The frequency and management of gallstone disease (GD) in bariatric patients, including the role of routine prophylactic concomitant cholecystectomy (CCY), are still a matter of debate. This study aims to assess the risk of de novo GD in patients undergoing bariatric surgery (BS) and their predictive factors, as well as mortality and morbidity in prophylactic CCY compared to BS alone.We performed a systematic review, searching PubMed, EMBASE, and Web of Science until April 2021. We performed a Bayesian meta-analysis to estimate the risk of GD development after BS and the morbidity and mortality associated with BS alone versus BS + prophylactic CCY. Sources of heterogeneity were explored by meta-regression analysis.I2 = 75.4%), and that of symptomatic GD was 8.2% . Pre-operative average BMI  and female patients’ proportion  were not associated with increased risk of symptomatic GD.The risk of de novo post bariatric GD was 20.7% . Mortality was not substantially different between the two approaches .BS + prophylactic CCY was associated with a 97% probability of a higher number of postoperative major complications compared to BS alone (The risk of de novo symptomatic GD after BS is not substantially high. Although mortality is similar between groups, odds of major postoperative complications were higher in patients submitted to BS + prophylactic CCY. It is still arguable if prophylactic CCY is a fitting approach for patients with a preoperative lithiasic gallbladder.The online version contains supplementary material available at 10.1007/s11605-022-05567-8. On the other hand, cholecystectomy after BS, for symptomatic GD, is also a procedure associated with technical difficulties.10 Despite these controversies, evidence on all of these options has not been systematically assessed.The varying incidence of symptomatic GD after BS has resulted in controversies regarding whether prophylactic concomitant cholecystectomy (CCY) should be performed. Currently, there are three approaches on this subject: (i) routine prophylactic cholecystectomy concomitant to BS for all patients (BS + prophylactic CCY), (ii) a selective prophylactic CCY only for those with positive findings on pre-operative ultrasound, and (iii) medical prophylactic treatment with ursodeoxycholic acid (UDCA).In this systematic review and meta-analysis, we aimed to (objective i) quantify the risk of de novo asymptomatic or symptomatic GD after BS, (objective ii) identify predictive factors associated with de novo GD after BS, and (objective iii) compare the morbidity and mortality of BS alone versus BS + prophylactic CCY.12This systematic review with meta-analysis follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement guidelines and the recommendations of the Cochrane Handbook for Systematic Reviews.2 or BMI ≥ 35 kg/m2 with weight-related comorbidities. For objectives i and ii (risk of de novo post-bariatric GD and its predictive factors), the outcome to be reported was GD development. It was defined as de novo episodes of symptomatic biliary colic, acute cholecystitis, choledocholithiasis, cholangitis, and acute pancreatitis, or de novo asymptomatic evidence of cholelithiasis on post-operative ultrasound. For objective iii , any of the following outcomes needed to be reported: postoperative mortality, duration of surgery, hospital length-of-stay (LOS), and major postoperative complications. BS + prophylactic CCY was defined as cholecystectomy concomitant to bariatric surgery for asymptomatic patients , who had not been submitted to a previous cholecystectomy.We included observational studies assessing BS as an obesity treatment for patients with a BMI ≥ 40 kg/mMore detailed inclusion and exclusion criteria, for each specific objective, are shown in Supplementary Table We searched three electronic databases  from inception until April 6, 2021 (when our search was performed). Search queries are detailed in Supplementary Table After removing duplicates, each study was independently assessed by two reviewers (F.C and M.R), first by title and abstract screening and then by full-text reading.Two reviewers independently extracted data from selected studies using a predefined form purposely built for this systematic review. For each primary study, the following information was retrieved: authors’ identification, year of publication, country, study design, number of enrolled patients, type of performed BS, follow-up period, patients’ characteristics ), frequency of co-morbidities, weight loss after surgery, and preoperative gallbladder status. The latter was classified as alithiasic or lithiasic gallbladder confirmed by ultrasonography. An alithiasic gallbladder was defined as a preoperative gallbladder without gallstones or sludge, and a lithiasic gallbladder was defined as a preoperative asymptomatic gallbladder with gallstones or sludge without being submitted to CCY.For objectives i and ii (risk of de novo post-bariatric GD and its predictive factors), we also retrieved information on the number of patients: (i) at risk of GD, (ii) at risk of symptomatic GD only , (iii) who developed GD, (iv) who developed symptomatic GD only, (v) who developed each GD presentation , and (vi) undergoing postoperative cholecystectomy. Both patients with no symptoms of cholelithiasis and either preoperative negative gallstone findings or preoperative positive gallstone findings were at risk of de novo symptomatic GD. In contrast, only patients with preoperative negative gallstone findings and primarily asymptomatic were considered at risk for de novo asymptomatic GD. Whenever provided, we retrieved data separately based on preoperative gallbladder status. Data related to other biliary conditions, such as gallbladder carcinoma or polyps, were not retrieved.For objective iii , the additional following information was concerned: (i) number of patients submitted to BS alone and BS + prophylactic CCY; (ii) reason for prophylactic CCY; (iii) surgery duration; (iv) LOS; (v) major postoperative complications , respiratory failure, pneumonia, sepsis, venous thromboembolism, acute renal failure, and bleeding requiring transfusion; surgical complications—anastomotic leakage, organ space surgical site infection, the conversion rate of laparoscopic surgery, number of reoperations, and hospital readmission within 30 days); and (vii) postoperative mortality.If distinct eligible publications reported data on the same patient cohort, the more recent and largest cohort was included. Authors were contacted whenever full texts were not available or to provide the relevant missing information. In study selection or data extraction, any disagreements between reviewers were resolved by consulting a third senior reviewer (H.S.S) to reach a final decision.13 To reach a consensus, divergent opinions regarding quality assessment were discussed with a third reviewer (H.S.S). This tool consists of a form with 14 yes-or-no questions  and a final quality rating , classifying the study according to its potential risk of bias.13 The question about assessors being blinded regarding the exposure status was not possible to assess in any of the included studies.The quality of primary studies was independently assessed by two reviewers (F.C and M.R) using the National Institutes of Health quality assessment criteria for observational studies.14 Compared to frequentist  approaches, Bayesian meta-analysis deals more adequately with proportions equal to zero.Given the inclusion of a large number of studies with no occurrence of events, we opted in performing a meta-analysis according to a Bayesian approach following a random-effects model based on a binomial likelihood.Bayesian methods provide estimations of posterior probability distributions of the parameters of interest, based on prior probability distributions and the observed data. In this study, for the risk of de novo post-bariatric GD, we computed the meta-analytical risk of GD and of symptomatic GD only. To compare outcomes between patients submitted to BS alone as index events versus those submitted to BS + prophylactic CCY, we computed meta-analytical odds ratio (OR) or mean differences (MD) depending on whether outcome variables were categorical or continuous, respectively. Of these results, we collected information on the mean values and respective 95% credible intervals .Comparison between concomitant CCY and postoperative cholecystectomy was not quantitatively synthesized, due to the low number of available studies and substantial missing information.I2 statistic—an I2 > 50% indicated substantial heterogeneity. Heterogeneity sources were explored through univariable meta-regression and subgroup analyses; – in particular, meta-regression allowed for the identification of potential predictive factors for the risk of de novo bariatric GD. Exponentials of the meta-regression coefficients were interpreted as OR. Finally, we also performed a separate meta-analysis for the development of symptomatic GD among patients with preoperative lithiasic versus alithiasic gallbladder.Heterogeneity was assessed through an estimate of the For both the effect size measure and the τ parameter, we used uninformative prior distributions  and dgamma , respectively). We ran at least 40,000 iterations for each analysis with a burn‐in of 15,000 sample iterations. Meta‐analysis was performed using the rjags package of software R (version 3.5.0).55 Hand-searching resulted in 23 additional articles, of which 8 were included.64 Ten authors were asked for additional information, as outcomes of interest were missing. Seven did not answer, and their studies were excluded from objectives i and ii. In total, 50 articles were included—39 for answering objectives i and ii (assessment of the risk of de novo symptomatic or asymptomatic GD and its predictive factors)62 and 14 for objective iii .64The electronic literature search resulted in 5082 articles, of which 1808 were duplicates. After excluding 3184 records in the screening phase, 90 articles were fully read, of which a total of 42 were included in the systematic review . The mean participants’ age was 40.9 years (SD = 9.3 years) with a female predominance (74.0%). Laparoscopic Roux-en-Y gastric bypass (LRYGBP) was the most-performed BS type . The mean follow-up period was of 29.0 months.For objectives i and ii, included studies were published between 2004 and 2019, with a cumulative sample size of 64,950 patients. Most were retrospective cohort studies . Among patients undergoing prophylactic CCY , 44% had negative findings for GD in pre-operative ultrasonography.For objective iii, included studies were published between 1995 and 2006, with a cumulative sample size of 685,994 patients. Open Roux-en-Y gastric bypass (RYGBP) was the most-performed BS type . A higher BMI was associated, – with a 96% probability, – with higher odds of de novo GD . Other results of univariable meta-regression are presented in Supplementary Table A total of 38,210 asymptomatic patients with only preoperative negative GD findings were at risk of de novo postoperative GD. The Bayesian meta‐analysis identified a post-bariatric risk of de novo GD of 20.7% , even though with severe heterogeneity I2 = 75.