Epidemiological studies have shown that eating fish significantly reduces cardiovascular disease (CVD) incidence and mortality. However, more focused meta-analyses based on the most recent results from prospective cohort studies are needed. This systematic review and meta-analysis aims to update the association between fish intake and cardiovascular disease (CVD) risk using recent prospective studies. A systematic review and meta-analysis following the PRISMA guideline was conducted based on a random effects synthesis of multivariable-adjusted relative risks (RRs) of high vs. low categories of fish intake in relation to CVD incidence and mortality. Non-linear meta-regression was applied to investigate the shape of the association between fish intake and CVD risk. Sensitivity analysis and stratifications by type of CVD outcome, type of fish intake and type of cooking were performed. Based on 18 papers reporting 17 independent estimates of CVD risk , high vs. low intake of fish corresponded to about 8% reduced CVD risk (RR = 0.93 [0.88–0.98]). According to a non-linear dose–response meta-regression, 50 g of fish intake per day corresponded to a statistically significant 9% reduced fatal and non-fatal CVD risk (RR = 0.92 [0.90–0.95]). Similarly, fish intake in the range of a weekly intake of two to three portions of fish with a size of 150 g resulted in 8% fatal and non-fatal CVD risk reduction (RR = 0.93 [0.91–0.96]). The recommended two portions of fish a week reduces the risk of CVD outcomes by approximately 10%. A full portion of fish a day reduces CVD risk by up to 30%. Globally, 41 million people  are estimated to die from non-communicable diseases (NCDs) every year with 17 million of these deaths occurring before 70 years of age . Among CThis systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . The PECThe systematic literature search was conducted using the database of the North-West University with more than 100 literature repositories, including MEDLINE-PubMed, Cochrane and CINAHL. The same search string was used to search Embase, which is not included in the above-mentioned repository. In addition, reference lists of previously published systematic reviews and meta-analyses were investigated for eligible studies.Two independent authors (HR and MG) used the Newcastle Ottawa Scale (NOS) to assess the risk of bias and overall study quality . The NOSi-th study being computed as wi = 1/(si2 + t2), where si2 was the variance of the i-th study and t2 was the overall variance. The fixed effect estimate was also illustrated using forest plots. In general, the included studies contributing to the meta-analyses had one risk estimate only. Results from a single study were pooled using a fixed effect meta-analysis when more than one risk estimate was provided, for example, for sex, or for specific types of fish intakes or CVD. Furthermore, we chose the study with the highest number of CVD cases when different studies or papers provided data from the same cohort. Results were kept separate if results from independent cohorts were reported by a single paper. The Cochrane Q test (if at least 10 studies were included) and the I2 statistic  were reported to show between-study heterogeneity. Between-study heterogeneity was investigated using stratification analyses and linear meta-regression. Sensitivity analyses were performed omitting one study at a time, and potential publication bias was detected using visual inspection of the funnel plot and using Egger’s test [Our main meta-analysis was based on a random effects synthesis of multivariable-adjusted relative risks (RRs) of high vs. low categories of fish intake in relation to CVD incidence and mortality. In this model, the study’s weight was given using inverse variance, with the weight of the r’s test . Finallyr’s test . All star’s test .Our search string resulted in 2410 records with three additional papers identified by screening the reference list of included systematic reviews and meta-analyses, resulting in a total of 2413 records. A total of 2348 records were excluded after reading the title and abstract, leaving 65 records. Of the remaining articles, 18 were included as they met our inclusion criteria ,38,39,402 = 72.3%) and a statistically significant Cochrane Q test (PQ-Cochrane < 0.001). The meta-analysis of the RR estimates of fatal and non-fatal CVD risk for high vs. low intake of fish is presented in 2 = 34.9%, PQ-Cochrane = 0.111). Finally, we considered 14 independent RR estimates for fatal CVDs in relation to high vs. low fish intake [2 = 70.9%, PQ-Cochrane < 0.001). The meta-analysis of the RR estimates of fatal and non-fatal CVDs for high vs. low intake of fish is presented in There were 17 independent risk estimates of high vs. low intake of fish included in the meta-analysis considering any type of fish intake and any type of CVD outcome ,37,39,40h intake ,38,39,402 = 57.9%). By comparison, based on the same included studies, a reduced fatal and non-fatal CVD risk was not observed when looking at high vs. low intake of lean fish . Two studies considered CVD risk in relation to intake of fried fish [2 = 0%). Also, based on three studies [2 = 83%). When looking at specific CVD outcomes, six studies [2 = 18.5%). Stroke risk in relation to fish intake was investigated by seven studies [2 = 27.0%). This result was confirmed when looking at specific types of stroke. Four studies [2 = 27.0%) and three studies [2 = 33.5%). Finally, no statistically significant association was observed when considering high vs. low intake of fish in relation to CHD risk . The three studies included in the paper of Mohan et al. [2 = 0%).Three studies provided data on intake of fatty fish ,27,29. Wied fish ,40. Here studies ,37,40, h studies ,32,34 in studies ,28,32,34 studies ,38 invesThere were 10 studies included in the analysis of non-linear dose–response meta-regression of fish intake in relation to fatal and non-fatal CVD risk ,34,38,402 = 57.5%, PQ-Cochrane = 0.002) and 0.94 , respectively. The exclusion of the two studies with increased CVD risk for higher fish intake and also lower NOS score [2 = 48.3%, PQ-Cochrane = 0.019). No evidence of publication bias emerged according to Egger’s test (PEgger = 0.726) or by the visual inspection of the funnel plot  and 0.96 , when excluding the studies by Hengeveld et al. [2 = 12.5%, PQ-Cochrane = 0.326). No evidence of publication bias was observed according to Egger’s test (PEgger = 0.193) or visual inspection of the funnel plot  and 0.92  when excluding the studies from Van der Brandt et al. [Egger = 0.765) and the visual inspection of the funnel plot .When considering only those estimates adjusted for the overall energy intake, we observed a relevant reduction in the between-study heterogeneity (from 72.3% to 59.3%) and an RR estimate of fatal and non-fatal CVD risk for high vs. low intake of fish of 0.91 (95% CI = 0.87 to 0.95). We also observed a reduction in the between-study heterogeneity (from 72.3% to 48.3%) when considering only studies of higher methodological quality (NOS ≥ 6). Likewise, we observed an 11% reduced risk of fatal and non-fatal CVDs for high vs. low intake of fish . The results from the stratified analyses are presented in A statistically significant risk reduction for fatal and non-fatal CVDs in association with fish intake was observed in this systematic review and meta-analysis. According to our analysis, we can estimate that high vs. low intake of fish would reduce CVD risk by a factor of up to 10%. This general result is broadly confirmed by the results from previous systematic reviews and meta-analyses ,10,41,42Specific stratified meta-analyses were conducted to investigate the association of different types of fish intake with different types of CVD events. We confirmed results from a previous meta-analysis, reporting that high intake of fatty fish resulted in a statistically significant 12% reduced fatal and non-fatal CVD risk . We alsoOur dose–response analysis provides certain useful information in terms of public health recommendations about fish intake. First, our results support the concept that even a small intake of fish is beneficial to cardiovascular health. Two or more fish servings per week are recommended by the American Heart Association . We confOur results are supported by numerous experimental studies and related meta-analyses and reviews ,13,43,44Our study has numerous strengths. First, this is a systematic synthesis of the most recent evidence from prospective cohort studies conducted using cutting-edge methodology. Our results are supported by a large set of data and number of CVD events. Our sensitivity analysis and stratification analysis demonstrated the robustness of our results with respect to the effect of outlier results, scientific quality and many methodological factors. Second, our study does not only represent an update of the scientific evidence accumulated so far but includes novel results on the association between fish intake and cardiovascular risk by evaluating different CVD outcomes and types of fish intake. Finally, we conducted a non-linear meta-regression analysis to provide quantitative information about the dose–response relationship between fish intake and cardiovascular risk. From this perspective, our work is innovative, as it confirms and extends existing scientific evidence. This work also has several limitations. First, probably because the studies used are from different sources and settings, a moderate to large between-study heterogeneity was demonstrated. This could have affected our analysis, resulting in overdispersed estimates and false-negative results. However, we believe this limitation is minor as we showed that excluding certain studies reduced the between-study heterogeneity without changing the risk estimates. Also, the possibility of false-negative results could have limited some of our stratified analyses, especially those with less than four included studies. However, we were able to detect up to a 5% statistically significant risk reduction. The detection of smaller risks would not be of any practical importance in this context. Second, it must be acknowledged that a high fish intake may result in the accumulation of toxic substances, such as heavy metal ions and mercury, micro plastics and other types of water pollutants. However, according to our analysis, it seems that any intake of such substances in relation to fish intake does not affect CVD risk. From this perspective, it seems that eating fish is beneficial to reducing CVD risk, despite a likely correlation between fish intake and mercury levels ,58. We cFish consumption, especially fatty fish intake, is beneficial to cardiovascular health, and it should be promoted through public health policies. A small serving of fish a day, or the recommended two portions a week, may reduce the risk of fatal and non-fatal CVD outcomes by approximately 10%. Up to 30% reduced CVD risk can be achieved by eating a full portion of fish a day.


