There is growing interest in the prediction of incident atrial fibrillation (AF). The 12-lead electrocardiogram (ECG) has been a particularly rich target for possible prediction strategies.The P-wave axis is an ECG parameter that reflects the dominant vector of atrial depolarisation and is usually 0° -75°. There is a large body of literature suggesting that AF reflects structural and conduction abnormalities of the atria, and thus the P-wave axis may represent a sensitive parameter to detect such changes.A systematic review and meta-analysis of published literature associating abnormal P-wave axis and the development of incident AF was performed. Electronic databases were systematically searched from inception to October 2021. A random-effects model with generic inverse variance weights was utilised to pool the most adjusted effect measure from each paper. A funnel plot was used to assess publication bias.After excluding duplicate studies, 568 studies were screened. A total of eleven studies were identified that associated an abnormal P-wave axis with the subsequent detection of AF. The eight studies that considered abnormal P-wave axis as being <0° or >75° were pooled for meta-analysis. In the pooled studies a total of 78,222 patients were included with 5656 cases of incident atrial fibrillation identified. The meta-analysis of the studies suggested that an abnormal P-wave axis was associated with a pooled risk ratio of 2.12 (95% CI 1.49 to 3.01) for the detection of incident atrial fibrillation.This comprehensive systematic review and meta-analysis, indicates the positive association of abnormal P wave axis and future detection of AF. Utilisation of abnormal P-wave axis, alongside other parameters, may allow clinicians to better risk-stratify individuals at increased risk of AF, and thus identify those who may benefit most from prolonged cardiac monitoring or targeted anticoagulation. The frontal P-wave axis reflects the dominant vector of atrial depolarisation, and can be calculated by analysis of the P-wave in the limb leads on a 12-lead electrocardiogram (ECG) with reference to the hexaxial system . More reThe normal P-wave axis is defined by angles between 0° and 75°. An abnormal P-wave axis may either be right-wardly displaced, which is typically defined as > 75°, or left-wardly displaced, defined as <0°. The former may be seen a variety of conditions, including right atrial enlargement, emphysema without right atrial enlargement and conduction abnormalities including ectopic atrial rhythms. Leftward deviation can be seen in left atrial enlargement as well as atrial conduction abnormalities.There have been several large cohort studies looking at the relationship between abnormal P-wave axis and detection of future incident AF, whilst there have also been smaller case-control studies considering specific patient sub-groups. The pathophysiological correlate for this relationship remains an area of active investigation. Gross structural changes in the atria such as dilatation are associated both with a change in P-wave axis and AF,  but variThis systematic review and meta-analysis aims to provide a summary of the literature pertaining to the potential role of P-wave axis as a predictor for future AF detection.The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)  and MetaThe electronic databases PUBMED, EMBASE, Web of Science and Cochrane were systematically searched using the key words “P-wave axis” and “P wave axis” from inception to October 2021. A subsequent “snowball” search was performed to identify further studies, by examining the reference lists of included studies.An initial titular analysis, followed by abstract and full text screening was performed. The following criteria were utilised a) any observational study including case-control, nested case-control, retrospective and prospective cohort studies; b) studies pertaining to the relationship between abnormal P-wave axis and AF; c) exclusion of baseline AF; d) full-text availability; e) human studies. For the purposes of this review, atrial flutter was considered alongside AF. Abstracts and non-peer reviewed studies were excluded.Data was extracted from the identified studies using a pre-specified electronic collection form. The data extracted included study location, population, population size, mean population age, population gender distribution, the number of individuals who developed incident AF, how incident AF was diagnosed, the follow up time, the definition of abnormal P-wave axis utilised, methodology for P-wave axis calculation, sample exclusion criteria, reported hazard (HR) or odds ratios (OR) and confounders utilised in multivariable assessment. The main outcome of interest was the development of incident AF.2 statistic. A two-tailed P-value <0.05 was considered statistically significant. A funnel plot was used to identify possible publication bias. All statistical analyses were conducted using the Review Manager (RevMan) software .For the purposes of the meta-analysis, where an effect size with 95% confidence interval from a multivariable analysis was available, this was used. Where a study quoted a hazard ratio, this was converted to an odds ratio, using methodology defined in the Cochrane Handbook for Systematic Reviews of Interventions . A randoThe quality of each study was assessed utilising the Newcastle-Ottawa scale (NOS) .A total of 855 studies were screened across the different databases. Following removal of duplicates, animal and paediatric studies, 568 studies were further examined. A total of eleven studies were identified that related an abnormal p-wave axis with the subsequent detection of atrial fibrillation, as outlined in Considering the three studies that were not included in the meta-analysis–Cho et al. utilised an upper P-wave axis limit of 90°; Hayashi et al. reported AF prediction with P-wave axis less than 74° in patients with P-pulmonale; Kreimer et al. did not report an overall numerical risk statistic for abnormal P-wave axis.2 value of 92%. The effect of this was reduced by utilising -a random effects model. To identify the source of heterogeneity, a sensitivity analysis was performed by removing one study at a time  1.48 to 2.72) for the detection of incident AF . Heterogt a time , which dA funnel plot looking for possible publication bias in the field is shown in This is the first systematic review and meta-analysis of the association of abnormal P-wave axis with AF.The results of this meta-analysis suggest that an abnormal P-wave axis is a positive predictor for the detection of incident AF. This was apparent in all but one of the eight studies that were appropriate for meta-analysis.Considering the large cohort studies, abnormal P-wave axes were shown to have an association with the development of future AF in the Action to Control Cardiovascular Risk in Diabetes (ACCORD), Cardiovascular Health Study (CHS), Atherosclerosis Risk in Communities (ARIC) and Perez’s Californian populations, over an average follow up time of between 5.3 and 20.3 years.In terms of studies that did not identify an association, both Li et al. and Kreimer et al. failed to identify a statistically significant association in smaller cohorts , 12, theLehtonen et al.’s  large asHayashi et al.  did lookOnly two of the studies made use of continuous ILR monitoring to detect incident AF, , 12 whilA criticism of other P-wave indices has been their susceptibility to lead related changes and poor short-term reproducibility . Since tThe P-wave axis, is just one of a number of different ECG based parameters that have been studied as a possible predictor of the development of future AF. Generally the most well studied parameters are P-wave related and include measures such as P-wave duration, PR segment duration and measures of inter-atrial block . More noVentricular parameters, such as ECG defined left ventricular hypertrophy, QT interval and QRS duration have also been investigated . PerhapsThere is likely to be overlap between the predictive role of these different ECG parameters, and larger, carefully designed studies are necessary to disentangle the effect of individual parameters. The strength of the P-wave axis as an ECG predictor lies in its reproducibility, and the fact that it is frequently reported on a standard 12-lead ECG.This finding is important, as it implies that patients with an abnormal P-wave axis, are at an increased risk of AF development. With the number of populations that this finding was demonstrated in, the consistency of this in meta-analysis, and the fact that P-wave axis is automatically reported on many digital ECG reports, this may represent an easy to identify predictor of future AF. The fact that this result persisted in multivariable analyses suggests that it may act synergistically with other predictors, such as hypertension, hyperthyroidism and obesity for AF. Ultimately, combining a large cohort study with methods of continuous monitoring such as an ILR, would help further establish the role of P-wave axis, although the follow up period would be limited to the battery life of the device.An abnormal P-wave axis may be used alongside other established parameters, to help refine AF prediction. Identifying individuals who are susceptible to the development of incident AF, is beneficial across different populations.In the general population, identifying such individuals can help to target continuous monitoring methods such as ILR implantation, improving the yield of AF screening approaches. Moreover, with the improved understanding of lifestyle factors that propagate atrial fibrillation, such as obesity  and exceIn the ESUS population, this group of individuals may provide a more promising target for empirical anticoagulation. NAVIGATE-ESUS  demonstrThis meta-analysis is composed of data from observational studies. As such heterogeneity was high which is typical in the diverse cohorts of patients seen in observation studies. Measures were taken however to minimise this effect including utilisation of a random effects model and a sensitivity analysis. Furthermore, both the follow up period between the studies, and the method of AF detection varied significantly.Finally, we were not able to include in the meta-analysis all the studies identified in the systematic review which might allowed a more accurate estimation of the risk associated with abnormal p wave axis. As mentioned in the results section, three studies could not be included in the meta-analysis. Two papers used different values to define an abnormal P-wave axis. Hayashi et al. used less than 74°, which is abnormal in their population of P-pulmonale patients, but would be considered normal in the general population. The Cho et al. paper used values greater than 90°, and therefore could not be included in our meta-analysis, as all of the other papers included considered P-waves axes of 75° to 90° abnormal. Kreimer et al. did not provide a numerical value for their effect size.This comprehensive systematic review and meta-analysis, including 78222 patients from eight studies, indicates the positive association of abnormal P-wave axis and future detection of AF. It thus confirms a two-fold risk of abnormal p-wave axis independent of other established predictive factors such as hypertension, age and abnormal systolic heart function. Utilisation of abnormal P-wave axis, can allow clinicians to better risk-stratify individuals and provide more frequent monitoring for AF in individuals at high risk.S1 Checklist(DOCX)Click here for additional data file.S1 Fig(TIF)Click here for additional data file.S2 FigSensitivity analysis demonstrating continued association of P-wave analysis despite exclusion of Rangel et al.(TIF)Click here for additional data file.