%. A highI2 = 66.9%, Table n = 1559, 65.5%), cholecystitis , and symptomatic choledocholithiasis  . The results of univariable meta-regression and subgroup analyses are presented in Table OR = 0.60; 95% CrI = 0.31–1.10).A total of 63 938 asymptomatic patients with either preoperative negative or positive gallstone findings were at risk of de novo symptomatic GD. A total of 3312 developed symptomatic GD, corresponding to a meta-analytical risk of 8.2% (95% CrI = 5.9–11.1%), even though with high heterogeneity  and female patients’ proportion  did not impact the risk of de novo symptomatic GD. Although none of the assessed bariatric surgery types had a strong impact on GD risk, laparoscopic gastric banding (LAGB) was associated, – with an 82% probability,—with lower odds of de novo symptomatic GD. Insufficient data on co-morbidities and weight loss after surgery did not allow meta-regression analysis models to include these variables.Pre-operative average BMI . BS + prophylactic CCY was associated with 97% probability of a higher number of postoperative major complications compared to BS alone . The odds of organ space surgical site infection were similar between groups   nor female patients’ proportion  were associated with a relevant impact on the association between BS alone versus BS + prophylactic CCY on the occurrence of postoperative major complications. Although any type of bariatric surgery had no strong impact on postoperative major complications, they slightly changed through bariatric procedures—laparoscopic gastric banding (LAGB) was the one associated with lower chances (87%) of postoperative major complications between BS + prophylactic CCY versus BS alone . Moreover, prophylactic cholecystectomy concomitant to laparoscopic sleeve gastrectomy (LSG), compared to prophylactic cholecystectomy concomitant laparoscopic Roux-en-Y gastric bypass (LRYGBP) , had a tendentially lower probability of postoperative major complications. Regarding Roux-en-Y gastric bypass, comparing open and laparoscopic approaches, the probability of postoperative major complications was not too dissimilar .Univariable meta-regression results are presented in Table I2 = 89.3%). There were no relevant differences in hospital LOS  (Table Patients submitted to BS + prophylactic CCY had a longer operative time—more than 29.2 min (95% CrI = 17.9–40.7), even though there was severe heterogeneity found  did not justify the sample size, and 39 studies (78%) did not adjust for any potential confounding variables. For the remaining parameters, most studies were associated with a low risk of bias. Bastouly et al.56 were considered to have a high risk of bias, namely selection bias since patients were selectively invited.The results of the risk of bias assessments for included primary studies are presented in Table I2 = 59.1%). Such a trend was not observed for asymptomatic or symptomatic GD. Having a high risk of bias was also related,—with 93% probability,—with a weak association between BS alone versus BS + prophylactic CCY on the occurrence of postoperative major complications .In fact, when considering only high-quality studies, the risk of symptomatic GD is of 7.5%  the risk of developing de novo symptomatic gallstone disease after BS is not substantially high (8.2%), although three times higher than the healthy population; (2) GD predictive factors after BS are not similar to those of the general population, except for preoperative average of BMI in asymptomatic or symptomatic GD; and (3) patients who underwent prophylactic CCY had a longer operative time and a higher rate of postoperative complications than those who underwent BS alone, but mortality and hospital LOS were similar.65 Our meta-analysis showed that the risk of developing symptomatic GD is 8.2%, in a mean follow-up of 29.0 months. Warschkow et al.8 reported a similar percentage (6.8%), although the cumulative sample size was lower and only LRYGBP was performed. Our risk might be slightly underestimated since a clear decrease in the risk of de novo symptomatic GD was observed for retrospective studies, which might be explained by information bias. In fact, considering only prospective studies, this risk rises to 11.2%. Therefore, our findings, regarding the risk of developing symptomatic GD after BS, may call into question the pertinence of prophylactic CCY. Theoretically, one of the reasons to routinely perform cholecystectomy concomitant to BS concerns the prevention of later biliary complications , mainly because endoscopic retrograde cholangiopancreatography (ERCP) is routinely impossible to perform after LRYGBP.66 In the present study, similar to other meta-analyses,67 symptomatic choledocholithiasis occurred in 37 patients (4.5%) and acute pancreatitis in 23 (2.8%). As a rare event, it does not uphold a prophylactic CCY.Some of the pathogenic mechanisms that can explain why patients after BS are at risk of developing GD include an increased biliary cholesterol concentration following rapid weight loss, gallbladder hypomotility secondary to vagal nerve resection and a decreased cholecystokinin secretion, an increased secretion of calcium and biliary mucin, and a disturbed enterohepatic circulation of biliary salts.68 On the contrary, in the RYGBP procedure, the altered anatomy, the division of the vagus nerve, and reduced cholecystokinin may lead to gallbladder dysmotility.69 It was not possible to understand the association between symptomatic GD and excessive weight loss. Although rapid weight loss is classically pointed to as the main predictive factor,7 it is not consensual across individual studies.36Understanding predictive factors for gallstone formation after BS could influence distinct patient management, including a selective approach for BS + prophylactic CCY. To the best of our knowledge, this is the first meta-analysis exploring this topic. Through meta-regression and subgroup analyses, we found that neither higher pre-operative BMI, nor female patients’ proportion appear to be risk factors. However, we were only able to assess data at the study level. Assessing whether having a high BMI or being a female as risk factors for GD development would require an assessment of individual participant data. In our study, LAGB was associated with lower odds of de novo symptomatic GD. This could be explained by the fact that this restrictive bariatric procedure does not alter gastrointestinal transit, biliary contraction mechanisms, and enterohepatic circulation.OR = 1.51; 95% CrI = 0.31–3.77). Moreover, according to the literature, severe biliary complications after bariatric surgery  are more common in patients with asymptomatic preoperative gallstones.71 These arguments might reinforce a more selective approach, where patients with asymptomatic GD would undergo prophylactic CCY, given that, after RYGBP, ERCP is impossible to perform. However, from an expectant management perspective, surgery would be avoided in 88% of these patients and, consequently morbidity of a concomitant procedure. Furthermore, as ultrasound has a low sensibility in patients with obesity, there is no ideal screening method for patient selection. In meta-regression, studies enrolling only patients with alithiasic gallbladders were associated with higher odds of de novo symptomatic GD compared to studies enrolling patients with alithiasic and lithiasic gallbladders. These two approaches  may seem to contradict each other. However, the first approach evaluates individual participant data, whereas the second evaluates data at a study level, aiming to measure covariable impact in heterogeneity.We performed a separate meta-analysis to understand the impact of preoperative gallbladder status  in the development of symptomatic GD. There is a 30% probability of symptomatic GD being more common in patients with preoperative lithiasic gallbladder than with preoperative alithiasic gallbladder , might be an explanation—some authorsThere are also strengths in our study. The main methodological strength of this study is its meta-analytical approach to quantitative synthesis. The main advantage of Bayesian meta‐analysis is its use of exact methods, dealing more adequately with zero‐cells. Second, we performed a comprehensive search, encompassing three different electronic bibliographic databases and not using exclusion criteria based on the date or language of publication. Third, regarding eligibility criteria, to estimate the risk of post-bariatric de novo GD, studies that included prophylactic treatment with UDCA after BS or patients submitted to cholecystectomy prior or concomitant to BS, were excluded avoiding the risk of underestimation. Finally, meta-regression and subgroup analysis allowed the identification of predictive factors for gallstone formation.In conclusion, after BS, the risk of developing GD is not substantially high, and severe biliary complications are extremely rare. Although there were no substantial differences in postoperative mortality or hospital length-of-stay, the determined risk of symptomatic GD and the higher risk of postoperative complications do not seem to justify performing prophylactic CCY in patients with alithiasic gallbladder. Doubts remain if a selective approach is advantageous since patients with preoperative gallbladder pathology have some increased risk of symptomatic GD. Randomized controlled studies might be considered to further clarify the role of prophylactic CCY as a selective approach. For future studies, we make the following recommendations: (i) postoperative cholecystectomy versus prophylactic CCY safety should be further explored; (ii) excess weight loss should be reported more consistently since findings are still not consensual regarding its lithogenic influence.Supplementary file1 (DOCX 121 KB)Below is the link to the electronic supplementary material.