Background and aims: Hypoglycemic agents are the primary therapeutic approach for the treatment of diabetes and have been postulated to impact pancreatic cancer (PC) incidence in diabetic patients. We conducted a meta-analysis to further evaluate and establish the associations between four common types of hypoglycemic agents  and PC incidence in individuals with diabetes mellitus (DM).Methods: A comprehensive literature search of PubMed, Web of Science, Embase, and the Cochrane Library identified studies that analyzed the relationship between hypoglycemic agents and PC published between January 2012 and September 2022. Randomized control trials (RCTs), cohorts, and case–control studies were included if there was clear and evaluated defined exposure to the involved hypoglycemic agents and reported PC outcomes in patients with DM. Furthermore, reported relative risks or odds ratios (ORs) or other provided data were required for the calculation of odds ratios. Summary odds ratio estimates with a 95% confidence interval (CI) were estimated using the random-effects model. Additionally, subgroup analysis was performed to figure out the source of heterogeneity. Sensitivity analysis and publication bias detection were also performed.Results: A total of 11 studies were identified that evaluated one or more of the hypoglycemic agents, including three case–control studies and eight cohort studies. Among these, nine focused on metformin, six on sulfonylureas, seven on TZDs, and seven on insulin. Meta-analysis of the 11 observational studies reported no significant association between metformin  or TZDs  and PC incidence, while the risk of PC increased by 79% and 185% with sulfonylureas  and insulin , respectively. Considerable heterogeneity was observed among the studies and could not be fully accounted for by study design, region, or adjustment for other hypoglycemic agents.Conclusion: Sulfonylureas and insulin may increase the incidence of pancreatic cancer in diabetic patients, with varying effects observed among different ethnicities (Asian and Western). Due to significant heterogeneity across studies, further interpretation of the relationship between hypoglycemic agents and pancreatic cancer incidence in diabetic patients requires well-adjusted data and better-organized clinical trials. Pancreatic cancer (PC) is a highly challenging gastrointestinal oncology malignancy with the poorest prognosis, which remains refractory to treatment and ranks the fourth leading cause of cancer-related mortality worldwide . The incAmong the risk factors, the most harmful risk factor is smoking . AnotherHypoglycemic agents are crucial components of the treatment regimen for patients with DM, and it is widely believed that they may have an impact on the incidence of PC in this population. Previous epidemiological and preclinical investigations have suggested that insulin may promote the development of pancreatic cancer, while metformin has been shown to exert anti-cancer effects through its actions on transformed pancreatic cells . SulfonyDue to the complicated associations between hypoglycemic agents and PC risk, as well as the poor prognosis of PC, we performed a meta-analysis to further evaluate and clarify the association between the use of hypoglycemic agents  and PC incidence in patients with DM.We searched MEDLINE , Web of Science, Embase (Elsevier), and the Cochrane Library for all relevant studies on hypoglycemic agents and PC incidence in diabetic patients published between January 2012 and September 2022. The Medical Subject Heading (MeSH) terms used in the search are “metformin,” “thiazolidinediones,” “insulin,” “sulfonylurea compounds,” “agents,” “hypoglycemic,” and “pancreatic neoplasms.” Different spellings of the drugs’ names were taken into consideration and included in the search strategy to complete the search results.Studies included in the meta-analysis were RCTs or observational studies that met the following inclusion criteria: 1) case–control study, cohort study, or RCT; 2) clear and evaluated defined exposure to the involved hypoglycemic agents; 3) reported PC outcome in patients with DM; and 4) reported relative risks or odds ratio (OR) or other provided data for the calculation of OR. In addition, studies were excluded when they were: 1) reviews, case reports, letters, editorials, or commentaries; 2) cancer treatment, prognosis, or mortality studies; 3) unable to extract needed data; and 4) from the same population but the less comprehensive one.The data of the studies were extracted independently by two researchers—Zimo Zhao and Xinyi He—to a standardized form. The results were cross-checked, and the differences were solved by consensus. The following data were collected from each study: the first author, year of publication, region, study design, study population, time period, hypoglycemic agents involved, reported primary outcome, frequency, dose and duration of usage (if reported), number of subjects in each group, OR, RR, 95% confidence intervals (CIs), and adjusted variables.The study quality was assessed with the Newcastle–Ottawa Scale (NOS)  for obse2 statistics, and it was considered statistically significant for heterogeneity if the p-value was <0.10 or the I2 value was >50% (p < 0.10 was considered to indicate significant publication bias) (The random-effects model described by was >50% . The cauon bias) . Stata 1The process of study selection is shown in The Newcastle–Ottawa quality score for observational studies ranges from 6 to 9, and the median quality score is 8. The methodological quality of all studies is depicted in p < 0.01, I2 = 86%), and it could not be explained by study design, region, or whether adjusted for other hypoglycemic agents in the subgroup analysis we conducted  . There wonducted . Furtherp < 0.01, I2 = 84.4%), which could not be fully explained by the subgroup analysis , which was statistically significant . The anaanalysis . The resp < 0.01, I2 = 87.3%), and it could not be fully explained by the factors in the subgroup analysis (The use of TZDs (as compared with the non-use of TZDs) was not associated with a significant increase in the risk of PC in patients with DM  . Consideanalysis . Howeverp < 0.01, I2 = 82.4%), and it could not be completely explained by the subgroup analysis we conducted  . Consideonducted . Howeverp = 0.860 for metformin, p = 0.986 for SU, p = 0.954 for TZDs, and p = 0.611 for insulin; p < 0.10 was considered to indicate significant publication bias) and qualitatively on visual inspection of the funnel plot.There was no indication of significant publication bias both quantitatively , while SU administration increased the PC incidence by 79% . TZDs were not associated with a significant increase in the risk of PC in patients with DM , and the use of insulin was associated with a statistically significant 185% increase in the risk of PC in patients with DM .We found that, in comparison with non-use, the use of metformin and TZDs had no statistically important associations with the incidence of PC in diabetic patients, while the use of SU and insulin was associated with an increase of 79% and 185% in the risk of PC, respectively. The results were stable across both cohort and case–control studies and persisted after adjusting for the concomitant effect of other hypoglycemic agents, whereas significant heterogeneity was observed across studies, which limited the meta-analysis. In addition, the subgroup analysis showed that SU may have an oncogenic effect, especially on the Asian population and those adjusted for other hypoglycemic agents. Apart from that, it also indicated that TZDs were associated with the protective effect on the Asian population, and the use of insulin was shown to have a greater oncogenic effect on the Western population in cohort studies and those not adjusted for other hypoglycemic agents.The strength of this meta-analysis is that it assessed the comprehensive and simultaneous effects of all conventional hypoglycemic agents on the risk modification of PC. Although in vitro experiments, so this signaling pathway cannot explain the actual effect of the clinical drug benefit. Metformin is one of the most commonly used drugs for the treatment of DM. In recent years, some clinical studies have found that in addition to lowering blood glucose levels, metformin also has certain effects on alleviating fatty liver, protecting the cardiovascular system, inhibiting tumor growth, and relieving symptoms of neurodegenerative diseases . It is g+ channels in islet beta cells to induce their closure, resulting in increased fasting and postprandial insulin levels, which is oncogenic.SU act on KFor insulin, it promotes the development of PC through the following biological effects: promoting cell proliferation and growth, activating the RTK signal pathway, and promoting angiogenesis . KarlstaHelicobacter pylori infection because Asian people are not used to serving of individual dishes. It can be seen that the regional discrepancy is caused by the combined influence of ethnic differences, environmental factors, and different lifestyles.We found a significant oncogenic effect of SU on the Asian population , which was not observed in the Western population . In addition, for TZDs, a statistically significant protective effect on the Asian population was observed . For insulin users, the oncogenic effect is 170% greater in the Western population than that in the Asian population. The regional discrepancy may be explained by ethnic differences, environmental factors, the gap in economic development, and different lifestyles, particularly in dietary habits. The Western diet (WD) is an unhealthy diet high in fat and characterized by binge eating, frequent snacking, and a prolonged postprandial state. Studies have shown that the Western diet leads to hyperinsulinemia, insulin resistance, dyslipidemia, and hyperactivity of the sympathetic nervous system and renin–angiotensin system . The AsiApart from that, most diabetic patients in the studies were simultaneously taking multiple hypoglycemic agents, which may influence the result, and this should not be neglected. For example, a patient in the “on metformin” group was on metformin and insulin medication at the same time, and metformin plays a neutral role in cancer risk, while insulin has a great oncogenic effect; the result may be magnified by the effect of insulin. In addition, the age of the patients should be considered. Aged patients tend to use insulin more, and the control of glycemic levels is relatively poor. Furthermore, elderly diabetic patients have more complications and concomitant diseases, thus causing polypharmacy. This may cause the potential overestimate of the oncogenic effect of insulin and the great heterogeneity seen in the study.As known, adherence and persistence to antidiabetic drugs are very low. This aspect could have contributed to the high risk of PC in diabetic patients. In other words, the higher risk of PC in patients receiving SU and insulin, in part, can be a result of non-adherence to the antidiabetic medication and, therefore, a direct consequence of T2D progression. Indeed, T2D itself is one of the major risk factors for developing PC.This meta-analysis has several limitations. First, the study only included observational studies because there was no relevant published RCT from 2012 to 2022, which may affect our results. Second, most studies assessed the cancer incidence caused by the use of more than one hypoglycemic agent, and the simultaneous effect of other agents was not excluded, which may modify the cancer risk. Third, the included studies were mainly conducted in East Asia and North America, while only one study was conducted in Italy and Europe, and none in other continents, which limited our study. Finally, the adjusted variables varied among studies, and many of them were insufficient, which may cause considerable heterogeneity and influence the results.In conclusion, SU and insulin may modify the incidence of PC in diabetic patients, and the effect of hypoglycemic agents may vary in regions (Asian and Western). There was considerable heterogeneity across studies, and the relationship between hypoglycemic agents and the incidence of PC in diabetic patients should be further interpreted with well-adjusted data and better-organized clinical trials.


