Our study aimed to investigate the association between epicardial adipose tissue (EAT) and atrial fibrillation (AF) recurrence risk after catheter ablation.We searched PubMed, Embase, and Cochrane Library databases up to November 30, 2021 without language restrictions. Outcome was the relative risk (RR) of EAT contributes to AF recurrence after catheter ablation. The RR and 95% confidence interval (CI) was pooled by the random-effect model.10 studies that contained 1840 AF patients were included in our study. The result of this study showed that EAT amount was associated with higher risk of AF recurrence after catheter ablation  and EAT related thickness was a risk factor for AF recurrence after catheter ablation . Sub-analysis showed that EAT was strongly associated with higher risk of AF recurrence common in Asian population , patients aged ≤ 60 years old , and follow-up more than 1 year .The meta-analysis demonstrated that EAT related thickness seems to be the marker most strongly associated with a greater risk of AF recurrences after catheter ablation. It should be included into risk stratification for predicting AF recurrent before catheter ablation.The online version contains supplementary material available at 10.1186/s12872-022-02703-9. Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide, it has been estimated that approximately 6–12 million people will develop AF in the US by 2050 and 17.9 million people will develop AF in Europe by 2060 . RecentlEpicardial adipose tissue (EAT), also referred to epicardial fat tissue (EFT), is located between the myocardium and the visceral pericardium and is commonly found in the atrioventricular and inter-ventricular grooves of the adult human heart  . PreviouSeveral previous retrospective studies reported that EAT was also associated with higher recurrence risk in AF patients after catheter ablation –16. HoweThis systematic review was conducted following the recommendations of the Cochrane Collaboration Handbook, observational studies in epidemiology statement , Meta-AnWe searched the databases PubMed, Embase, and Cochrane Library until November 30, 2021. Search keywords were “atrial fibrillation,” “AF,” “epicardial adipose tissue,” “epicardial fat,” “catheter ablation,” and “radiofrequency ablation,”. We also searched two clinical trials registers as well as previous systematic reviews and reference lists of included studies. No language restrictions were applied. Our search strategy combined text words and subject headings, with details presented in Additional file We included studies of all designs that produce estimates of test accuracy or provide data from which we can compute estimates, including the following: (1) Reported relevant EAT parameter  or with other statistical indexes ; (2) Available data of relative risk (RR), or hazard ratio (HR) and their 95% confidence intervals (CI) for EAT contribute to AF recurrence risk after catheter ablation; (3) Follow-up more than 6 months; Exclusion criteria including the following: (1) For duplicated reports, the last published study was included; (2) Conference papers without available data; (3) Not catheter ablation for AF.Three independent reviewers  screened titles, abstracts for potential eligible studies, and assessed full-text articles against the eligibility criteria. Disagreements were resolved through consensus with the fourth reviewer (LQ). Data was extracted including author, study type, region, study size, the measurement of EAT, the interesting indicator  of each study included as the main outcomes. The baseline characteristic of each study population was also documented.The quality of observational studies were evaluate by the Newcastle Ottawa quality assessment scale (NOS) . The ass2 < 50%; and random-effect models for high heterogeneity: P ≤ 0.05 or I2 ≥ 50%). We performed subgroup analysis to further explore the effect of different factors on the final results. First subgroup analysis investigate which EAT parameters  were significantly associated with AF recurrence after catheter ablation, other subgroup analysis mainly investigate the source of heterogeneity according to population average age (≥ 60 years old vs. < 60 years old), ethnicity (Asian vs non-Asian), follow-up duration of study (> 1 year vs. ≤ 1 year) and the study sample size (> 200 patients vs. ≤ 200 patients). Sensitivity analysis was conducted to assess the impact of each study on the final results by eliminating one study and meta-merged the left ones. Sequentially deleting the later study and then meta-merged the left ones to investigate every study’s effect on the final results. Publication bias was resented by a funnel plot. Stata 15.0  and Review Manager version 5.4  were used to conduct our data and pool the meta-analysis.We used relative risk (RR) and their associated 95% confidence intervals (Cl) to evaluate the association between EAT amount and AF recurrence after catheter ablation, and considered a P value ≤ 0.05 to be statistically significant. The effect size conduction was merged by fixed-effect models or random-effect models according to the heterogeneity  compared with those population average age over 60 years old study , as shown in Additional file Our meta-analysis based on observational retrospective studies that pooled together 10 studies with 1840 AF patients. The result showed that EAT was associated with higher risk of AF recurrence after catheter ablation. Further analysis demonstrated that this association was more common in Asian AF population, younger AF patients (age < 60 years old), and long-term follow-up (> 1 year).Previous meta-analysis have reported the association between EAT and AF recurrence after ablation based on comparing the relevant epicardial fat parameters  between the AF recurrence group and non-recurrence group. The results of previous meta-analysis showed that LA-EFT, EFT thickness, and total EFT volumes were increased in AF recurrent subjects . Since tObesity is a worldwide healthcare problem, which affected 670 million adults in 2016 around the world . GloballEAT was unique fat tissue that distinguishes from other depots of visceral fat. Epicardium shares an unobstructed microcirculation with the underlying myocardium without distinct boundaries, and produces cytokines that nourish the heart in healthy conditions . HoweverEAT maybe a tool for identify those individuals more susceptible to recurrent after catheter ablation. However, the evaluation indexes of EAT in current studies are not uniform, EAT volume, EAT thickness, EAT volume index or LA EAT volume/thickness are common in present studies. Early studies (published before 2015 years) were focused on the volume or thickness of EAT, while subsequent studies (published after 2015 years) were turn to the index parameter related to EAT. In terms of the thickness of EAT, Chao et al. and Canpolat et al. indicated that 6.9 mm may be a good cut-off value for predicting the recurrence after ablation , 14. MaeSome limitations should be taken into account in our study. First, all included studies for meta-analysis were retrospective studies, which may exist some bias compared with prospective cohort studies. Our study confirmed that there was a certain publication bias in the present study. Future prospective cohort studies are needed to provide more convincing evidence on this topic. Second, the sample size was not large enough among each study, and a total of 1840 AF subjects were included in the present meta-analysis, however, it’s the largest study for investigating the association between EAT and AF recurrence after catheter ablation. Third, although we have made subgroup analysis across EAT related parameters, population average age, region, follow-up duration, and the study sample size, however, the result of our meta-analysis remained a high heterogeneity. We refer to previous two meta-analysis of this area, there were also a nonnegligible heterogeneity in their studies , 26. We Our study demonstrated that EAT was associated with a higher risk of AF recurrence after catheter ablation. EAT related thickness seems to be the marker most strongly associated with a greater risk of AF recurrences after catheter ablation. It is necessary to perform an evaluation of EAT for AF individuals before catheter ablation. In addition, we hope future researches will provide more evidence for making a unified standard for EAT evaluation, and include it in risk stratification for predicting AF recurrence after catheter ablation.Additional file1: PRISMA-P  2015 checklist: recommended items addressed in our systematic review and meta-analysis.Additional file2: Search strategy.Additional file3: Quality evaluation scale for prevalence studies.Additional file4: Fig. S1. The forest plot of subgroup analysis (population average age) for the association between the EAT amount and recurrence risk after catheter ablation in atrial fibrillation patients. The risk ratio (RR) is used to evaluate the association.Additional file5: Fig. S2. The forest plot of subgroup analysis (The regions) for the association between the EAT amount and recurrence risk after catheter ablation in atrial fibrillation patients. The risk ratio (RR) is used to evaluate the association. (PNG 16 KB)Additional file6: Fig. S3. The forest plot of subgroup analysis (The follow-up duration) for the association between the EAT amount and recurrence risk after catheter ablation in atrial fibrillation patients. The risk ratio (RR) is used to evaluate the association.Additional file7: Fig. S4. The forest plot of subgroup analysis (The study size) for the association between the EAT amount and recurrence risk after catheter ablation in atrial fibrillation patients. The risk ratio (RR) is used to evaluate the association.