We further analyzed the relationship between PM2.5 exposure and different chronic liver diseases. The results showed that increments in PM2.5 exposure significantly increased the risk of liver cancer, liver cirrhosis, and fatty liver disease (hazard ratio (HR) = 1.23, 95% CI: 1.14–1.33; HR = 1.17, 95% CI: 1.06–1.29; HR = 1.51, 95% CI: 1.09–2.08, respectively). Our meta-analysis indicated long-term exposure to PM2.5 was associated with increased risk of chronic liver disease. Moreover, future researches should be focused on investigating subtypes of chronic liver diseases and specific components of PM2.5.Although fine particulate matter (PM2.5) is a known carcinogen, evidence of the association between PM2.5 and chronic liver disease is controversial. In the present meta-analysis study, we reviewed epidemiological studies to strengthen evidence for the association between PM2.5 and chronic liver disease. We searched three online databases from 1990 up to 2022. The random-effect model was applied for detection of overall risk estimates. Sixteen eligible studies, including one cross-sectional study, one retrospective cohort study, and 14 prospective cohort studies, fulfilled inclusion criteria with more than 330 thousand participants from 13 countries. Overall risk estimates of chronic liver disease for 10 μg/m Fine particulate matter PM2.5), responsible for most air pollution, has been increasingly affecting human health with exploding urbanization . PM2.5 i.5, respoChronic liver disease has become one of the leading causes of death worldwide with the increasing number of cases . ChronicAn epidemiological study by Copeland et al. demonstrated that inflammation was identified as a signature of liver fibrosis and elevated risk for liver disease progression . In a ra3 increase in PM2.5 increased metabolic dysfunction-associated fatty liver disease with odds ratio (OR) (95% CI) of 1.29 (1.25–1.34) [3 increase in PM2.5 levels increased NAFLD with HR (95% CI) of 1.06 (1.04–1.07) [Current meta-analyses of PM2.5 and chronic diseases primarily focus on the morbidity and mortality of respiratory system diseases, cancer, cardiovascular and cerebrovascular disease ,16,17,1825–1.34) . Another04–1.07) . TherefoWe searched PubMed, Web of science, and the Cochran Library in May 2022 using common keywords related to PM2.5 and incidence and mortality of chronic liver diseases without language restriction. Searches were limited to original research articles published in between January 1990 and May 2022. The keywords were: “particulate matter “, “fine particulate matter”, “air pollution”, “atmospheric particulate matter” “ambient fine particle”, “ambient PM2.5”, and “PM2.5” for exposure factors, AND “Liver Disease”, “Liver Dysfunction”, “Nonalcoholic Fatty Liver Disease”, “NAFLD”, “Nonalcoholic Fatty Liver”, “Fatty Liver”, “Cirrhosis”, “Liver cirrhosis”, “Liver Fibrosis”, “Nonalcoholic Steatohepatitis”, “Liver Neoplasm”, “Hepatic Neoplasm”, “Liver Cancer”, “Hepatocellular Cancer”, “Hepatic Cancer”, “HCC”, and “Liver Cancer” for outcome factors. We also reviewed the reference lists of the original documents to identify additional pertinent data.The selected inclusion criteria were as follows: (1) observational epidemiological studies, (2) investigation of the association between PM2.5 and the incidence and mortality of chronic liver diseases, (3) data of PM2.5 exposure levels were collected from monitoring station, horizontal–vertical locations, or satellite, and (4) outcome measures with adjusted relative risk (RR) or hazard ratio (HR) and 95% CI reported. We included comprehensive analysis to re-calculate duplicated or shared data appeared in two or more analyses ,20. The A further collection from eligible articles were performed by J.S. and Q.Z. The collected data in each article were as follows: the publication year, first author name, type of study, study period, location of the study, number of participants, type of liver disease, adjustment variables, and adjusted RR/HR, 95% CI, etc.We estimated the quality of eligible studies with Newcastle–Ottawa Scale (NOS) . We defi3 increment, and recalculated the RR/HR with the following Formula [2 were performed to evaluate heterogeneity in selected studies [p value for heterogeneity was less than 0.10 or I2 value was <50%, fixed effects model (FEM) was applied for the null hypothesis. Otherwise, we applied the random effects model (REM). Begg’s funnel plot and Egger’s test were used to calculate publication bias [p value for Egger’s test was less than 0.05, it indicates that there is publication bias in enrolled studies. We used Stata statistical software 11.0 to conduct all statistical analyses. We standardized the PM2.5 increment to a 10 µg/m Formula :RRStanda studies . If p vaion bias . If the n = 19), no PM2.5-increment data (n = 3), insufficient incidence and outcome data on liver disease (n = 62), and duplicate data (n = 2). The remaining 16 studies, which included one cross-sectional study [A flow diagram of literature screening process is shown in al study , one retal study  and 14 pal study ,40,41,42The characteristics of 16 studies included in the meta-analysis were shown in n = 7), Europe (n = 4), and the Americas (n = 5). The number of participants in these studies ranged from less than 300 to more than 180 thousand. All studies included both male and female participants. The NOS score for methodological quality of the included studies ranged from 8 to 9 points, with an average of 8.9 points, and 16 studies were of high quality (NOS score ≥ 8). Years Enrolled, data collection time; NOS, Newcastle–Ottawa Scale.Studies were conducted in multiple countries, mainly in Asia , indicating that maternal exposure to PM2.5 was positively correlated with chronic liver diseases. The result of the Egger’s test for asymmetry showed p = 0.28, indicating no publication bias  in Then, we presented the association between PM2.5 and risk of chronic liver diseases in subgroup analyses by incidence and mortality. Across all selected studies, in total, PM2.5 significantly increased both the incidence and mortality of chronic liver diseases  through targeting the liver with persistent proinflammation [Several potential mechanisms related to our findings have been proposed. Firstly, long-term exposure to PM2.5 induced local tissue or systemic inflammatory response through stimulating inflammatory cells . Zhang eammation .Another key potential mechanism was caused by oxidative stress. An in vivo study showed that continuous exposure to PM2.5 activated hepatic stellate cells through oxidative stress and increased the risk of liver fibrosis . Ding etn-terminal kinase signaling pathway, increased insulin receptor substrate-1 phosphorylation, and caused significant liver damage with hepatic insulin resistance [Gut microbiota dysbiosis and insulin resistance might be one of possible mechanisms. Both in vivo and prospective studies have indicated that chronic exposure to PM2.5 caused dysbiosis of the gut microbiota and may subsequently contribute to the development of abnormal glucose metabolism and insulin resistance ,56,57,58sistance . Moreovesistance . Thus, gStudies have reported that exposure to some chemical compounds, carcinogenic compounds, and metals also increased the risk of chronic liver disease. Polychlorinated biphenyls, as environmental endocrine and metabolism disrupting chemicals, were associated with the genesis and progression of steatohepatitis and liver cancer induced by insulin resistance, dyslipidemia, proinflammatory cytokines ,64. BothThe main strengths of our present meta-analysis are the inclusion of various of chronic liver diseases, separation incidence from mortality of chronic liver diseases, and the coverage of more participants and countries than previous studies. Previous meta-analysis focused on the relationship between PM2.5 exposure and liver cancer. However, in the present meta-analysis, we included the studies to comprehensively analyze the relationship between PM2.5 exposure and other chronic liver diseases as well. All included data were adjusted for multiple hypothesized confounders in the present study, which was also free from publication bias. Overall, as far as we know, this is the first study that has comprehensively demonstrated the relationship between different types of chronic liver diseases and PM2.5 exposure.Additionally, our study also has several limitations. First, each included study has different adjusted confounders. Thus, there may be information bias in our study, which reduced the accuracy. Second, there was a lack of data on other types of chronic liver disease except liver cancer. Third, we did not distinguish between indoor and outdoor PM2.5 pollution, and did not explore the source and composition of PM2.5 pollution. Fourth, heterogeneity might be generated from difference between individuals and between various observational studies to influence the result. Finally, the number of included studies is not enough; therefore, more studies are needed.Our results suggested that PM2.5 exposure was associated with an increased risk of different chronic liver diseases. Although data for specific liver diseases were restricted, our results suggested that PM2.5 can increase the risk of fatty liver disease, liver cirrhosis, and liver cancer. The current meta-analysis indicated that diverse biological mechanisms might play a role in the numerous subtypes of chronic liver disease. More and more studies focus on the effects of various ambient air pollution on the risk of chronic liver diseases. Therefore, future research is needed to strengthen the association between certain types of air pollutants and specific chronic liver diseases.


Objective: This study explores associations between recurrent kidney stones and genetic polymorphisms.Methods: Meta-analysis of polymorphisms in renal stone cases versus control groups. Four electronic databases  were searched up to 30 May 2021, using the keywords: “kidney stone” or “kidney calculi,” or “urolithiasis” or “nephrolithiasis” or “urinary calculi” and “genome” or “genetic” or “mutation” or “single nucleotide polymorphism.” Forrest plots, ORs, 95% CI, Chi-square (χ2)-test, and index of heterogeneity (I2) were calculated. Only studies with Newcastle–Ottawa scale (NOS) ≥ 6 were included for quality control, and Funnel, Begg’s, and Eager’s plots assessed publication bias. PROSPERO: CRD42022250427.Results: Among 7,671 searched articles, 72 were included. Polymorphisms in VDR , CASR , Osteopontin , and Urokinase genes  showed a significant association with risk of urinary stone formation, while Klotho gene showed a protective effect . The VDR gene polymorphism was frequent in Asians, whereas CASR polymorphism was frequent in European and North American populations.Conclusion: Multifactorial nature of the stone formation, emphasizing the role of environmental factors, might explain contradictory results in the literature. While polymorphisms in VDR, CASR, Osteopontin, and Urokinase genes were associated with urinary stone formation, the Klotho gene showed a protective effect. Urolithiasis is a worldwide problem with increasing incidence and prevalence (varying worldwide from 5 to 20%) and has substantial health and socioeconomic burden . It is aSingle nucleotide polymorphisms (SNPs) are the most common population-dependent genetic variation. SNPs are ethnicity-dependent variations that occur commonly throughout a person’s DNA. They appear almost once in every 1,000 nucleotides, meaning roughly 4 to 5 million SNPs in a person’s genome. In particular, genetic variants in the population may contribute significant risk for manifesting such multifactorial disorders, including kidney stone formation and recurrence .Vitamin D Receptor (VDR), calcium-sensing receptor (CASR), and Urokinase .We conducted a review following the Systematic Reviews and Meta-Analyses (PRISMA) guideline . The revp-value (p < 0.05). Exclusion criteria: unrelated titles and abstracts, case reports, qualitative studies, in vitro experiments, animal studies, conference or poster abstracts, duplicated data, book chapters, letters, reviews, insufficient population demographic data, and unavailability of detailed data or full text.The outcome of interest comprised associations between gene polymorphisms and recurrent kidney stones. Inclusion criteria: data available to determination of odds ratios (OR), 95% confidence intervals, and associated Two investigators independently performed a quality assessment and data extraction under the supervision of a third investigator. The methodological quality of studies was assessed by Newcastle–Ottawa scale (NOS), and only studies with a quality score of 6 or better were considered in the meta-analysis. For all studies, beyond gene polymorphisms and recurrent kidney stones, the extracted information included: the first author, country, continent, ethnicity, and year of publication. We also collected a sub-population of Caucasians for further analysis.2) test consider the possibility of heterogeneity between studies. The random-effect approaches were adopted to compensate for the high values of heterogeneities between studies (I2 >50%).Effect estimates for Odds Ratio (OR) and its associated 95% Confidence Interval (CI) were calculated individually for each genetic model  using Hardy-Weinberg Equilibrium (HWE) values. Then, Forest plots were used to show the pooled estimates of ORs, and associated 95% CIs served to determine the degree of association between urolithiasis risk and SNPs. The Chi-square (χ2)-test and index of heterogeneity , CASR (n = 40), Osteopontin (OPN) (n = 20), Urokinase (n = 7), and Klotho gene (n = 16) were eligible for systematic review. Seventy-two articles were included in the meta-analysis to estimate the overall odds ratio (OR) of gene expression in renal stone cases versus control groups . The OR in European and North American patients was statistically significant , while it was not meaningful in the Asian subgroup . With regards to SNP subgroups, the rs1801725 and rs1501899 served as a risk factor with OR values of 1.44 (95% CI: 1.06–1.97) and 1.65 (95% CI: 1.08–2.51), respectively. The rs1042636 and rs1801726 did not show significant odds ratios . As well, studies on rs7652589 , rs6776158, and rs10190  did not show statistically significant association.The results related to OR for Osteopontin (OPN) are shown in Finally, we performed the meta-analysis for Urokinase . The oddUrinary stone disease is a complex phenomenon with a multifactorial etiology, with varying incidence in different continents and climates  ; . The mosvitamin D receptor gene (VDR). VDR gene has an essential role in calcium metabolism and is located in human chromosome 12q13–12q14 , showing