PROCR gene  results in a serine-to-glycine substitution at codon 219 of endothelial protein C receptor (EPCR). We performed a case–control study followed by an updated meta-analysis of the association between this polymorphism and the risk of venous thromboembolism (VTE).The rs867186 single-nucleotide polymorphism in the We enrolled 263 VTE patients and 320 unrelated healthy controls for the case–control study. The total number of cases and controls for the meta-analysis were 5,768 and 30,017, respectively. A new online MetaGenyo Statistical Analysis System software was used to perform the current meta-analysis. Furthermore, a reproducibility study was conducted to validate our results.p < 0.001), while there was no difference in mutation frequency of prothrombin 20210G>A polymorphism between the two groups. There was no difference in the mutation frequency of Factor V Leiden and prothrombin 20210G>A between cases with and without provoking factors and cases with and without VTE recurrence. The rs867186 “G” carriership did not influence the risk of VTE  in our study. No significant differences could be demonstrated among the rs867186 genotype frequencies between VTE cases with and without provoking factors (p = 0.430). PROCR rs867186 was associated with an OR of 1.72  in terms of VTE recurrence. In the meta-analysis, a significant association was found between EPCR Ser219Gly polymorphism and VTE under the dominant model , the recessive model , the GG vs. AA contrast model , and the GA vs. AA contrast model .Among well-defined thrombosis risk factors, Factor V Leiden was more frequent in the VTE group (The rs867186 was not associated with the first VTE risk in our case–control study; however, a tendency to VTE recurrence was observed. Based on the results of our reproducibility study, MetaGenyo is acceptable for meta-analysis in case of genetic epidemiology studies. Although the risk conferred by the rs867186 is mild in all meta-analyses, including ours, identifying patients carrying the minor allele might have an impact on personalized VTE risk assessment, risk-score calculation, and patient management. VTE is agulants –9. WhilePROCR) gene (20q11) causes a p.Ser219Gly substitution , which increases the solubility relative to membrane-bound EPCR levels and explains 75% of the variability of plasma-soluble EPCR levels and also has an effect on PC levels (Protein C (PC) is a natural, endogenous anticoagulant protein with anti-inflammatory properties, which interacts with the EPCR . The EPCC levels .PROCR rs867186, rs6060278 , and rs8119351  with PC levels in VTE patients explaining 20% of the variance  with the p.Ser219Gly according to the study by Germain et al.  elevated the risk of VTE. PROCR rs8119351 G>A leads to elevated PC levels, but its mechanism is unknown  studies are also available . The MARvariance . The rs6n et al. . The adj unknown . The mec unknown . Several unknown , 28 wereRecently, evidence for an association between the EPCR gene p.Ser219Gly gene polymorphism and venous thrombosis is still conflicting. Previously published studies showed that rs6088735 and rs867186 could act additively on the risk of VTE , 29.Therefore, this population-based case–control study and an updated, comprehensive meta-analysis aimed to investigate the potential relationship between EPCR gene p.Ser219Gly gene polymorphism and VTE risk.2.2.1.n = 263) and of apparently healthy unrelated adults .Our study population consisted of non-related individuals with VTE in their case histories  or drugs influencing hemostasis ; there was no venous or arterial thrombosis in their case histories .Individuals with antithrombin, protein C, or protein S deficiencies with causative mutations in the background were excluded from the whole study population. Individuals with chronic illnesses  were also excluded. Hypertension, diabetes mellitus, and their therapy were allowed in the study population. We also let in women taking oral anticontraceptive pills (OAC).The work was carried out according to the principles laid down in the Declaration of Helsinki and amended in 2008 by the World Medical Assembly in Seoul, Korea. Ethical approval for the study was obtained from the National Ethical Council (3166/2012/HER), and informed consent was obtained from all participants.2.2.Blood samples were collected from the antecubital vein into vacutainer tubes  with anticoagulant (1/10 volume of 0.109 M citrate). DNA was isolated from the buffy coat of citrated blood samples by QIAamp DNA Blood Mini Kit . Factor V Leiden mutation (FVL) and prothrombin (FII) 20210 G>A mutation were analyzed by standard molecular genetic methods , 32.PROC, PROCR, PROS1, and SERPINC1 genes were analyzed using the ABI PRISM SNaPshot Multiplex Kit , among which only the effect of EPCR p.Ser219Gly (rs867186) was investigated in this study. The effects of two other PROCR polymorphisms, namely, rs8119351 and rs6088735, were also taken into consideration. Using this procedure, we identified the SNPs by utilizing fluorescently labeled dideoxynucleotides (ddNTPs) during the elongation of template-specific primers in thermocycling. PCR primers for multiplex reactions (provided upon request) and the single base extension primers (SNP-specific primers) were designed to have an annealing temperature of 58°C using Primer3Plus free online software. Primers were synthesized by Integrated DNA Technologies . After PCR amplification and purification, multiplex minisequencing was performed in a 10 µl reaction volume using 3 µl purified PCR products, 2 µl SNP-specific primers, and 5 µl of SNaPshot ready reaction mix. Sequence cycling consisted of 40 cycles of denaturation at 96°C for 10 s, primer annealing at 50°C for 5 s, and primer extension at 60°C for 30 s. The amplified products were treated with 0.7 µl SAP  to prevent further binding of ddNTPs. The mixture was incubated for 60 min at 37°C followed by 15 min incubation at 75°C. The SAP-treated products (0.5 µl) were mixed with 9 µl HiDi formamide  and 0.5 µl of GeneScan 120-LIZ size standard , denatured at 95°C for 5 min, and kept on ice for at least 1 min. The fluorescently labeled fragments were separated in POP7 polymer on an ABI 3130 Genetic analyzer (Applied Biosystems). Data analyses were performed using GeneMapper Software v4.1. The detailed protocol is available upon request.Twelve SNPs, located in the Thrombophilia investigation including plasma assays for antithrombin, protein C, and protein S deficiencies were performed using Siemens reagents  on a BCS-XP automated coagulometer . Plasma was separated by centrifugation at 1,500 g for 20 min, and 500 μl aliquots were stored at −70°C until determination.2.3.PROCR rs867186 polymorphism between the cases and controls were examined by using the χ2 test. To assess the associations between PROCR rs867186 polymorphism and VTE risk, unconditional logistic regression for crude OR with 95% CI and adjusted OR with 95% CI were calculated. Continuous variables were expressed as median, minimum–maximum values, and interquartile ranges (IQR). IQR is the region between the 25th and 75th percentile. The statistical analysis for the case–control study was performed using Statistical Package for Social Sciences  software and Stata 17 . A p-value of 0.05 or less was considered to indicate statistical significance.The differences in the distribution of demographic characteristics and genotypic frequencies of 2.4.Meta-analysis was executed on high methodology quality based on the recommended list of the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) .2.4.1.PROCR.” Only those studies that investigated the association between EPCR gene polymorphism and venous thromboembolism risk were included in our meta-analysis. This current search was done through May 2023, and our search strategy had no language restrictions.A primary search was conducted to find all relevant studies through MEDLINE using the following terms of combination, including “6936A/G,” “rs867186,” “4600AG,” “thromboembolism,” “thrombosis,” “EPCR,” and “2.4.2.All the selected studies met the following criteria: (1) available studies investigate the association between EPCR gene polymorphism and venous thromboembolism risk; (2) case–control or cohort studies; (3) the studies have proper allele and/or genotype frequency information for cases and controls. The exclusion criteria were the following: (1) no properly provided information about the predictor and the outcome variable; (2) reviews, abstracts, or conference materials; (3) duplicated data.2.4.3.Two authors were responsible for the literature screening and the data extraction procedure from the included studies. The following data were extracted from all included studies: first author, publication year, sample size and the number of cases and controls, ethnicities, additional pieces of information on the study population , genotype, and allele distribution of cases and controls.2.4.4.PROCR rs867186 polymorphism and venous thromboembolism risk. We analyzed the following genetic models: AG vs. AA, GG vs. AA, GG + AG vs. AA (dominant model), GG vs. AG + AA (recessive model), and G vs. A . The MAF was considered for the G allele. To analyze between-study heterogeneity, the Cochran Q-statistic and I2-statistic were used. I2 value was used to describe the percentage of variation across studies due to heterogeneity. I2 values of 25%, 50%, and 75% show low, medium, and high between-study heterogeneity, respectively .Based on the different genetic models, the ORs and their corresponding 95% CIs were used to determine the association between ectively . Cochranogeneity , 36. Theogeneity , 38. Theogeneity . The sigweb tool  was usedweb tool . In the 3.3.1.n = 263 VTE cases and n = 320 unrelated healthy control patients were included in the study , while there was no difference in mutation frequency of prothrombin 20210G>A polymorphism between the two groups. There was no difference in the mutation frequency of FV Leiden and prothrombin 20210G > A polymorphism between cases with and without provoking factors.After informed consent, he study . Both VT factors . There wp = 0.7687, p = 0.5521, p = 0.6701, respectively). The three SNPs showed a strong LD in our study population. Upon investigating the combination of the three SNPs, the most frequent haplotype was “ACG” (frequency 0.659), followed by “ATG” (frequency 0.232), while haplotypes “GCA” (frequency 0.094) and “GCG” (frequency 0.014) were rare variants.The p.Ser219Gly polymorphism and the rs6088735 and rs8119351 in the study population met the criteria of Hardy–Weinberg equilibrium (2 or age younger than 60 years (below the 75th percentile of VTE cases), the number of wild-type and mutation carriers of rs867186 did not differ significantly. If only rs6025 (FV Leiden) or rs1799963 (FII2021G>A) wild-type or carrier individuals were taken into consideration, no significant differences in genotype frequencies of the rs867186 were demonstrated. We analyzed our study group in terms of VTE recurrence and PROCR rs867186 and we found an OR of 1.72 , which remained similar even in the adjusted model. FV Leiden and FII 20210A did not influence VTE recurrence risk in our analysis.In the whole study population, without any adjustments or subgroup analysis, no significant differences could be demonstrated among the rs867186 genotype frequencies between VTE cases and controls and between cases with and without provoking factors , 2 Subgrn = 3), median PC activity was 160%.Since the vast majority of our patients were on vitamin K antagonist therapy at the time of recruitment and no therapy modification was allowed during the study; protein C (PC) anticoagulant activity could not be interpreted in them. However, in healthy individuals, who were not on anticoagulant therapy, we demonstrated that the presence of rs867186 increased the PC activity significantly having extremely high plasma PC activity in homozygote mutants. In wild-type individuals, median PC activity was 112% (IQR24); in heterozygotes, median PC activity was 128.5% (IQR32); and in homozygotes . In the eligibility phase, four additional studies were excluded. Among them, two did not meet HWE (p = 0.07), the recessive model (GG vs. GA + AA) (p = 0.58), the dominant model (GG + GA vs. AA) (p = 0.05), and the GG vs. AA contrast model (p = 0.43). Even the funnel plot—the plot of the log-odds ratio against the reciprocal of its standard error—did not demonstrate publication bias in these genetic models. The Egger regression asymmetry test has shown a significant difference under the GA vs. AA contrast model (p = 0.04), and the funnel plot suggested a publication bias . We found no discrepancies in the meta-analysis study results obtained by STATA or MetaGenyo  stimulation. This led to higher sEPCR levels in the conditioned media of p.219Gly cells. They also demonstrated that the A3 haplotype (which includes the p.219Gly variant) is not only associated with an increased sEPCR level but is also associated with decreased PC activation  technology, genetic testing has become more and more reasonable and widely available. The whole genome or exome sequencing is still not a reality, even not necessary in thrombophilia if a well-defined panel of candidate genes is created. To