Studies on the susceptibility of vitamin D receptor (VDR) polymorphisms to coronary artery disease (CAD) reached controversial results. We performed this study for a more accurate evaluation between the VDR polymorphisms and CAD susceptibility.PubMed, Embase, CNKI, Wan Fang, and VIP databases were searched. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to evaluate the associations. Trial sequential analysis (TSA) was introduced to estimate the positive associations. The potential functions of the VDR polymorphisms were analyzed based on the SNPinfo and ENSEMBL databases.Thirteen studies were finally included. In the overall analysis, increased CAD risks were observed in the VDR rs1544410 polymorphism and verified by the TSA; for the rs2228570 and rs731236 polymorphisms, significant associations with high heterogeneity were detected; decreased risk was remarkably observed for the rs7975232 polymorphism. In the subgroup analysis, wide associations with reduced heterogeneity were observed in the rs2228570, rs1544410, and rs731236 polymorphisms. The RNAfold analysis indicated the mutant G allele of the rs1544410 polymorphism was easier to disperse from the DNA double helix structure and may have a potential crucial role in the VDR transcription process.Our analysis supports the role of the rs1544410 polymorphism in the VDR gene as a risk factor for CAD. The VDR rs2228570 and rs731236 polymorphisms were associated with increased CAD risks in the White population. Restrict decreased CAD risk was firstly discovered in the rs7975232 polymorphism.Firstly, the language was restricted to English and Chinese, which will cause the limited number of studies included; secondly, other unknown polymorphisms in VDR polymorphisms could also be associated the CAD susceptibility, and more case-control studies with comprehensive clinical outcomes and GWAS studies were required; thirdly, the rs1544410, rs7975232 and rs731236 polymorphism are in strong LD, haploid factors with CAD risk need to be considered; fourthly, the mechanisms of the VDR polymorphism on the VDR gene or RNA or protein were not discussed enough, further mechanistic studies are required; at last, genetic factor was the one side for CAD susceptibility, the interaction between environmental risk factors should be considered. Risk factors have always been a hot topic in the study of coronary artery disease (CAD), which is the main leading cause of death in the world –3. TradiVDR gene is located on chromosome 12q13.1, and has four common single nucleotide polymorphisms (SNPs) which are rs2228570 (FokI F/f in exon 2), rs1544410 (BsmI B/b in intron 8), rs7975232 (ApaI A/a in intron 8) and rs731236 (TaqI T/t in exon 9) .–16.13–16Review Manager, Version 5.3  and STATA 12.0  were used for all analysis. P < 0.05 was considered to be significant. Hardy–Weinberg equilibrium (HWE) was evaluated for each study by Chi-square test in control groups, and P < 0.05 was considered as a significant departure from HWE. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated. The odds ratio (OR) is the ratio of odds of an event in one group versus the odds of the event in the other group. An odds ratio (OR) of 1.0 indicates that there is no difference in risk (or odds) between the groups being compared. An OR of more than 1.0 indicates an increase in risk (or odds) among the exposed compared to the unexposed, whereas an OR <1.0 indicates a decrease in risk (or odds) in the exposed group . Pooled 2 statistic (greater than 50% as evidence of significant inconsistency). If the P value for heterogeneity was >0.10 and I2 <50%, indicating an absence of heterogeneity between studies, the fixed-effects model (the Mantel-Hasenszel method) would be used; If the P value for heterogeneity was ≤0.10 or I2 ≥50%, indicating a high exist of heterogeneity between studies, and the random-effects model (the DerSimonian and Laird method) would be used. Besides, subgroup analyses were stratified by Race , Hardy-Weinberg equilibrium , sample size , genotyping method , and random-effects model were applied in subgroup analysis for more conservative results. We applied the Bonferroni method, which controls for the false discovery rate (FDR), to adjust for multiple comparisons.Heterogeneity was evaluated by Q statistic (significance level of P < 0.1) and Ihttp://www.ctu.dk/tsa). If the data in included studies are sparse or if there is repeated testing for significance in conducting an updated meta-analysis, the type I errors and type II errors are unavoidable [TSA  is a methodology that combines an information size calculation  for a meta-analysis with the threshold of statistical significance  assumption of 20% . A contihttp://asia.ensembl.org/index.html). SNPinfo is an important bioinformatics analysis tool that predicts SNP function. The SNPinfo database can help researchers specify genes or linkage regions and select SNPs based on GWAS results, calculate linkage disequilibrium (LD), and predict functional characteristics of both coding and non-coding SNPs (https://snpinfo.niehs.nih.gov/) [Ensembl is a genome browser for vertebrate genomes that supports research in comparative genomics, evolution, sequence variation and transcriptional regulation, and this database provides the genomic context, genes and regulatory elements, flanking sequence, population genetics, phenotype data, sample genotypes, linkage disequilibrium and phylogenetic context of a single nucleotide polymorphism (ih.gov/) . In addiih.gov/) . TherefoThe PRISMA flow diagram of the literature selection process was showed in Thirteen studies were finally included in our manuscript , 25–36. The results of overall and subgroup populations were showed in For the rs2228570 polymorphism, the pooled results showed significant associations with high heterogeneity in all genetic model: allelic genetic model  , dominanFor the rs1544410 polymorphism, significant associations with low heterogeneity were discovered in both pooled and subgroup analyses. From the pooled results, increased risk of CAD were observed in all genetic models: allelic genetic model  Same as the rs2228570 polymorphism, significant associations with high heterogeneity were widely observed in overall and subgroup analysis. In the overall analysis, increased risk in allelic  , dominanInterestingly, decreased risks of CAD were firstly discovered in overall analysis and subgroup analysis based on Race and Sample size. In overall analysis, decreased CAD risks were detected in allelic  , heterozWe conducted the sensitive analyses on VDR polymorphism and CAD risk by omitting one study at a time in the calculation of the summary outcome . The resThe Egger’s test was introduced to analyze the publication bias, the P value for the test of these four VDR polymorphisms were 0.423 (rs2228570), 0.218 (rs1544410), 0.396 (rs731236) and 0.980 (rs7975232), respectively. Moreover, the Begg’s funnel plots of these four polymorphisms were symmetrical . The resBased on our analysis, increased CAD risks with low heterogeneity in the overall analysis of the rs1544410 polymorphism and the White population of the rs2228570 and rs731236 polymorphisms were discovered. Therefore, a trial sequential analysis was introduced to validate that our discoveries above were not false positive results. The allelic genetic model is a natural model of inheritance with a stronger genotype-phenotype association, which also does not pre-assume any interactions between the numbers of variant alleles. Therefore, we chose the allelic genetic model of the rs1544410 polymorphism in overall population and the rs2228570 and rs731236 polymorphism in the White population to conduct the trial sequential analysis. The X and Y axes represent the number of patients and the cumulative Z score, respectively. Within the designed assumptions of confidence and effect size, the information size for the rs1544410 polymorphism are 152472, the Z curves not only cross the statistical significance line , but also cross the O’ Brien Fleming boundaries , indicatBased on the genomic context obtained from the Ensembl database, the VDR rs2228570 polymorphism caused a “start lost”, the rs1544410 and rs7975232 polymorphisms were intron variants, the rs731236 polymorphism was the synonymous variant. Hence, we analyzed the sequences of the four polymorphisms and the results from the SNPinfo database showed the VDR rs2228570 and rs731236 polymorphism were predicted the function of Splicing . In addiCoronary artery disease (CAD) is a disease with very high morbidity and mortality. Early prevention based on genetic polymorphism can reduce the incidence of CAD , 38. In In the previous meta-analysis –41, incrIn the overall analysis, the rs1544410 polymorphism was discovered to be associated with an increased risk of CAD in all five genetic models and the positive results were verified by TSA in the allelic genetic model, which indicate that the role of the rs1544410 polymorphism in the VDR gene as a risk factor for CAD. For the mutant b allele, it has a 15% increased CAD risk compared to the B allele. In terms of genotype, the Bb and bb genotype have 22% and 29% increased CAD risk compared to the BB genotype, respectively. As for the rs2228570 and rs731236 polymorphism, increased risk with high heterogeneity were widely observed, the mutant f allele has a 27% increased risk compared to the F allele for the rs2228570 polymorphism; for the rs731236 polymorphism, the mutant t allele has a 19% increased risk compared to the T allele. Interesting findings emerged on the rs7975232 polymorphism, decreased risks were firstly observed. The mutant a allele has a 7% decreased CAD risk compared to the A allele, and the aa genotype has a 13% decreased CAD risk compared to the AA genotype, however, the relative small sample size could have an influence on the evaluation of the rs7975232 polymorphism, and more well-designed studies were required to solidate the potential protective role of the rs7975232 polymorphism.In the subgroup analysis, the high heterogeneity of the rs2228570 and rs731236 polymorphisms were significantly reduced in the White population. In the White population, increased CAD risks were extensively detected in the rs1544410, rs2228570 and rs731236 polymorphism. However, in Asian subgroup, an 60% increased CAD risk of the ff genotype is observed in the rs2228570 polymorphism compared to the Asian FF genotype, and no association is detected in the rs1544410 and rs731236 polymorphisms. The results in subgroup analysis stratified by race may indicate the White population with rs2228570, rs1544410 and rs731236 are more susceptible to CAD. As for the rs7975232 polymorphism, in the White population, the mutant a allele has a 7% decreased CAD risk compared to the A allele. Sample size is an important parameter in the case-control studies. In the subgroup analysis based on sample size, we detected that increased or decreased risks of the four VDR polymorphisms were widely observed in the large subgroup, which implied case-control studies with sufficient sample size could discover more meaningful data. Homogeneity is a crucial factor in the statistical Analysis, therefore HWE and genotyping typing method were analyzed in different subgroups, however, the results showed these two-subgroup analysis did not seem to affect the high heterogeneity. Compared to the traditional risk factors like smoking, being overweight, and lack of exercise et al., the VDR polymorphisms associated with CAD susceptibility we found could help the population identify CAD earlier and provide individualized treatment.Lower plasma level of vitamin D was associated with increased risk of CAD , 44–46. The VDR rs2228570 polymorphism caused a “start lost”, the rs1544410 and rs7975232 polymorphisms were intron variant, the rs731236 polymorphism was the synonymous variant. The VDR rs2228570 and rs731236 polymorphism were predicted the function of Splicing. In addition, the secondary structure of DNA at the VDR rs1544410 sequences was predicted by using the RNAfold, which indicated that the mutant G allele could cause an easier dispensation from the DNA double helix structure. The SNP in rs2228570 polymorphism is located in the exon 2, which is near the translation start sequence, and the mutant T allele causes a structural modification of three amino acids longer protein leading to the change of potential protein function . Unlike There were several limitations in our meta-analysis. Firstly, the language was restricted to English and Chinese, which will cause the limited number of studies included; secondly, other unknown polymorphisms in VDR polymorphisms could also be associated the CAD susceptibility, more case-control studies with comprehensive clinical outcomes and GWAS studies were required; thirdly, the rs1544410, rs7975232 and rs731236 polymorphism are in strong LD, haploid factors with CAD risk need to be considered; fourthly, the mechanisms of the VDR polymorphism on the VDR gene or RNA or protein were not discussed enough, further mechanistic studies are required; at last, genetic factor was the one side for CAD risk, the interaction between environmental risk factors should be considered.Our analysis supports the role of the rs1544410 polymorphism in the VDR gene as a risk factor for CAD. The VDR rs2228570 and rs731236 polymorphisms were associated with increased CAD risks in the White population. Restrict decreased CAD risk was firstly discovered in the rs7975232 polymorphism.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.