a significant difference between the two study groups .The most investigated gene in the literature related to the renal stone disease is the 13–12q14 . There a13–12q14 . From 19analysis . The oveVDR gene in a study by Wang et al., with OR of 11.5 (CI = 6.41–20.6)  .VDR gene polymorphism regarding the increased risk of nephrolithiasis in a systematic review. Their results did not confirm the association of FokI, TaqI, BsmI, and ApaI with nephrolithiasis. However, ApaI and TaqI SNPs were related to urolithiasis in East-Asian and Caucasians populations. Our results revealed a significant association in the overall pooled meta-analysis . In subgroup analysis, rs2228570 (FokI) showed a significant relationship  with urolithiasis  was associated with recurrent urolithiasis   . In a si9–10.22) .CASR polymorphism in ninety-nine patients with recurrent urinary stones compared to 107 healthy control. They found that the 990G (rs1042636) and 986S (rs1801725) were associated with recurrent calcium urolithiasis   . In two ctively) . A studyctively) . In a stctively) . Li et apulation .CASR gene showed a significant association with stone formation . In the subgroup analysis by continents, the OR was statistically significant only in European and North American patients . Regarding SNP subgroups, the rs1801725 and rs1501899 served as a risk factor for urolithiasis with OR values of 1.44 (95% CI: 1.06–1.97) 1.65 (95% CI: 1.08–2.51), respectively.In our meta-analysis, the overall estimate of OR for the The third evaluated gene was the Klotho gene. This gene is a type-1 transmembrane protein with glucuronidase activity that has a proposed role in renal calcium and phosphate homeostasis . In fiveOur analysis shows that the Klotho has a protective effect on the outcome of interest . All studies on this gene were conducted in Asian countries, so we did not perform subgroup analysis by continent. According to Osteopontin   . Gao et 7–67.04) . Gogebak7–67.04) .OPN gene polymorphism. The rs1126616 was significantly discovered in kidney stone cases  (p = 0.021), rs2728127 GG genotype , and rs2853744 GG genotype  had a strong relation with nephrolithiasis. However, the rs9138 AA genotype was protective regarding stone formation     . Safarin= 0.004) . Tugcu e63–5.32) . Amar etctively) .OPN polymorphism in renal stone formation. In their study, three SNPs, including rs28357094, rs11439060, and rs11730582, were genotyped in 230 renal stone patients. The only SNP that related to nephrolithiasis was rs11439060 compared with the controls  = 1.08–2.22)  .Our results related to OR for Osteopontin are shown in Urokinase. The Urokinase is a multifunctional protein produced in the kidney. The proposed mechanism in nephrolithiasis inhibitory affects calcium oxalate crystallization (p < 0.05)  . In a si < 0.05) . Ozturk  < 0.05) . Kim et  < 0.05) . In a st < 0.05) . Jawad e < 0.05) .Urokinase gene polymorphism. The overall odds ratio was statistically insignificant . A significant association was also found in SNP subgroup of rs4065 , but the values in other SNP subgroups were not statistically significant  and .The overall publication bias of our study  was acceCASR gene polymorphism (rs1042636) was associated with nephrolithiasis risk in this ethnicity . A study by Hamilton et al. found a significant relation between CASR gene polymorphism (rs1801725) and nephrolithiasis  in the Caucasian population. Gögebakan et al. found an association between osteopontin gene polymorphism (rs1126616) and nephrolithiasis in the Caucasian population   .Osteopontin, Klotho, and Urokinase gene polymorphisms were performed in Asia, so we recommend more studies regarding these genes in other continents, including Europe and North America.Our study has some limitations. First, some of the studies were in Asia, but we do not have any data regarding the patients’ ethnicity. Multi-ethnicity may be considered as a confounding factor. The second one is restraining the search to only English-language articles. Third, most studies on VDR, CASR, Osteopontin, and Urokinase genes were associated with urinary stone formation, the Klotho gene showed a protective effect.The multifactorial nature of the stone formation, emphasizing the role of environmental factors, might explain contradictory results in the literature. While polymorphisms in


Background: Observational studies have reported inconsistent findings in the relationship between metabolic syndrome (MetS), its components, and loss of renal function, mainly including eGFR decline, new-onset CKD, and ESRD. This meta-analysis was performed to investigate their potential associations. Methods: PubMed and EMBASE were systematically searched from their inception to 21 July 2022. Observational cohort studies in English assessing the risk of renal dysfunction in individuals with MetS were identified. Risk estimates and their 95% confidence intervals (CIs) were extracted and pooled using the random-effects approach. Results: A total of 32 studies with 413,621 participants were included in the meta-analysis. MetS contributed to higher risks of renal dysfunction  and, specifically, rapid decline in eGFR , new-onset CKD , as well as ESRD . Moreover, all individual components of MetS were significantly associated with renal dysfunction, while elevated BP conveyed the highest risk , impaired fasting glucose with the lowest and diabetic-dependent risk . Conclusions: Individuals with MetS and its components are at higher risk of renal dysfunction. Chronic kidney disease (CKD) is an emerging major global public health problem, with increasing incidence and prevalence, adverse outcomes, and substantial cost . BesidesMetabolic syndrome (MetS) is a cluster of metabolic traits including obesity, impaired fasting glucose (IFG), elevated blood pressure (BP), and dyslipidemia . Its indGiven the clinical uncertainty, we conducted this meta-analysis to evaluate the effect of MetS on renal function, giving particular attention to the risk conveyed by each trait of MetS and updating the evidence in the context of individuals with reduced baseline renal function and a broader kidney outcome.This meta-analysis was registered in the International Prospective Register of Systematic Reviews—PROSPERO (CRD42022349368) and conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines .A comprehensive literature search was performed to identify related studies in PubMed and Embase databases from their inception to 21 July 2022. Medical subject headings (MeSH) terms and synonyms for the different terms including “metabolic syndrome”, “kidney function”, “chronic kidney disease” and “end-stage renal disease” were used and combined with Boolean operators and wildcards . A manuaStudies were included in the current meta-analysis if they fulfilled the following criteria: (1) observational cohort studies; (2) studies with a clear definition of MetS. The risk estimate in individuals with three or more prespecified metabolic abnormalities was considered, in which studies did not report the definition; (3) studies reporting following outcome measures: rapid eGFR decline, 50% reduction in eGFR or doubling of serum creatinine, new-onset CKD, progression to ESRD, or a composite of the above components. The definitions of each outcome were varied across studies, and we used these outcomes reported in each study; (4) relative risks (RRs) [or odds ratios (ORs) or hazard ratios (HRs)] with 95% confidence intervals (CIs) could be obtained; (5) articles published in English; (6) full text available.Studies were excluded if they met the following criteria: (1) non-original articles ; (2) studies with overlapped subjects; (3) studies that reported risk estimates for metabolic syndrome components only; (4) studies that reported effect estimates only by subgroups instead of the total sample; (5) studies reporting a composite outcome including death. Two reviewers  independently screened studies against the inclusion and exclusion criteria. A third author (J.F.Z.) adjudicated any discordance in assessments.After determining the qualified articles, the following data were extracted from the included studies: name of the first author, year of publication, study location, participant characteristics including sample size, gender proportion, mean age, follow-up duration, MetS definition, number of renal events, definition used for kidney outcome, risk estimates and their 95% Cis, and variables adjusted for multivariate analysis. We preferentially adopted outcomes using the modified NCEP-ATP III criteria for Asian participants for this analysis, but we accepted data on other definitions where these were the only ones reported. If one study had reported more than one kidney outcome, we extracted the data for the composite kidney outcome for the primary risk estimates as well as the data for each kidney outcome component, when available. If the study didn’t report the overall effect, the data related to declined GFR, a valid end point for chronic kidney damage ,12, was The quality of studies was assessed according to the Newcastlee-Ottawa Scale (NOS) for quality assessment of cohort studies  by two o2 statistic [In order to examine the effect of MetS and its components on renal function, the study-specific maximally adjusted RRs, ORs, or HRs were collected. The primary outcome was defined as renal dysfunction, a composite of rapid eGFR decline, new-onset CKD, 50% reduction in eGFR, or doubling of serum creatinine and ESRD. We also estimated the risk effect on each kidney outcome, when available. HRs and ORs were converted to RRs before pooling based on the formulae in tatistic  with 25%tatistic .p value < 0.05. Analyses were performed using Comprehensive Meta-Analysis , version 3.0.We compared the effect of MetS on renal function in the following subgroups: age range of participants, country, follow-up duration, diabetes status, and baseline kidney function. Leave-one-out sensitivity analyses was used to identify the stability of the results. Publication bias was assessed using the Egger’s test, and funnel plots were drawn . The staThe database searches identified 10,539 papers. After removal of duplicates, the included articles were selected from a pool of 8661 articles obtained from digital sources and a manual search. Of these, 288 papers retrieved for full-text screening against the inclusion and exclusion criteria. Eventually, a total of 32 studies published between 2005 and 2022 were included .The study participants were followed up for an average of nearly five years. Mean patient age ranged from 37  to 73 1 years, aQuality assessments of all included studies showed a Newcastle-Ottawa score range of 7–9 (out of 9), which indicates a good quality .2 = 72.57%, p < 0.001) , new-onset CKD , as well as ESRD  , with evidence of moderate heterogeneity across studies (I< 0.001) , Table 1< 0.001) . Specifi= 0.084) .2 = 51.92%, p = 0.023). There were no differences among follow-up duration subgroups. Additionally, the strength and direction of this association was found to be independent of diabetes status; however, diabetic patients with MetS did confer a higher risk than non-diabetic subjects . Similarly, the risk estimates did not differ among participants with or without baseline renal dysfunction   participants was equal to the original estimate  .The pooled risk estimates of renal dysfunction for individual MetS components are presented in t = 3.27, p = 0.003, t = 5.03, p = 0.010, After visually examining the funnel plots and performing Egger tests for every parameter, possible publication bias was observed for the associations of MetS . The risk estimate kept consistent regardless of different age range, duration of follow-up, country, diabetic status, or baseline kidney function. Besides CKD development, our findings revealed that MetS maintained its prognostic value for disease progression, including rapid eGFR decline and ESRD. The risk conveyed by all individual components of MetS varied and was strongest for elevated BP.Prior meta-analysis studies have suggested that individuals with MetS are at increased risk of developing CKD, reflected by albuminuria or proteinuria  and eGFRThe meta-analysis of individual components was done to explore the relative contribution of the individual components of MetS to renal dysfunction risk. Diabetes and hypertension are the leading causes of both CKD and ESRD in all developed and many developing countries . However2 were associated with 18%, 69%, and 102% higher risk of eGFR decline ≥40%, and the association was fairly similar in patients with and without baseline CKD [This study also revealed that apart from hyperglycemia and raised BP, as traditional risk factors of CKD, other components of MetS, including obesity, increased triglyceride, and reduced HDL-cholesterol are also reported to be important factors in new-onset CKD and subsequent disease progression in observational studies ,62,63 anline CKD . Dyslipiline CKD . The assline CKD . Data frline CKD . There wline CKD . HDL-C wline CKD . Anotherline CKD . In thisline CKD . In our line CKD . HoweverLarge pooled sample size, detailed subgroup analysis, and a prespecified study protocol that included a systematic search of PubMed and EMBASE databases for cohort studies were the chief strengths of the present study. However, several limitations should be recognized. First, we noted significant clinical heterogeneity in the analysis which limited the interpretation of our findings. The heterogeneity for renal dysfunction in relation to the presence of MetS could not be explained on the basis of age range, geographic region, duration of follow-up, diabetic status, or baseline renal function. Other underlying diseases, and variables used among studies, could have contributed to the heterogeneity. In addition, we focused on the baseline metabolic status, while the duration of MetS or the metabolic status during follow-up might impact the result. Secondly, the present meta-analysis has focused only on papers published in English. Those reported in other languages may be the source of publication bias. Thirdly, the inclusion of proteinuria or albuminuria may strengthen the findings as extra confirmation of renal dysfunction. However, another recent meta-analysis with 10,603,067 subjects from 57 studies on this topic had been performed , so it wThe present meta-analysis showed that there was a remarkable association between MetS, its components, and the risk of renal dysfunction. Among individual components of the syndrome, the most predictive factor was elevated BP. Identifying risk contribution will help clinicians prioritize treatment for patients with MetS. These findings may have important clinical implications in terms of risk stratification and preventive strategies.