In addition to adiposity, lifestyle factors such as poor diet, low physical activity, alcohol intake and smoking are noted to be associated with the development of colorectal cancer (CRC). This study aims to investigate the association and dose-response relationship between adherence to a healthy lifestyle and CRC risk.A systematic literature search was conducted in MEDLINE and EMBASE for studies examining multiple lifestyle factors with risk of CRC, incident colorectal adenoma (CRA), and CRC-specific mortality through June 2021 without restrictions on language or study design. Meta-analysis was performed to pool hazard ratios using random-effects model. Subgroup analyses were performed based upon study and sample characteristics. Random-effects dose-response analysis was also conducted for CRC risk to assess the effect of each additional healthy lifestyle factor.A total of 28 studies  were included. When comparing subjects with the healthiest lifestyle to those with the least healthy lifestyle, the pooled HR was statistically significant for CRC , colon cancer , rectal cancer , CRA , and CRC-specific mortality . The pooled HR for CRC was 0.91 (95% CI: 0.88-0.94) for each increase in the number of healthy lifestyles. The inverse association between healthy lifestyle and CRC risk was consistently observed in all subgroups (HR ranging from 0.26 to 0.86).Adoption of a higher number of healthy lifestyles is associated with lower risk of CRC, CRA, and CRC-specific mortality. Promoting healthy lifestyle could reduce the burden of CRC.https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=231398, identifier CRD42021231398. Globally, colorectal cancer (CRC) ranks the third most commonly diagnosed malignancy and the second leading cause for cancer mortality . In 2020While the associations between CRC and single lifestyle factors have been extensively investigated in previous studies –21, far Hence, this systematic review aims to investigate the association between adherence to a healthy lifestyle and the risk of CRC, CRA, and CRC-specific mortality, and to examine whether the association is dose-dependent and any potential effect modification by population characteristics.This systematic review was registered on PROSPERO (CRD42021231398) and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) .We searched MEDLINE and EMBASE for relevant studies from their inceptions through June 2021. The search strategy combined three groupings of keywords with their derivatives and synonyms related to the following concepts: 1) combined or integrated effect; 2) lifestyle factors or health behaviors; and 3) colorectal cancer and adenoma. The search terms of these three concepts were combined using the Boolean operator “AND”. More details on search strategy is described in We included epidemiological studies that investigated the association between combined lifestyle factors and colorectal outcomes. The exposure was combination of lifestyle factors, including but not limited to diet, smoking, alcohol consumption, physical activity, overweight/obesity, sleep duration, and others. The primary outcomes were risk of CRC, colon cancer, and rectal cancer. The secondary outcomes included risk of incident CRA, advanced colorectal neoplasia, and CRC-specific mortality. We included cross-sectional studies, case-control studies, and cohort studies. For CRC-specific mortality, we included studies of healthy population or CRC patients, while for the other outcome, the study population should be free of the outcomes at baseline if the study design was prospective cohort.We excluded studies if they were (1) reviews, protocols, conference abstracts or not peer-reviewed publications, (2) focusing on a single lifestyle factor or a combination of less than three factors, (3) development or validation of prediction models, or (4) not reporting relevant data. For duplicate reports from the same cohort, we only included the report that had examined the largest number of lifestyle factors.We used a two-step study selection procedure. The title and abstract of all electronically and manually identified records were screened first to identify potentially eligible studies. Second, full texts of the potentially eligible studies were examined for final eligibility. Two authors independently performed the selection process. All disagreements were resolved by discussion with a third reviewer until consensus was reached.a priori designed form which collected the following information: (1) basic characteristics of study and subjects , (2) basic characteristics of participants ; (3) methodological characteristics, including study design, exposure definitions, outcome attainment, and follow-up period (for cohort studies) (4) effect estimates for the associations of interest, and (5) other information for quality assessment.Data were extracted by using an The methodological quality of cohort studies, case-control studies, and cross-sectional studies were assessed by the Newcastle-Ottawa Scale, which covers three domains: selection of participants, comparability of study groups, the ascertainment of exposure (for case-control studies) or outcomes  , 28. A sThere has been no universal consensus on the quantification of combined lifestyle factors. Most studies constructed a simple unweighted lifestyle score, where one point was given to each of the present healthy lifestyles, although the exact lifestyle factors may vary across studies; for example, in Carr 2018 , Hang 200)+(P0*OR)], where P0 is the risk of an event in the non-exposed group (HR ln(1-r))/r, where r is the rate of outcome in reference group  with 95% confidence intervals (CIs) was the most commonly used as the measure of effect in original studies and was therefore used in this meta-analysis. Odds ratios, where applicable, were transformed into RR using the following formula: RR=OR/, examined factors , and study quality . Cochran’s Q test and Iogeneity , 39. Potogeneity . P-valueth, 50th, and 90th percentiles of the exposure category , 46% , and 49%  lower risk of CRC, colon cancer and rectal cancer, respectively. After pooling the studies using continuous lifestyle scores, the results showed that the per 1-unit increase in healthy lifestyle score was associated with a pooled HR of 0.88 (95% CI 0.84-0.92) for CRC, 0.87 (95% CI 0.83-0.92) for colon cancer, and 0.86 (95% CI 0.79-0.90) for rectal cancer , 11 studies  and 8 studies  in the meta-analyses of CRC, colon cancer and rectal cancer, respectively Figure 2Nine studies were included in the dose-response meta-analysis for risk of CRC , 55, 65.The result of subgroup analyses was presented in In sensitivity analysis, we conducted separate meta-analysis for risk of CRC of (1) all studies after excluding the two studies of low quality , 45; and2 = 90.1%). Two studies reported the risk for advanced colorectal neoplasia and the pooled HR for the healthiest group was 0.43 .Four studies  reporting risk for incident colorectal adenoma using categorical lifestyle variables were included in the analysis Figure 22 = 37.5%) compared to the group with lowest score . The funnel plots for these two outcomes with more than 10 studies showed overall asymmetrical pattern  could reduce all-cause mortality by 66% compared to those with no more than one healthy lifestyle . Our resThis study is the first systematic review and meta-analysis to reveal the dose-response relationship between the number of healthy lifestyles and CRC risk. Given the lack of large randomized controlled trials to examine the effect of adopting multiple healthy lifestyles on the risk of CRC and CRA as well as the survival outcomes of CRC patients, our study has provided high quality evidence by including a pooled sample of more than one million participants and generating results that are unlikely to be affected by publication bias. Our findings support the recommendations by the World Health Organization , AmericaA few limitations should be noted when interpreting the study results. First, composition of healthy lifestyle and definitions of lifestyle factors varied considerably across studies, which may introduce heterogeneity to meta-analysis. We used random-effects model to minimize the effect of heterogeneity on the overall estimates. To explore the potential heterogeneity caused by this variation, we conducted subgroup analysis based on scoring system and factor composition. Although heterogeneity remained substantial within subgroups, the protective effect was still consistent within each group. For dose-response relationship, we only included studies using unweighted score system to exclude this attrition. Second, most original studies are from high-income, Western settings whose populations are comprised predominantly of Caucasians. Hence, more evidence from other populations, particularly Asian and African populations is needed. Third, only five studies have reported on CRC-specific mortality, which may restrict the power of performing stratified analyses. Fourth, socio-economic status is a key determinant for individual lifestyles –89, but In conclusion, the number of healthy lifestyle attributes is inversely correlated with the risk of colorectal adenoma, cancer, and CRC-specific mortality. Lifestyle interventions could effectively reduce incidence of CRC. Future research may explore the effect of complex interventions targeting multiple lifestyle factors on prevention and management of CRC; randomized controlled trial is needed to provide high-quality evidence on the combined effect of healthy lifestyles and CRC risk.The original contributions presented in the study are included in the article/JY, QF, and YZ designed the research. JY and QF conducted literature search and performed data extraction and meta-analysis. JHK and YZ reviewed studies for inclusion. JY, QF, JHK, and YZ contributed to the interpretation of data. JY drafted the paper. QF, JHK, and YZ made substantial contribution to the critical revision and editing of the manuscript. All authors contributed to the article and approved the submission version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Lyme borreliosis is a vector-borne disease of concern in Europe. While neuroborreliosis data are reportable at EU level, it can nevertheless be difficult to make comparisons of disease risk between neighbouring countries. This study used proportion meta-analyses to compare environmental markers of disease risk between woodland sites in two countries in North-Western Europe . 73 site-visits from 12 publications were analysed, resulting in a significantly higher pooled nymphal infection prevalence (NIP) in Ireland (8.2% (95% CI: 5.9–11.4%)) than Scotland (1.7%(95% CI 1.1–2.5%)). All other analysed parameters of disease risk were also higher in Ireland than Scotland. Subgroup-meta-analyses and meta-regressions were used to assess the influence of environmental variables on NIP. NIP increased significantly with increasing woodland size in Ireland, but not Scotland, which may be accounted for by Ireland's highly fragmented landscape.Assuming the application of strict inclusion/exclusion criteria and control of variables, proportion meta-analysis can provide useful insights in disease ecology, as it allows for the achievement of high study powers incorporating samples collected across multiple sites, which is otherwise often a prohibitively difficult and resource-heavy feat in environmental studies in disease ecology. A standardised approach to data collection is recommended to achieve more robust meta-analyses in future in conjunction with additional research on environmental factors affecting Lyme borreliosis risk in Europe, particularly pertaining to the impact of host species on NIP. Its most common vector is the ectoparasite I. ricinus   , which pis virus . Lyme diis virus . While tis virus , the oveis virus . Symptomis virus . The suris virus . A rangeis virus . These mis virus ; and b) is virus  which inis virus .1.1Due to differences in data collection methods, and an inherent difficulty in the diagnosis of Lyme borreliosis in humans, it can often be difficult to compare disease risk between different countries, even neighbouring jurisdictions, using human epidemiological data alone. In Ireland, a HPSC  report estimated the overall incidence of Lyme borreliosis at approximately 2–200 cases per annum , while noting that figures based on notified case rates usually underestimate overall rates of disease . In neigB. burgdorferi s.l. present in a given country or region, with Borrelia garinii being the strain most associated with neurological symptoms  and density of infected nymphs (DIN) as markers of disease risk to humans . As not s method .B. burgdorferi s.l., with B. burgdorferi sensu stricto (s.s.) largely dominating the North American disease system, while the burden of disease in Europe is chiefly due to five pathogenic strains – Borrelia afzelii, B. burgdorferi s.s., B. garinii, Borrelia bavariensis, and Borrelia spielmanii  . ConversHence, a proportion-based meta-analysis in which markers of infection