratio (OR) 1.02, 95% confidence interval (CI) 1.01–1.03 per SD-increase, Our study provides MR evidence of a robust causal association of WHR, WHRadjBMI and education attainment with POP.The online version contains supplementary material available at 10.1186/s40001-023-01148-w. Pelvic organ prolapse (POP), also called urogenital prolapse, is a disorder that is exclusive to women, especially among those who have given birth and who are postmenopausal. It can affect the anterior vaginal wall, posterior vaginal wall and uterus or apex of the vagina, usually in some combination and thus, it involves the descent of pelvic organs such as the womb (uterus), bladder, bowel and vagina within and outside of the vaginal opening . Loss ofEpidemiological and observational studies have revealed several possible risk factors for POP, including obesity –10, diabThe Mendelian randomization (MR) design is an emerging genetic method that can strengthen causal inference regarding an exposure–outcome association by leveraging genetic variants as instrumental variables for exposure . The desHerein, we conducted a two-sample MR investigation to explore the potential causal associations of genetic liability for lifestyle and metabolic factors with POP risk based on the most recent and largest genome-wide association studies (GWAS). Given that education level is strongly correlated with the onset of obesity , 19, we As a genetic variant is usually deemed a proxy for a risk factor in an MR design, the choice of a genetic instrument variable (IV) is particularly important for a successful MR study. MR requires three basic IV assumptions to validate a genetic variant as valid IVs for causal inference: 1) the genetic variant should be robustly associated with the exposure; (2) the genetic variant is not related to potential confounders of the exposure–outcome association; and (3) the genetic variant should have no effect on the outcome other than through the exposure. Additional file  the geneP < 5 × 10–6) were identified at the genome-wide significance level (P < 5 × 10–8) and without linkage disequilibrium . Linkage disequilibrium among the SNPs was estimated using the 1000 Genomes European panel as the reference population. We harmonized all variants serving as IVs between the exposure and outcome data by effect allele. Given that a few SNPs were unavailable in the outcome data, we did not find proxies to replace missing single nucleotide polymorphisms. The F-statistic was used to assess the strength of IVs. It is a measure of instrument strength that is related to the proportion of variance in the phenotype explained by the genetic variants (R2), sample size (N) and the number of instruments (k) by the formula F = R2(N − k − 1)/k(1 − R2). Generally, an F-statistic of > 10 suggests a relatively low risk of bias caused by weak IVs in MR analysis. SNPs associated with body mass index (BMI) . The UK Biobank consortium is an ongoing cohort containing over 500,000 adults at the baseline of recruitment between 2006 and 2010. The study included up to 337,199 individuals , after excluding those with sex mismatch, non-Caucasian ethnicity, excess heterozygosity, a low genotype call rate and high relatedness. The seventh release of FinnGen consortium data contains integrated genetic data and disease trajectories from up to 309,154 Finnish biobank participants, 16,962,023 variants and 3095 disease endpoints . For theWe included GWAS data sources of potential mediators (obesity-related phenotypes) to investigate potential intermediate factors that are on the causal pathway from exposure to POP. The potential mediators included the following information: BMI from the GIANT consortium with 322,154 individuals of European ancestry ; WHR andQ statistics; a P value of < 0.05 would be regarded as indicative of significant heterogeneity. The weighted median method specifies that the MR estimates are robust even when up to 50% of the information comes from invalid instrumental variables [P-value of the MR-Egger intercept was used to examine the existence of directional pleiotropy. We performed MR-PRESSO analysis to identify possible outliers and generate estimates corrected for outliers [I2 statistic for the assessment of heterogeneity in the meta-analysis. I2 values of 25%, 50% and 75% were defined as low, medium and high heterogeneity, respectively [We used the method of inverse-variance weighting (IVW) with random effects to estimate MR associations between genetic liability to lifestyle factors, metabolic factors and the risk of POP. The IVW method assumes that all SNPs are valid instrumental variables and that the estimates can be interpreted to reflect the total effect of the exposure . It was ariables . MR-Eggeoutliers . Distortectively . All