save time and cost, and to avoid false-positive interpretations, the so-called “thrombophilia gene panel” should include only those genes, whose alterations have proven biological consequences. In the case of tivation . Irelandtivation .PROCR have an effect on PC levels. It was demonstrated by Athanasiadis et al. that they were responsible for 10.27% and 9.56% of the variance in PC plasma levels, respectively  in the Chinese population (n = 338 cases and n = 338 controls), the rs867186 increased the risk of VTE even in the multivariate analysis including age, sex, FV Leiden, and FII20210A  (n = 90 cases and n = 90 controls (The genotype frequencies of EPCR p.Ser219Gly polymorphism were 75% (AA), 24% (AG), and 1% (GG) in the cases, and 81% (AA), 18% (AG), and 1% (GG) in the controls in our case–control study; and carriership of the “G” allele was without a significant effect on the risk of VTE . The majority of the case–control studies conducted by others and included in our meta-analysis, however, described a significant risk-increasing effect of rs867186 in their whole population . In the small study by Chen et al. investigating pulation . Signifipulation . In a Frcontrols .n = 111 cases and n = 73 controls), the rs867186 was without a significant VTE risk-increasing effect, although the sEPCR level was elevated in “GG” homozygous individuals (n = 114 cases and n = 114 controls), no effect of this polymorphism on the risk of VTE was described   . SaposniPROCR rs867186 from the point of view of first VTE and VTE recurrence. The level of sEPCR might be modified not only by PROCR genotype but also by different genetic and environmental factors. The reason for heterogeneity in different studies investigating the risk conferred by rs867186 and sEPCR levels might be the difference among populations in terms of influencing factors. It would be, therefore, beneficial to determine the factors—genetic and environmental—which have an effect on sEPCR levels. However, it should be taken into consideration that changes in sEPCR levels may also be consequences of different medical conditions, like thrombotic diseases, rather than being a risk factor. Large prospective studies could answer for the question, whether PROCR genotype or sEPCR levels are better predictors for VTE risk.Based on these studies, the question is still open, whether to quantify sEPCR levels or simply determine the genotype of n = 5,768 VTE cases and n = 30,017 controls found a significant association between the EPCR gene p.Ser219Gly and VTE, under the dominant model , the recessive model , the GG vs. AA contrast model , and the GA vs. AA contrast model . In the previous meta-analysis conducted by Dennis et al., including a smaller number of cases and controls , the main message was similar to our present analysis  . Here, we confirmed the results of these two previous meta-analyses. Moreover, we validated the novel, online free-access MetaGenyo Statistical Analysis System software by a reproducibility study. Based on our findings, this online platform is acceptable for meta-analysis in case of genetic epidemiology studies.Due to heterogeneity in the results of the individual studies, we performed a meta-analysis in order to clarify the effect of rs867186 on the risk of VTE. Our meta-analysis of 11–1.33) . In the PROCR is currently not included in the panel of the Thrombogenomics platform (https://www.isth.org/page/GinTh_GeneLists). Including PROCR in the gene panels may help collect more experience of the role of its variants in VTE not only from the point of view of absolute VTE risk but also from the point of view of VTE recurrence and risk modifying effect in individuals with PC deficiency.The risk conferred by the rs867186 is significantly increased but mild in all meta-analyses, including ours. However, in the concept of personalized medicine including personalized risk assessment, every factor might have an impact. Collection as many pieces of information including environmental and genetics as it is possible may serve as a basis of the personalized risk management of VTE. The availability of high-throughput genetic methods, like next-generation sequencing technology, supports the acquisition of large-scale genetic data from the patients. Upon performing gene panel sequencing, the simultaneous investigation of candidate genes can be executed. The platform , even miPROCR polymorphisms on the PC levels and the risk of VTE, a study directly recruiting PC-deficient individuals would be beneficial. In a previous study, Fidalgo et al. investigated Portuguese PC-deficient families and suggested that rs867186 explained differences in PC plasma levels in individuals with the same PROC genotype (PROCR rs867186 (There were only two cases detected with PC deficiency in our study group during the recruitment period. The first patient had the c.811C > T (p.Arg271Trp) and the second carried the c.169C > T (p.Arg57Trp) mutation both in heterozygous forms. These mutations are listed in various databases as pathogenic/likely pathogenic variants and associated with PC deficiency and thrombotic phenotype. Both individuals carried the rs867186 in heterozygous form. The first patient had one thrombotic episode at the age of 29 years; no recurrence has been registered until now. The second had venous thrombosis first at the age of 29 years and one recurrent event at the age of 33 years while on oral anticoagulant therapy. Upon including these two PC-deficient patients in the statistical analysis, no modifications in the results were observed. To study the modifying effect of genotype , and verrs867186 . Homozygrs867186 . These sThe strength of the current meta-analysis is that it updated the previous results with a large-scale study  and addeOur study had limitations that should be acknowledged. Our case–control study might have limited generalizability through the use of strict exclusion criteria regarding the selection of the control group. Therefore, we are not sure to what extent the absence of chronic diseases and arterial thrombosis might influence the results on the risk of EPCR polymorphism on VTE.Our meta-analysis detected potential publication bias under the GA vs. AA contrast model. Furthermore, we must consider the potential selection bias and possible misclassification of the genotype and phenotype results regarding the individual studies. We were not able to perform any further subgroup analysis because of the small group number of similar ethnicities. On the other hand, due to the non-standardized data availability of the individual studies included in our meta-analysis, we could also not create a dedicated analysis by other factors such as age, gender, smoking, alcohol consumption, and other environmental or lifestyle factors.


Urolithiasis is one of the most prevalent diseases worldwide. Its prevalence is rising, both in developing and developed countries. It is known that genetic factors play big roles in the development of urolithiasis. One of the suspected factors is gene polymorphism. This study aims to find an accurate estimate of the association between genetic polymorphism and the risk of recurrent urolithiasis.A systematic review and meta-analysis were performed on 12 studies from 3 databases that investigated gene polymorphism as an risk factor of urolithiasis. The review was done using Review Manager® version 5.3.Insignificant heterogenicity was found in this study. Populations from Asia and the Middle East are more likely to experience recurrent urolithiasis. Additionally, variation in the VDR and urokinase genes, particularly in the Asian population, increases the risk of developing recurrent urolithiasis.Gene polymorphisms have significant roles in the development of urolithiasis, especially in the Middle Eastern region. Approxieroscopy . Howevereroscopy . The receroscopy . The higeroscopy .+ antiporter (e.g. CLCN5), β-glucuronidase (e.g. KLOTHO) and bicarbonate exchanger (e.g. soluble adenylate cyclase) [Researchers, through numerous epidemiological studies, have far known that the occurrence of urolithiasis is hereditary related . Numeroucyclase) . These gcyclase) .Although various genes responsible for urolithiasis have been mapped extensively, the risk of urolithiasis remains unknown let alone how urolithiasis recurrence could occur . ResearcDue to the huge variety of genetic polymorphisms and their small prevalence in the population, the journey to locate these genetic polymorphisms as the risk of recurrent urolithiasis can be challenging. Therefore, this systematic review and meta-analysis are performed to obtain eligible studies to provide a more accurate estimate of the association between genetic polymorphism and the risk of recurrent urolithiasis.The study was conducted through a comprehensive search from Medline/PubMed, Scopus, and Cochrane electronic databases for studies published between January 2000 and June 2023. We used the search terms: ‘urolithiasis’, ‘nephrolithiasis’, ‘recurrent’, ‘calculi’, ‘stone former’, ‘bladder stone’, ‘kidney stone’, and ‘polymorphism’. The list of references in the included study was manually searched for additional studies.Two investigators (NR & SS) independently performed the study selection. The studies were selected manually for duplication. Duplication-free articles were further examined using predetermined inclusion and exclusion criteria from the titles and abstracts of the articles. The inclusion criteria were considered eligible when the studies  include adults (aged more than 18 years) who had at least more than one case of stone formation along the urinary tract condition. Moreover, the odds ratio (OR) estimate and 95% confidence interval (CI) with a significant p-value (p < 0.05) should be reported or at the very least data to calculate the OR is provided.Studies were excluded if they were case reports or studies conducted on other than humans. Studies that did not discuss recurrent urolithiasis or polymorphisms that did not relate to recurrent urolithiasis will also be excluded. No other restrictions were being imposed. Any differences in opinions were discussed and agreement was reached by consensus.The manuscripts, after undergoing intense selection, were then reviewed by two investigators (NR & SS) independently. The information collected from each study includes the first author’s name, the year of publication, the location, the sample size, the age, the polymorphic gene, and the alleles.The risk of bias was assessed by two authors (NR & SS) independently. Bias assessment was done using Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for observational studies Table . The bia2) test [2 value of ≥ 50% was assigned as high heterogeneity, meanwhile, values < 50% were assigned as low heterogeneity. High heterogeneity would be analyzed using random effect, meanwhile, low heterogeneity would be analyzed with fixed effect [All analysis was performed using Review Manager version 5.3. Meta-analysis was performed when there were at least two similar genetic studies. The strength of association between the polymorphisms in subjects was measured using OR and 95% CI. The OR was calculated for the allelic frequency of the SNP. The statistical significance of OR was measured by using the p-value from the Z test. This model was used to compare the allelic variation within SNP to measure the ratio of recurrence in individuals with certain alleles. The heterogeneity between studies was measured with the Chi-square test Cochrane Q-test and inconsistency index (I2) test . The I2 d effect . P valued effect .There were a total of 322 articles initially identified by using the search terms and methodology described above. After reviewing the title and abstract of each article by using the inclusion and exclusion criteria, 293 articles were excluded and 29 articles were selected. All these twenty-nine studies were further assessed and 17 articles were considered irrelevant. Finally, there were only 12 case-control studies that met our criteria and were included in the meta-analysis. The details of the study selection process are depicted in Fig. The twelve selected studies contained 1773 recurrent urolithiasis patients (mean age range ± standard deviation: 40.2 ± 12.0 to 53.87 ± 9.83) and 1946 non-stone former participants (mean age range ± standard deviation: 38.4 ± 6.9 to 53.2 ± 9.9). Three studies were conducted in Italy, two were in the Middle East (Iran and Turkey), and seven were in Eastern Asia (Taiwan and Japan). There were three studies on vitamin D receptor (VDR), two on urokinase, one on calcitonin receptor, one on a calcium-sensing receptor, one on interleukin-18, one on interleukin-1Ra, one on melatonin receptor 1 A, one on ORAI 1, one on osteopontin, and one on TAP2-2. STROBE quality assessment ranging from 10.73 to 17.7. The characteristics of each study are presented in Table Some of the studies discussed multiple SNPs within the polymorphic gene. We identified these SNPs along with their particular alleles. Each genotype consists of 2 alleles which we categorized into “allele 1” and “allele 2”. The categorization was used because “allele 2” was deemed to be the allele that caused recurrent urolithiasis. It is evidenced that the OR of most allele 2 showed