Periprosthetic joint infection (PJI) after shoulder arthroplasty is a devastating complication that requires several additional surgeries. The purpose of this study was to assess the evidence regarding risk factors for PJI and identify those that contribute to infection by performing a meta-analysis. We searched the PubMed, Embase, and Cochrane Library databases for studies that assessed the risk factors for infection after shoulder arthroplasty. After performing screening and quality assessment on the articles, we obtained two case-control studies and six retrospective cohort studies . Review Manager 5.4 was used to assess the heterogeneity and odds ratio for 20 different factors that broadly included demographic factors, perioperative factors, and comorbidities. Factors that are markedly associated with PJI after shoulder arthroplasty were male sex, operation history, revision arthroplasty, acute trauma, and non-osteoarthritis as a preoperative diagnosis. Statistical analysis revealed that diabetes mellitus, liver disease, alcohol overuse, iron-deficiency anemia, and rheumatoid arthritis were risk factors for PJI after shoulder arthroplasty. The result of analysis shows that several specific factors can be targeted to prevent infections after shoulder arthroplasty. Surgeons should consider the risk factors and perform the appropriate management for patients. Shoulder arthroplasty is a relatively common procedure for acute trauma, such as proximal humerus fracture, and degenerative diseases such as cuff tear arthropathy, rheumatoid arthritis (RA), and osteoarthritis (OA) ,3,4,5,6.The present systematic review was conducted in accordance with PRISMA guidelines .We searched for relevant articles from January 2010 to December 2021 by using PubMed, Embase, and Cochrane Library to identify all published studies in which the risk factors for infection were assessed after shoulder arthroplasty. Each paper had a different definition for infection. Therefore, for accurate meta-analysis, the authors put the most effort into selecting the criteria for PJI. We considered the Musculoskeletal Infection Society (MSIS) criteria for PJI to be the most objective and useful tool. We excluded all papers that did not provide a clear definition of infection. Only when the definitions described in the paper met the MSIS criteria were they included in the analysis .In MSIS criteria, there are major criteria and minor criteria; PJI is present when 1 major criterion exists or 4 out of 6 minor criteria exist. The major criteria were as follows: (1) two positive periprosthetic cultures with phenotypically identical organisms; and (2) a sinus tract communicating with the joint. The minor criteria were as follows: (1) elevated serum erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) concentration; (2) elevated synovial leukocyte count; (3) elevated synovial neutrophil percentage; (4) presence of purulence in the affected joint; (5) isolation of a microorganism in one culture of periprosthetic tissue or fluid; and (6) greater than five neutrophils per high-power field in five high-power fields observed from histologic analysis of periprosthetic tissue at ×400 magnification.The following search terms were used: (“factor” or “predictor” or “risk”), (“infection” or “periprosthetic infection” or “periprosthetic joint infection”), and (“shoulder arthroplasty” or “shoulder replacement”). We applied the following inclusion criteria for the selection of articles: (1) studies published in English; (2) quantitative studies, such as cohort studies or case-control studies; (3) studies with demographic, comorbid, and perioperative risk factors; and (4) studies with adequate control groups and that reported the actual numbers of patients; (5) studies that clearly describe the definition of infection and conform to the MSIS criteria .The exclusion criteria were as follows: (1) case reports, reviews, or other indistinct forms; (2) studies that do not focus on risk factors; and (3) studies that repeatedly publish the same data.We excluded all papers that did not provide a clear definition of infection. Only when the definitions described in the paper met the MSIS criteria were they included in the analysis.Two of three authors  independently evaluated the potentially eligible studies. After excluding duplicate studies, the remaining studies were screened for eligibility based on the title and abstract. Disagreements were resolved via consensus. After screening, the full texts of the eligible articles were read independently by the two authors, and the eligibility of each article was reassessed. The third author (J.-J.P.) was included in the discussion when conflicts occurred.The methodological quality of the included papers was assessed using two different tools. For case-control studies, the Newcastle–Ottawa scale for case-control studies was used for the quality assessment . For cohTwenty different factors were investigated for their association with infection after shoulder arthroplasty. Demographic factors include sex, age, obesity, ASA scale, and race. Among them, age was divided into a group over 65 years old, which is generally defined as the elderly, and a group under 65 years old. Obesity is defined as a BMI of 30 or more by the World Health Organization, so it was divided into a group with a BMI of 30 or more and a group with a BMI of less than 30. The ASA scale was divided into ASA I or II, and higher groups. Finally, race was divided into two groups: white and other races. Non-arthroplasty surgery on the ipsilateral shoulder before arthroplasty, revision arthroplasty, surgery for acute trauma, and surgery for a diagnosis other than osteoarthritis were considered potential risk factors. For the type of devices, total shoulder arthroplasty including both anatomic and reverse and hemiarthroplasty was compared. In addition, the relationship between comorbidities and PJI after arthroplasty was assessed. The comorbidities used in the analysis are as follows: DM, HTN, smoking, alcohol overuse, liver disease, renal failure, iron-deficiency anemia, pulmonary disease, RA, and steroid use.2 statistics for each analysis. An I2 value < 50% indicates the homogeneity of the pooled data, and the fixed-effects model was used for the analysis. On the other hand, an I2 value ≥ 50% indicates heterogeneity of the pooled data, and the random-effects model was used. We analyzed the odds ratios (OR) and 95% confidence intervals (CIs) to analyze dichotomous factors such as demographic factors, perioperative factors, and presence of comorbidities. A p-value < 0.05 was considered significant.RevMan 5.4 software was used for the statistical analyses of pooled data. To measure the extent of inconsistency among the results, a heterogeneity test was performed using ISex2 = 4%).All studies can be used to assess sex as a risk factor. Our results suggested that males were more likely to develop infection after shoulder arthroplasty than females .Almost all of the related articles reported on age. However, the criteria for age in each study were different. Only three studies could be used for analysis. No correlations were revealed between age and PJI , suggesting that obesity is not a risk factor for PJI. On the contrary, patients with BMI < 30 kg/m2 have a higher risk of PJI than obese patients.Among the six studies that reported on BMI, three studies ,24,25 prASA scale2 = 82%).The data of three studies ,25,30 coRace2 = 0%).Two studies can be used for analyses with race as a factor ,27. We pPrevious operation history on shoulder (non-arthroplasty surgery)2 = 0%).Four studies ,23,26,29Diagnosis prior to shoulder arthroplasty2 = 0%), and arthroplasty for OA has a lower risk of PJI than other diagnoses . Five trauma-related studies [Several studies reported on the diagnosis prior to arthroplasty. In this meta-analysis, we attempted to determine whether the acute trauma-related diagnosis was a risk factor of PJI. Furthermore, we performed an analysis of OA compared with other diagnoses. In conclusion, preoperative diagnosis related to acute trauma is a risk factor for PJI .Three studies ,27,30 prTotal arthroplasty versus hemiarthroplasty2 = 45%) Then, aTSA versus rTSA , aTSA versus HA, and rTSA versus HA  were analyzed, respectively. Among these, only the analysis comparing aTSA and HA  showed a significant result, and in the case of aTSA, the risk of PJI was higher than that of HA.Anatomic total shoulder arthroplasty (aTSA), reverse TSA (rTSA), and hemiarthroplasty (HA) are three of the most common procedures in shoulder arthroplasty. Two studies ,26 incluSeveral studies have reported comorbidities such as diabetes and metabolic syndrome as risk factors for PJI after shoulder arthroplasty ,23,32. I2 = 0%). Furthermore, patients with liver disease have a higher risk for postoperative infection after shoulder arthroplasty than that of the control groups . RA was also found to be a risk factor for PJI as a result of the analysis .2 = 0%) and iron-deficiency anemia  were provided only in two articles. Both of them were identified as risk factors for PJI as a result of the meta-analysis. By contrast, statistical analysis revealed no correlation between HTN , smoking , pulmonary disease , renal failure , or steroid use , and PJI.Data required for the analysis of alcohol overuse .A funnel plot analysis was performed for demographic characteristics, perioperative factors, and comorbidities. In addition, Egger’s test was performed for factors that have been reported in more than three studies. The Accordingly, there have been various studies ,23 on thTherefore, in this study, we planned a meta-analysis of postoperative infection risk factors of shoulder arthroplasty including HA, aTSA, and rTSA, which are types