anaP = 0.03) for genetically predicted 50% increase in coffee consumption. Nonetheless, this observed association between coffee consumption and POP did not remain in the UK Biobank data and meta-analysis result. Vigorous physical activity was suggestively inversely associated with the risk of POP in the FinnGen consortium. The OR of POP was 0.83  for genetic predisposition to vigorous physical activity. Likewise, we have still not observed the consistent association between vigorous physical activity and POP in the UK Biobank data and meta-analysis result.Sample overlap was 0–11.8% between the exposures and the outcome data source. Among lifestyle factors, in the primary analyses using IVW, no significant evidence showed that smoking initiation, alcohol drinking and heavy physical work were associated with an increased risk of POP in the UK Biobank study consortium and FinnGen consortium. Univariable MR analysis result from the FinnGen consortium showed a protective causal relationship between coffee consumption and POP. The odds ratio (OR) of POP was 0.67  0.47, 0.96; P < 0.05)  per 1-SD increase in WHR and 1.017  per 1-SD increase in WHRadjBMI. Higher genetically predicted BMI seemed not to be associated with POP in the FinnGen consortium data and the UK Biobank data. It is worth noting that although pooled OR of POP was 1.007  for genetically predicted 1-SD increase in BMI, we should be cautious about interpreting this result. In addition, there was suggestive evidence for the potential benefits of genetically higher HDL-C  on the risk of POP in the FinnGen consortium data, but not in the UK Biobank data and meta-analysis. No significant associations of POP risk were observed for genetically determined type 2 diabetes, SBP, DBP, LDL-C and triglycerides. We observed a strong protective causal relationship between education attainment and POP in FinnGen consortium data, UK Biobank data and meta-analysis (P < 0.05). The ORs of POP were 0.81  in the FinnGen consortium, 0.986  in the UK Biobank consortium and 0.986  in the meta-analysis for genetically predicted 1-SD change of education attainment.Genetically predicted higher WHR and WHRadjBMI was associated with an increased risk of POP in FinnGen consortium data, UK Biobank data and meta-analysis (05) Fig. . The comThe observed associations were consistent across sensitivity analyses and between FinnGen consortium data and UK Biobank data overall Table . Moderatβ = − 0.196, 95% CI − 0.268 to − 0.125, P = 7.43 × 10–8) and decreased WHRadjBMI . In the second step, we estimated the causal effect of the mediators on POP risk. We identified causal evidence for effects of WHR  and WHRadjBMI  on POP in both the FinnGen consortium and UK Biobank study . Nevertheless, our findings were not in line with this cohort, suggesting no causal association between heavy physical work and POP in the FinnGen consortium, the UK Biobank study and the meta-analysis. Evidence from epidemiological and observational studies illustrated that most physical activity would not harm the pelvic floor and facilitate the genesis of POP [The association between smoking and risk of POP has not been consistent in observational studies. An observational study involving 906 participants showed that smoking was an independent risk factor for POP, while another case–control study including 662 women referred for pelvic floor dysfunction revealed that smoking was not a significant risk factor for POP , 36. A rs of POP , 39, 40.P = 0.047) for a genetically predicted 1-SD increase in BMI in this study. WHR, representing abdominal obesity, can be used to estimate the fat distribution of our body and help indicate a person’s overall health. We also observed suggestive positive associations between genetically determined WHR and the predisposition to POP. The combined OR of POP was 1.02  per 1-SD increase in WHR. WHRadjBMI is a surrogate measure of abdominal adiposity and can also be used to indicate a person’s overall health [P < 0.001) per 1-SD increase in WHRadjBMI, indicating that WHRadjBMI was a possible causal risk factor of POP. Other metabolic traits, including type 2 diabetes, SBP, DBP, HDL-C, LDL-C and triglycerides, are usually closely related to overweight and obesity [P = 0.049).Review articles concerning the association between obesity and POP have revealed consistent evidence that obesity was significantly related to an elevated risk of POP –10, 41. l health . In the  obesity . We alsoP < 0.001). Considering that education level is tightly correlated with obesity [β = − 0.004, 95% CI − 0.005 to − 0.003), which is aligned with our findings in the first step with regard to direction and magnitude. The second MR step demonstrated that genetically predicted higher WHR and WHRadjBMI were