significantly higher prevalence within the recurrent urolithiasis population compared to 1(p < 0.05). The summary of the studies is shown in Table 2 = 85%, p < 0.00001). Therefore we used random effect for the analysis of all genetic studies. Meta-analysis of genetic effect on recurrent urolithiasis involved 12 studies, among 5019 allele frequency in recurrent stone formers and 5446 allele frequency in controls. We found 14 SNPs within 10 genes had a significant association with recurrent urolithiasis . In the Italian population, there was no significant association between genetic polymorphism and recurrent urolithiasis  with high heterogeneity . Meanwhile, in the Middle East population, there was a significant association between genetic polymorphism and recurrent urolithiasis  with no significant decrease of heterogeneity . We found a significant difference between each population subgroup .As shown in Fig. The meta-analysis of the VDR gene involving 5 studies with a total of 1672 allele frequency in recurrent stone formers and 1286 allele frequency in controls, also showed a significant association with recurrent urolithiasis . There’s no publication bias in the included studies.Two studies were included for the polymorphism of the urokinase gene. There were a total of 462 recurrent stone formers and 544 controls. We found a strong association between polymorphism of the urokinase gene and recurrent urolithiasis . Therefore, subgroup analysis was performed based on the populations . We found that genetic polymorphism in the East Asian population showed the highest risk of developing recurrent urolithiasis with an increased risk of 2.84 times with no significant heterogeneity (I2 = 49%), followed by the Middle East population with an increased risk of 2.25 times also with no significant heterogeneity (I2 = 29%). However, the risk of developing recurrent urolithiasis in the Italian population is little or none with high heterogeneity (I2 = 79%). These findings were probably caused by the difference in genetic polymorphism within the population. The difference between the Asian population (East Asia and the Middle East) with the Italian might be due to the number of allele frequencies included, especially in the Middle East population (708 cases and 1096 controls). There might be some other causes of differences within ethnicity such as other factors affecting the genetic polymorphism. Therefore, an epidemiological study might be needed to investigate probable factors.In this meta-analysis, we aim to find the correlation between various genetic polymorphisms with recurrent urolithiasis. To the best of our knowledge, this is the first meta-analysis to investigate the association between recurrent urolithiasis risk and multiple gene polymorphisms. Overall, individual bearing the allele correlated with recurrent urolithiasis has an increased risk by 1.85 times to develop recurrent urolithiasis. There was also high heterogeneity within the included studies (I2 = 36%). The SNPs for VDR genes included in this study were BsmI, ApaI, and TaqI. All of these SNPs are located at the 3’ UTR region of VDR gene mRNA and correlate with increased stability and higher vitamin D activity [ApaI and TaqI polymorphisms are known to be associated with urolithiasis [TaqI, ApaI and BsmI SNPs in the Asia population are more prone to develop urolithiasis [TaqI polymorphism in Asians increased the risk of urolithiasis, but not in Caucasians [TaqI polymorphism to be closely related to Asians, a recent meta-analysis opposed the previous claims and reported no association between TaqI, ApaI, and BsmI with urolithiasis in the Asian population [When considering the potential impact of various SNPs, we performed analyses on VDR and urokinase gene polymorphisms. Our result showed that VDR gene polymorphism increases the risk of recurrent urolithiasis by 1.22 times with no significant heterogeneity  with no significant heterogeneity (I2 = 0%) than VDR gene polymorphism. Urokinase prevents the breakdown of the protein matrix within the stone and retains the formation of the stone [ApaLI is one of the SNP located at this site [ApaLI is still limited and all studies available are located in Asia. Preceding our study, a meta-analysis confirmed that urokinase 3’UTR T/C polymorphism is linked with urolithiasis in the Asian population, thereby confirming our findings that urokinase gene polymorphism can cause both single and recurring urolithiasis [In the urokinase gene subanalysis, only a single SNP, he stone . Urokinahe stone . Of theshe stone . ApaLI ihis site . Neverthithiasis .Urolithiasis is a multifactorial disease and gene polymorphism is one of the factors . The othWe should consider the effect of heterogeneity and publication bias within our analysis. Our overall genetic polymorphism studies showed significant heterogeneity, which we suspect was caused by the difference in population or genetic polymorphism. After the subgroup analysis of the population, we found no significant heterogeneity in the East Asian population and the Middle East population, and also after performing analysis based on the genetic polymorphism (VDR and urokinase) the heterogeneity effectively disappeared. We can conclude that most of the heterogeneity was caused by population and genetic polymorphism differences. We found publication bias in the overall studies with could also impact our result of finding, but analysis based on vitamin D receptor and urokinase gene didn’t show any publication bias.There were some limitations within our study. The number of studies included in this meta-analysis was considerably small. A lot of relevant published/unpublished studies might be missed out. The studies we included only consisted of East Asian, Italian, and Middle East populations which might not represent all general populations. We also couldn’t analyze the gene-gene interaction and gene-environment interaction due to a lack of information within the included studies. Other risk factors like urinary tract infection, hypercalciuria, or microscopic hematuria also couldn’t be analyzed because most of the studies didn’t provide any information regarding the case and control with associated risk factors. Finally, we only managed to perform an analysis of VDR and urokinase gene polymorphism on recurrent urolithiasis due to a lack of studies regarding other genetic polymorphism and recurrent urolithiasis.In conclusion, Asia and Middle Eastern populations have a higher risk of developing recurrent urolithiasis. Additionally, both VDR and urokinase gene polymorphism contributes to the susceptibility of recurrent urolithiasis particularly for the Asian population in the latter. Studies with a variety of population characteristics are recommended to be performed to further support our results.


This meta‐analysis systematically reviewed and identified the effects of WeChat‐based continuous care (WCC) interventions on various outcomes in cancer patients.Systematic review and meta‐analysis.Fail‐safe and Begg's tests were performed to evaluate publication bias, and sensitivity analysis was performed to evaluate the robustness of the meta‐analysis results.In this study, outcome measures included somatic function, anxiety, depression, social function, and cognitive function. The standardized mean differences and 95% CIs of pooled effect sizes were calculated using fixed‐ and random‐effects models. NThe meta‐analysis included 18 RCTs of moderate quality. WCC interventions significantly improved somatic function, depression, anxiety, social function, and cognitive function in cancer patients. There was no significant publication bias, and the sensitivity analysis indicated robust results.WCC interventions improved depression, anxiety, social function, and cognitive function in cancer patients. The search date ended on Dec 31, 2020.2.2A study was included in the present analysis if (a) the participants were cancer patients; (b) the intervention involved WCC; (c) the outcomes included somatic function, anxiety, depression, social function, or cognitive function; and (d) the study was an RCT. If the study included multiple assessment time points, data from the post‐intervention time point were chosen for the analysis. A study was excluded from the present study if (a) the articles received a poor quality evaluation  or (b) the data for the study were incomplete or unavailable.Two researchers independently searched and screened the literature in strict accordance with the inclusion and exclusion criteria and then extracted and cross‐checked the data, which included author, date of publication, country, sample size, age, gender, interventions, and outcome indicators of the included subjects. A third researcher was consulted to resolve any disagreement in the screening results.2.3The PEDro scale . The group mean deviation and the pooled SD were calculated . When 2 or more intervention groups were included, the ES for only the most active group was calculated. Given that these variables are continuous outcome measures with different units of measurement, standardized mean differences (SMDs) were estimated using fixed‐ or random‐effects models with 95% confidence intervals (CIs).2.5χ2 and I2. I2 is the proportion of total variation observed between studies that are attributable to differences between studies rather than sampling error (chance). When I2 > 50%, the studies in the meta‐analysis were considered to be heterogeneous, and a random‐effects model was used .The Begg test and fail‐safe number (NFS) were used to determine whether there was publication bias .33.1A total of 418 articles were retrieved from the 4 electronic databases . Of these, 277 duplicate articles were excluded, 79 articles were excluded because they were not relevant to our study, and 44 articles were excluded because they did not meet the inclusion criteria. Thus, 18 RCTs were included in this study, and there were no significant differences between the general information of patients in the experimental and control groups in each study. A total of 1622 cancer patients were included in the 18 studies, including 815 in the experimental group and 807 in the control group. The article selection process is described in the flow diagram  mixed interventions   using a random‐effects model, suggesting that WCC improves somatic functioning in cancer patients. Figure Nine studies measured the somatic function of cancer patients Guolian, . Of the 3.3.2I2 = 63.2%, and the SMD of the combined ES was −1.104 , suggesting that WCC can improve depression symptoms in cancer patients. Figure Eight studies measured depressive symptoms in cancer patients , suggesting that WCC could improve the anxiety symptoms of cancer patients. Figure Nine studies measured anxiety symptoms in cancer patients , suggesting that WCC can improve the social competence of cancer patients. Figure Eleven studies measured the social function of cancer patients Guolian, . Of the 3.3.5I2 = 49.8%, and the SMD of the combined ES using a fixed‐effects model was 1.038 , suggesting that WCC can effectively improve the cognitive ability of cancer patients. Figure Four studies measured the cognitive function of cancer patients  or NFS values (NFail‐safe > criterion) for other outcome indicators. The results of the heterogeneity tests and publication bias assessments are shown in Table In the 5 meta‐analyses, a large publication bias was found with the Begg test for the somatic function outcome, with the exception of the outcome indicator of physical function, which was found to be robust when recalculated without the safety factor. No significant publication bias was found with the Begg test (3.6p < 0.05). Regarding physical function, SMD1 > SMD3 > SMD2 among the three interventions, which indicated that the mixed interventions resulted in better improvements in physical function in cancer patients. Regarding depression, SMD1 > SMD3 > SMD2 among the three interventions, which indicated that the mixed interventions resulted in better improvements in depression in cancer patients. Regarding anxiety, among the three interventions, SMD3 > SMD1 > SMD2, which indicated that the mixed interventions resulted in better improvements in anxiety in cancer patients. Regarding social function, among the three interventions, SMD1 > SMD3 > SMD2, which indicated that the mixed interventions resulted in better improvements in the social function of cancer patients. Regarding cognitive function, among the three interventions, SMD3 > SMD1 > SMD2, which indicated that the mixed interventions resulted in better improvements in cognitive function in patients with cancer.Subgroup meta‐analyses were performed to better understand the effects of different interventions within the WCC interventions for cancer patients Table . In a fi4The reliability of the results of this meta‐analysis was closely related to the quality of the literature included in the original study. Of the 18 studies, 12 studies . Although caregivers were able to remind patients to take their medications through the WeChat platform, clarify the side effects of relevant medications, and reinforce their compliance behaviours .This review was not registered.Appendix S1Click here for additional data file.