prevalence in a disease vector are summarised and sub-grouped by country has the potential to allow for the statistically robust comparison of risk markers of vector-borne diseases such as Lyme borreliosis between countries. This can, in turn, provide useful data to aid in disease surveillance decision making.B. burgdorferi s.l. disease system.Given the somewhat surprising differences in human-centric estimates of disease incidence between Ireland and Scotland, it was decided (using published data from each country) to test whether a meta-analytical approach might be a useful tool for comparative purposes. Both countries are geographically similar with an oceanic climate and they both represent the North-Western European This study uses a structured literature review and meta-analysis of proportions with sub-group analysis to compare environmental markers of disease risk  between Scotland and Ireland, thus creating a risk-comparison based on standardised data, which can be added to the data generated by epidemiological reports and serological studies. The study also uses the technique of sub-group meta-analysis to determine the impact habitat factors described in the literature have upon disease risk in a geographically isolated and host-species poor region of Europe. Finally, the study appraises the use of meta-analytic techniques in the field of disease ecology with a view to making recommendations for streamlining reporting methods used in the literature for the benefit of future meta-analyses.22.1Borrelia’, and ‘Ireland’ or ‘Scotland’ or ‘UK’, with no year cut-off. After removal of duplicates, 102 results were returned  on the n Europe  met thes2.3Most papers included data from several different study sites, each of which had varying properties . As the authors of this paper were interested in establishing the effects of site-related variables on NIP and DIN, it was necessary to extract data from papers on a site-by-site basis. Therefore, some papers which did not provide site-specific data on nymph numbers and infection rates were excluded at this stage . For papWoodland site on mainland Ireland/Scotland.B. burgdorferi s.l. reported.Total nymphal ticks collected and number/percentage positive for No conditions  attached to testing of ticks for pathogen.Following the application of these criteria, there remained 74 eligible site visits from 12 papers .Table 1C2.4All papers were closely scrutinised as an initial step. Data on the following were extracted from each paper for each site:Number and (where provided) density of nymphal ticks collected.B. burgdorferi s.l. and (where provided) number/percentage of nymphal ticks positive for specific strains of B. burgdorferi s.l.Number/percentage of nymphal ticks positive for Each paper was then combed for data on habitat-related variables known to impact NIP and DIN, i.e. habitat type, habitat size, and hosts present.2.4.1As ‘woodland site’ was an eligibility criterion, data on woodland type were available for all included sites. Woodland type was categorised as ‘deciduous’; ‘coniferous’; or ‘mixed deciduous and coniferous’ for the purposes of this analysis. This categorisation was based on what was reported by study authors.2.4.2To ensure that woodland sizes were compared in a standardised way, Corine landcover data (100 m resolution)  from the2.4.3Data on the presence or abundance of vertebrate host species (aside from deer) were rarely reported by authors, and when included, were collected in a highly variable way. Thus, this parameter was excluded from the meta-analysis, except for ‘deer’ (not deer species specific) as most studies contained some reference to the presence/exclusion/ability to record deer at specific sites. Some studies made reference to deer ‘herd size’ or to abundance estimated from faecal transects. To standardise across studies, deer data were only extracted where a herd size was mentioned by authors or where deer density was specifically included. Where herd size was measured, density was calculated by placing this number against the size of the woodland. A deer density of ‘0’ was only included where deer were specifically studied and deemed absent, or where the site in question was expressly within a deer exclusion fence.2.4.4All available site locations included in the meta-analysis were mapped using QGIS 3.14  Fig. 2)Fig. 2). 2.4.5The number of papers with the data needed for inclusion in each analysis is listed in 2.4.62 statistic was used to interpret the heterogeneity of the data used in each meta-analysis. This statistic refers to variability in the data between studies. It is often high (e.g. 90%) in a proportion-based meta-analysis  studies, the prevalence outcomes of papers included in this analysis were unlikely to affect the likelihood of publication – there can be no negative/null result . Neverth33.13.1.1B. burgdorferi s.l. complex) was higher in woodland sites in Ireland (8.2% (95%CI 5.9–11.4%), heterogeneity = 90%, n = 4107, 30 sites from 8 papers) than in Scotland (1.7% (95%CI 1.1–2.5%), heterogeneity = 89%, n = 8373, 42 sites from 4 papers)  .Fig. 3FoB. burgdorferi s.l. were reported in both Ireland and Scotland: B. garinii, B. afzelii, B. burgdorferi s.s., and Borrelia valaisiana. The overall prevalence of each individual strain was consistently higher in Ireland than in Scotland , between Ireland and Scotland. The numerator for each site included in the meta-analysis was ([Density per m2] x [Infected ticks]) and the denominator was [n] – the number of ticks collected at each site.2, 95% CI 2.6–8%, heterogeneity = 90%, data from 12 sites from 3 papers, n = 2551) was significantly higher than that of the Scottish subgroup   .Fig. 5Fo2 to Density/m2 before performing the meta-analysis. The reason for this was that the meta-analysis could only be performed when the numerator was a smaller number than the denominator. For consistency, all density-related results have been reported in m2 (rather than 10m2).Note that the density was converted from Density/10mB. burgdorferi s.l., a higher overall NIP for B. burgdorferi s.l. complex as a group, and a higher DIN in Ireland than in Scotland.Taking into account varying levels of heterogeneity, this set of meta-analyses indicates a consistently higher NIP across four strains of 3.2B. burgdorferi s.l. complex infection prevalence in nymphal ticks. In some, but not all cases, these factors could also be assessed against DIN and against individual strains of B. burgdorferi s.l. (Appendix A).Data on woodland site type , woodland size, and deer density were incorporated into separate meta-analyses on 3.2.1The overall NIP was significantly lower in Irish coniferous woodlands , compared with mixed  and deciduous  woodlands .Fig. 6FoThe DIN did not vary between woodland types in Ireland, however, it should be stressed that the dataset for this subgroup meta-analysis came from only three papers , the decB. burgdorferi s.l. complex was also lowest in coniferous sites in Scotland (1.3% (95% CI 0.7–2.5%), I2 = 76%, 14 sites from 1 paper). The NIP was lower in coniferous sites than in mixed  and deciduous sites , but not significantly so . None of the genospecies reported at Scottish sites displayed a significant relationship between NIP and site size, though in most cases there was again a trend towards increasing NIP with increased site size. The exception was B. burgdorferi s.s, which, in contrast to the Irish sites, showed a non-significant trend towards decreasing NIP with increased site size in the Scottish sites studied. (Appendix A).The overall oodlands . When ea3.2.3Dama dama), red (Cervus elaphus), and sika deer (Cervus nippon). There was a trend towards decreasing NIP with increasing deer density, which was non-significant , of 8.2% (95% CI: 5.9–11.4%). Interestingly, this infection prevalence was higher than the weighted overall prevalence in Scottish sites, with an NIP of just 1.7% .The primary aim of this study was to undertake a structured literature review and meta-analysis to compare environmental markers of disease risk  between Scotland and Ireland. We found a weighted overall prevalence of B. burgdorferi s.l. complex were reported for both countries – B. garinii, B. afzelii, B. valaisiana, and B. burgdorferi s.s., with B. valaisiana, which is not a significant human pathogen , and accordingly, the DIN for included sites was significantly higher in Ireland  than in Scotland . All analyses performed in this study indicate that the examined markers of disease risk were higher in Ireland than in Scotland. This is interesting because, as previously mentioned, the estimated incidence of Lyme borreliosis based on human epidemiological data is considerably higher in Scotland than in Ireland. It is important to stress that this study relies exclusively on environmental data, and does not take human factors  into account. However, even bearing this caveat in mind, the results imply that further investigation is needed on the incidence of Lyme borreliosis in Scotland and Ireland, and highlights the utility of incorporating environmental markers into disease risk surveillance.The same four strains of pathogen , accountB. burgdorferi s.l. infection prevalence of nymphal ticks in Ireland has not changed since the 1990s. This provides some reassurance that data that was incorporated into this analysis from older papers remains reliable.Of note, the papers which provided data for sites in Ireland  tended t2 = 89%) was lower than a previous study by James et al. , which put the average NIP of 25 Scottish sites at 5.6% . These differences in outcomes may be accounted for by geographic site differences, in that James et al. concentrated on more northerly areas of Scotland, whereas the meta-analysis in this study also included several sites from the southern half of the country, potentially reflecting a difference in NIP in different areas of Scotland. Similarly, a recent study of Irish sites , Is et al. 2013, whish sites  put the The second aim of this meta-analytic study was to assess the impact of habitat factors described in the literature on disease risk markers in Ireland and Scotland. These countries were chosen as examples of host-species poor regions in North-Western Europe. The selected articles provided sufficient data to assess the following parameters: woodland type, woodland size, and deer density. As mentioned, the power of a meta-analysis is highly dependent on the type of data reported in the literature. Many sub-studies were excluded and some analyses could not be run due to lack of reporting of site-specific data, usually because a site-specific analysis was not relevant in the context of the original study.The subgroup-analysis which looked at woodland type as a factor affecting infection prevalence found that the NIP was lowest in coniferous sites. This was true for sites in both Scotland and Ireland – though there were overlaps between confidence intervals, indicating that these differences were not statistically significant. The fact that overall NIP was lowest in coniferous sites is in keeping with a Scottish study, which found that NIP was higher in mixed/deciduous than coniferous woodlands . FurtherB. burgdorferi s.l. complex) NIP with increasing site size in Irish woodlands and a trend towards increasing NIP with increasing site size in Scottish woodlands. This differs from US data, which indicate that rates of infected nymphs and human Lyme borreliosis rates are both inversely related to habitat fragment size  are not provided by the authors, a paper should be excluded, whereas it may have been included in a traditional meta-analysis of proportions used in epidemiology, where site-specific influences and characteristics are less important variables.2 rather than 10m2) to overcome this limitation, but this may not be the case for all datasets.Furthermore, data on density are often important in interpreting risk in disease ecology , whereas density is not included in a traditional meta-analysis in epidemiology. The ‘metaprop’ function in R , while eFinally, meta-analyses of proportions use observational  rather than comparative statistical methods, to obtain an accurate prevalence measurement . While tThe strength of this statistical technique lies in its ability to combine measures of effect size from multiple studies onto one measurement scale, allowing for the synthesis of a robust effect measure with a higher n-value than might be achieved by an individual study, while taking individual study power into account, thus reducing the under- or overrepresentation of small/large studies . It is t4.1I. ricinus may have different research questions, the authors have identified several gaps in the literature which, if addressed, would help in conducting future meta-analyses in disease ecology or which would answer questions pertaining to Lyme disease risk in North-Western Europe  be considered by those working in the field so that robust meta-analysis can be achieved in the future to further our understanding of this disease.The authors declare no conflicts of interest.