associated with higher odds of POP. In the FinnGen consortium, we found that an estimated 25% and 14% of the total effect was mediated by WHR and WHRadjBMI, respectively. Similarly, in the UK Biobank study, we found that an estimated 27% and 13% of the total effect was mediated by WHR and WHRadjBMI, respectively. These results indicated that the indirect effects of education attainment on POP were partly mediated by WHR and WHRadjBMI.Epidemiological studies have concluded that obvious regional differences regarding the prevalence of POP and rural areas exist and seem to be correlated with a high prevalence of POP , 47, 48. obesity , 49, 50, obesity  reportedOur study has several strengths. The major one lies in the use of an MR design based on large-scale GWAS summary datasets to avoid possible bias caused by residual confounders and reverse causality, which are difficult to exclude completely in traditional observational studies. In addition, we combined data from two independent study populations including a huge number of cases with POP, which strengthened the power of the analysis. The current study was confined to subjects of European ancestry, which diminished the population structure bias, so the findings may be specifically generalizable to the European population. Our study has several limitations. First, differences existed regarding the quality control criteria of GWAS for POP between the UK Biobank and FinnGen. We observed high heterogeneity in the combined effects of education attainment, WHR and WHRadjBMI on POP risk; this difference may result in heterogeneity between causal estimates of association. Second, the limitation of our analyses to populations of European ancestry may lead to reduced reliability when extrapolating our findings to individuals of non-European descent. Finally, the major issue for any MR approach is horizontal pleiotropy that means selected genetic instrument variables influence the risk of outcome not via the exposure but confounders. Although we incorporated a range of sensitivity analyses to prevent confounding affecting our conclusions, this possibility cannot be entirely excluded. Lifestyle factors, metabolic factors and socioeconomic status may influence the risk of POP via other pathways. It will be of great significance to identify potential confounders that can detect and predict clinical outcomes among patients with POP.In summary, our MR study provided robust genetic evidence for the causal role of education attainment, WHR and WHRadjBMI in the risk of POP development. Mediation effects of WHR and WHRadjBMI in the association between education attainment and POP suggest the important role of the management of overweight and obesity in POP prevention. The inverse associations for genetically predicted coffee consumption, vigorous physical activity and HDL-C warrant validation in well-powered studies.Additional file 1: Figure S1. Directed acyclic graph and key assumptions of MR design. For details of assumptions, please refer to the MR design part in the manuscript.Additional file 2: Figure S2. Forest maps of each SNP’s effect for WHR on POP.Additional file 3: Figure S3. Forest maps of each SNP’s effect for WHRadjBMI on POP.Additional file 4: Figure S4. Forest maps of each SNP’s effect for education attainment on POP.Additional file 5: Table S1. Genetic instruments in relation to pelvic organ prolapse.Additional file 6: Table S2. Characteristics of the genetic instrument variables for exposures in both the FinnGen consortium and UK Biobank.


The most common cause of revision arthroplasty is prosthetic joint infection (PJI). Chronic PJI is commonly treated with two-stage exchange arthroplasty involving the placement of antibiotic-laden cement spacers (ACS) in the first stage, often containing nephrotoxic antibiotics. These patients often have significant comorbidity burdens and have higher rates of acute kidney injury (AKI). This systematic review aims to assess the current literature to identify (1) AKI incidence, (2) associated risk factors, and (3) antibiotic concentration thresholds in ACS that increase AKI risk following first-stage revision arthroplasty.An electronic search was performed of the PubMed database of all studies involving patients undergoing ACS placement for chronic PJI. Studies assessing AKI rates and risk factors were screened by two authors independently. Data synthesis was performed when possible. Significant heterogeneity prevented meta-analysis.Eight observational studies consisting of 540 knee PJIs and 943 hip PJIs met inclusion criteria. There were 309 (21%) cases involving AKI. The most commonly reported risk factors included perfusion-related factors , older age, increased comorbidity burden, and nonsteroidal anti-inflammatory drug