The relative risk for cerebrovascular disease (CVD) is increased in patients with head and neck cancer (HNC) treated with radiotherapy (RT). However, the current relative risk for CVD following RT has not been well clarified. The purpose of this study was to analyze the effect of RT and update the risk of CVD following RT in HNC patients through a systematic review and meta-analysis.We conducted an online database search and systematic review of observational studies that reported on CVD and extracranial carotid stenosis in patients with HNC who had undergone RT. Articles published in Medline and PubMed from 1980 to 2021 were identified and collected.Of the forty-seven articles identified from PubMed and forty-four articles identified from 3 systematic reviews, twenty-two studies were included. We found that neck RT was a significant risk factor for CVD . Patients with HNC treated by RT had an increased OR  for CVD, and approximately 26% (95% CI: 22%-31%) of HNC patients treated with RT were at risk for CVD with more than 50% reduction in carotid diameter.The risk of CVD is increased in patients with HNC treated by RT, and recent improvements in RT techniques may have contributed to the decreased risk of CVD. These results suggest that regular follow-up and appropriate screening for CVD should be required for patients with HNC. In the United States, cancer-related mortality has declined with improved treatment, and consequently, the number of cancer survivors increased to 17 million in 2019 (Radiotherapy (RT) or concurrent with chemoradiation therapy (CCRT) is an essential therapeutic modality for patients with head and neck cancer (HNC). However, CVD in patients with HNC is under-identified and undertreated . The incIn the current study, a quantitative meta-analysis of the risk of CVD in post-RT/ CCRT HNC patients was designed and studied. Moreover, the assessment/screening for CVD in post-RT/CCRT HNC patients and the prevention/treatment of CVD in post-RT/CCRT HNC patients were investigated to provide potential clinical applications.We conducted a search on Medline and PubMed with the MeSH terms “Cerebrovascular disease AND head and neck cancer AND Radiotherapy (((head and neck cancer) AND radiotherapy [MeSH Terms]) AND Cerebrovascular disease [MeSH Terms] in the PubMed database)” in October 2021 following the PRISMA  guidelines Figure 11) Studies that were original research; 2) studies that evaluated patients with histopathologically proven head and neck cancer who underwent radiotherapy; 3) studies that provided data about cerebrovascular events, such as carotid stenosis, carotid intima-media thickness or ischemia stroke; 4) studies published between 1980 and 2021; an 5) studies published in English.1) Studies that did not meet our inclusion criteria, 2) studies for which the data had already been published or were duplicate data and 3) studies with incomplete raw data.1) The general information extracted included the title, first author, and publication date. 2) The relative risk (RR) or hazard ratio (HR) and 95% CI were extracted for cohort studies; the number of patients with RT-related treatment and the number of patients in the control group were extracted for case–control studies; and the number of cases of CVD among the total number of RT patients was extracted for prevalence studies.The hazard ratio (HR) with 95% confidence interval (CI) was calculated to evaluate the risk of CVD in the general population and in those receiving different treatment modalities by using a random-effects model meta-analysis. The odds ratio (OR) with the corresponding 95% CI was used to compare the clinical characteristics of the post-RT vs. non-RT groups. The cumulative incidence of carotid stenosis and the 95% confidence interval (CI) were computed to estimate the prevalence of CVD (more than 50% of carotid artery diameter stenosis). The I-squared statistic was used to assess heterogeneity. An I-squared greater than 50% indicated significant heterogeneity. A random-effects model was used to pool the effect size of significant heterogeneity. A forest plot was used to graphically display the effect size in each study and the pooled estimates. A p value < 0.05 was considered significant. We performed the meta-analysis with two R software packages: “meta”  was usedThe search process is shown in ).Twenty-two studies were included –7, 14–31). Additionally, concurrent chemoradiation therapy also increased the HR [3.26 (2.43-4.38)] for CVD. Interestingly, compared to RT with surgery, RT alone significantly increased the risk of CVD  .Comparing the HR of CVD in the general population (Pop) with that of patients receiving different treatment modalities, RT alone for head and neck patients indeed increased the risk of CVD [HR 3.97(2.89-5.45)] compared with that in the general population in the random-effects model (Thirteen case–control studies reported carotid stenosis in patients with HNC Table 1.). In meta-regression analysis to clarify the possible factors contributing to the heterogeneity among studies, we found that the publication year was a significant factor that contributed to the heterogeneity . Post-RT head and neck cancer patients had an increased OR  for the risk of CVD, and approximately 26% of patients were at risk for CVD, defined as having more than 50% carotid diameter reduction. Our findings provide scientific evidence and are helpful for the development of protocols for the diagnosis and prevention of CVD.Another meta-analysis of eight studies reported the pooled relative risk  and RR . Our OR The cost-effectiveness of carotid artery stenosis screening depends on the prevalence. One study revealed that the prevalence of carotid stenosis in the general population was 0% to 7.5% for moderate stenosis (carotid stenosis >50%) and 0% to 3.1% for severe stenosis (carotid stenosis >70%) . CVD scrCVD is an underestimated condition for head and neck cancer patients . Okoye eRadiation-related carotid vasculopathy is a dynamic and progressive process that can result in the depletion of parenchymal and vascular endothelial cells, with both macro- and microvascular effects . OxidatiNeck irritation will induce inflammation in the arteries; however, the mechanism through which this occurs is still poorly understood. To date, there are no guidelines for medication in the prevention of radiation-associated CVD. In radiotherapy-induced carotid artery vasculopathy, CIMT was reported to be related to LDL cholesterol levels . AccordiThe treatment of head and neck cancer requires a multidisciplinary team, including head and neck surgeons, radiation oncologists, hemato-oncologists and cardio-oncologists. Novel models for comprehensive head and neck cancer survival are necessary to provide a multidisciplinary approach to the prevention, screening and treatment of radiation-related CVD.Due to technical innovations, the prevalence of radiation-related carotid vasculopathy may be decreased. In our studies, we found that publication year was an important factor in the heterogeneity among studies. One study reported that IMRT can reduce the risk for CVD compared to 2D RT . HoweverThere are limitations in the current study. First, there was significant heterogeneity among the collected studies, which may be due to various radiation dosages, radiation protocols, radiation techniques, and follow-up times. However, there were no sufficient information about the radiation dosages, protocols, and techniques from the included studies. The follow-up duration of the included studies was varying. The radiation dosages were either recorded as main tumor, neck or carotid region. The radiation protocols and techniques were mostly not mentioned. Thus, we cannot achieve further analysis. Second, the enrolled studies were nonrandomized and were observation studies. Only four of the included reports were prospective cohort studies, and others were retrospective studies. Third, there are still no solid guidelines for screening and treatment, and further studies are necessary to develop cost-effective methods in the management of radiation-related CVD. Fourth, the timeframe of the included articles is very large, the CVD risk may be change by radiation technique, HPV status and patients’ survival condition.The included studies demonstrated that the prevalence of CVD with more than 50% carotid stenosis in post-RT HNC patients was 26%. Based on our analysis, RT for HNC patients can increase the risk of CVD. To combat this complication, close follow-up studies and appropriate screenings for CVD are recommended for HNC patients who receive RTThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.1. Conceived and designed the study: P-CC, W-LH, and L-JL; 2. Collected the data: P-YL, P-CC, W-LH, W-CL, C-HH, P-WS, and L-JL; 3. Performed the analysis P-CC, W-LH, and L-JL; 4. Wrote the paper: P-YL, P-CC, W-LH, W-CL, C-HH, P-WS, and L-JL. All authors contributed to the article and approved the submitted version.This work was supported by grants from the Far Eastern Memorial Hospital  and National Science Council of the Republic of China (MOST-109-2314-B-418-004).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.