of shoulder arthroplasty. We broadly classified the factors into demographic factors, perioperative factors, and comorbidity.First, among the demographic factors in the meta-analysis, the factors related to postoperative infection were sex and BMI < 30. Sex was mentioned in all included literature. In the included studies, male sex was reported as a significant risk factor in four articles, and this finding was consistent with the results of the meta-analysis ,24,26,27The results of meta-analysis showed that patients who underwent shoulder arthroplasty for OA have a lower PJI risk than that of patients with other diagnoses, and shoulder arthroplasty for acute trauma is a risk factor for infection. Arthroplasty associated with acute trauma, including open fracture, is more likely to cause delayed infection and osteomyelitis, than other diagnoses. In addition, compared to the control group, the difficulty of the operation and the operation time is increased in patients who underwent shoulder arthroplasty because of damage to the surrounding soft tissues when the fracture occurs. According to the contents of the paper, infection increases when the operation time increases during knee arthroplasty surgery . This maAs a result of the analysis in this study, DM, liver disease, alcohol overuse, iron-deficiency anemia, and RA were considered risk factors among comorbidities. Many studies have reported that DM is a major risk factor for PJI after orthopedic surgery ,37. The This study has some limitations. First, the quality of the final included studies in the meta-analysis was not high. High-quality studies, such as prospective cohort studies and randomized controlled trials, are ideal for meta-analyses, but the articles included in this study consist of two case-control studies and eight retrospective cohort design studies. Second, age and BMI were factors in a number of articles dealing with postoperative infection after shoulder arthroplasty. However, the limitation of the study was that the classification criteria for age and BMI were different for each paper; it was possible to analyze only three papers each, so the desired volume of patients could not be obtained. Lastly, a relatively low number of studies was included in our analysis. For accurate analysis, we included only ten papers in which the number of experimental groups and control groups were clearly described; therefore, a relatively small number of papers were included. Quantitative synthesis was not possible for all variables evaluated in the included studies because of the small number of studies examining some individual factors or the heterogeneity of measures.The results of the meta-analysis suggested that the risk factors include male, BMI < 30, previous non-arthroplasty operation history on ipsilateral shoulders, revision arthroplasty, diagnosis prior to arthroplasty (non-OA and acute trauma), DM, liver disease, iron-deficiency anemia, alcohol overuse, and RA. Surgeons should consider the risk factors and perform the appropriate management, such as the perioperative usage of antibiotics, when planning shoulder arthroplasty for patients.


Depression is a possible influence factor for the increased risk of incident atrial fibrillation (AF). Although several investigations have assessed their association, the results are still controversial. Therefore, we conducted a meta-analysis to evaluate the association between depression or using antidepressants and AF.We systemically performed the literature retrieval from two electronic databases PubMed and EMBASE until March 2022 to extract relevant data. The hazard ratios (HRs) and odds ratios (OR) from included studies with 95% confidence intervals (CIs) were adjusted into the risk ratio (RR) and pooled by using the random-effects model.P < 0.01). In addition, the use of antidepressants can also increase AF risk . These results remained unchanged when we remove the source of heterogeneity or adjust the analysis model into the fixed-effects model.Totally 9 studies about the associations between depression or antidepressants and incident AF risk were included in this meta-analysis. Among them, 5 studies specifically analyzed the impact of antidepressants on the risk of AF. The outcomes of our analysis indicated that depression or depressive symptoms could increase AF risk (RR = 1.15, 95% CI, 1.03–1.27, Based on existing investigations, both depression and the use of antidepressants are closely related to the increase of incident AF risk. Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia with an age-related increase in incidence . It is sIn recent years, the association between depression and AF has been confirmed in several basic and epidemiological studies , 12. TheAs for antidepressants which are divided into three categories including selective serotonin reuptake inhibitor (SSRI), tricyclic antidepressants and monoamine oxidase inhibitor, their cardiotoxicity has also been reported in previous studies , 24. TriConsidering that whether depression and the use of antidepressants could increase the risk of AF remains a controversial issue in previous studies, herein, we performed a meta-analysis including all of the existing studies to detect the association between AF risk and depression.This meta-analysis was based on the preferred reporting items for systematic review and meta-analysis (PRISMA) 2020 guidelines. Ethical approval was not provided since all data included in this study was from the published studies. The data, techniques, and materials that support the findings of this study will be available from the corresponding author according to reasonable requests.The PubMed, and EMBASE electronic databases were selected for systemic search in this study. Two independent reviewers identified potentially eligible studies that reported the relationship between depression and the risk of AF. There were no language restrictions in the retrieval process. Terms used in screening include  AND (depression OR depressive symptom OR antidepressant). The literature search strategy is resented in Literatures meeting the following criteria were included in this study: (1) Studies that reported the relationship between depression, depressive symptoms or the use of antidepressants and the risk of incident AF; (2) Cohort or case-control studies included both comparison and control groups, and data were obtained through follow-up; (3) Studies defined the depression and depressive symptoms according to definite criteria. There was no limitation on the follow-up period. Specific literature forms including reviews, case reports, case series, editorials and meeting abstracts were excluded from this study. In addition, studies with insufficient clinical data were also decided for exclusion.Two authors extracted data independently through screening the literature titles and abstracts. Then the full-text screening was conducted to detect whether the literature met the inclusion criteria. All discrepancies were resolved by discussing with the third researcher. If multiple studies from the same data source were suitable for this meta-analysis, only the study that best matched the eligibility criteria were included. Studies with later publication years and longer follow-up periods were preferentially included.The relevant information of each study was recorded, including the first author, publication year, data source, information of participants , the definition of depression, adjusted confounders, and follow-up period. For the included studies that reported the adjusted RRs by using multiple models, only the most adjusted data was used in this meta-analysis.The quality of eligible studies was assessed by using the Newcastle-Ottawa Scale tool, which covers three aspects, ranging from 0 to 9 stars: the cohort selection (0–4 stars), cohort comparability (0–2 stars), and the evaluation of study outcomes (0–3 stars). Studies with NOS results of <6 points were considered as low quality.https://community.cochrane.org/). The statistical heterogeneity was evaluated by I2 statistic and the Cochrane Q-test. Either P < 0.1 for the Q-test or I2 ≥ 50% was considered as the indication of substantial heterogeneity. For the results, P < 0.05 was considered to have statistical significance. To the extent possible, we used the same treatment effect indicators in cohort and case-control studies. Reported maximally adjusted hazard ratios (HRs) or odds ratios (ORs), and 95% confidence intervals (CIs) were extracted. For studies that reported multiple categories of psychological factors , HR in the most severe category was used. In the results section, we refer to all relative effects metrics as “risk ratios” (RRs), which do not affect the study results or their interpretation. The corresponding natural logarithm (Ln[RR]) and standard error (SE) of each investigation were used for calculation. Given the intrinsic heterogeneity of these included studies, the inverse-variance weighted random-effects model was applied to pool the Ln [RR] and its SE. The publication bias was assessed by funnel plots as well as Egger's and Begg's tests.The statistical analyses were performed by using the Review Manager version 5.4 software . However, this result represented relatively high heterogenicity (I2 = 88%). In order to detect the source of heterogeneity, we screened and analyzed all of the data in the included studies by the exclusive method. As shown in I2 = 42, P < 0.01). Also, this result was not changed when we adjusted the analysis into the fixed-effects model . The heterogenicity of included studies was acceptable (I2 = 42%). This result remained unchanged when we adjusted the analysis model into the fixed-effects model .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.