consumption. Only two studies found increased risk with greater ACS antibiotic concentration ; however, these were reported from univariate analyses not accounting for other potential risk factors.Patients undergoing ACS placement for chronic PJI are at an increased risk for AKI. Understanding the risk factors may lead to better multidisciplinary care and safer outcomes for chronic PJI patients.Level of evidence III. As total joint arthroplasty (TJA) becomes more prevalent in the USA, the burden of revision arthroplasty is expected to increase as well . One of One such complication is acute kidney injury (AKI), which has been extensively studied in primary TJA but less so in the two-stage revision arthroplasty setting , 11. ThiThe goals of this systematic review were to assess the existing literature to (1) establish an incidence of AKI following first-stage exchange arthroplasty, (2) identify perioperative risk factors for AKI risk, (3) determine the antibiotic concentration thresholds in ACS over which AKI risk is significantly increased.This systematic review was conducted in accordance with the PRISMA  guidelines . An elecN ≥ 10 (case series and case reports excluded).Studies were included for review if they (1) involved subjects undergoing ACS placement in the first stage of treatment for PJI, (2) included AKI as an outcome, as defined by either the Kidney Disease Improving Global Outcomes (KDIGO)  or the RAll screening and text review was conducted independently by two authors (YPC and ML). All disagreements were resolved through discussion among screening authors, with senior author involvement included as needed (RMA).All data extraction was performed by three authors . Extracted variables included country in which the study was conducted, study inclusion and exclusion criteria, patient characteristics , procedure type (knee vs. hip revision), cement spacer type, antibiotic impregnated in the spacer, quantity of antibiotic used, systemic antibiotics administered during the study period, AKI definition, and incidence of AKI. Risk factors for AKI based on univariate and multivariate analysis were also extracted, as well as the subsequent odds ratios (OR) with 95% confidence intervals (CI). Given the high heterogeneity in antibiotics and spacer types, a meta-analysis could not be performed.Quality appraisal was performed using the Methodological Index for Non-Randomized Studies (MINORS) criteria for non-randomized studies, which is scored out of a maximum 16 points for non-comparative studies and 24 points for comparative studies [A total of 882 citations were identified Fig.  and screPerfusion-related factors such as lower preoperative hemoglobin, higher median number of units of blood transfused or intraoperative transfusion, and postoperative hypovolemia were commonly found to have an association with increased risk for AKI. Other commonly reported risk factors included increasing age, perioperative use of nephrotoxic medications such as nonsteroidal anti-inflammatory drugs, and comorbidity burden . Six studies performed multivariate analysis along with univariate analysis, while two studies only performed univariate analysis , 23. OneTwo studies reported thresholds of antibiotic concentration in ACS associated with increased AKI risk. One found that > 3.6 g of vancomycin or aminoglycosides per batch of cement in first-stage knee revisions was associated with increased AKI risk ), while The results of quality appraisal for the included studies are presented in Table Acute kidney injury (AKI) has been shown to increase morbidity and mortality following revision TJA. The incidence of AKI after the first stage of a two-stage revision arthroplasty in the current literature ranges between 10 and 33%. Although current evidence is limited and precludes meta-analysis, the most commonly associated risk factors reported include perfusion-related factors , older age, increased comorbidity burden, and perioperative nephrotoxic drug use. Only two studies found that certain antibiotic concentration thresholds in ACS were linked to increased AKI risk, but neither of these were the result of multivariate analysis accounting for other risk factors.A similar systematic review performed by Luu et al. in 2013 on ten studies consisting of 544 patients reported an AKI incidence of approximately 5% , a substIn assessing the risk factors for AKI following ACS implantation, the most commonly reported were related to poor perfusion, such as low hemoglobin, and perioperative blood transfusions or hypovolemia. These are well-established risk factors in primary TJA literature, but it is important to recognize the increased rates of blood loss and transfusion with septic revision arthroplasty , 28. ThiRegarding the ideal