Left atrial (LA) appendage closure (LAAC) is effective in patients with atrial fibrillation who are not candidates for long‐term anticoagulation. However, the impact of LAAC on LA function is unknown. The aim of this study is to evaluate the impact of LAAC on atrial function.This meta‐analysis was conducted according to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. A search strategy was designed to utilize PubMed/Medline, EMBASE, and Google scholar for studies showing the effect of LAAC on the LA function from inception to November 20, 2021. The standardized mean difference (SMD) was calculated from the means and standard deviations.p = .03; I2 = 75%). In contrast, there were no significant differences in LA volume  peak atrial longitudinal strain , peak atrial contraction strain , strain during atrial contraction , strain during ventricular systole , strain during ventricular diastole .Of 247 studies initially identified, 8 studies comprising 260 patients were included in the final analysis. There was a significant increase in LA emptying fraction following LAAC compared with preoperative function (SMD: 0.53; 95% confidence interval [CI]: 0.04–1.01; LAAC is associated with improvement in the left atrial emptying fraction, but did not significantly influence other parameters. Afibatrial fibrillationCABGcoronary artery bypass graftCHFcongestive heart failureCMRcardiac magnetic resonanceFDAFood and Drug AdministrationHFpEFheart failure preserved ejection fractionHFrEFheart failure with reduce ejection fractionLAleft atriumLAAleft atrial appendageLAACleft atrial appendage closureLAEFleft atrial emptying fractionLVleft ventricleNVAFnonvalvular atrial fibrillationPACSpeak atrial contraction strainPALSpeak atrial longitudinal strainTAEFtotal atrial emptying fraction1Standard treatment in nonvalvular atrial fibrillation is oral anticoagulation, either direct oral anticoagulants or warfarin.These devices prevent systemic embolization by closing off the LAA, which is considered the source of thrombus formation in more than 90% of the cases.22.1The present meta‐analysis was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines and the Cochrane handbook.We systematically searched MEDLINE/PubMed, EMBASE, and Google scholar from inception to November 30, 2021. The search included the following key terms:  AND ) AND (“echocardiography” OR “speckle tracking echocardiography”). We further reviewed the references list of the included articles in this review to include other relevant studies.2.2We included articles that demonstrate the impact of LAA exclusion on LA functions assessed by speckle tracking echocardiography. Articles using other methods other than speckle echocardiography for assessment were excluded from our analysis. In‐vitro studies, non‐English papers, reviews and data that could not be extracted were also excluded.2.3While the primary outcome in our study is to assess LA reservoir function and LA contractile function, the secondary outcome is to assess LA systolic function by strain rates. LA reservoir function is assessed by LAEF and peak atrial longitudinal strain (PALS), and LA contractile function is assessed by peak atrial contraction strain (PACS).Initial title and abstract screening were conducted by two reviewers (M.R.M and M.M) and all disagreements were discussed to reach a consensus, otherwise, a third opinion from W.S was obtained.2DS2‐VASc score mean, hypertension (HTN) %, diabetes mellitus (DM) %, hyperlipidemia %, congestive heart failure %, coronary artery disease (CAD) %, prior ablation % and stroke %.Potentially eligible articles were imported for full‐text review and assessed for inclusion. We extracted data using an Excel sheet. Examples of data collected are sample size, mean of age, female gender %, CHAWe assessed the quality of the included studies using the Newcastle–Ottawa Scale for cohort studies, as shown in Table 2.4I2 to measure heterogeneity over the included studies  to calculate the standardized mean difference (SMD) from the means and standard deviations. The means and standard deviations were calculated as described by Wan et al.33.1A total of 247 articles were screened from a comprehensive electronic database search. After thorough review, we found 8 retrospective or prospective observational studies (one of them was only published as an abstract) that evaluated the LA function after LAAC.3.2p = .03; I2 = 75%)  PALS , PACS , strain during atrial contraction , strain during ventricular systole , strain during ventricular diastole   Figure . There w) Figure .3.3−I2 from 75% to 31% without significant changes to the results. Omitting Murtaza et al.,Total atrial emptying fraction (TAEF): Yang et al.−I2 dropped only from 92% to 85%. Leave‐one‐out analyses did not show any significant changes in the results  systole, usually correlates with LA compliance. During ventricular diastole, the mitral valve opens with movement of blood from the LA to the LV, which reflects the conduit function of LA. LA contraction follows at the end of diastole, which represents the contractile function of LA.Our study has demonstrated significant improvement in LA reservoir function assessed by LAEF after LAA closure. One possible etiology is increased venous return after LAAC since LAA plays a vital role in volume balance by regulating both atrial and BNPs. Majunke et al.Total LAEF is identified as an important prognostic marker in various cardiac pathologies. For instance, Yang et al.Moreover, impaired LAEF in heart failure patients with concomitant atrial fibrillation is associated with worsening New York heart association classification. Intriguingly, impaired total LAEF in HFpEF patients was correlated with a higher mortality rate in those subsets of the population.Moreover, our study showed no difference in LA contractile function assessed by PACS before and after LAA exclusion. While Coisne et al.Last, the Data included in our analysis exhibits significant heterogeneity, which might be due to the differences in the study population. Variable follow‐up durations have been identified as well. Different techniques for LAA closure have been used, including Watchman, Lariat, and ACP devices. More studies are needed to compare the efficacy of various LAAC devices on LA deformation.5LAA exclusion is associated with improvement of LA reservoir function assessed by TAEF. PALS and LA contractile function did not differ significantly after LAA exclusion. More research is warranted for better understanding of LA hemodynamics and its implications in clinical vignette.The authors declare no conflicts of interest.Supporting information.Click here for additional data file.


Peri-implantitis was an inflammatory progress on the tissue around the implant. The Osteoprotegerin G1181C (rs2073618) polymorphism was reported to be related to the increased risk of the peri-implantitis, whereas another found no relationship. The present study was conducted to research the relationship between Osteoprotegerin rs2073618 polymorphism and peri-implantitis susceptibility.The meta-analysis was performed according to the Preferred Reporting Items for Systematic reviews. Electronic databases including PubMed, Web of science, Springer Link and Embase  were retrieved. The cohort study, case-control study or cross-sectional study focusing on the Osteoprotegerin rs2073618 polymorphism and peri-implantitis were retrieved. The data included basic information of each study and the genotype and allele frequencies of the cases and controls.Three studies were finally included, including 160 cases and 271 controls. Allelic model, homozygote model, recessive model, dominant model, and heterozygous model were established to assess the relationship between OPG rs2073618 polymorphism and peri-implantitis susceptibility. The Osteoprotegerin rs2073618 polymorphism was significantly associated with peri-implantitis in Recessive model and Homozygote model.OPG rs2073618 polymorphism in Recessive model and Homozygote model was highly likely related to the risk of peri-implantitis.PROSPERO registration number: CRD42022320812The online version contains supplementary material available at 10.1186/s12903-022-02657-6. With the development and maturity of implant technology, dental implants have become the main means of restoring missing teeth, in the train of which follows is the appearance of peri-implantitis . Peri-imBone resorption is a complex mechanism involving the release of several cytokines and apoptosis. Osteoprotegerin (OPG) is closely related to bone resorption process, which is involved in the regulation of osteoclast formation, and belongs to the tumor necrosis factor (TNF) receptor superfamily, which is also known as osteoclastogenesis inhibitory factor (OCIF) . As a rePrevious findings are inconsistent. Therefore, a meta-analysis evaluating the association between OPG rs2073618 polymorphism and peri-implantitis susceptibility was performed in this study. Through the screening of published works, the information about OPG rs2073618 polymorphism from patients with peri-implantitis was gathered for collecting analysis. Do adults with OPG rs2073618 polymorphism, compared to those do not have OPG rs2073618 polymorphism, have higher prevalence of peri-implantitis? To our knowledge, this is the first meta-analysis focusing the relationship between OPG rs2073618 polymorphism and peri-implantitis susceptibility.Journal of Clinical Periodontology, Journal of Periodontology, Clinical Oral Implants Research published in 2021 were manually searched.The meta-analysis was performed on the basis of the Preferred Reporting Items for Systematic reviews . The curTwo reviewers (M.X and CR.Z) independently screened the literature. Preliminary screening was conducted by reading the title and abstract to sort the articles adhering to the inclusion standards. Then the second screening was carried out by reading the full text of the literature. If the two reviewers held different opinions, another investigator (JX.H) would join the discussion to make a decision. The selected studies would be double-checked by another investigator, to ensure the integrity of the results.Eligible studies should meet the following criteria: (1) Types of studies: cohort study, case-control study or cross-sectional study; (2) Patients: subjects with peri-implantitis, diagnosed according to the criteria including peri-implant probing depth more than 5 mm, bleeding on probing, progressive crestal bone loss; (3) Index: allelic variants at OPG rs2073618; (4) Control: systemically healthy subjects with healthy implants and no periodontitis history; (5) Outcome: peri-implantitis susceptibility assessed by odds ratio; (6) Studies published in English; (7) Studies providing enough data, including genotypes and simple size etc. Animal experiments, abstracts and reviews were excluded.Newcastle-Ottawa scale (NOS)  was usedThe data extraction was carried out independently by two reviewers (M.X and CR.Z). Another investigator (JX.H) would finally check the extracted data. The content of data extraction included: (1) basic information of the study ; (2) study race; (3) characteristics of the participants ; (4) Hardy-Weinberg equilibrium (HWE) for the healthy control; (5) genotype, allele frequencies of the cases and controls.For the eligible studies, Pearson’s chi-square test was applied to assess the HWE of genotype of the controls. Odds ratio and 95% confidence interval were calculated using Allelic model (C versus G), Heterozygote model (GC versus GG), Recessive model (CC versus GC + GG), Dominant model (GC + CC versus GG), and Homozygote model (CC versus GG).2 statistics [2 > 50%, assuming a high degree of heterogeneity between the studies, therefore a random effects model was used. Otherwise, the fixed effects model (Mantel-Haenszel method) was used for analysis. Begg’s was adopted to evaluate the publication bias. Data analyzing and processing were conducted by STATA version 12.0 .Heterogeneity between studies was assessed using Iatistics . When P None.There were 42 studies identified in the electronic databases. None eligible study was found in other sources. After eliminating the repeated researches, irrelevant studies and reviews, three researches , 13, 17 The general information of included studies, containing first author, publication year, country, ethnicity, genotyping methods and number of each genotype. Abbreviations: HWE, Hardy-Weinberg equilibrium; NOS, Newcastle-Ottawa scale.P = 0.765 for heterogeneity) and Homozygote model , not in Allele model, Dominant model and Heterozygote model. The results were showed in Fig. Three studies were adopted to assess the association between the OPG rs2073618 polymorphism and peri-implantitis. The OPG rs2073618 polymorphism was significantly associated with peri-implantitis in Recessive model  of OPG, which was located in the in the promoter region . T950C p of OPG, Receptor activator of nuclear factor k ligand (RANKL) belongs to tumor necrosis factor ligand super-family. RANKL combined with RANK to promote alveolar bone resorption, on the contrary of OPG . OPG wasAnother systematic review  found thThere were some limitations in this study. The number of eligible studies was small. Therefore, we could not conduct subgroup analysis to find the differences between different races. More studies of good quality were required.OPG rs2073618 polymorphism in Recessive model and Homozygote model was highly likely related to the risk of peri-implantitis. OPG might be the potential biomarker for identification of peri-implantitis, which is worthy of further exploration.Additional file 1. Table S1: Quality assessment and risk of bias of the included studies by NOS.