Helicobacter pylori (H. pylori) infection may play a pathogenic role in CSX. Therefore, we conducted a meta-analysis to explore the relationship between H. pylori infection and risk of CSX.Cardiac syndrome X (CSX) is a condition with normal coronary angiography but angina pectoris. Chronic inflammation caused by H. pylori infection and the risk of CSX were included and were analyzed by R software (version 4.1.0).A systematic search in the Web of Science, Medline, Embase and Chinese databases (CNKI and Wanfang) was conducted up to October 2021. Articles on the association between H. pylori infection was associated with an increased risk of CSX . We also found a significant association in those 25–40 years of age , those 40–50 years of age , those over 50 years of age , those in developing countries [Iran  and China ]. However, this association was not apparent in a developed country [Italy ].Ten case-control studies involving 703 CSX patients and 731 healthy controls were included. H. pylori infection and the risk of CSX. Its pathogenicity is stronger in middle-aged individuals and some developing countries. However, more studies are needed to further investigate whether early eradication of H. pylori can reduce the incidence rate of CSX, especially in middle-aged individuals and some developing countries.Our study suggested a possible association between  Helicobacter pylori (H. pylori) is a gram-negative bacterium that causes a variety of gastrointestinal disorders, including chronic gastritis, duodenal ulcer and gastric cancer  or exercise treadmill test, normal coronary angiography with the exclusion of coronary artery spasm. In angina patients undergoing angiography, up to 20% of patients have this symptom . DespiteH. pylori infection in CSX, their results are contradictory. Thus, we conducted a meta-analysis of relevant articles in an attempt to reveal the association between H. pylori infection and the risk of CSX.While many studies have attempted to reveal the role of Our meta-analysis strictly adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) .H. pylori” or “Helicobacter pylori,” combined with “Cardiac syndrome X,” “microvascular angina,” “CSX,” and “MVA” were used as search terms. There were no language restrictions in the search. The references in the identified articles were checked and if suitable, were also included in the search. The deadline for searching was October 2021.The meta-analysis was performed with a structured articles search, using the Web of Science, Medline, Embase and Chinese databases (CNKI and Wanfang). The keywords “We repeated all selections. The final inclusion of articles was decided upon by consensus, and when this decision failed, the third author (LXL) made a ruling.Observational studies  were included if the following criteria were met:Studies were conducted in humans.H. pylori infection was determined by serological tests, including antigen-specific enzyme-linked immunosorbent assay (ELISA) and Western blotting, or non-serological tests including rapid urease test, and 13C-urea breath test (UBT) according to the manufacturer's instructions.The diagnosis of CSX included the following criteria: typical history of angina and normal coronary angiography; atypical chest pain with an abnormal myocardial perfusion Image; or exercise electrocardiogram and completely normal results on coronary angiography, with no inducible spasm on ergonovine-provocation test.H. pylori infection and the risk of CSX were selected.A control group was included. Studies with matched and sufficient information on the association between For articles with data published more than once, only the article with an adequate study strategies and large number of cases was selected.Patients with evidence of left or right ventricular dysfunction, cardiomyopathy, valvular heart disease, myocardial infarction, concomitant acute and chronic disease were excluded.Two well-trained researchers (LSP and LFH) independently extracted the following data based on the pre-specified scheme: first author or second author; average age of case group; year of publication; country; study size; case type; control type; and matching variables. All data were double input.I2 statistics were used to assess statistical heterogeneity. A value >50% was considered to have significant heterogeneity and random effect models were used to pool data. Otherwise, the fixed effects model was used. The estimated effect measure was the odds ratio (OR) with 95% confidence intervals (95% CIs) for the dichotomous data. If the 95% CI did not contain the value one, the OR was considered to be statistically significant.Our meta-analysis was conducted according to the recommendations of Cochrane Collaboration and meta-analysis report quality guidelines , 10 and H. pylori detection method, socioeconomic status and year of publication.The Egger's and Begg's tests were used to assess potential publication bias. Each article in this analysis was sequentially deleted to determine how much it contributed to the overall effect size. The Newcastle-Ottawa Scale (NOS) was adopted to score all articles. Articles that scored ≥7 points were considered “high-quality articles.” Several subgroup meta-analyses were performed based on country, mean age, case type, in vitro studies, animal studies, or epidemic pathological studies focusing on the relationship between H. pylori infection and coronary artery disease, rather than CSX. After this exclusion, 10 articles remained in our study  They were comments/reviews/case reports without raw data; or (2) They were other special studies, such as ur study –19. The H. pylori infection with the risk of CSX. The combined random effect odds ratio (OR) was 8.29 (95% CI: 4.64–14.82) (We found 10 articles that reported an association of 4–14.82) . After e4–14.82) . We also4–14.82) .H. pylori diagnostic methods, socioeconomic status and publication year. Two parallel meta-analyses were performed in each subgroup. Those results are presented in H. pylori infection with the risk of CSX may be much stronger in middle-aged individuals. Similarly, we found that this association is also more common in developing countries (China and Iran), but was not apparent in developed countries . When we excluded articles with six points, the meta-analysis was performed again. Differences in age and developing countries were still related to bacterial pathogenicity. Whether the articles with six points only or all included articles were analyzed, factors such as age or developing country were consistently observed to influence bacterial pathogenicity.The data were separately stratified by country, mean age, case type, We also found three studies focusing on the association of CagA strain infection with the risk of CSX. The combined random effect OR was 3.29  and Begg's test (P > 0.05) and the results suggested no potential publication bias in our meta-analysis, assuring confidence in our results.In the meta-analysis, all articles achieved satisfactory scores (≥ six points) for quality assessment. Included articles with seven points yielded more reliable results, and there was no difference between studies with low scores (six points) and studies with high scores (seven points). We performed Egger's test  antibody test cannot indicate current infection and may overestimate the relationship between the bacteria and the risk of CSX, it is consistent with the results obtained by the urea breath test (UBT) test detects current infection.According to subgroup results, we found that the association between d people . We alsothogenic . AdditioH. pylori infection was significantly increased with concurrent diseases, such as diabetes and malignant tumors , Interleukin-1 (IL-6), and tumor-necrotic factor (TNF-1), which can affect vascular activity and lead to endothelial dysfunction  and developing . An expansion of this analysis to other countries is needed to further verify our conclusions. Finally, the sample size of this meta-analysis is relatively small, which may affect the accuracy of our results. Therefore, additional, larger, well-designed studies should be encouraged to validate our results.The strength of our study is that it is the first attempt using meta-analysis to identify the association of H. pylori infection and the risk of CSX. Its pathogenicity is stronger in middle-aged individuals and some developing countries. However, more studies are needed to further investigate whether early eradication of H. pylori can reduce the incidence rate of CSX, especially in middle-aged individuals and some developing countries.In conclusion, our meta-analysis suggested a possible association between The original contributions presented in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding author/s.D-HZ, KC, CY, and X-JD designed and analyzed the study. D-HZ, KC, CY, X-JD, and B-BW wrote and revised the manuscript. S-PL, F-HL, Z-XH, and X-LL collected the data. All authors have read and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This study aimed to explore the prevalence and clinical risk factors in patients diagnosed with incidental prostate cancer (IPC) during certain surgeries  after clinically suspected benign prostatic hyperplasia (BPH).Literature search of the MEDILINE, Web of Science, Embase, and Cochrane Library databases was performed to identify eligible studies published before June 2021. Multivariate adjusted odds ratios (ORs) and associated 95% confidence intervals (CIs) of the prevalence and clinical risk factors of IPC were calculated using random or fixed-effect models.Twenty-three studies were included in the meta-analysis. Amongst the 94.783 patients, IPC was detected in 24.715 (26.1%). Results showed that the chance of IPC detection  in patients treated with TURP is similar to that of patients treated with HoLEP . However, the pooled prevalence estimate of patients treated with OP was 11%  with no statistical significance. We observed increased incidence of IPC diagnosis after BPH surgery amongst patients with higher prostate-specific antigen (PSA) level , whereas