concentration of antibiotics in an ACS, this review included two studies that demonstrated ACS antibiotic concentration thresholds associated with increased risk of AKI , 20. DagA significant limitation of the current review was the heterogeneity of the included studies with regards to ACS type, concentrations, concomitant systemic antibiotics, and study design. This variation unfortunately did not allow for meta-analysis. Additionally, AKI is a multifactorial diagnosis—it is difficult to state a cause–effect relationship regarding systemic antibiotic use in two-stage revision. Strengths of this review include the strict inclusion criteria when screening studies, particularly the requirement for a clear and widely recognized definition for AKI. Additionally, revision TJA for PJI is difficult to study in volume, as coding for these procedures is notoriously inaccurate making database studies unreliable . Large dThe high incidence rates of AKI following the first stage of two-stage revision arthroplasty must be considered by providers in the treatment of chronic PJI. Identification of associated risks should be used to better guide preoperative optimization and treatment of these patients, such as reducing the risk of perioperative hypovolemia. Further study is warranted to identify the AKI risk attributed to ACS versus other potential causes of nephrotoxicity as well as the ideal dosage of antibiotics added to ACS constructs.


Background: Chronic obstructive pulmonary disease (COPD) affects approximately 400 million people worldwide and is associated with high mortality and morbidity. The effect of EPHX1 and GSTP1 gene polymorphisms on COPD risk has not been fully characterized.Objective: To investigate the association of EPHX1 and GSTP1 gene polymorphisms with COPD risk.Methods: A systematic search was conducted on 9 databases to identify studies published in English and Chinese. The analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines (PRISMA). The pooled OR and 95% CI were calculated to evaluate the association of EPHX1 and GSTP1 gene polymorphisms with COPD risk. The I2 test, Q test, Egger’s test, and Begg’s test were conducted to determine the level of heterogeneity and publication bias of the included studies.Results: In total, 857 articles were retrieved, among which 59 met the inclusion criteria. The EPHX1 rs1051740 polymorphism  was significantly associated with high risk of COPD risk. Subgroup analysis revealed that the EPHX1 rs1051740 polymorphism was significantly associated with COPD risk among Asians  and Caucasians . The EPHX1 rs2234922 polymorphism  was significantly associated with a low risk of COPD. Subgroup analysis showed that the EPHX1 rs2234922 polymorphism  was significantly associated with COPD risk among Asians. The GSTP1 rs1695 polymorphism (homozygote and recessives model) was significantly associated with COPD risk. Subgroup analysis showed that the GSTP1 rs1695 polymorphism (homozygote and recessives model) was significantly associated with COPD risk among Caucasians. The GSTP1 rs1138272 polymorphism (heterozygote and dominant model) was significantly associated with COPD risk. Subgroup analysis suggested that the GSTP1 rs1138272 polymorphism  was significantly associated with COPD risk among Caucasians.Conclusion: The C allele in EPHX1 rs1051740 among Asians and the CC genotype among Caucasians may be risk factors for COPD. However, the GA genotype in EPHX1 rs2234922 may be a protective factor against COPD in Asians. The GG genotype in GSTP1 rs1695 and the TC genotype in GSTP1 rs1138272 may be risk factors for COPD, especially among Caucasians. Chronic obstructive pulmonary disease (COPD) is a common disease that is characterized by persistent airflow limitation and the associated respiratory symptoms. Oxidative stress and chronic inflammation are important components of the mechanism contributing to COPD . It has GSTP1) and microsomal epoxide hydrolase (EPHX1) are typical detoxification enzyme genes known to be highly expressed in the lungs and are closely associated with oxidative stress and inflammatory responses in COPD (Cigarette smoke contains many toxic constituents which stimulate the release of vast amounts of reactive oxygen species (ROS) and reactive nitrogen species (RNS) by airway epithelial cells, granulocytes, and macrophages, leading to oxidative stress, oxidative inactivation of antiproteases, alveolar epithelial damage, increased neutrophils in pulmonary microvessels, and enhanced proinflammatory gene expression. Some of the genes involved in the metabolism of toxic substances found in cigarette smoke are thought to participate in COPD pathogenesis  is located on chromosome 1q42.1 and contains 9 exons and 8 introns (EPHX1 enzyme activities (EPHX1 