Current studies indicate a contradictory relationship between decreased mortality risks of spontaneous intracerebral hemorrhage (sICH) and elevated low-density lipoprotein cholesterol (LDL-C) levels. Thus, this meta-analysis was designed to examine the involvement of high LDL-C levels in a lower mortality risk of sICH patients.PubMed, Cochrane, and Embase databases were searched up to the date of August 3rd, 2022. Pooled odds ratio (OR) with a 95% confidence interval (CI) was estimated for the higher vs. lower serum LDL-C level groups. Subgroup and sensitivity analyses were also carried out. Egger's test was applied to detect any potential publication bias.2 = 47.8%); however, the LDL-C level change wasn't significantly associated with in-hospital mortality risks  among sICH subjects. All studies included were classified as high-quality investigations.Of 629 citations reviewed, 8 eligible cohort studies involving 83,013 patients were enrolled in this meta-analysis. Compared with lower serum LDL-C levels containing patients, higher serum LDL-C patients exhibited significantly decreased risks of 3-month mortality (OR: 0.51; 95%CI: 0.33–0.78; IThis meta-analysis suggests a higher LDL-C level may decrease the mortality risk in sICH patients. LDL-C level increase is inversely associated with the 3-month mortality risks in these patients but not significantly correlated with the in-hospital mortality risks. Further well-designed prospective studies with extended follow-up periods are needed to confirm these findings and explore underlying cross-talks.https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022318318, identifier: PROSPERO 2022 CRD42022318318. Spontaneous intracerebral hemorrhage (sICH) remains the most devastating form of stroke with high morbidity and mortality rates, accounting for over 10% of all stroke cases, and is estimated to affect nearly 2 million people worldwide each year . DespiteLow-density lipoproteins (LDLs) are the primary transporters of cholesterol across cells and tissues, contributing to atherosclerotic lesions of the blood vessel. Studies have consistently indicated that a high LDL-C level can elevate the risks of ischemic stroke and coronary heart dysfunctions, and the causal association between these two factors is well recognized –9. InterA systematic literature search was performed in the PubMed, Cochrane Library, and EMBASE databases for studies published up to August 3, 2022, by the pre-established search strategy, using the keywords “cerebral hemorrhage,” “ICH,” “intracerebral hemorrhage,” “low-density lipoprotein cholesterol,” and “LDL-C.” The searches were conducted without language restrictions and adapted for each electronic database. The specific terms used for searching in each database, along with the number of records retrieved, are detailed in Eligible studies satisfied the following selection criteria: (1) either retrospective or prospective cohort studies in nature; (2) enrolled sICH patients who were diagnostically confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) examinations; (3) assessed the correlation between baseline serum LDL-C levels and the mortality risks in sICH patients, and (4) provided with univariate or multivariate-adjusted effect estimates [odds ratio (OR) with corresponding 95% confidence interval (CI)] for the association between LDL-C levels and sICH risks of mortality. The studies were excluded if: (1) these were either reviews, letters to the editor, comments, or meeting abstracts; (2) they included ICH participants with primary traumatic injuries; and (3) these were either duplicate publications or multiple articles based on the same cohort studies with overlapping data. In this case, the one with the most comprehensive results, or the largest sample size, was included.Two investigators (JL and GL) independently searched and identified eligible literature for extracting relevant data for the meta-analysis, per the pre-determined selection criteria and data extraction strategies concerning the PRISMA recommendations (#PROSPERO CRD42022318318) as illustrated in The Newcastle-Ottawa Scale (NOS) rating was applied to assess the methodological qualities of eligible articles . The scaQ-test and I2 index were used to determine the heterogeneity across studies  and design . The sensitivity analysis was conducted by sequential dropping of individual studies to measure the contribution of the respective study to the overall risk assessment. Egger's test was employed to determine any potential publication bias of enrolled studies  was executed for meta-analyses. The Cochran's  studies . Results studies . Stata vThe results of the literature search and the literature screening process are shown in Most studies were rated with NOS scores ranging between 7 and 9 stars , with siP = 0.647) in sICH patients, with substantial heterogeneity across studies .P = 0.002) and no statistically significant heterogeneity  across studies. In summary, a higher serum LDL-C level may have a beneficial effect on decreasing the risk of death in sICH patients.Moreover, five studies including 6,122 patients showed that alteration in LDL-C levels and the risk of 3-month mortality had a strong association, with a pooled risk estimate of 0.51 . However, the pooled results for the Western subgroup were significant , with almost no heterogeneity among the studies   were not statistically significant and highly heterogeneous (= 0.466) .P > 0.05)  .Overall, the study design variation did not have any effects on the LDL-C level's association with the in-hospital mortality risks of sICH patients, unlike the association with the 3-month mortality risk. Interestingly, the region of the study conducted seemed to influence the association of LDL-C level modulation with either in-hospital or 3-month mortality risk in sICH individuals. In other words, a higher LDL-C level may be associated with decreased in-hospital mortality risks in the West and 3-month mortality risks in China.P > 0.05). Likewise, the leave-out one study sensitivity analysis of 3-month mortality also indicated a significant (P < 0.05) stable pooled OR (95%CI), ranging from 0.47  to 0.62 .As shown in P = 0.724) and 3-month mortality (P = 0.100) risks for analyzed studies  might mask the exact association of altered LDL-C levels with in-hospital mortality risks . To overcome that, we conducted subgroup and sensitivity analyses, revealing no considerable heterogeneity without any adjustment for significance thresholds. The observed heterogeneity for in-hospital mortality risk might stem, in part, from a broad range of confounding factors that different studies had adjusted for at the cost of power reduction. Besides, the heterogeneity might correlate with participants' characteristics , as well as genetic polymorphisms   –31. AlsoThe effect of serum LDL-C level on ICH mortality risk may vary depending on the follow-up duration, which could partially explain the observed association of LDL-C level variation with the 3-month mortality risk but not in-hospital mortality, which could be related to severe ICH-associated higher mortality than LDL-C-induced ICH risk in the early stage. Hence, under aggravated ICH conditions, the correlation between mortality risks and LDL-C levels may not be crucially important , 32. It'Above all, our findings indicated that sICH patients having lower serum LDL-C levels could be at higher mortality risks. Our study supported the potential of LDL-C level alteration as an independent predictor for 3-month mortality risks in sICH patients and suggested outlines for risk stratification and clinical outcomes in ICH in designing patient-specific therapy.Several different explanations regarding underlying mechanisms may be considered in this context.First, LDL-C plays key functions in many physiological processes, such as maintaining vessel wall integrity. Reportedly, most healthy individuals are born with LDL-C levels ranging from 40 to 60 mg/dL . While lSecond, the inclusion of observational studies prevented establishing a causal relationship in this meta-analysis. An excessively low LDL-C level can reversibly increase the mortality risk , but it Although conventionally lowering lipid levels is considered the best to control atherosclerotic cardiovascular diseases , the effWe found that the elevated level of LDL-C exhibits an inverse relationship with the in-hospital and 3-month mortality risks, respectively, among post-ICH patients in western countries and China. To the best of our knowledge, this is the first meta-analysis reporting an assessment of LDL-C level variation in relation to sICH mortality risk. The strengths of the study include its extensive literature search, stringent criteria, and thorough scrutinization of included studies. Despite the limited number of articles, the sample size was considerably large, and the accuracy of the meta-analysis results was relatively satisfactory. Moreover, the methodological quality control for included reports matched the international standard. Despite the influence of confounding factors, like pre-treatment medications, ICH volumes, admission NIHSS scores, and hypertension, all studies produced highly objective and reasonable observations after multiple factor adjustments. Furthermore, the sensitivity analyses and Egger's test suggested the good reproducibility and high credibility of the pooled results across the included studies. Finally, we strictly adhered to the PRISMA recommendations for study screening, data extraction, quality control checking, and analyses to reduce recall bias, especially for observational studies.Yet, we note that this review does have some limitations. First, being a study-level meta-analysis, this study could not consider methodological variations in analyzed articles. It wasn't possible to adopt a uniform adjustment of variables for all studies. Also, a standardized analysis of the age and sex of the participants could not be performed to identify potential confounding factors for heterogeneity. An individual-level meta-analysis will be appropriate to evaluate the relationship between ICH mortality risks and low LDL-C levels in terms of demographics, existing medications, and comorbidities.Second, in all cases, only one-time measured post-ICH serum LDL-C level values were included for analysis, which might introduce classification bias. There were no pre-ICH onset data for these patients, and possible variations in LDL-C levels during the hospital stay and follow-up periods were not considered. It remains unclear whether an acute sICH condition induces LDL-C level alteration and/or whether the reverse phenomenon is the actual culprit in elevating the mortality risk. Time-average serum LDL-C level analysis can be useful to verify the association of pathological LDL-C levels with higher mortality risks.Third, different cutoffs for LDL-C levels were used in the prediction of mortality risks across studies, and the methodological heterogeneity might lead to the discrepancy in results, which prevented us from determining the optimal value of LDL-C level in better predicting ICH survival. And the enrolled studies were ineligible for the dose-response analysis because they lacked the necessary data . Additionally, abnormally low LDL-C levels might have underpowered our results. We expect future studies to analyze clinically uncommon subsets of patients critically for better understanding.Fourth, all eligible studies involved cohort analyses, which had a higher susceptibility to bias from confounding factors than randomized controlled trials. Residual confounding biases are sometimes unavoidable due