no effect of age  and prostate volume  were observed.The prevalence of IPC was similar amongst patients undergoing TURP, HoLEP, and OP for presumed BPH. Interestingly, increased PSA level was the only independent predictor of increasing risk of IPC after BPH surgery rather than age and prostate volume. Hence, future research should focus on predictors which accurately foretell the progression of prostate cancer to determine the optimal treatment for managing patients with IPC after BPH surgery. Prostate cancer is the most common malignant tumor amongst ageing male patients, with an estimated 41.000 Americans dying from prostate cancer annually –4. MoreoIn the present study, we conducted a systematic review and meta-analysis of previous literature to explore the prevalence and clinical risk factors in patients diagnosed with IPC for surgery after clinically suspected BPH. We also performed subgroup and meta-regression analyses to determine how the potential variables affected the merged results and the level of heterogeneity of the meta-analysis.The methods of this meta-analysis were conducted in accordance with the Cochrane Collaboration criterion . The PreLiterature search of the MEDILINE, Web of Science, Embase, and Cochrane Library databases were performed to identify eligible studies on the prevalence and clinical risk factors in patients diagnosed with IPC during surgery after clinically suspected BPH published before June 2021. Each database was searched without restrictions in language, publication type, or region by using the following combination of Medical Subject Headings (MeSH) and non-MeSH search terms: (‘prostate cancer’ OR ‘prostate neoplasm’) AND  AND (‘benign prostatic hyperplasia’). Moreover, a freehand search was conducted for additional relevant articles of interest in journals not listed in these databases. Any discrepancy was settled by consulting amongst investigators.All publications regarding the prevalence and risk factors in patients diagnosed with IPC after BPH surgery were included if they met the following eligibility criteria:  originalData extraction was conducted by two independent investigators using a pre-established data extraction form, and another investigator checked the correctness of all extractions. Any disagreement was resolved by the adjudicating senior authors. The following data were extracted using a standardized Excel (Microsoft Corporation) file: first author, publication year, country, database source and duration, study design, participants characteristics , prevalence, and risk estimates with their corresponding 95% CIs or sufficient original data. Moreover, if potentially eligible records did not provide sufficient information, we contacted the primary authors to acquire missing data.The quality of the included studies was assessed by two independent reviewers according to the Newcastle-Ottawa scale (NOS) , which cThe overall prevalence of IPC and risk estimates of the predictors were calculated through the prevalence and odds ratios (ORs) with their corresponding 95% CIs by using STATA software . The I-square (I2) test was applied to evaluate the study heterogeneity, with I2 values of 0%, 25%, 50%, and 75% representing no, low, moderate, and high heterogeneity, respectively. Heterogeneity amongst the studies was evaluated by random or fixed-effect models, and a considered severe heterogeneity of I2≥50% was evaluated by random-effect models. Otherwise, a fixed-effect model was used. Statistical significance was set at P <0.05 through two-sample t-test. To explore the influence of various clinical characteristics on heterogeneity, we performed subgroup analyses stratified by different geographic distributions. Sensitivity analysis was conducted by omitting each study individually to assess the quality and consistency of the results. To investigate the possible sources of heterogeneity, a meta-regression analysis was conducted and the restricted maximum likelihood method was applied for analysis. Finally, the test of Egger et al.  and BeggStudy identification and selectionA total of 410 records were identified initially based on the comprehensive search strategy described at the search stage. Overall, the basic characteristics of the included studies are illustrated in In general, the methodological quality of the included studies was evaluated on the basis of the NOS. One study  acquiredAll included studies reported sufficient data on IPC prevalence , 16–37. In the subgroup analysis stratified by different geographic distributions in patients with IPC after TURP, a higher prevalence was observed in Oceania  and Africa , followed by Asia , Europe , and North America . We also conducted a meta-regression analysis to further investigate the possible sources of heterogeneity, and results revealed that none of the covariate  resulted in heterogeneity amongst the included studies. Moreover, sensitivity analysis demonstrated that the stability of the results exhibited no significant change by omitting each study individually . FinallyNine retrospective cohorts comprising 6.241 patients reported data on risk factors of IPC , 34, 35.Uncertainty currently exists about the prevalence and risk factors of IPC with conflicting opinions based on single institutional research. Accordingly, we performed this systematic review and meta-analysis to address these issues. Our results revealed that the prevalence of IPC was similar amongst patients undergoing TURP, HoLEP, and OP for presumed BPH. Higher prevalence was also observed in Oceania and Africa, followed by Asia, Europe, and North America. Notably, sensitivity analysis indicated that the stability of the results had no significant change by omitting each study individually, although the subgroup and meta-regression analyses could not identify the potential factors that may affect the level of heterogeneity between studies. However, potential publication bias was likely to exist according to inspection of formal statistical tests. Interestingly, increased PSA level was significantly associated with increased risk of IPC after BPH surgery rather than age and prostate volume.Although our results showed that PSA was a highly sensitive predictor for IPC detection, it may have a higher rate of false positives because its specificity was not high. Indeed, almost all included studies reported a significant association between PSA and IPC detection, whereas two studies yielded conflicting results , 28. KimA significant increase has been observed in the number of minimally invasive surgical treatments for BPH, which is considered to be a factor affecting the incidence of IPC detection after BPH surgery . In factOur meta-analysis exhibited crucial strengths in several ways. Firstly, to our knowledge, the present meta-analysis is the first one focusing on the prevalence and clinical risk factors of IPC after BPH surgery. Moreover, sensitive and meta-regression analyses were performed to determine the potential factors that moderated the level of heterogeneity and results of the meta-analysis according to the PRISMA guidelines. Secondly, multivariate-adjusted risk estimates were applied to minimize the other relevant confounding factors that may influence the overall results. Lastly, the results of the sensitivity analysis and meta-regression validated the rationality and reliability of this meta-analysis.However, some limitations should also be addressed and merit further discussion when interpreting our results. Firstly, significant heterogeneity was observed. Therefore, the introduction of potentially significant heterogeneity was imminent even though meta-regression was conducted. The reason may be that all included studies were observational design with the disadvantages of heterogeneity and variations in terms of histopathological examination. Secondly, we did not evaluate data regarding the cancer clinical stage (TNM system) of patients because few studies have reported related information. Thirdly, potential publication bias is likely to exist, although our data search included a number of databases combined with freehand search. Moreover, related results may be affected with the continuous advancement of surgical techniques. Finally, our understanding of predictors which accurately foretell prostate cancer progression remains insufficient because related data have been investigated inadequately.The prevalence of IPC was similar amongst patients undergoing TURP, HoLEP, and OP for presumed BPH. Moreover, increased PSA level was an important predictor of the presence of IPC after BPH surgery. However, no effect of age and prostate volume was observed. Therefore, further prospective studies should be conducted in a multicentric population to evaluate other relevant variables that can accurately predict the progression of prostate cancer to determine the optimal treatment for IPC patients after BPH.Trial and protocol registration: PROSPERO CRD42021268051.Zunguang Bai 1*, Jun Pan, MD, 1*