rs1051740 genetic variations increased the risk of COPD (EPHX1 rs2234922 variation decrease the risk of COPD (GSTP1 (≈3 kb long), a member of the GST superfamily, is located on chromosome 11q13 and contains 6 introns and 7 exons. Compared to other GSTs, it is highly expressed in respiratory tissues including the alveoli, alveolar macrophages as well as bronchioles  and GSTP1 (rs1695 and rs1138272) polymorphisms with the risk of COPD risk, with the aim of providing evidence-based information on COPD pathogenesis which can be used to develop potential strategies for its diagnosis, prevention and treatment. The analysis was conducted in line with the PRISMA 2020  between groups; and ④ Involved human subjects.The inclusion criteria for studies were: ①Explored the association of The exclusion criteria for studies were: ① Were repeat published studies; ②Case reports, comments, or expert opinions; ③ Included other genetic polymorphisms; ④ Involved a non-healthy  control group; and ⑤ Lacked data that could be extracted from text, tables, or charts, or that could be obtained from the authors upon request.Two researchers (QY and WH) independently searched for the articles, assessed the inclusion/exclusion parameters, and conducted data extraction. Any discrepancies were resolved through discussions between two reviewers (JT and ZL). The extracted data included the first author’s name, year of publication, sample size, ethnicity, genotype, genotyping method, genotype count, allele count, and whether it met the Hardy Weinberger equilibrium (HWE). Using the Newcastle-Ottawa Scale (NOS) , the quaEPHX1 (rs1051740 and rs2234922) and GSTP1 (rs1695 and rs1138272) polymorphisms with the risk of COPD was analyzed using homozygote, heterozygote, dominant, recessive, and allele models. Higgin’s I2 and Cochran’s Q tests were used to evaluate heterogeneity between studies. Where heterogeneity was significant , the random-effects model (DerSimonian–Lloyd method) was used, and in contrast , the fixed-effects model (Mantel‒Haenszel method) was used. The pooled odds ratio (OR) and 95% confidence interval (95% CI) were used as effect measurement indicators for each result. Furthermore, we conducted subgroup analyses according to different ethnic information. Egger’s and Begg’s tests were used to assess the publication bias, with p > 0.05 indicating no significant publication bias. If publication bias was found, the trim-and-fill method was used to assess the stability of the pooled results, and a funnel plot was drawn. A non-significant change in p values indicated that publication bias had little influence on the results. Sensitivity analysis was performed by excluding the studies one by one to determine the impact of each study on the total effects value and to assess the stability of results. All statistical analyses were done using Stata 17.0 .The association of EPHX1 rs1051740 and involved 5007 cases and 5476 controls, 26 explored EPHX1 rs2234922 and involved 4840 cases and 5326 controls, 31 investigated GSTP1 rs1695 and comprised 3975 cases and 4301 controls, while 7 explored GSTP1 rs1138272 and involved 1170 cases and 1455 controls. A schematic presentation of the literature screening process is shown in We employed an unrestricted literature search and a repeated search review procedure. Based on our inclusion and exclusion criteria, 59 articles containing genetic data were selected for analysis. Among them, 28 investigated EPHX1 rs1051740 polymorphism with the COPD risk as shown in 2>50%, PQ<0.10). Therefore, the random-effects model was used to determine the pooled OR and its 95% CI. For the homozygote model , heterozygote model , dominant model , recessive model  and allele model , EPHX1 rs1051740 was significantly associated with COPD risk, indicating that the C allele is a risk factor for COPD. Subgroup analysis based on ethnicity showed that in the homozygote model , heterozygote model , dominant model , and allele model , EPHX1 rs1051740 was significantly associated with COPD risk among Asians, suggesting that the C allele is a risk factor for COPD in Asians. In addition, we also found that in the homozygote model , dominant model , recessive model  and allele model , EPHX1 rs1051740 was significantly associated with COPD risk among Caucasians, indicating that the CC genotype is a risk factor for COPD in Caucasians. Since 8 studies had PHWE<0.05 , recessive model  and allele model ] was significantly associated with COPD risk, consistent with findings from the overall analysis. Thus, studies with PHWE<0.05 did not affect the overall results, and the findings were generally reliable.The results of meta-analyses of various models and subgroup analyses were utilized to explore the association of HWE<0.05 , we condPEgger = 