To assess the risk of hypovolemia for sodium–glucose cotransporter-2 (SGLT2) inhibitors treatment.A systematic literature retrieval was performed in PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and Scopus from inception up to 4 October 2022, Data for study characteristics and outcomes of interest were extracted from each eligible study. Risk ratios (RRs) with a 95% confidence interval (CI) for hypovolemia were calculated using a random-effect model.n = 68,622) were included in our meta-analysis, with a result of 1,972 hypovolemia incidents . The pooled RR was 1.12 (95% CI: 1.02–1.22). It is evident that receiving SGLT2 inhibitors increased the risk of hypovolemia. When stratified by category of SGLT2 inhibitors the result was consistent; when the subgroup was analyzed by age, the pooled RR was 1.07 (95% CI: 0.94–1.23) in patients aged ≥65 years and 1.14 (95% CI: 1.02–1.28) in those aged <65 years. When comparing the baseline estimated glomerular filtration rate (eGFR) of less than or equal to 60 mL/min/1.73 m2 with a baseline eGFR greater than 60 mL/min/1.73 m2, the pooled RR was 1.21, (95% CI: 1.00–1.46) and 1.08, (95%CI: 0.98–1.20), respectively.A total of 57 studies . It is necessary to pay attention to the risk of hypovolemia associated with SGLT2 inhibitors, especially in older individuals and those with moderate renal impairment.https://www.crd.york.ac.uk/prospero/], identifier [CRD42020156254].[ Type 2 diabetes mellitus (T2DM) is an important health problem worldwide, which is characterized by insulin resistance, β-cell dysfunction, and impaired glucose tolerance . The preSodium–glucose cotransporter-2 (SGLT2) inhibitors are a new class of drugs, which improves glycemia by enhancing glycosuria, subsequently reducing blood pressure by osmotic diuresis and natriuresis . There aAs for the above reasons, our systematic review targeted to investigate the hypovolemia incidents related to SGLT2 inhibitors by meta-analyzing, and we also performed subgroup analysis depended on the category of SGLT2 inhibitors, patients’ age, and baseline estimated glomerular filtration rate (eGFR) to evaluate whether the risk of hypovolemia could be affected by clinical variables.We performed a systematic and comprehensive literature search in PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and Scopus from inception up to 4 October 2022. And we adhered to the 2020 PRISMA  statement in conducting this study and reporting the results . The seaTwo authors (Xinran Li and Qiling Gou) independently reviewed all relevant studies according to prespecified criteria. Inclusion criteria were: (a) RCTs reported in the English language and included adult patients with T2DM; (b) SGLT2 inhibitors compared with placebo or active comparator; (c) duration of follow-up of at least 12 weeks; and (d) the hypovolemia adverse events, which were investigated using a pre-specified list of Medical Dictionary for Regulatory Activities (MedDRA) preferred terms to identify events of hypotension, dehydration, or hypovolemia in the database . Data frTwo researchers (Xinran Li and Qiling Gou) independently screened and extracted the data using a previously defined standardized Microsoft excel sheet; the following information was extracted from each eligible trial: first author, year of publication, trial identifier, study duration, intervention drug, control drug, sample size, patients characteristics, duration of T2DM, and incident of hypovolemia events. These data were further examined by another investigator (Xi Rong), and any discrepancies were resolved by discussion. If hypovolemia events were not reported in the published paper, then these data were instead extracted from the trial register website. If the trial register website also did not provide the data on hypovolemia events, we attempted to contact the author to get the data. Two reviewers independently applied Cochrane risk-of-bias tool  to asses2) and I2 statistics were used to assess heterogeneity, Heterogeneity was assessed as low, moderate, and high with I2 values of 25, 50, and 75%, respectively. A random-effects model was adopted if there was evidence of statistical heterogeneity or clinical diversity ; otherwise, a fixed-effects model was used if there was no statistical significance of heterogeneity . The presence of publication bias was evaluated by visual inception for funnel plot asymmetry; Begg’s test and trim-and-fill method were also performed using STATA  to assess publication bias.Most of the analyses were performed by using RevMan . For dichotomous data, risk ratios (RRs) and 95% confidence interval (CI) were calculated to appraise the risk of hypovolemia with SGLT2 inhibitors treatment. Furthermore, subgroup analyses were conducted on the category of SGLT2 inhibitors, patients’ age, and baseline estimated glomerular filtration rate (eGFR) to evaluate whether the risk of hypovolemia could be modified by clinical variables. Sensitivity analysis was assessed by omitting one study at a time and re-estimated the combined RR for the remaining studies yielding consistent results to determine whether the result of the original analysis was robust. The Chi-square test  evaluated canagliflozin, 22 RCTs  evaluated dapagliflozin, 13 RCTs  evaluated empagliflozin, four RCTs (n = 970) evaluated luseogliflozin, two RCTs (n = 310) evaluated ipragliflozin, two RCTs (n = 440) evaluated tofogliflozin, and the remaining one RCT (n = 312) evaluated bexagliflozin. The last one RCTs  evaluated sotagliflozin. Among those 57 studies 51 studies compared SGLT2 inhibitors with a placebo, and another six studies compared SGLT2 inhibitors with other antidiabetic drugs. All eligible studies were randomized and double-blind design, and the publication year of studies ranged from 2009 to 2022, The follow-up duration of studies varies from 12 weeks to 208 weeks. The overview of the characteristics of included studies is presented in We applied Cochrane risk-of-bias tool to assess the study quality. Detailed information about risk-of-bias is presented in z = 0.06; P = 0.954). We performed the trim-and-fill method to detect and adjust for publication bias; after trim-and-fill, the pooled RR was 1.117 , which was approximately equal to the original pooled RR (1.12). Collectively, in the result of the funnel plot, Begg’s test, and trim-and-fill method, there was no evidence of publication bias. The result of sensitivity analyses indicated that the combined RRs were all not statistically significant and were similar to one another, with a range from 1.14  to 1.20 . This implied that the result of our meta-analysis was robust.A symmetrical funnel plot of SGLT2 inhibitors vs. placebo for hypovolemia indicated no evidence of publication bias . Begg’s I2, was 0% (P = 0.99), suggesting there was no significant heterogeneity between studies , but there was no statistical significance for eGFR subgroup differences (p = 0.30) . The heterogeneity, as assessed by  studies . Additio studies . When th studies . The poo = 0.30) .With 57 included RCTs involving 68,622 patients, this meta-analysis indicated that SGLT2 inhibitors increased the risk of hypovolemia, especially in patients with older age and lower eGFR. Both EMPA-REG OUTCOME trial and the CANVAS trial demonstrated that prescribing SGLT2 inhibitors reduces the risk of hospitalization for heart failure , 63. Res2 were more predisposed to hypovolemia; the deteriorative kidney function could be responsible for the conclusion.Our meta-analysis also investigated the category of SGLT2 inhibitors, patients’ age, and baseline eGFR impact on the risk of hypovolemia associated with SGLT2 inhibitors treatment. When stratified by category of SGLT2 inhibitors, luseogliflozin, Tofogliflozin and ipragliflozin had RRs greater than 2. It should be noted that they exist a broad 95% CIs as well, which implies the imprecision of statistics. It should be cautious to interpret this point. Canagliflozin showed an increased risk of hypovolemia compared with dapagliflozin or empagliflozin. This might be explained by canagliflozin having the lowest SGLT2/SGLT1 affinity ratio and empagliflozin the highest . People We further noticed that our meta-analysis included several trials that tested high doses of SGLT2 inhibitors, such as Dapagliflozin 50 mg, Empagliflozin 12.5 mg, Empagliflozin 25 mg, and so on. With the concerns of whether the result may be influenced by these dosages, we performed an additional subgroup analysis depending on the dosage of SGLT2 with U.S. Food and Drug Administration (FDA) approval. As presented in P for interaction is 0.57, which implied the difference of subgroup did not be attributed to diuretic treatment.Because diuretics might augment the effect of SGLT2 inhibitors, with increasing risk of hypovolemia. The issue of whether the increased risk of hypovolemia associated with SGLT2 inhibitors ascribes to the diuretic treatment should be examined. Among the included 57 studies, there were 15 citations , 60, 61 Collectively, the result of our meta-analysis, that SGLT2 inhibitors increased the risk of hypovolemia, was robust.This meta-analysis also had some limitations. First, the assessment of hypovolemia was based on a predefined list of preferred terms. This strategy may underestimate the risk of hypovolemia associated with SGLT2 inhibitors. Second, the pooled data was basically drawn from 22 RCTs evaluating dapagliflozin,12 RCTs with canagliflozin, and 13 RCTs with empagliflozin, it should be cautious to extrapolate the conclusion to another category of SGLT2 inhibitors. Finally, we were unable to further stratify the concomitant drug, due to the paucity of data provided by eligible RCTs.In conclusion, our present meta-analysis indicated that increased risk of hypovolemia associated with SGLT2 inhibitors in T2DM patients. The incidence of hypovolemia is different among the category of SGLT2 inhibitors and may keep rising with the age, and degeneration of renal function. To achieve an optimal fluid volume in patients with heart failure is an exquisite skill, hypovolemia in HF patients may be detrimental . Our metIn summary, the present meta-analysis indicated that SGLT2 inhibitors increased the risk of hypovolemia in patients with T2DM. The incidence of hypovolemia may increase with the decreasing of eGFR and growth of age. It is important to pay attention to the potential adverse event, except the common adverse event such as hypoglycemia, and genitourinary infection. Our meta-analysis indicates that there is an increase in hypovolemia associated with SGLT2 inhibitors treatment. It is necessary to be concerned about the risk of hypovolemia associated with SGLT2 inhibitors, especially in older individuals and those with moderate renal impairment.The original contributions presented in this study are included in the article/XR was involved in designing the study, literature retrieval, quality assessment, and manuscript writing. YZ, BW, XL, and QG contributed to the extract data. KL provided suggestions on carrying out the study. XC was involved in manuscript preparation. All authors contributed to the study’s conception and design.