to the omission of or insufficiently measured variables. Some important confounding factors related to mortality risk should be adjusted as comprehensively and consistently as possible in the statistical model, while the severity of ICH (GCS and NIHSS scores), hypertension, pre-medications, divergent inciting causes of ICH , complete neuroimaging data , and time from ICH occurrence to cranial CT scan were not fully captured in several of these studies. Inadequate adjustment may have resulted in an overestimation of the risk estimate.Fifth, most participants were Han Chinese and Caucasians, which limited the generalizability of our observations to the general population, but it might have some reference values. Caution should be paid to extrapolating these results to other ethnic groups. The association and optimal range of LDL-C level change may differ across ethnic groups due to their varying baseline LDL-C levels, environments, and individual risk factors.In conclusion, an increase in LDL-C level is inversely associated with 3-month mortality risks in sICH patients but not significantly correlated with in-hospital mortality risks. Serum LDL-C level can be a potential independent biomarker of mortality risk evaluation in sICH patients and may be helpful in early decision-making in clinical practices and contribute to identifying those at higher risks of mortality. Nevertheless, the subgroup analyses revealed inconsistencies with the original pooled results, indicating further well-designed studies with stringent quality control and larger sample sizes are recommended to validate the stability and extrapolation of these results as well as to determine an appropriate LDL-C range.The original contributions presented in the study are included in the article/XS and JL were involved in the conception and design of the study. JL, GL, and YZ contributed to the literature screening, data acquisition, statistical analysis, and interpretation. JL and GC wrote the manuscript, which was revised, and approved by all the authors for publication. XS and JZ participated in the review, editing, and supervision of the article. All authors contributed to the study and approved the submitted manuscript.


The aim of this study is to determine the predictors of mortality in patients with systemic sclerosis-induced pulmonary arterial hypertension (SSc-PAH). This systematic review and meta-analysis were carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Statement guidelines. We searched the PubMed, EMBASE, and Web of Science databases from January 2010 to April 2023 using the following keywords: "systemic sclerosis," "pulmonary arterial hypertension," "death," and "predictors," along with medical subject headings (MeSH), to identify relevant studies. A total of eight studies with a total of 530 patients were included in the present systematic review and meta-analysis. The pooled one-year, three-year, and five-year survival was 90% (95% CI: 86-93%), 66% (95% CI: 59-72%), and 44% (95% CI: 23-65%), respectively. Factors associated with mortality in SSc-PAH included age , male gender , pericardial effusion , cardiac index , six-minute walking distance , pulmonary arterial pressure (PAP) , and New York Heart Association (NYHA) classification . The findings of this study have important clinical implications. Assessing and managing the identified predictors, such as age, gender, pericardial effusion, PAP, cardiac index, and NYHA class, could help identify individuals at higher risk of mortality and guide treatment strategies. Systemic sclerosis (SSc) is a chronic autoimmune disease that affects multiple systems in the body. It is characterized by abnormalities in blood vessels, tissue scarring (fibrosis), and immune system activation. SSc can be classified into two types based on the degree of skin involvement: limited cutaneous SSc or diffuse cutaneous SSc . SSc preIndividuals with SSc-related PAH (SSc-PAH) generally have a less favorable prognosis compared to those with idiopathic PAH (iPAH) -5. PAH iAlthough there have been advancements in therapies that have improved survival rates, individuals with SSc-PAH continue to have lower survival rates compared to those with iPAH and connective tissue disease-associated PAH . The oneSeveral studies have assessed the risk factors affecting mortality in SSc-PAH. It is vital to identify such factors to ensure optimal care and facilitate appropriate monitoring. However, there is no consensus regarding the factors affecting mortality in SSc-PAH. Therefore, a systematic review and meta-analysis are needed to understand the different factors associated with mortality in SSc-PAH. The aim of this systematic review and meta-analysis is to determine the predictors of mortality in patients with SSc-PAH.MethodologyThis systematic review and meta-analysis were carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Statement guidelines.Search Strategy and Study SelectionWe searched the PubMed, EMBASE, and Web of Science databases from January 2010 to April 2023 using the following keywords along with their synonyms: "systemic sclerosis," "pulmonary arterial hypertension," "death," and "predictors," along with medical subject headings (MeSH), to identify relevant studies. Additionally, the reference lists of all included articles were manually searched to identify additional relevant records. All records were manually screened independently by two authors. Initially, screening was done using titles and abstracts. Full texts of all eligible records were obtained, and a detailed assessment was conducted based on pre-defined inclusion and exclusion criteria. Studies were included if they fulfilled the following criteria: (a) the study included individuals with a diagnosis of SSc-associated PAH; (b) assessed predictors of mortality; and (c) included adult patients. We excluded reviews, case reports, case series, and studies published in languages other than English. Any disagreements in the study search and selection process were resolved through discussion.Data Extraction and Statistical AnalysisData from the included studies were independently extracted by two authors using a pre-designed standardized data collection form. The collected data from the included studies included author name, year of publication, region, sample size, and data on factors . To assess the relationship of each factor associated with mortality in patients with SSc-associated PAH, hazard ratios (HR) were calculated along with 95% confidence intervals (CI). A p-value less than 0.05 was considered significant. Heterogeneity was determined using I-square statistics, with an I-square value of more than 50% considered significant for heterogeneity, and a random-effects model was used. Otherwise, a fixed-effect model was used. Data analysis was performed using RevMan Version 5.4.1  and STATA Version 16.0ResultsOur search of online databases from January 2010 to April 2023 retrieved 788 citations. After the abstracts and titles were evaluated, 737 studies did not fulfill the inclusion criteria. The full text of the remaining 21 studies was evaluated. Finally, eight studies with a total of 530 patients were included in the present systematic review and meta-analysis. Figure Predictors of mortalityAgeFive studies were included in the pooled analysis of the effect of age on mortality. The pooled analysis showed that an increase in age is associated with a greater risk of mortality , as shown in Figure GenderA total of six studies were included in the analysis, examining the risk of mortality as an outcome in relation to gender as the independent factor. When compared to the reference category of female, the HR for mortality in the male gender was 1.67 (95% CI: 1.15-2.44) with a statistically significant p-value of 0.008 as shown in Figure Pericardial EffusionThe risk of mortality was assessed as the outcome variable, with pericardial effusion serving as the independent factor. The reference category for comparison was no pericardial effusion. The pooled analysis of four studies revealed that the presence of pericardial effusion was associated with a higher risk of mortality, as indicated by an HR of 1.73 (95% CI: 1.21-2.48). This association was statistically significant, with a p-value of 0.003 as shown in Figure Cardiac IndexThe risk of mortality was examined as the outcome variable, with the cardiac index as the independent factor. The cardiac index was treated as a continuous variable in the analysis. The pooled results from four studies indicated that a higher cardiac index was associated with a significantly reduced risk of mortality, with an HR of 0.51 (95% CI: 0.38-0.69). The association was highly significant, as evidenced by a p-value of 0.0001 as shown in Figure Six-Minute Walking DistanceThe risk of mortality was assessed as the outcome, with the six-minute walking distance considered as the independent factor. The six-minute walking distance was treated as a continuous variable in the analysis. The pooled results from four studies showed that there was a slight, but statistically significant, association between the six-minute walking distance and the risk of mortality. The HR was 0.98 (95% CI: 0.97-1.00), indicating a slightly reduced risk of mortality with a higher walking distance. The p-value was 0.04, suggesting statistical significance as shown in Figure Pulmonary Arterial PressureThe pooled analysis of six studies revealed that an increase in pulmonary arterial pressure (PAP) was associated with a slightly higher risk of mortality, with an HR of 1.03 (95% CI: 1.02-1.04). The association was statistically significant, as indicated by a p-value of 0.01 as shown in Figure Pulmonary Vascular ResistanceThe pooled analysis of four studies indicated a slight increase in the risk of mortality with higher pulmonary vascular resistance (PVR) values, as reflected by an HR of 1.05 (95% CI: 0.99-1.11). However, the association did not reach statistical significance, as the p-value was 0.11 as shown in Figure New York Heart Association ClassificationThe pooled analysis of four studies revealed a strong association between higher New York Heart Association (NYHA) classification and an elevated risk of mortality. The HR was 3.26 (95% CI: 1.76-6.03), indicating a substantially increased risk. The association was highly significant, as evidenced by a p-value of 0.0002 as shown in Figure DiscussionIn this meta-analysis, we explored the mortality rate in SSc-PAH and the associated predictors. The pooled one-year, three-year, and five-year survival rates were 90% (95% CI: 86-93%), 66% (95% CI: 59-72%), and 44% (95% CI: 23-65%), respectively.Age was found to be a significant predictor of mortality in the present meta-analysis. Increased age is associated with a higher risk of mortality in patients with SSc-associated pulmonary hypertension (PH). The pooled analysis also reported a higher risk of death in males compared to women. Chung et al.  reportedIn the study conducted by Lefevre et al. , a correThe meta-analysis also revealed that a higher cardiac index, which measures the efficiency of the heart's pumping function, is associated with a reduced risk of mortality in these patients. This suggests that maintaining a higher cardiac index can potentially prevent death in individuals with SSc-PAH. Studies have shown that a higher cardiac index is associated with better survival outcomes in SSc-PAH patients. For instance, in a systematic review and meta-analysis by Hachulla et al., a higher cardiac index was found to be a positive prognostic factor in SSc-PAH patients . By mainOur study revealed that the six-minute walk distance also