Lung cancer screening in high-risk populations with low-dose computed tomography is supported by international associations and recommendations. Overdiagnosis is considered a risk of screening with associated harms. The aim of this paper is to determine the prevalence of subclinical lung cancer diagnosed post-mortem to better understand the reservoir of subclinical lung cancer.We searched EMBASE, PubMed, and MEDLINE databases from inception until March 2022 with no language restrictions. We considered all studies with ≥100 autopsies in adults. Two reviewers independently assessed eligibility of studies, extracted data, and assessed risk of bias of included studies. We performed a meta-analysis using a random-effects model for prevalence of subclinical lung cancer diagnosed post-mortem with sensitivity and subgroup analyses.2 = 84%, tau2 = 1.19, low certainty evidence,16 730 autopsies). We performed a sensitivity analysis excluding studies which did not specify exclusion of children in their cohort, with a pooled prevalence of subclinical lung cancer of 0.87% .A total of 13 studies with 16 730 autopsies were included. Pooled prevalence was 0.4% (95% CI 0.20 to 0.82%, IThis is the first published systematic review to evaluate the prevalence of post-mortem subclinical lung cancer. Compared to autopsy systematic reviews in breast, prostate and thyroid cancers, the pooled prevalence is lower in lung cancer for subclinical cancer. This result should be interpreted with caution due to the included studies risk of bias and heterogeneity, with further high-quality studies required in target screening populations.The online version contains supplementary material available at 10.1186/s12885-023-11224-3. Lung cancer is the second most diagnosed cancer in the world and remains the leading cause of cancer-related death, responsible for almost 1.8 million deaths globally in 2020 .A recent systematic review of randomised controlled trials (RCTs) using low-dose computed tomography (LDCT) for lung cancer screening in high-risk populations (current or former smokers) concluded a reduction in lung cancer-related mortality of 21% compared with control groups (no screening or chest radiograph screening), (relative risk (RR) 0.79, 95% confidence interval (CI) 0.72 to 0.87) . AdditioWhilst there are limited data on the harms of LDCT screening, one significant consideration is the risk of overdiagnosis. Overdiagnosis refers to detection and diagnosis of lung cancer that would never have caused the patient harm or death . In lungThere are many different histological subtypes of lung cancer as defined by the World Health Organization (WHO) . Of noteSystematic reviews of cancers diagnosed at autopsy have already contributed immensely to understanding the risk of overdiagnosis and reservoir of subclinical cancer in prostate, breast, and thyroid cancers –12. In pThere has been no previously published systematic review of the prevalence of subclinical lung cancer diagnosed at autopsy. However, in one Swedish autopsy study of 7020 adults with a mean age of 55 years for men and 58 years for women, only 5 had a post-mortem diagnosis of subclinical lung cancer  . This reThis review aims to describe the prevalence (or reservoir) of subclinical lung cancer detected at autopsy in adults.The systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO registration: CRD42020140747) and reporting has been guided by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist .We considered all studies with more than 100 autopsies in adults (aged 18 or over) who were not known to have lung cancer ante-mortem. We included studies which specified information about whether lung cancer caused or contributed to death or was subclinical.We searched EMBASE, PubMed, and MEDLINE databases from inception until March 2022 using the following search strategy.exp Lung Neoplasms/.).tw.Autopsy/.(autops* or post-mortem* or post mortem*).tw.(#1 or #2) AND (#3 or#4).limit 5 to humans.At least two review authors  independently screened all titles and abstracts retrieved by electronic searches using Covidence . At leasThe review authors  developed a data extraction form of which parts were adapted from the Checklist for Prevalence Studies . Two revWe collected the following data.Source: citation, contact details.Eligibility criteria and reasons for exclusion.Methods: study design, total duration of study, number of centres and locations, autopsy rate.Characteristics of participants: number of participants, demographics .Autopsy: methodology.Results: lung cancer diagnoses, histology, stage of lung cancer, cause of death.Miscellaneous: funding source, conflicts of interest.There were no validated tools for assessing the quality of autopsy studies for prevalence of subclinical cancer. The authors (AB and RM) developed a risk of bias (RoB) tool with components adapted from previous tools used in prevalence and diagnostic accuracy studies , 21. TwoSelection bias -patient selection: we scored ‘low risk’ when consecutive autopsy cases were included and there was avoidance of inappropriate exclusions, ‘high risk’ when non-consecutive autopsy cases were enrolled and/or there were inappropriate exclusions, and ‘unclear risk’ when there was insufficient information