T1 rectal cancer (RC) patients are increasingly being treated by local resection alone but uniform surveillance strategies thereafter are lacking. To determine whether different local resection techniques influence the risk of recurrence and cancer-related mortality, a meta-analysis was performed.A systematic search was conducted for T1RC patients treated with local surgical resection. The primary outcome was the risk of RC recurrence and RC-related mortality. Pooled estimates were calculated using mixed-effect logistic regression. We also systematically searched and evaluated endoscopically treated T1RC patients in a similar manner.I2 = 68.3%). In meta-regression, the recurrence risk was associated with histological risk status  and local surgical resection technique . In 641 unique T1RC patients treated with flexible endoscopic excision (16 studies), the risk of recurrence , cancer-related mortality , and cancer-related mortality among patients with recurrence  were comparable to outcomes after TEM/TAMIS .In 2585 unique T1RC patients (86 studies) undergoing local surgical resection, the overall pooled cumulative incidence of recurrence was 9.1% (302 events, 95% CI 7.3–11.4%; Patients with T1 rectal cancer may have a significantly lower recurrence risk after TEM/TAMIS compared to other local surgical resection techniques. After TEM/TAMIS and endoscopic resection the recurrence risk, cancer-related mortality and cancer-related mortality among patients with recurrence were comparable. Recurrence was mainly dependent on histological risk status.The online version contains supplementary material available at 10.1007/s00464-022-09396-3. The introduction of population-based screening has resulted in an increased number of early invasive, or T1, rectal cancers (T1RC) [The decision whether to perform additional total mesorectal excision (TME) after local resection mainly depends on the oncological risk  ), operatSurveillance after local resection of T1RC is currently quite heterogeneous , and neeThis meta-analysis was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement . InformaA systematic literature search was conducted in PubMed, Embase, Web of Science and Cochrane Library from inception until May 19, 2021. Inclusion criteria were: 1. histologically confirmed pT1RCs 2. local surgical resection alone, 3. the proportion of recurrences after local surgical resection of T1RCs was reported 4. original peer-reviewed articles. Exclusion criteria were: 1. prior or additional therapy , 2. hereditary predisposition for CRC, 3. inflammatory bowel disease, 4. studies with < 5 patients with T1RC undergoing local surgical resection, 5. studies without original patient data , 6. conference abstracts, 7. animal studies and 8. non-English or non-German articles. In case of overlapping cohorts, the cohort with the largest number of patients, or covering the largest period of time was selected.T1RCs were defined as rectal tumors with histologic tumor invasion through the muscularis mucosae and into, but not beyond, the submucosa. Local surgical resection was defined as any type of local resection that was used to excise a rectal tumor without lymph node dissection, and that did not use flexible endoscopy , endoscopic full-thickness resection (eFTR), endoscopic mucosal resection (EMR), or snare polypectomy). High-risk criteria for LNM defined by The Japanese Society for Cancer of the Colon and Rectum (JSCCR) include: positive resection margins, deep submucosal invasion, grade 3 differentiation, lymphovascular invasion and high-grade tumor budding .Data of endoscopically treated T1RC patients were extracted from our previous meta-analysis on recurrences after local endoscopic resection of T1 colorectal cancer. This seData extraction and risk of bias assessment were independently performed by 3 authors . In case of disagreement without consensus after discussion, a fourth assessor (JB) was decisive. Relevant study-level parameters and individual patient-level data of recurrence cases were extracted. The risk of bias was assessed using a modified Newcastle–Ottawa Scale . An addiThe primary outcome was the cumulative incidence of RC recurrence  and RC-related mortality during follow-up. Locoregional recurrence was defined as endoluminal cancer at the primary resection site or pelvic LNM. Distant recurrence was defined as any metastasis outside the pelvic area. Secondary outcomes were the cumulative incidence of locoregional RC recurrence only, any locoregional RC recurrence and any distant recurrence.metafor v3.0.1 [All analyses were performed in R v4.1.0  using thr v3.0.1 . Cumulatr v3.0.1 .I2 statistic and tau-squared (τ2). Univariable meta-regression and subgroup analyses were performed to explore possible sources of heterogeneity with predefined potential predictors: study characteristics , individual items from the risk of bias assessment, follow-up characteristics , and clinical characteristics . Only studies with subgroups of ≥ 5 patients, for whom the exact number of events could be determined, were included in meta-regression and subgroup analyses. Meta-regression was only performed when at least 10 studies could be analysed [p values < 0.05 were considered statistically significant.Statistical heterogeneity was quantified using analysed . p valueOur search identified 5910 articles, of which 86 reported unique patient cohorts and were included , followed by North America , Asia , South America  and Australia . No obvious asymmetry was observed in the funnel plot .The extracted data and risk of bias assessment of the included studies are shown in Supplementary analyses. Most studies were performed in Europe  technique was investigated and transanal minimally invasive surgery (TAMIS) in 4. The majority of patients in the remaining 41 studies underwent other local surgical resection techniques with direct visualization; these were grouped as “local excision” . Fifty-five studies reported data on the resection plane; almost all patients in these studies underwent a full-thickness resection 99.2%). The mean and minimum follow-up could be determined in 15  and 51 studies (range 1–60), respectively. Complete data on follow-up schemes  was reported in 42 studies; schemes were classified as “not strict” in 6 (14.3%), “strict” in 13 (31.0%), and “very strict” in 23 studies (54.8%). The definitions used for these groups are shown in the Supplementary methods. A flow diagram of the study process is shown in Fig. %. The meI2 = 68.3%; Fig. Overall, 302 out of 2585 patients experienced recurrence after local surgical resection. The pooled cumulative incidence of any RC recurrence was 9.1%  and, local surgical resection technique  were associated with the risk of recurrence (Supplementary Tables 2 and 3). Therefore, subgroup analyses were performed for histological risk status and local surgical resection technique. Further analyses were stratified according to the duration of follow-up because risk of recurrence increased with longer mean follow-up duration (Supplementary Table 2). Results for studies with ≥ 2-year follow-up are shown below; results for all studies, for studies with a ≥ 5 years follow-up and detailed information regarding the meta-regression results are shown in Supplementary results.I2 = 60.8%; Supplementary Fig. 2). Pooled incidences of all secondary outcomes are shown in Supplementary analyses. The pooled incidence of RC-related mortality was 1.9% . The RC-related mortality rate among patients with recurrence was 28.7% (31/108). All of these patients died of disease progression.The pooled cumulative incidence of any RC recurrence was 9.2%  and 28.2% for high-risk T1RCs  . The cumulative incidence of any RC recurrence was 6.6% for low-risk T1RCs  and 10.8% after local surgical excision techniques with direct visualization   and 7.2% for local excision . This subgroup analyses confirmed that TEM/TAMIS is superior to other local surgical excision techniques with regard to recurrence. Outcomes of the TEM/TAMIS technique will therefore be compared to the endoscopic data. Secondary outcomes for all subgroup analyses are detailed in Supplementary results and Supplementary analyses.The cumulative incidence of RC recurrence was 7.7% after TEM/TAMIS  and TEM/TAMIS-treated patients  and among the recurrence cases . The timing of the recurrences after endoscopic resection is shown in Supplementary Fig. 6. The overall pooled incidence of RC recurrence after TEM/TAMIS and endoscopic resections combined was 7.7% .The previous meta-analysis and search update yielded 16 eligible studies with 641 patients and 51 recurrences  and 3.1% after endoscopic resection . Twenty-four of these low-risk recurrences were endoluminal , the other 7 were distant metastasis. For 29 of the 31 low-risk T1RC recurrences it was stated that the local resection was complete. For the other 2 recurrence cases this was not stated explicitly. For high-risk T1RCs the risk of recurrence was 29.7% after TEM/TAMIS  and 12.5% after endoscopic resection . In 29 of the 43 studies on local endoscopic resections for T1RC, 4–5 JSCCR risk criteria were used; for studies on TEM/TAMIS this was 5 of the 33 studies . Other secondary outcomes are shown in Supplementary results.The risk of recurrence for low-risk T1RC was 5.9% after TEM/TAMIS , RC-related mortality rates  and mortality rates among recurrences  were quite similar. A randomized non-inferiority trial is pending to confirm these results . DespiteThe risk of recurrence after local resection seems higher for T1 cancers in the rectum compared to T1 cancers throughout the colon. Here, we found a risk of recurrence for rectal T1 cancers of 7.7% (after endoscopic resection or TEM/TAMIS), which is higher than the 3.3% for endoscopically treated T1 cancers at sites throughout the colorectum . A similThe most important limitation of this meta-analysis relates to the quality of the included studies. The selection of studies for this meta-analysis was performed as thoroughly as possible, to prevent the exclusion of important studies. However, several studies did not specifically study T1RC patients treated by local resection alone. Therefore, data on patient, treatment, tumor size, tumor height, histological, follow-up and individual recurrence characteristics could not always be fully extracted. This resulted in a smaller number of studies in various subgroup analyses and for some studies in not receiving the maximum assessment scores on risk of bias. Secondly, there was some statistical heterogeneity, which could be expected a priori considering the heterogeneity in the resection techniques and follow-up. Therefore, we performed extensive meta-regression and subgroup analyses, which yielded lower heterogeneity