0.031), recessive model (PEgger = 0.029) and allele model (PEgger = 0.023)] showed that publication bias might have been present, but Begg’s test did not reveal any publication bias (PBgge>0.05) . The nonparametric trim-and-fill method was used to reduce the deviation in the combined effects. The trim-and-fill method is used to correct the impact of publication bias on the combined effect of meta-analysis. If the result of funnel plots show symmetry and Pz > 0.05 based on the trim-and-fill method results, the publication bias is not considered to significantly affect the reliability of the pooled results (PZ = 0.012) and the allele model , indicating that the publication bias was too small to affect the stability of subgroup analysis results  . Given the high heterogeneity  among the five genetic models, we conducted sensitivity analyses by excluding the studies one by one. The OR values of all studies fell within the 95% CI , and thus the fixed-effects model was used to determine the pooled OR and it is 95% CI. For the heterozygote model , dominant model  and allele model , EPHX1 rs2234922 was found to be significantly associated with a lower risk of COPD, indicating that the G allele may be a protective factor for COPD. Subgroup analyses based on ethnicity showed that in the heterozygote model , dominant model  and allele model , EPHX1 rs2234922 was significantly associated with reduced COPD risk among Asians, indicating that the GA genotype may be a protective factor for COPD among Asians. Considering that 2 studies had PHWE<0.05  and allele model ] were associated with a lower risk of COPD, consistent with findings from the overall analysis, and indicating that some studies with PHWE <0.05 did not affect the overall results, which were reliable.The results of meta-analyses of various models and the subgroups used to explore the association between HWE<0.05 , we condPEgger>0.05, PBgge>0.05) , and therefore, the fixed-effects model was used to determine the pooled OR and its 95% CI. The other models had significant heterogeneity . Thus, the random-effects model was adopted. For the homozygote model  and recessive model , GSTP1 rs2234922 was found to be significantly associated with COPD risk, indicating that the GG genotype is a risk factor for COPD. Subgroup analysis based on ethnicity showed that in the homozygote model  and recessive model , GSTP1 rs1695 was significantly associated with COPD risk among Caucasians, while the association among Asians was not significant. Since 4 studies had PHWE <0.05  and recessive model ] was significantly associated with COPD risk, consistent with findings in the overall analysis, indicating that some studies with PHWE <0.05 did not affect the overall results, which were reliable.The results of the meta-analysis among various models and subgroups used to explore the association between WE <0.05 , we condPEgger>0.05, PBgge>0.05) among the included studies . In addition, sensitivity analysis was performed by excluding the studies one by one to determine the impact of each study on heterogeneity . The OR values for all studies were within the 95% CI . Therefore, the random-effects model was used to determine the pooled OR and its 95% CI. For the heterozygote model  and dominant model , GSTP1 rs1138272 was significantly associated with COPD risk, indicating that the TC genotype is a risk factor for COPD. Subgroup analysis by ethnicity revealed a significant association of GSTP1 rs1138272 with COPD risk among Caucasians for the homozygote model , heterozygote model  dominant model  and allele model . These results indicate that the TC genotype might be a risk factor for COPD among Caucasians. Since 2 studies had PHWE <0.05 , heterozygote model , dominant model , recessive model , and allele model ], inconsistent with findings from the overall analysis.The results of the meta-analysis of various models and subgroups used to explore the association between WE <0.05 , we condPEgger>0.05, PBgge>0.05) . Given the significant heterogeneity  and inconsistent results caused by articles with PHWE<0.05, we performed a sensitivity analysis by excluding the studies one by one. The OR values of all studies were within the 95% CI  and GSTP1 (rs1695 and rs1138272) polymorphisms with the risk of COPD. Since the ethnic background of gene-gene and gene-environment interactions affect SNP and disease risk, we conducted subgroup analysis based on ethnicity to determine the association between EPHX1 and GSTP1 gene polymorphisms and COPD risk in different ethnic groups.Chronic obstructive pulmonary disease (COPD) is a polygenic disease that is caused by various environmental factors and genetic factors . The gene oxides . AlthougEPHX1 rs1051740 showed that the C allele of EPHX1 rs1051740 may