AA homozygotes had smaller improvements in parameters pertaining to lung functions  in a subgroup of patients with non-selective CysLT receptor antagonists and patients without inhaled corticosteroids (ICS) , but not in other subgroups. Variability exists in the pharmacogenomics of LTMs treatment response. Our meta-analysis and systematic review found that LTC4S-444A/C may influence the treatment response of patients taking non-selective CysLT receptor antagonists for asthma, and patients taking LTMs not in combination with ICS for asthma. Future studies are needed to validate the pharmacogenomic influence on LTMs response.Pharmacogenetics research on leukotriene modifiers (LTMs) for asthma has been developing rapidly, although pharmacogenetic testing for LTMs is not yet used in clinical practice. We performed a systematic review and meta-analysis on the impact of pharmacogenomics on LTMs response. Studies published until May 2022 were searched using PubMed, EMBASE, and Cochrane databases. Pharmacogenomics/genetics studies of patients with asthma using LTMs with or without other anti-asthmatic drugs were included. Statistical tests of the meta-analysis were performed with Review Manager  and R language and environment for statistical computing  software. In total, 31 studies with 8084 participants were included in the systematic review and five studies were also used to perform the meta-analysis. Two included studies were genome-wide association studies (GWAS), which showed different results. Furthermore, none of the SNPs investigated in candidate gene studies were identified in GWAS. In candidate gene studies, the most widely studied SNPs were ALOX5 (tandem repeats of the Sp1-binding domain and rs2115819), LTC4S-444A/C (rs730012), and SLCO2B1 (rs12422149), with relatively inconsistent conclusions. LTC4S-444A/C polymorphism did not show a significant effect in our meta-analysis (AA vs. AC (or AC + CC): −0.06, 95%CI: −0.16 to 0.05,  However, patients with asthma vary in disease onset, exacerbating stimuli, severity, and response to these medications  OR "Anti-Asthmatic Agents"[MeSH Terms]) OR (asthmatic*)) AND  OR ) OR "montelukast" [Supplementary Concept]) OR "zafirlukast" [Supplementary Concept]) OR "pranlukast" [Supplementary Concept]) OR "zileuton" [Supplementary Concept])AND(((("Pharmacogenetics"[Mesh]) OR "Polymorphism, Genetic"[Mesh]) OR "Genome-Wide Association Study"[Mesh]) OR "Genetic Association Studies"[Mesh] (((("Pharmacogenetics"[Mesh]) OR "Polymorphism, Genetic"[Mesh]) OR "Genome-Wide Association Study"[Mesh]) OR "Genetic Association Studies"[Mesh]) OR (candidate genes)))p-value. The significance of MD was determined by Z-test, and a p-value less than 0.05 was considered statistically significant. Heterogeneity was assessed by I2 statistic and χ2 test. I2 value greater than 50% was considered as the signal of heterogeneity. In cases of heterogeneity, subgroup analyses were conducted to find the source of heterogeneity, and sensitivity analyses that excluded a single study each time were used to test the stability of results. Subgroup analyses were performed by ethnicity, asthma severity, types of drugs, concomitant medication, and follow-time. The change in significance of p-value in sensitivity analyses indicates that the results may be unstable. In addition, we used Pearson’s χ2 test to examine HWE in each study included, and for p-values greater than 0.05 it was considered that the genotype distribution among participants was in HWE. The quality of each study was evaluated by Newcastle–Ottawa Scale (NOS), which included aspects of selection, comparability, and exposure, and a score less than 5 was considered unacceptable. The possible publication bias was investigated using Begg’s funnel plot and Egger’s test, and funnel plot asymmetry and p-value less than 0.05 were considered as indicators of publication bias.We analyzed the data using Revman 5.4 and R-4.1.0 software. The primary outcome was analyzed by the dominant model, i.e., AA vs. AC (or AC + CC) genotype. Meta-analysis was performed by combining each study’s results using the inverse variance statistical method and the random effects model. The strength of the association between LTC4S-444A/C polymorphism and improvement of lung function parameters was evaluated by mean difference (MD) with 95% confidence intervals (CI) and We identified 80 cohort or case-control studies in PubMed, 491 in EMBASE, and 47 in Cochrane. The screening process for this systematic review is shown in After screening titles and abstracts of studies included in this systematic review, we identified 14 studies with 873 participants related to LTC4S-444A/C polymorphisms. Five studies on the association between LT4CS-444A/C polymorphisms and improvement of lung function parameters were eventually included in the meta-analysis. Due to the limited number of current studies, we included all measures of improvement of lung function parameters. Considering the lack of patients with the CC genotype, we aggregated AC and CC genotypes and compared them to the AA genotype.1 response and less β2 rescue medication [1 response compared with others in white adults [ALOX5 encodes lipoxygenase which catalyzes the conversion of arachidonic acid to leukotriene A4. Leukotrienes play an important role in inflammatory conditions. Two of the most studied SNPs about ALOX5 were ALOX5 (tandem repeats of the Sp1-binding domain) and ALOX5 rs2115819). ALOX5 (tandem repeats of the Sp1-binding domain) is likely to influence asthma exacerbations in patients taking LTMs ,15,16,17819. ALOXdication ,18,19. Le adults ,18. Kotae adults  , is the endmost and sole committed enzyme in the generation of the proinflammatory mediators . LTC4 isAccording to existing research, LTC4S-444A/C probably has no effect on lung function in asthmatics treated with LTMs. Nonetheless, some studies showed a significant influence of LTC4S-444A/C polymorphism on response to LTM. Thus, we performed an additional meta-analysis to evaluate the association between the SNP and lung function.1) as the outcome indicators of lung function, and one study that used HS required to cause a 20% drop in FEV1 (HS-PD20) as an indicator of LTMs response were excluded from the meta-analysis but are still described in our systematic review.Study characteristics of the five studies included in the meta-analysis were shown in All studies included in our meta-analysis were cohort studies. All DNA samples studied were from blood samples. Among the five studies, two did not provide clear grades of asthma severity for the included patients; instead, they provided laboratory indicators for inclusion, which is equivalent to diagnostic criteria for asthma ,24. All p = 0.31). Heterogeneity was observed between studies (I2 = 77%), implying that a subgroup analysis was needed to explore the heterogeneity. In subgroup analysis for types of drugs, the result in patients with non-selective CysLT receptor antagonists was significant , despite the seemingly asymmetric shape of the funnel plot.Publication bias was evaluated using Begg’s funnel plot  and Egge1 [FENO/Ƭ, Ƭ = the duration of the measurements) vs. time curve, Whelan et al. found that children with AC genotype had a more significant reduction than the AA genotype (p = 0.027) [p = 0.023) [Additionally, Asano et al. found a significant association between LTC4S-444A/C polymorphism and responsiveness to pranlukast . In cont1 . Accordi= 0.027) . In addi= 0.027) ,31,32,33= 0.023) . SLCO2B1 encodes organic anion transporting polypeptide 2B1 (OATP2B1), an organic anionic transporter that mediates sodium-dependent uptake of a variety of endogenous compounds, including leukotriene C4 . Montelup = 0.02). In addition, some studies focused on CysLTR1, CysLTR2, MRPP3, MLLT3, TBXA2R, CYP2C9, PLA2G4, PTGD2, and IL-13 . CysteinThromboxane A2 (TBXA2) also plays an important role in the development of asthma . TBXA2 cPhospholipase A2 (PLA2) catalyzes the hydrolysis of membrane phospholipids to AA, implying that genes coding PLA2 might influence the process of asthma . Rava etProstaglandin D2 (PGD2), the major cyclooxygenase metabolite of AA, produces an effect through the PGD2 receptor (PTGDR) . SeveralIL-13 induces Arachidonic Acid 15-Lipoxygenase (ALOX15) expression, an enzyme oxidizing polyunsaturated fatty acids, and causes eosinophil-mediated airway inflammation . Some stIt has been proved that uridine diphosphate-glucuronosyltransferase (UGT) mediated glucuronidation takes part in LTMs clearance . Mostellp = 9.40 × 10−8) in LOCCS (discovery cohorts), and rs12659144 (p = 2.2 × 10−6), as the top-ranked SNP of 25 SNPs which approached genome-wide significance (p < 10−5), did not replicate in LODO (discovery cohorts) [p = 4.95 × 10−8) in LODO, though this result was not replicated in LOCCS. The 200 top-ranked SNPs from discovery cohorts were evaluated in CLIC and PACT (replication cohorts) and only four SNPs survived in the correction for multiple testing (combined p < 0.00025), including MLLT3 (rs6475448), WBSCR17 (rs7794356), rs953977, and rs1364805. Among these SNPs, MLLT3 (rs6475448) had a great influence on the response to montelukast. In the 2016 GWAS, Abbott trial 1 and Abbott trial 2 were used as discovery cohorts, and LOCCS and LODO were used as replication cohorts [p-values from discovery and replication cohorts, MRPP3 (rs12436663) achieved genome-wide significance [Two of the pharmacogenetics studies on LTMs were genome-wide association studies (GWAS) ,43. Dahlcohorts) . rs224792-adrenergic receptor agonists has become a popular topic in the study of asthma pharmacogenomics, focusing primarily on the improvement or asthma exacerbation after taking short-acting β2-agonists (SABA) or LABA [Asthma is a heterogeneous inflammatory disease, and genetic factors are a major contributor to asthma susceptibility and treatment response. Several studies have demonstrated that drug response to ICS might be associated with genetic factors, including CRHR1, GLCC1, FCER2, and TBX21 ,70,71,72 or LABA ,75,76,77p = 0.31). However, in the subgroup of patients with CysLT1 and CysLT2 receptor antagonists, the wild-type AA homozygous showed poor responses to LTMs treatment compared with C allele carriers (p = 0.002). This result was not presented in the subgroup of patients with selective CysLT1 receptor antagonists. This suggests that non-selective CysLT receptor antagonists  may be more easily affected by LTC4S polymorphism than selective CysLT1 receptor antagonists . Montelukast, a selective and potent LTD4 receptor antagonist, inhibits the bronchoconstriction by LTD4 binding to the CysLT1 receptor, which is inactive for CysLT2 receptor binding [This meta-analysis included 120 patients with AA genotype and 68 patients with AC (or AC + CC) genotype to investigate the association between LTC4S-444A/C that codes LTC4S, and improvement of lung function parameters after LTMs treatment. Our results indicated that, according to improvement of lung function parameters and LTC4S-444A/C polymorphism, no significant association was found in asthmatics treated with LTMs , but not in patients with ICS (p = 0.78). This result suggests that ICS may interfere with LTMs responses in patients with LTC4S-444A/C polymorphism. Corticosteroid has been shown to upregulate the transcriptional activity of LTC4S gene and subsequently the activity of the LTC4S enzyme [We also performed a subgroup analysis of concomitant medication. A significant effect was found in patients without ICS  and the group of different types of drugs overlap. This is one of the limitations of our meta-analysis, though patients with AIA made up only a small percentage (5.7%) and thus may not have significantly impacted our results. 