estimates. Lastly, the definition of the rectum was left to the discretion of the authors of included studies, to avoid exclusion of many relevant articles that did not clearly state a definition. However, due to the technical limitations of transanal local excisions proximal to the rectum, it is not likely that cancers outside the rectum were included in this meta-analysis.Based on our study findings, we propose the following surveillance recommendations and key points for future research. Firstly, T1RC patients should be offered a different follow-up than T1 colon cancer patients and the surveillance should be stratified for histological risk status. There is no need to stratify surveillance for local resection technique when the T1RC is removed endoscopically or by TEM/TAMIS. All T1RCs that are removed locally should be offered surveillance  because even for low-risk T1RCs the recurrence risk is 3.1–5.9%. Patients with locally resected low-risk T1RC should be offered surveillance rather than completion TME because we think that in these patients the potential drawbacks from oncological surgery are greater than the possible benefits. We propose a 5-year moderately intensive follow-up scheme that should focus on the local-endoluminal site where most recurrences seem to develop sigmoidoscopies the first 2 years, and then yearly until 5 years; and 6 monthly CEA). Patients with high-risk T1RC should be offered completion TME surgery because of the relatively high-risk of recurrence, as is recommended in current guidelines . If oncoPatients with T1 rectal cancer may have a significantly lower recurrence risk after TEM/TAMIS compared to other local surgical resections. After TEM/TAMIS and endoscopic resection the recurrence risk, cancer-related mortality and cancer-related mortality among patients with recurrence were comparable. Recurrence was mainly dependent on histological risk status. Based on our findings we propose a more uniform histology-based surveillance strategy for T1 rectal cancer patients treated by local resection alone.Supplementary methods and results (DOCX 51 kb)Supplementary figure 1. Funnel plot for the cumulative incidence of any rectal cancer recurrence. The points correspond to the incidences of individual studies, and the vertical line in the funnel plot indicates the summary estimate. To visualize studies with 0 events, a continuity correction of +0.5 was applied (TIF 147486 kb)I2 and τ2 are calculated using a model without continuity correction (TIF 147486 kb)Supplementary figure 2. Forest plot with cumulative incidences of any RC recurrence after local surgical resection in patients with ≥ 2 years follow-up. To visualize incidence estimates of studies with 0 events, a continuity correction of +0.5 was applied. Values of the pooled estimates, I2 and τ2 are calculated using a model without continuity correction (TIF 147486 kb)Supplementary figure 3. Forest plot with cumulative incidences of rectal cancer-related mortality after local surgical resection in patients with ≥ 2 years follow-up. To visualize incidence estimates of studies with 0 events, a continuity correction of +0.5 was applied.Values of the pooled estimates, TEM transanal endoscopic microsurgery, TAMIS transanal minimally invasive surgery, JSCCR Japanese Society for Cancer of the Colon and Rectum (TIF 147486 kb)Supplementary figure 4. Number of JSCCR criteria used for histological risk stratification for studies on TEM/TAMIS and endoscopic resection. TEM transanal endoscopic microsurgery, TAMIS transanal minimally invasive surgery (TIF 147486 kb)Supplementary figure 5. Strictness of follow-up for studies on endoscopic resection and TEM/TAMIS. Supplementary figure 6. Time to any rectal cancer recurrence after endoscopic resection (TIF 147486 kb)Supplementary figure 7. Time to any rectal cancer recurrence after local surgical resection (TIF 147486 kb)TME total mesorectal excision, CRT chemoradiotherapy (TIF 2367 kb)Supplementary figure 8. Treatment of recurrence after local surgical resection. a. local endoluminal recurrence, b. locoregional recurrence, c. local/locoregional + distant recurrence, d. distant recurrence. Supplementary figure 9. Time between rectal cancer recurrence and rectal cancer-related mortality (TIF 831 kb)CRC colorectal cancer, RC rectal cancer (DOCX 14 kb)Supplementary table 1. In- and exclusion criteria for the endoscopic sub-section. Supplementary table 2. Meta-regression with study characteristics and risk of bias. Potential predictors of statistical inter-study heterogeneity for the outcome "any rectal cancer recurrence". (DOCX 21 kb)LE local excision, TEM transanal endoscopic microsurgery, TAMIS transanal minimally invasive surgery, AV anal verge, DL dentate line, LVI lymphovascular invasion (DOCX 20 kb)Supplementary table 3. Meta-regression with clinical characteristics. Potential predictors of statistical inter-study heterogeneity for the outcome "any rectal cancer recurrence". Supplementary analyses (DOCX 11 kb)Supplementary file: Prisma checklist (DOCX 31 kb)Below is the link to the electronic supplementary material.


Background: Fourteen meta-analyses reported the individual effects of the GSTM1 and GSTT1 polymorphisms on leukemia risk. However, over 40 studies were not included in previously published meta-analyses. Moreover, one key aspect was that previous meta-analyses did not conduct the false-positive test on the aforementioned issues. Furthermore, previous meta-analyses did not observe the combined effects of GSTM1 present/null and GSTT1 present/null polymorphism with leukemia risk. Therefore, we conducted the current study to further analyze these associations.Objectives: This study aimed to investigate the association between the individual and combined effects of the GSTM1 present/null and GSTT1 present/null polymorphisms and the risk of leukemia.Methods: A meta-analysis was performed applying Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines. Moreover, false-positive report probability (FPRP) and Bayesian false discovery probability (BFDP) were applied to investigate the false-positive results.Results: The individual GSTM1 and GSTT1 null genotypes and combined effects of the two genes were associated with a significantly increased leukemia risk in overall and several subgroup analyses, such as Asians, Caucasians, and so on. Then, further analysis was conducted using FPRP and BFDP. Significant associations were considered as “positive” results on the GSTM1 null genotype with leukemia risk in overall populations (FPRP < 0.001 and BFDP = 0.006), Asians (FPRP < 0.001 and BFDP < 0.001), and East Asian population (FPRP < 0.001 and BFDP = 0.002). For the GSTT1 null genotype, significant associations were regarded “positive” results in overall populations, acute myeloid leukemia (AML), Asians, and East Asian population. For the combined effects of the GSTM1 and GSTT1 polymorphisms, significant associations were also considered “positive” results in the overall analysis of Asians, Indians, and East Asian population.Conclusion: This study strongly indicates that the individual GSTM1 and GSTT1 null genotypes and combined effects of the two genes are associated with increased leukemia risk in Asians, especially in the East Asian population; the GSTT1 null genotype is associated with increased AML risk; the combined effects of the two genes are associated with increased leukemia risk in Indians. Leukemia, commonly diagnosed in childhood, is a complex and heterogeneous disease caused by irreversible genetic lesions in initially normal hematopoietic cells . ChronicGSTs) are a family of multifunctional enzymes, which play an important role in the detoxification of toxic, potentially carcinogenic compounds and a series of basic physiological processes of the human body  and chromosome 22 (22q11.2), respectively (GSTM1 and GSTT1 result in gene deletions (null genotype), resulting in loss of expression and enzyme activity loss  AND  AND (leukemia OR leukaemia). In addition, studies were also identified by a search of the reference lists of reviews and retrieved studies. Moreover, all eligible studies were retrieved, and their bibliographies were checked for other relevant publications.A comprehensive literature search was conducted applying the PubMed, EMBASE, ISI, CNKI, and WanFang databases for relevant articles published (the last search update was 26 February 2022). The search strategy (it was designed to be sensitive and broad) was as follows  complete genotype data between leukemia cases and controls. Exclusion criteria were as listed below: 1) Duplicate genotype data; 2) no case–control studies; 3) Meta-analyses, reviews, or letters; and 4) other SNPs.Inclusion criteria were as listed below: 1) Case–control or cohort studies; 2) publications on the individual or combined effects of Data were extracted independently by two investigators according to the inclusion criteria. The scale of quality assessment criteria was designed based on one previous meta-analysis  Supplem. StudiesGSTM1 and GSTT1 polymorphisms on leukemia risk. Between-study heterogeneity was assessed by applying the Q statistic and I2 value. A random-effect model (DerSimonian–Laird model)  was used (Crude odds ratios (ORs) with 95% confidence intervals (CIs) were applied to evaluate the associations between the individual and combined effects of d model)  was applwas used . Subgrouwas used  and Eggewas used . If publwas used  was applGSTM1 null genotype, 94 studies from 79 publications , Caucasians , and Indians . Moreover, significantly increased leukemia risk was found for the GSTM1 null genotype among countries of East Asia , North Africa , South Asia , and Southeast Asia , as shown in GSTM1 null genotype frequencies were different in the different populations  for the control groups.Overall, the GSTT1 null genotype was associated with a significantly increased leukemia risk , Caucasians , and Indians . Moreover, significantly increased leukemia risk was found for the GSTT1 null genotype among countries of East Asia , North Africa , South Asia , and West Asia , as shown in GSTT1 null genotype frequencies were also different in the different races  for the control groups.Overall, the GSTM1 present/null and GSTT1 present/null genotypes were associated with a significantly increased leukemia risk  for the control groups.Overall, the combined effects of the p = 0.007) were sources of heterogeneity for the GSTM1 null genotype. For the GSTT1 null genotype and combined effects, meta-regression analyses did not find sources of heterogeneity. Moreover, we did not observe any change when one study and low-quality studies were excluded from the overall analysis.Between-studies heterogeneity was observed, as