Inflammatory cytokines have been considered to be significant factors contributing to the development and progression of non-alcoholic fatty liver disease (NAFLD). However, the role of inflammatory cytokines in NAFLD remains inconclusive.This study aimed to evaluate the association between inflammatory cytokines and NAFLD.PubMed, Web of Science, the Cochrane Library, and EMBASE databases were searched until 31 December 2021 to identify eligible studies that reported the association of inflammatory cytokine with NAFLD and its subtypes. We pooled odds ratios (ORs) and hazard risk (HRs) with 95% confidence intervals (CIs) and conducted heterogeneity tests. Sensitivity analysis and analysis for publication bias were also carried out.The search in the databases identified 51 relevant studies that investigated the association between 19 different inflammatory cytokines and NAFLD based on 36,074 patients and 47,052 controls. The results of the meta-analysis showed significant associations for C-reactive protein (CRP), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and intercellular adhesion molecule-1 (ICAM-1) with NAFLD . In contrast, we observed non-significant associations for interferon-γ (IFN-γ), insulin-like growth factor (IGF-II), interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-7 (IL-7), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-12 (IL-12), monocyte chemoattractant protein-1(MCP-1), and transforming growth factor-β (TGF-β) with NAFLD. Our results also showed that CRP, IL-1β, and TNF-α were significantly associated with non-alcoholic steatohepatitis (NASH) and hepatic fibrosis.Our results indicated that increased CRP, IL‐1β, IL-6, TNF‐α, and ICAM-1 concentrations were significantly associated with increased risks of NAFLD. These inflammatory mediators may serve as biomarkers for NAFLD subjects and expect to provide new insights into the aetiology of NAFLD as well as early diagnosis and intervention. Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide, with a global prevalence of 25% in the general population , and 80%The pathogenesis of NAFLD has not been fully elucidated. The mechanism of progression is usually explained by the classic “multiple strikes” theory of NAFLD pathogenesis, which states that lipid accumulation triggers hepatic steatosis, leading to multiple injuries, including adipokine secretion, inflammation, lipotoxicity, and dysregulation of glucose and lipid metabolism, which may eventually cause non-alcoholic steatohepatitis (NASH) and cirrhosis –6.It is widely accepted that cytokines play a critical role as mediators of inflammation, fibrosis, and cirrhosis in NAFLD . PreviouSeveral studies have reviewed inflammatory mediators and molecular pathways involved in the development and progression of NAFLD –18. HoweThe aim of this study was to provide a complete review of existing cross-sectional studies, case-control studies, and cohort studies on the association between inflammatory cytokines and NAFLD. Furthermore, we classified NAFLD into different types by disease spectrum , and performed subgroup analyses to elucidate the essential association between inflammatory cytokines and NAFLD.This review and meta‐analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) .Potentially relevant articles were searched using electronic databases. We systematically searched PubMed, Web of Science, the Cochrane Library, and EMBASE databases for articles published from 1 January 1960 to 31 December 2021. The search strategy included all possible combinations of keywords from the three groups related to non-alcoholic fatty liver disease, inflammatory cytokines , and their associated outcomes. The specific search strategy is provided in Studies that met all of the following criteria were included in the study: (a) the patients in the studies were diagnosed with NAFLD, including hepatic steatosis, NASH, and hepatic fibrosis; (b) observational studies  that reported the estimates of the effect of inflammatory cytokines on NAFLD, including odds ratios (ORs), relative risks (RRs) or hazard ratios (HRs), and 95% confidence intervals (CIs); (c) study subjects were human populations; and (d) articles were written in English.in vivo or in vitro cell experiments; (b) with incomplete data in the original studies; (c) duplicated studies retrieved from various databases; and (d) reviews, meta-analyses, clinical guidelines, comments, letters to the editor, or case reports.Studies that met any of the following criteria were excluded from the study: (a) only conducted 2), sample type, subtypes of NAFLD, the effect of inflammatory cytokines on the ORs/RRs/HRs and 95% CIs of NAFLD, diagnostic methods for NAFLD, and measurements of inflammatory cytokines.A standardized data extraction form was used to extract data from each eligible study by two reviewers (YD and XP) independently. Any further inconsistencies were addressed by a joint discussion. The following data were recorded: name of the first author, publication year, country, sample size, type of case/control, mean age (years), BMI  .This ass2I). The level of heterogeneity measured by 2I was interpreted as modest (2I ≤ 25%), moderate (25%< 2I ≤50%), substantial (50% < 2I ≤ 75%), or considerable (2I > 75%). Q-statistic tests were also conducted, where P < 0.1 indicates the presence of heterogeneity among studies. If 2I ≥ 50% or P < 0.1, the random effect model was used, otherwise the fixed effect model was applied. Subgroup analyses were used to explore the potential sources of heterogeneity. Sensitivity analyses were performed to evaluate the availability and reliability of the results by deleting one study at a time and combining the effect values of the remaining studies. Funnel plots with Begg’s tests and Egger’s tests were used to assess publication bias. All statistical tests were two-sided; P < 0.05 was considered statistically significant except for the evaluation of heterogeneity (P < 0.1). All meta‐analyses were performed using Stata v12.0 .Each inflammatory cytokine with more than two identified studies was included in the meta-analysis. The ORs with 95% CIs were used to describe the effect of inflammatory cytokines on NAFLD. The heterogeneity was evaluated by I-squared (Characteristics of the 51 eligible studies are summarized in P<0.001) (P=0.006) (P=0.001) (P=0.031) (P=0.008) , interleukin-13 (IL-13), and interleukin-34 (IL-34), were excluded as they were only reported by one study. We found significant associations between CRP , studies that examined the plasma samples  and diagnosing NAFLD by ultrasonography examination . With regard to TGF‐β, heterogeneity was reduced in the BMI ≥ 30 group . Moreover, heterogeneity was reduced in the serum samples  about MCP-1.Significant heterogeneity was observed in studies investigating the inflammatory cytokines mentioned above , with P=0.003) and hepatic fibrosis , which were consistent with overall effect (P=0.206), 0.94 , and 1.09 , respectively.Considering NAFLD consists of different clinical subtypes, we performed subgroup analyses by classification of NAFLD as hepatic steatosis, NASH, and hepatic fibrosis. The association between inflammatory cytokines and NAFLD varied among different subtypes of NAFLD. We found significant associations for CRP with NASH  - induced inflammatory mediator . The proOur results showed that there were no significant associations between IFN-γ, IGF-II, IL‐2, IL‐4, IL‐5, IL‐7, IL‐8, IL‐10, IL‐12, MCP‐1, and TGF-β and NAFLD. The main reason for this result may be the limited number of included studies. Besides, the negative findings were strongly linked to multiple characteristics of these inflammatory cytokines involved in the progression of NAFLD. Notably, although the non‐significant associations were observed in the overall population, opposite associations were observed in subgroup analyses. These results may suggest that the true association between inflammatory cytokines and NAFLD was masked or diluted when analyzing the overall population. Therefore, further studies are necessary to establish the true association. Remarkably, the meta-analysis showed that the association between IL-10 and NAFLD reached borderline significance. Due to the limited number of included studies and previous findings, we still considered IL-10 to be an important anti-inflammatory cytokine. IL-10 may have a role by affecting the myeloid-differentiation factor 88 (MyD88)-TLRs-NF-κB signalling pathway . PreviouMoreover, recent studies suggested that inflammasome is an intracellular multi-protein complex that is thought to be a trigger for inflammatory cytokines in NAFLD . AlthougThis study has some potential limitations that should be considered. First, some inflammatory cytokines were only reported by fewer than three studies, thus more studies are needed in the future to confirm this result in different populations. Second, some of the included studies used ultrasonography examination to diagnose NAFLD, which may increase the risk of false positives compared to a diagnosis with the gold standard, i.e. liver biopsy. Finally, there were different cut-off values for inflammatory cytokines in the included studies, which may have increased heterogeneity among studies.This review and meta-analysis indicated that increased CRP, IL-1β, IL-6, TNF-α, and ICAM-1 concentrations were significantly associated with increased risks of NAFLD. Furthermore, the results of subgroup analyses showed the characteristics of different inflammatory cytokines involved in the NAFLD progression progress. These inflammatory mediators may serve as biomarkers for the prediction of NAFLD. These findings may provide new insights into the aetiology of NAFLD as well as early diagnosis and intervention.The original contributions presented in the study are included in the article/DY, LuJ, PX and LM designed the study. DY and PX collected the data, and wrote the manuscript with support from other authors. XX and LiJ contributed to the statistical analysis and preparing the tables. LM, LuJ, DY, PX and BPL reviewed and revised the manuscript. All authors approved the final version of the article, including the authorship list.This work was supported by the National Natural Science Foundation of China (81872641) and the Natural Science Foundation of Hunan Province (2021JJ30901).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.