2 statistic and χ2 test, there exists heterogeneity in our meta-analysis (I2 = 77%). Consequently, subgroup analysis was performed to investigate the heterogeneity. Heterogeneity was significantly reduced when we grouped by types of drugs (I2 = 57% and 17%) and concomitant medication (I2 = 0% and 85%), implying that that heterogeneity may have derived from the selectivity of LTMs and concomitant ICS. However, sensitivity analysis showed statistically significant results if Pan’s study was omitted, suggesting that our result might be a false negative. This is also one of the limitations of our meta-analysis. We suggest that the unreliability may be caused by the following reasons: (1) Pan’s study only investigated 18 patients; thus, its results and statistical power are affected by sample size; (2) lack of patients with CC genotype may increase the heterogeneity of the study; (3) follow-up time was too short to observe valid results; and (4) 18 of 102 patients in the cohort were selected for pharmacogenomics studies, but the reasons for the selection were not explained explicitly in original studies, which potentially introduced selection bias. Publication bias in this meta-analysis was assessed by Begg’s funnel plots and Egger’s test. No significant result was detected; therefore, publication bias is unlikely.According to IFor nearly two decades, more than 50 researchers have studied how genetic factors affect asthma treatment, and more than 20 studies have investigated the role of gene polymorphism in response to LTMs. However, these findings are still inconclusive. To date, the most widely studied gene polymorphisms in pharmacogenomics of LTMs treatment response were ALOX5 (tandem repeats of the Sp1-binding domain and rs2115819), LTC4S-444A/C, and SLCO2B1 rs12422149). We performed a meta-analysis to examine the specific association, and achieved a negative result. Despite the positive results obtained in subgroup analyses, we cannot draw a firm conclusion due to the limited number of available studies. It is worth noting that there are currently two GWAS studies in pharmacogenomics of LTMs treatment. MLLT3 (rs6475448), WBSCR17 rs7794356), MRPP3 (rs12436663), and GLT1D1 (rs517020) approached or achieved replicated significance [2149. We 56, MRPP3In general, three different mechanisms are involved in the effect of gene polymorphisms on treatment response: (1) variations that affect drug metabolism, (2) variations associated with the mechanisms that lead to adverse reactions, and (3) variations in therapeutic targets or pathways activated by medications . Our sysIn conclusion, there is still great variability in the pharmacogenomics of LTMs treatment response, partly due to differences in study design, characteristics of included patients, and the limited number of available studies. Our meta-analysis and systematic review suggest that LTC4S-444A/C may influence the treatment response of patients taking non-selective CysLT receptor antagonists for asthma and patients taking LTMs not combined with ICS for asthma. However, the influence of LTC4S, ALOX5, and the other gene polymorphisms warrants further investigations.


The estimated global latent tuberculosis infection (LTBI) burden indicates a large reservoir of population at risk of developing active tuberculosis (TB). Previous studies suggested diabetes mellitus (DM) might associate with LTBI, though still controversial. We aimed to systematically assess the association between DM and LTBI.We searched PubMed, Embase, Cochrane Library and Web of Science. Observational studies reporting the number of LTBI and non-LTBI individuals with and without DM were included. Random-effects or fixed-effects models were used to estimate the pooled effect by risk ratios (RRs) and odds ratios (ORs) and its 95% confidence interval (CI), using the original number of participants involved.RR = 1.62, 95% CI: 1.02–2.56; for cross-sectional studies, OR = 1.55, 95% CI: 1.30–1.84). The pooled OR was high in studies with healthcare workers , refugees , sample size of 1,000–5,000 , and male participants accounted for less than 40% . Prediabetes also associated with LTBI .20 studies involving 4,055,082 participants were included. The pooled effect showed a significant association between DM and LTBI (for cohort studies, The risk of LTBI was found to be a 60% increase in DM patients, compared with non-DM patients. LTBI screening among DM patients could be of vital importance. More studies are needed to explore appropriate strategies for targeted LTBI screening among DM patients. M. tuberculosis antigens with no evidence of clinically manifest Tuberculosis disease (Tuberculosis (TB) is a major infectious disease and one of the top ten causes of death worldwide, which has caused 1.4 million deaths in 2020 ( disease –5. Activ disease . For higDiabetes mellitus (DM) is a chronic and metabolic disease characterized by elevated levels of blood glucose (or blood sugar), which can impair the immunity of individuals and increase the susceptibility to various infectious diseases , 8. The However, people with DM are not recommended to get systematic LTBI testing and TPT, unless they also belong to other risk groups . EvidencOur methods have been described in detail in our published protocol  [PROSPERWe included articles that met the following criteria: (1) cohort studies and cross-sectional studies, (2) studies reporting the number of LTBI patients with and without DM, and non-LTBI people with and without DM. Articles were excluded if met any following criteria: (1) irrelevant to the subject of the meta-analysis, (2) studies with insufficient data to calculate the odds ratio or assess the pooled effect of diabetes mellitus on risk of latent tuberculosis infection, (3) duplicated or overlapped articles, (4) studies in lack of the definition of DM or LTBI patients, and (5) if articles were not written in English or Chinese.M. tuberculosis antigens with no evidence of clinically manifest Tuberculosis (TB) disease  . With prStudies were identified by four investigators  independently following the criteria above, and each abstract and full text article was reviewed in duplicate by at least two reviewers. Discrepancies were reconciled by a fifth investigator (LJ).We evaluated the risk of bias using the Newcastle-Ottawa quality assessment scale for cohort studies and case-control studies . Cohort The primary outcome was the impact of DM on LTBI in different people groups. Data were extracted using a predesigned form that had been piloted. The following data were extracted independently by four investigators  from the selected studies: (1) basic information of the studies including first author, publication year and research type; (2) characteristics of the study population including sample sizes and locations; (3) primary outcomes: the number of people with or without DM in the total population and by laboratory diagnosis results of LTBI; and (4) diagnostic methods of LTBI: tuberculin skin test (TST), QuantiFERON-TB Gold In-Tube test (QFT-GIT), and interferon gamma release assays (IGRAs). The data in each article were extracted independently by at least two investigators, and discrepancies were reconciled by a fifth investigator (LJ).I2 ≤ 50%, P > 0.10, which represents insignificant heterogeneity; while random-effects models used if I2 ≥ 50%, P < 0.10, representing significant heterogeneity.We performed a meta-analysis to summarize data from cohort and cross-section studies and assessed the overall effect of DM on LTBI, using the original number of participants involved and adjusted OR across the studies. Fixed-effects or random-effects models were used to obtain the pooled effect across studies, according to the heterogeneity between estimates. Fixed-effects models were used if P < 0.05 was considered significant. If substantial heterogeneity was observed, we conducted subgroup analyses to investigate the possible sources of heterogeneity, by using population group, study location, sample size, proportion of male, and risk of bias as grouping variables. We used the Q-test to conduct subgroup comparisons and variables were considered significant between subgroups if the subgroup difference p-value was less than 0.05. Sensitivity analyses were performed by omitting one study at a time, trying to discover articles that have notable impact and examine the stability of the overall effect. Publication bias was assessed by funnel plot and Egger’s regression test. Additionally, we extracted information about pre-DM patients and also performed a meta-analysis to investigate if there was any association between pre-DM and the risk of LTBI. We analyzed data using Stata version 16.0.The pooled effect of DM on LTBI was described by forests plots, quantified by OR/RR , and the corresponding 95% confidence intervals (CI). A value of A total of 14,937 records were searched from the four databases by terms mentioned above. 