shown in GSTM1 null genotype (p = 0.005) and the combined effects of GSTM1 and GSTT1 (p = 0.035), according to Begg’s funnel plot shape and Egger’s test in the current meta-analysis. GSTM1 present/null polymorphism with risk of leukemia , Asians (FPRP < 0.001 and BFDP < 0.001), and East Asian population (FPRP < 0.001 and BFDP = 0.002), as shown in GSTT1 null genotype, significant associations were regarded as “positive” results in overall population (FPRP < 0.001 and BFDP = 0.008), AML (FPRP = 0.062 and BFDP = 0.778), Asians (FPRP = 0.001 and BFDP = 0.052), and East Asian population (FPRP = 0.009 and BFDP = 0.367), as shown in GSTM1 and GSTT1 polymorphisms, significant associations were also considered as “positive” results in overall analysis (FPRP = 0.001 and BFDP = 0.027), Asians (FPRP = 0.005 and BFDP = 0.040), Indians (FPRP = 0.035 and BFDP = 0.095), and East Asian population (FPRP = 0.014 and BFDP = 0.040).To investigate the false-positive results, FPRP and BFDP were applied. For the GSTM1 and GSTT1 null genotypes and combined effects of the two genes were associated with significantly increased leukemia risk in the overall analysis and several subgroup analyses, such as Asians, Caucasians, and so on. However, the current study applied several subgroup analyses at the expense of multiple comparisons. Therefore, FPRP and BFDP values were applied to conduct the test of false-positive results.Overall, the individual GSTM1 present/null and GSTT1 present/null polymorphisms, we expected that the individual and the combined effects of the two genes were associated with the risk of leukemia in any population. However, we only found that the individual GSTM1 and GSTT1 null genotypes and combined effects of the two genes are associated with increased leukemia risk in Asians, especially in the East Asian population, and the combined effects of the two genes are also associated with increased leukemia risk in Indians when we used the FPRP and BFDP values. These results showed that the same genes may play different roles in leukemia susceptibility in different races and countries because leukemia is a complicated multigenetic disease and different genetic backgrounds and environmental factors may contribute to the discrepancy  are a group of enzymes that play vital roles in regulating the cellular detoxification of various exogenous carcinogens . Moreovecrepancy . MoreoveGSTM1 and GSTT1 polymorphisms with leukemia risk. GSTM1 and GSTT1 null genotypes were significantly associated with elevated individual susceptibility to acute lymphoblastic leukemia (ALL) and AML; the GSTT1 null genotype was also significantly associated with elevated individual susceptibility to chronic leukemia; the GSTM1 and GSTT1 null genotypes were significantly associated with elevated individual susceptibility to leukemia in Caucasians and West Asians; the GSTM1 null genotype was also significantly correlated with elevated individual susceptibility to leukemia in East Asians. GSTM1 and GSTT1 polymorphisms were both significantly correlated with hematological malignancy in Caucasians, East Asians, and West Asians, and positive results were found for the GSTM1 and GSTT1 polymorphisms in patients with certain types of acute leukemia. GSTM1 null genotype was associated with increased childhood ALL risk and the GSTT1 null genotype was not associated with childhood ALL risk. GSTM1 null genotype was associated with an increased risk of AML in East Asians and the GSTT1 null genotype in Caucasians. GSTM1 and GSTT1 null genotypes might be a potential risk factor for acute leukemia in Asians. GSTT1 null genotype and the double-null GSTT1 and GSTM1 genotypes were associated with an increased risk of CML. GSTT1 null variant was significantly associated with susceptibility to childhood ALL in Asians. GSTM1 null polymorphism was caused by childhood acute leukemia susceptibility. GSTM1 null genotype was significantly associated with increased risk of childhood acute leukemia in the Chinese population. GSTM1 null genotype was significantly associated with increased risk of childhood acute lymphoblastic leukemia, but should be interpreted with caution. GSTM1 null genotype and CML risk, while the GSTT1 null genotype was associated with increased risk of CML, especially in Indians. GSTM1 null genotype, while borderline significance was seen with the GSTT1 null genotype. GSTM1 and GSTT1 null genotypes appeared to be associated with a modest increase in the risk of ALL. GSTM1 null genotype was associated with increased childhood ALL risk. These results might be not credible because many original studies were not included in previously published meta-analyses. Moreover, previously published meta-analyses did not conduct the false-positive test using FPRP and BFDP values. Therefore, we performed the current study to further explore these associations.Fourteen meta-analyses  reportedThe present study had several limitations. First, only published studies were selected. Second, the confounding factors closely related to the outcome were not controlled, such as gender, smoking, and some other factors. The current study also has several advantages over previously published meta-analyses. First, the sample size was larger. Second, we investigate the false-positive results by applying the FPRP and BFDP values.GSTM1 and GSTT1 null genotypes and combined effects of the two genes are associated with increased leukemia risk in Asians, especially in the East Asian population; the GSTT1 null genotype is associated with increased AML risk; the combined effects of the two genes are associated with increased leukemia risk in Indians.In summary, this study strongly indicates that the individual


Toll-like Receptors (TLRs), such as the TLR4, are genes encoding transmembrane receptors of the same name, which induce a pro- or anti-inflammatory response according to their expression as the host’s first line of defense against pathogens, such as infectious ones. Single nucleotide polymorphisms (SNPs) are the most common type of mutation in the human genome and can generate functional modification in genes. The aim of this article is to review in which infectious diseases there is an association of susceptibility or protection by the TLR4 SNP rs4986790. A systematic review and meta-analysis of the literature was conducted in the Science Direct, PUBMED, MEDLINE, and SciELO databases between 2011 and 2021 based on the dominant genotypic model of this SNP for general and subgroup analysis of infectious agent type in random effect. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated for genotypic comparison. I2 statistics were calculated to assess the presence of heterogeneity between studies and funnel plots were inspected for indication of publication bias. A total of 27 articles were included, all in English. Among the results achieved, the categories of diseases that were most associated with the SNP studied were in decreasing order of number of articles: infections by bacteria (29.63%); caused by viruses (22.23%); urinary tract infection—UTI (7.4%), while 11 studies (40.74%) demonstrated a nonsignificant association. In this meta-analysis, a total of 5599 cases and 5871 controls were finalized. The present meta-analysis suggests that there is no significant association between TLR4-rs4986790 SNP and infections , but in the virus subgroup it was associated with a higher risk . The subgroups of bacteria and parasites did not show statistical significance . Therefore, it has been shown that a diversity of infectious diseases is related to this polymorphism, either by susceptibility or even severity to them, and the receptor generated is also crucial for the generation of cell signaling pathways and immune response against pathogens. Infectious diseases are the second leading cause of mortality worldwide and the main factor in generating disability-adjusted life years (DALYs), which a DALY corresponds to the loss of 1 year of healthy life . They arIn a population endemic to a disease, some individuals are diagnosed with active infection, which can generate unfavorable clinical outcomes and even death, while others remain asymptomatic . This caSingle nucleotide polymorphisms (SNPs) are the most frequent type of mutation in the human genome. They can serve as important biological markers for defining therapeutic, diagnostic, and prophylactic strategies for diseases, including infectious ones . Thus, aMycobacterium tuberculosis (Toll-like Receptors (TLRs) are a family of type 1 transmembrane receptors and are evolutionarily characterized and conserved proteins in vertebrates and invertebrates . In thisrculosis . The phyrculosis .TLR4 can be activated by oxidized phospholipids, which also appear in viral lung infections, such as in the detection of respiratory syncytial virus fusion protein  and seveTLR4 gene is located on the human chromosome 9q33.1 and has three exons and two introns  to a guanin (G) at position 896 (896A>G) which leads to modification of the conserved residue of aspartic acid to a glycine in amino acid 299 of the protein sequence (Asp299Gly) on, in or at the domain of the extracellular structure of TLR4. It is responsible for causing change in the function of the encoded protein, diminished function, i.e. missense , Cochrane Collaboration and Medical Literature Analysis and Retrieval System Online (MEDLINE), Scientific Electronic Library Online (SciELO) and Science Direct.The following keywords (MeSH) were selected as search strategy: “Available, complete open access of the original categories in Portuguese, English, or Spanish, of the types of cross-sectional studies, clinical trials, case-control, and cohort studies were defined as inclusion criteria between 2011 and 2021. This period was used to condense updates on the subject over the last decade. Exclusion criteria were articles published prior to 2011, articles that were duplicated, available only abstract, letters to the editor, inaccessibility to important information in the article and articles with topics not pertinent to the research question. Thus, the final sample was reached, characterizing all stages, inclusion, and exclusion.Excel software was used for organization and screening of titles and abstracts and grade pro GDT software for classification of articles in the system. To classify the studies, the Grading of Recommendations Assessment, Development and Evaluation (GRADE system) was used, which is a system created to identify the degree of evidence and the strength of health recommendations . For thep < 0.05) were considered statistically significant correlations between the SNP and each infectious disease studied. The Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) flowchart, based