be a risk factor for COPD. It was reported that a T/C mutation on codon 113 of exon 3 of EPHX1, substituting Tyr113 with His113, reduces the enzymatic activities of EPHX1 by 40%–50%, which increases the oxidation rate beyond the antioxidative capacity, resulting in the accumulation of reactive oxygen species in the organism and eventually, cell and lung tissue damage  and Caucasians   . HoweverEPHX1 exon 4 replaces Hisl39 with Arg139, it increases the activities of EPHX1 by 25%   are significantly associated with COPD risk.Furthermore, when a G/A mutation on codon 139 of 1 by 25% . Our met = 0.65) . Lee J e1 enzyme . We postEPHX1 and GSTP1 gene polymorphisms, and alterations in the combined EPHX1-GSTP1 detoxification activity may affect COPD development  but not among Asians   . Howeveric model . The asscapacity . It resucapacity . This isevidence .GSTP1 rs1138272 showed that the TC genotype is a risk factor for COPD, and subgroup analysis showed that Caucasians carrying the TC genotype are more likely to suffer from COPD. It has been shown that the frequency of GSTP1 rs1138272 TC genotype in COPD patients was significantly higher than in normal people (28.57% vs. 14.45%), indicating that the GSTP1 rs1138272 polymorphism may be associated with COPD risk . It is reported that the T/C variant of GSTP1 on exon 6 replaces Ala114 with Val114 without changing enzymatic activities  mutations are associated with an increased risk of COPD. Given the correlation between GSTP and EPHX1, further studies should be performed to establish if EPHX1-GSTP1 interactions influence COPD development.Our meta-analysis of OPD risk . In contOPD risk  concludetivities . HoweverPHWE<0.05 of the control group in the original article indicates that there may be a potential deviation in the study during control selection or genotyping errors  could not be calculated using the factor model and another 3 studies had a high heterogeneity , indicating that the deviation may be caused by the high heterogeneity between studies and the small number of studies. Sensitivity analysis showed that OR values for all of the studies were within the 95% CI, indicating that the results were stable and reliable. After subgroup analysis according to PHWE≥0.05, the heterogeneity of EPHX1 1051740 , EPHX1 rs2234922 , and GSTP1 rs1695  were decreased, so whether the control group included in the study conformed to PHWE ≥0.05 may be one of the sources of partial result heterogeneity.The g errors . To avoiEPHX1 (rs1051740 and rs2234922) and GSTP1 (rs1695 and rs1138272) with the risk of COPD. Moreover, subgroup analysis was performed on different ethnicities to determine the effects of these polymorphisms on COPD susceptibility in diverse populations. However, this study has some limitations. For instance, our results are based on individual unadjusted estimates, and therefore, a more accurate prediction model need to be established after adjusting for potential confounding factors, such as sex, age, body mass index, lung functions, smoking status, and other environmental factors. However, subgroup analysis did not reveal whether these factors are associated with gene polymorphisms. Secondly, the results obtained from the subgroup analyses may be limited by the small number of studies involving African populations. Thirdly, although genetic and environmental factors may increase COPD risk, gene-gene and gene-environment interactions could not be assessed because of the limited data available. Finally, some of the studies included in this meta-analysis had significant heterogeneity which decreases the reliability of the final results.The key strengths of this study are as follows. Firstly, strict inclusion and exclusion criteria were used to comprehensively assess the association of the polymorphisms of EPHX1 (rs1051740 and rs2234922) and GSTP1 (rs1695 and rs1138272) polymorphisms are associated with the risk of COPD. The C allele of EPHX1 rs1051740 may increase the risk of COPD, especially among Asians, whereas the CC genotype may be a risk factor for COPD among Caucasians. In contrast, the G allele of EPHX1 rs2234922 may protect against COPD, especially the GA genotype significantly reducing COPD risk in Asians. The G allele of GSTP1 rs1695 may increase COPD risk, especially among Africans, whereas the TC genotype of GSTP1 rs1138272 may increase COPD risk, especially among Caucasians. These results indicate that EPHX1 and GSTP1 gene polymorphisms play key roles in COPD pathogenesis. Therefore, they are potential diagnostic and therapeutic targets in COPD. However, our conclusions should be validated in larger studies. Moreover, further analysis of gene-gene and gene-environment interactions should be performed to elucidate the mechanisms of COPD pathogenesis.