6,612 duplicates were excluded. After reading titles and abstracts, we excluded 7,976 reviews, conference papers, animal experiments, case reports, and other studies irrelevant to the subject. Among the 349 articles under full-text review, 329 articles were excluded for lacking targeted data or meeting any one of the exclusion criteria . UltimatOR = 1.55, 95% CI: 1.30–1.84, OR = 1.36, 95% CI: 1.01–1.84, OR = 1.20, 95% CI, 1.11–1.29, In the cohort studies, DM was associated with 62% higher risk of LTBI, with the pooled risk ratio (RR) 1.62  , carried out in Africa , with a sample size of between 1,000 and 5,000 , with male accounted for less than 40% . There were no significant differences in studies classified by the risk of bias . Population group, study location, sample size, and proportion of male might be the potential source of heterogeneity in the association between DM and the risk of LTBI.Given the substantial heterogeneity among the studies, we did subgroup analyses by population group, study location, sample size, proportion of male, and study quality for cross-sectional studies . In the t = 2.87, p = 0.01) indicated that publication bias might exist.In the sensitivity analyses, the pooled results were consistent and all the results showed that DM has an effect on LTBI when omitting one study at a time, which demonstrated that the pooled estimation was stable. Funnel plot was shown in RR = 4.40, 95% CI, 0.50–38.55) for a cohort study, which was contradictory to our study , and the pooled OR for the 17 cross-sectional studies was 1.55 (95% CI: 1.30–1.84), both revealing a significant increased risk of LTBI among DM patients. A previous meta-analysis conducted by Lee and colleagues identified 13 cross-sectional studies and 1 cohort study . They four study . Moreoveur study , 42, whiur study . Both peur study . Therefo+ and CD8+ T-cell responses . Pre-DM, or intermediate hyperglycemia, is a high-risk state of DM that is defined by glucose values higher than normal, but lower than DM threshold  were used to identify the status of LTBI in all studies, since there was no gold standard test for direct identification of LTBI in humans . HoweverThe risk of LTBI was found to be a 60% increase in DM patients, compared with individuals without DM. Pre-DM was also associated with increased risk of LTBI. Our findings highlight the importance of LTBI screening among DM patients. More studies are needed to explore appropriate strategies and tools for targeted LTBI screening among DM patients, thereby decreasing global burden of TB disease and improving the prognosis of DM.The original contributions presented in the study are included in the article/JL and ML conceived and designed the study. QL and RL carried out the literature searches. QL, WY, RL, and EB extracted the data. QL, WY, and JL assessed the study quality. QL and WY performed the statistical analysis and wrote the manuscript. JL, ML, QL, and WY revised the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Kidney stone disease (KSD) is a common illness that causes an economic burden globally. It is easy for patients to relapse once they have suffered from this disease. The reported recurrence rate of KSD ranged from 6.1% to 66.9%. We performed this meta-analysis to identify various potential risk factors for the recurrence of KSD.The PubMed, Embase and Web of Science databases were searched using suitable keywords from inception to Mar 2022. A total of 2,663 records were collected initially. After screening the literature according to the inclusion and exclusion criteria, 53 articles  including 488,130 patients were enrolled. The study protocol was registered with PROSPERO (No. CRD42020171771).The pooled results indicated that 12 risk factors including younger age (n = 18), higher BMI (n = 16), family history of kidney stones (n = 12), personal history of kidney stones (n = 11), hypertension (n = 5), uric acid stone (n = 4), race of Caucasian (n = 3), suspected kidney stone episode before the first confirmed stone episode (n = 3), surgery (n = 3), any concurrent asymptomatic (nonobstructing) stone (n = 2), pelvic or lower pole kidney stone (n = 2), and 24 h urine test completion (n = 2) were identified to be associated with KSD recurrence. In the subgroup analysis, patients with higher BMI (OR = 1.062), personal history of nephrolithiasis (OR = 1.402), or surgery (OR = 3.178) had a higher risk of radiographic KSD recurrence.We identified 12 risk factors related to the recurrence of KSD. The results of this analysis could serve to construct recurrence prediction models. It could also supply a basis for preventing the recurrence of KSD.The online version contains supplementary material available at 10.1186/s12894-022-01017-4. Kidney stone disease (KSD) is a common issue with a high health care burden that affects the quality of life among the global population. The incidence rate of nephrolithiasis increases annually, estimated to be 14% in England and 10.1% in the United States . Its etiThe recurrence of KSD varies greatly among different patients. Some patients have nephrolithiasis only once, while others have frequent recurrences. Although preventive measures such as diet and drugs have been implemented and have achieved significant results, the effectiveness of these interventions is still limited , 9. IdenExisting studies have only summarized limited risk factors for KSD recurrence , 11. NevThe Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analysis of observational studies in epidemiology (MOOSE) guidelines were utilized when this meta-analysis was conducted . The PubEligible studies were screened according to the following criteria: (1) any prospective or retrospective study reported the risk factors for recurrence of KSD; (2) sufficient data to estimate the odds ratio (OR), relative risk (RR), or hazard ratio (HR) and their 95% confidence intervals (CIs) reported according to the risk factors; and (3) only complete or the latest studies were included in several studies reported the same risk factors in the same cohort. The recurrence of KSD was defined as the symptomatic, radiographic appearance, or repeated interventions of stones. Reviews, case reports, nonhuman trials, letters, conference abstracts and comments were excluded. Cross-sectional studies were excluded. Studies whose control groups contained healthy subjects or sample sizes were < 40 or lacked key data were also excluded. If only the Kaplan–Meier curves of risk factors for recurrence of KSD were available, we extracted the HR and 95% CI data. The titles and abstracts of all literature were first independently screened by two authors. Further evaluation was conducted by browsing the full texts. Any disagreement was eventually resolved.DMC and YHS independently extracted the data required from all eligible studies. JW and DW assessed the quality of each study according to the Newcastle–Ottawa Quality Assessment Scale (NOS) as described in our previous work , 15. InfI2 > 50% and/or P < 0.1, a random-effects model was used. Otherwise, a fixed-effects model was applied. Publication bias was detected with an asymmetrical funnel plot and cross-checked by Begg’s and Egger’s tests. The trim-and-fill method was used if publication bias existed. Subgroup analysis was conducted based on the definition of radiographic KSD relapse to reduce the impact of heterogeneity. All data were analyzed by STATA software version 12.0 . P < 0.05 was considered statistically significant.Any RR and HR with similar values were merged into OR. Pooled ORs and their 95% CIs were used to describe the relationship between various risk factors and recurrence of KSD. A minimum of 2 studies for a risk factor were analyzed. Heterogeneity was assessed by Cochran’s Q test and Higgins’ I-squared statistics. When First, a total of 2,663 records  were collected. A total of 399 articles were further evaluated carefully after deduplication and reviewing the title and abstracts. A total of 344 studies were further excluded, which lacked important data. 2 cross-sectional studies were also excluded. Eventually, 53 articles, including 488,130 patients, were enrolled in this analysis –67 . All the studies including 48 high-quality and 5 moderate-quality studies were performed using an improved methodology. For further analysis, all the studies mentioned above were enrolled.Eleven variables, including age , 48, 50,The pooling data suggested that the patients with older age would have a lower risk for recurrence of KSD. Caucasian and the patients with higher BMI or hypertension would have a higher risk for recurrence of KSD  stone, pelvic or lower pole nephrolithiasis, or uric acid stone would have a higher risk for recurrence of KSD . Thus, the pooled result for diameter of largest nephrolithiasis was reliable. No publication bias appeared in other analysis of risk factors.The Three variables containing stone prevention medications treatment, surgery treatment and extracorporeal shock wave lithotripsy (ESWL) were available for data pooling Table .I2 = 76.0%, P < 0.001; OR = 0.752, 95% CI = 0.548–1.033, P = 0.078)    . Thus, the pooled result for ESWL was reliable.The pooling data from 4 studies , 52, 59 Eleven variables of 24-h urine test including baseline urine volume , 50, 54,After pooling the data of the risk factors mention above, 24 h urine test completion was suggested to be a risk factor for recurrence of KSD  stone, hypertension, uric acid stone, pelvic or lower pole nephrolithiasis, surgery, and 24 h urine test completion were identified to be associated with relapse of KSD. Additionally, the patients with ureterovesical junction stone might have a lower risk in the relapse of KSD. These results could serve as the risk factors for constructing recurrence prediction models. It also supplied a basis for preventing the recurrence of KSD. Although all conclusions were obtained from results of this analysis directly, several risk factors should be interpreted with caution. More well-designed researches on this topic are needed.Additional file 1: Table S1. Keywords and search hits in PubMed, Web of Science, and Embase databases. Table S2. Newcastle-Ottawa Quality Assessment Scale for case–control studies. Table S3. Newcastle-Ottawa Quality Assessment Scale for cohort studies.Additional file 2: Figure S1. Forest plots of studies evaluating association between identified three demographic risk factors and KSD relapse. Figure S2. Forest plots of studies evaluating association between identified nine kidney stone-related risk factors and KSD relapse. Figure S3. Forest plots of studies evaluating association between the risk factors of surgery and 24 h urine test completion and KSD relapse.