on the PRISMA protocol, was used to present the steps followed for the present study , country, Ethnic Group and results. Degrees of significance  independently, thus ensuring their reliability. Evidence is graded by research design, providing standards that establish the appropriate grade for medical decision making. The types of studies included in this article were composed according to the degree of evidence in decreasing order of clinical trials, cohort, case-control, and cross-sectional studies .TLR4 SNP. Heterogeneity between studies for comparisons was assessed using I2 statistics; A score of 25% indicates the absence of substantial heterogeneity, a result of 5% or more shows substantial heterogeneity, and a result of 75% or more indicates considerable heterogeneity. One of the most popular methods to determine the importance of heterogeneity is the chi-square test, with a conventional level of more conservative significance of p < 0.10, instead of the usual p < 0.05.The meta-analysis was carried out using Review Manager 5.4.1 . Only genotypic comparison was performed employing a dominant genetic model (AG + GG vs AA) was performed due to the rarity of the GG genotype  . SummaryEscherichia coli infection  in the analysis of both subgroups and in general.The forest plot of the meta-analysis was represented by TLR4 rs4986790 did not show a significant association with susceptibility to infections . Regarding the subgroups, for bacteria, although this SNP was not statistically significant, it showed a greater strength of association for the protection of infections related to them . It should be taken into account that, in the meta-analysis, the etiological agent of UTI considered was bacteria. Regarding viruses, a significantly positive relationship was found between the presence of this mutant SNP allele and the risk of contracting viral infections . For parasites, only one study was included, and therefore it was not possible to observe significant associations in this subgroup (no effect estimate).In a generalized analysis, the SNP A total of 5599 cases and 5871 controls were included. The numerical configuration of researches was composed of 19 studies (70.37%) for the bacteria subgroup, with 3848 cases and 4301 controls, while six researches (22.22%) were in virus subgroup (constituted of 1149 cases and 1233 controls) and only one for parasites (3.7%), forming a subgroup with 74 patients and 37 controls. A symmetrical funnel plot presented the reduced risk of bias in TLR4 in Schematic presentation of the data found for TLR4 Signaling Transduction Pathways was performed in via IFN-β, while interleukin (IL) - 12 is crucial for defense against intracellular infections. TLR-mediated up-regulation of inducible NO synthase contributes to macrophages’ ability to destroy phagocytosed bacteria.TLR4 mutation change the structure of TLR4 and limit its ability to interact with LPS, CD-14, and/or MD-2. The TLR4 SNP rs4986790 acts by decreasing the expression of TLR4 by 2 times. In this sense, the absence of myeloid differentiation factor 2 (MD-2), which forms a complex with TLR4 and LPS, this decrease is elevated in 10 times. From this binding, in phase (2), both MyD88-dependent and independent routes are affected by the presence of this mutation and there is the generation of TLR4 signaling pathways: the aforementioned vias (2.1), (2.2), (2.3), and (2.4). This mutation leads to suppressed recruitment of downstream adapter molecules and kinases involved in the TLR4 pathways, such as IRAK4, NEMO, IKKe and IRF3, which can thus eliminate signaling activity. In stage (3), there is suppression of all these vias, including, the NF-κB transactivation and translocation in human monocytes with the 896A/G TLR4 expression, which could lead to the development of adaptive immunity. In step (4), this dysfunctional stimulation of TLR4 is characterized by suppression of recognition and immune response to pathogens, generating an uncoordinated immune response and, consequently, in most cases, a poor prognosis to infectious diseases.The analysis of host genetic factors such as SNPs can become a useful strategy to identify people at increased risk of specific infections, patients at higher risk of unfavorable disease outcomes, and contribute to more effective therapeutic interventions . The proTLR4 gene due to the absence/presence of the mutant allele of SNPs, in addition to genetic, epigenetic, and environmental factors  did not report the ethnic group belonging to the investigated population, most of them coming from the Asian and African continent  and, with respect to the country, mostly from the United States . Therefore, there is a great bias in reporting these ethnic terms in these studies, especially from the United States.In the present systematic review, most of the studies were observed to come from populations in the United States (5 studies - 18.51%) and the number of studies associated with susceptibility to infectious diseases was higher for the African continent . Despite the numerical supply of articles and the number of positive associations relating bacterial infections to the present SNP of In our analysis, the most studied diseases for SNP were those caused by bacterial infections (with 17 studies—62.96%), followed by viral infections, with seven studies, equivalent to 25.93% and urinary tract infection (UTI) with two studies (7.4%). The excess percentage was delimited by studies involving parasitic agents .TLR4 SNP and susceptibility were those caused by viruses . The infectious diseases that for this SNP were most associated with protection in different countries had several studies in decreasing order among those caused by bacteria infections , viruses , and UTI .The most commonly associated infectious diseases in different countries for E. coli infection in Mexico population  ; malariapulation .The main association found in this review in a numerical offer for susceptibility to SNP and infectious diseases is correlated with the main TLR4 ligand (LPS) and reveals the effect of the G allele in various functional studies for Gram-negative bacteria .TLR4 activation and its main ligand (LPS) emphasizes its activity in detecting the molecular patterns associated with pathogens (PAMPs) of Gram-negative bacteria . TLR4 has been reported to control the immune response to infection of epithelial cells that line the mucosa of the urinary tract and the signaling response of this TLR regulates cell balance and death by releasing some urothelium cytokines . Finallybacteria .E. coli (with about 80%), followed by Klebsiella, Staphylococcus, and Streptococcus with a frequency of 62%, 13%, 12%, and 11%, respectively , in Asian populations, the mutation in rs4986790 may make them more susceptible to urinary tract infections . This inEscherichia coli and TLR4 mice −/− develop asymptomatic bacteriuria instead of severe infection. Low levels of TLR4 expression have also been observed in children with asymptomatic bacteriuria. In addition to being related to susceptibility and protection agaisnt UTI, the SNP can distinguish phenotypes from symptomatic and asymptomatic patients, it determines the severity of acute infection, as well as the long-term effects on the integrity of the renal tissue. On the other hand, susceptibility to UTI can also be discussed in terms of social and environmental factors or dysfunctional urination , with no significant association. At the molecular level, this receptor can function as an upstream sensor for GSPL and induce the intracellular inflammatory signaling necessary to kill parasites .Candida albicans and Paracoccidioides brasiliensis. In this sense, it directly protects the oral mucosa from fungal infection by Candida through a process mediated by polymorphonuclear leukocytes (PMNs)  can use TLR4 to gain access to neutrophils that pathogenically produce interleukin (IL)—eight and IL-10, increasing the inflammatory process and thus patient morbidity  . What coorbidity .SNPs can be associated or involved, or they can even determine the differential risks of infection. This is due to the fact that in some infections the immune response leads to a protective inflammatory response, while in others this response may be essential in the pathogenesis of the infectious process .At this conjuncture, TLR4 signaling is mediated by four adapting molecules: myeloid differentiation factor 88 (MyD88); adapter-type protein MyD88 , also known as the TIR domain adaptor protein (TIRAP); TIR-containing ligant-induced interferon-beta (TRIF), also known as TLR-containing ligant molecule 1 (TICAM-1); TRIF-related ligant molecule (TRAM), also known as IRR-containing protein (TIRP) or ligating molecule 2 (TICAM-2). TLR4 requires all four ligands to mediate a comprehensive immune response .MyD88 propagates through the factor associated with tumor necrosis factor receptor—TNF (TRAF)—6, which induces the production of an inflammation regulator, the nuclear factor - kappa beta (NF-κB). This regulator triggers the genes encoding the immune activators, which include tumor necrosis factor alpha (TNF-α) and interleukins (IL) -1, IL-8, IL-12, and IL-6. However, uncontrolled defense processes of organisms against infectious agents can lead to a number of organic dysfunctions, including coagulation dysfunction, fever, vasodilation, and decreased blood pressure, leading to necrosis of tissues and organs caused by the accumulation of cytokines .TLR4 was associated with susceptibility to a diverse spectrum of infections and has a complex effect of the TLR4 variant on susceptibility to infectious diseases. However, a greater association with parasitic diseases is recorded in a study by TLR4 SNPs, with a different time frame, different types of epidemiological studies and only open access studies  linker for SNP rs4986790 and infectious agents, since the most associated and studied infectious diseases were infections by Gram-negative bacteria, mediated by LPS, even with nonsignificant association here. This meta-analysis also indicates a new association between infections and this In the same way that there are controversial results on susceptibility to infectious diseases, we report the need for immunogenetic studies that are performed in different populations. Furthermore, the study reveals the characterization of pathophysiology in clinical conditions of diseases associated with this SNP. From this perspective, new omic studies can help close the gaps in understanding the extent to which immunogenetics interferes with the outcome of infectious diseases. Therefore, this study provides an overview for the creation of strategies in the field of medicine with respect to the treatment of infectious diseases.