served as a factor, contrary to expectations. Traditionally, this test is considered inadequate for evaluating the severity of PH in patients with SSc -24. The The findings suggest that patients with pericardial effusion are at an elevated risk of mortality due to systemic-induced PAH. This implies that the presence of pericardial effusion may be associated with more severe forms of PAH in SSc patients, leading to worse outcomes and an increased risk of death. The exact mechanisms underlying this association are not fully understood and may require further research. However, it is plausible that pericardial effusion contributes to the development or progression of PAH through various factors such as increased right-sided heart pressures, impaired diastolic function, or other related pathophysiological processes .The current meta-analysis showed an association between higher NYHA classes and the risk of death in SSc-PAH. The NYHA class is a grading system used to assess the functional capacity and symptom severity in patients with heart failure or PAH. The increased risk of death in patients with a higher NYHA class may be attributed to factors such as more advanced disease progression, greater hemodynamic impairment, reduced functional capacity, and increased susceptibility to complications. Additionally, patients with higher NYHA classes often require more intensive treatment and may have poorer responses to therapy .Study LimitationsOur meta-analysis has certain limitations. Some factors were evaluated in less number of studies, therefore, weakening the role of meta-analysis. Secondly, the number of studies included in this meta-analysis and the number of patients included in each study was low, therefore, reducing the power of the results. Studies were conducted in a few countries only. Therefore, the generalizability of these studies is lower. In the future, more studies are required with a larger sample size and in various regions to evaluate the risk factors of mortality in SSc-PAH.In conclusion, this systematic review and meta-analysis investigated the mortality rate and predictors of mortality in SSc-PAH. The pooled analysis of eight studies with a total of 530 patients revealed that the one-year, three-year, and five-year survival rates were 90%, 66%, and 44%, respectively. The study identified that increased age, male gender, pericardial effusion, lower cardiac index, higher PAP, and NYHA class are significant predictors of mortality in SSC-PAH patients. The findings of this study have important clinical implications. Assessing and managing the identified predictors, such as age, gender, pericardial effusion, pulmonary arterial pressure, cardiac index, and NYHA class, could help identify individuals at higher risk of mortality and guide treatment strategies. Strategies aimed at reducing pulmonary arterial pressure, optimizing cardiac index, and addressing pericardial effusion may improve survival outcomes in SSc-PAH patients.


Postoperative delirium (POD) is a frequent neurologic dysfunction that often leads to more negative outcomes. Early identification of patients who are vulnerable to POD and early implementation of appropriate management strategies could decrease its occurrence and improve patient prognosis. Therefore, this meta-analysis comprehensively and quantitatively summarized the prevalence and related predictive factors of POD in head and neck cancer surgical patients.PubMed, Embase, and Cochrane Library were searched for observational studies that reported the prevalence and risk factors for POD after head and neck cancer surgery and were published from their inception until December 31, 2022. Two reviewers independently selected qualified articles and extracted data. The qualities of related papers were assessed using the Newcastle-Ottawa scale (NOS). RevMan 5.3 and Stata 15.0 were applied to analysis the data and conduct the meta-analysis.2 = 93.2%). The results of this pooled analysis demonstrated that the statistically significant risk factors for POD were increased age , age > 75 years , male sex , higher American Society of Anesthesiologists grade , diabetes mellitus , and history of smoking .Sixteen observational studies with 3289 inpatients who underwent head and neck cancer surgery were included in this review. The occurrence of POD ranged from 4.2 to 36.9%, with a pooled incidence of 20% (95% CI 15–24%, IPOD frequently occurs after head and neck cancer surgery. Several independent predictors for POD were identified, which might contribute to identifying patients at high risk for POD and play a prominent role in preventing POD in patients following head and neck cancer surgery.The online version contains supplementary material available at 10.1186/s12883-023-03418-w. Head and neck cancer is one of the most frequent malignancies, including cancers of the oral cavity, pharynx, larynx, paranasal sinuses, and nasal cavity . There wBased on different clinical psychomotor behaviours, POD could be further categorized into three subtypes: hyperactive, hypoactive, or mixed. The subtype of POD may be influenced by factors related to specific surgical patient populations. For example, hypoactive-type POD, characterized by lethargy, apathy, and reduced motor activity, occurs more frequently after cardiac and hip fracture surgery , 11, whiOur meta-analysis strictly complied with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) .PubMed, Cochrane Library, and Embase were comprehensively searched for articles published from their inception until December 31, 2022. Based on the combination of medical subject heading terms and text words, a basic search strategy was conducted using the following terms: “delirium”, “postoperative delirium”, “mixed origin delirium”, “head and neck”, “neoplasms”, “cancer”, and “risk factors”, etc. See Additional File Inclusion criteria included the following: (1) studies designed as cohort, case-control, or cross-sectional studies; (2) studies including patients undergoing surgery for head and neck cancer; (3) studies reporting the prevalence and risk factors for POD in patients undergoing surgery for head and neck cancer; (4) studies in which POD was diagnosed by some validated methods, such as the Nursing Delirium Screening Scale (Nu-DESC), Intensive Care Delirium Screening Checklist (ICDSC), Confusion Assessment Method (CAM) or Diagnostic and Statistical Manual of Mental Disorders (DSM); (5) studies written in English; and (6) studies with complete data that could be extracted, including ORs of multivariable risk factors with 95%CIs. Exclusion criteria included the following: (1) reviews, letters, abstract-only publications, animal experiments, and case reports; (2) studies with overlapping populations or duplicate publications; (3) studies that did not investigate the predictors for POD by multivariate logistic regression analysis; and (4) articles with insufficient data for statistics.Two authors screened the full text of the articles, extracted the data and assessed the quality of the papers separately. The extracted data comprised authors, year of publication, country, study design, sample size, mean age of the patients, diagnostic methods for POD and its incidence, risk factors for POD, and study quality score. Since all the selected studies were observational studies, the quality of the eligible papers was rated using the Newcastle-Ottawa Scale (NOS), which is recognized as a standardized method for the quality assessment of non-randomized studies . The maxP < 0.05 was regarded as statistically significant. I2 values and Q-test statistics were applied to detect heterogeneity among articles, where P < 0.1 and I2 > 50% were deemed to indicate significant heterogeneity. If the articles showed high heterogeneity, a random-effect model analysis was utilized; otherwise, a fixed-effect model was chosen. The final result for each relevant variable was presented as forest plots. When the heterogeneity of the pooled effect was significant (I2 > 50%), we further explored the source of heterogeneity using the sensitivity or subgroup analysis. Publication bias with a funnel plot was also conducted.Stata 15.0 and RevMan 5.3 were used to analyze all data. If multivariable risk factors were reported in more than two studies, we performed a meta-analysis. Pooled ORs with corresponding 95% CIs were applied to assess the relationship between the predictors and POD, and n = 122), Embase (n = 354), and Cochrane Library (n = 66). After the removal of duplicate articles (n = 113) by EndNote X9, 429 articles were retained. After preliminary headline and abstract screening, 394 studies were eliminated. The 35 remaining studies consequently underwent full-text review. Subsequently, 19 papers were eliminated for the following reasons: conference abstract (6 studies); not conducting multivariate analysis (3 studies); systematic review or letter (3 studies); without validated POD tools (3 studies); incomplete data (2 studies); randomized controlled trial (1 study);and duplicated population (1 study). Ultimately, 16 articles were eligible for this meta-analysis. The detailed process of the database search is shown in Fig. The initial literature search retrieved 542 citations from the PubMed n = 22, EmbasIn total, 16 observational studies with 3289 patients were published from 2009 to 2022, and the sample size ranged from 69 to 515. Of these 16 observational studies included, 1 was a case-control study, 14 were retrospective cohort studies, and 1 was a prospective cohort study. Of the 16 articles, 12 studies were conducted in Asia  , with mild heterogeneity  with no heterogeneity , which was consistent with a previous meta-analysis [Our study was not the first systematic review and meta-analysis exploring the risk factors for POD after head and neck cancer surgery. Compared with a previous meta-analysis , our sysanalysis . The hetanalysis . In addiIt is widely accepted that advanced age is an important predisposing predictor for POD . In thisASA classification is a well-known grading system for evaluating patients’ tolerance to anesthesia and their physical status before surgery. In line with our recent study , our resSeveral studies have demonstrated that a history of smoking was associated with surgical complications, including postoperative pneumonia and wound infection . HoweverThis meta-analysis did not conclude that operative time and intensive care unit duration were predictive factors of POD after head and neck cancer surgery, which might be related to the small number of studies included. However, according to the Consensus-based Guideline on POD of the European Society of Anesthesiology, operative time and ICU stay time should be considered as risk factors for POD after surgery . Thus, tThere were some limitations in our study. First, only articles published in English were included in the current study, resulting in unavoidable selection bias. Second, we identified several risk factors for POD after head and neck cancer surgery, however, the association between these risk factors and POD in other surgical populations still need to be explored further. Third, some significant risk factors were identified in a few studies with small sample sizes, which should be interpreted with caution.To sum up, our meta-analysis indicated that POD was common after head and neck cancer surgery. Based on the multivariate analysis, some significant predictors were identified, including increased age, age > 75 years, male sex, higher ASA grade, diabetes mellitus, and history of smoking, which might play a critical role in optimizing clinical management of POD.Additional file 1.