to make this judgement.Detection bias- autopsy procedure: we scored ‘low risk’ when autopsies were standardised, lung examination methods were described, and there was adequate correlation with medical history, ‘high risk’ when there was non-standardised approach to autopsy or inadequate correlation with medical history, and ‘unclear risk’ when there was insufficient information to make this judgement.Detection bias- clinical criteria: we scored ‘low risk’ when studies described adequate detail on methods used to classify lung cancer as incidental as opposed to clinically significant, ‘high risk’ when there was no differentiation between subclinical and clinically significant, and ‘unclear risk’ when there was insufficient information to make this judgement.Incomplete outcome data: we scored ‘low risk’ when all autopsy cases were included in results, ‘high risk’ when not all cases where included, ‘unclear risk’ when there was insufficient information to make this judgement.External validity-generalisability: we scored ‘low risk’ when the study participants were representative of the population, ‘high risk’ when they were not representative, and ‘unclear risk’ when there was insufficient information to make this judgement.Other sources of bias: we scored ‘low risk’ when the study did not appear to have other sources of bias, ‘high risk’ when there was at least one other important bias, for example, deviations to protocol, and ‘unclear risk’ when there was insufficient information to make this judgement.2 statistic and between-study variance with tau2 [We performed meta-analyses of prevalence using a random intercept logistic regression model in R version 4.2.2 , using tith tau2 .We performed subgroup analyses for the following;Consecutive versus non-consecutive case selection.Setting – hospital or forensic versus population-based studies.Location – continent.Age – median/mean study age of 40–59 years, 60–89 years, and 90 or greater years.Risk factors.Histological types.Lung cancer stage.Sex was assessed using mixed-effects model meta-regression analyses.We performed two sensitivity analyses (1) including high quality studies only, i.e. excluding studies which potentially included people under the age of 18 years old, and (2) including those with low risk of bias autopsy procedures.Publication bias was assessed using the Luis Furuya-Kanamori asymmetry index (LFK index) and the Doi plot.5233 citations were identified during our database search, of which 170 were selected for full text review. 4501 records were excluded after review of the title and/or abstract as they were judged irrelevant. 13 studies  with a total of 16 730 autopsies were included in this systematic review. 155 studies did not meet inclusion criteria and were excluded, and reasons are detailed in Fig. Of the 13 studies, 6 were conducted in North America –31, 5 inIshii 1979 , 39 was Five studies  had primary objectives focused on malignancy. Four studies  had a primary objective focused on subclinical or clinically unsuspected cancer. Three studies  primarily focused on diagnostic accuracy and the value of autopsy. One study (Ishii 1979) had no specified objective other than to present autopsy findings in general.We excluded 155 studies. 107 for wrong outcomes, 29 had the wrong patient population, 9 studies were the wrong study design, 8 studies were abstracts only and provided insufficient information to evaluate eligibility for inclusion, and 2 studies were duplicates.We performed risk of bias assessment for all included studies and summarised the results in Fig. Prevalence of lung cancer in the included studies is summarised in Table 2 = 84%, tau2 = 1.19; low certainty evidence, 16 730 autopsies, Fig. 2 = 71%, tau2 = 0.49, 7532 autopsies, Fig. We pooled the prevalence of subclinical lung cancers diagnosed post-mortem for all 13 trials. The evidence showed a pooled prevalence of 0.4% .When we performed another sensitivity analysis of studies with low risk of bias for autopsy procedure. Four studies were included , 37, 39,We performed a meta-regression analysis  using the 9 available studies –37, 39 wWe performed the following subgroup analyses.By location: All 13 studies were included in this analysis by continent. Analysis provided in supplementary material .Asia: Two studies , 39 were2 = 76%, tau2 = 0.88, 8153 autopsies).Europe: Five studies , 35, 36 2 = 54%, tau2 = 0.98, 6340 autopsies).North America: Six studies –31 were 2 = 2.09, df = 2 (p = 0.35).There was no statistically significant difference between subgroups. Test for subgroup differences: ChiBy age: Ten studies provided information regarding age. Analysis provided in supplementary material . Gezelius 1988 [For those with a median or mean age of 40 to 59 years old , 31: preius 1988  did not 2 = 79%, tau2 = 0.57, 6907 autopsies Sens 2009 [2 = 83%, tau2 = 0.0.78, 5 studies, 6495 autopsies).For those with a median or mean age of 60 to 89 years old , 37, 39:ens 2009  did not 2 = 0%, tau2 = 0, 410 autopsies). All studies clearly specified they did not include children.For those with a median or mean age of ≥90 years old , 36: pre2 = 5.29, df = 2 (p = 0.07).There was no statistically significant difference between subgroups. Test for subgroup differences: ChiSubgroup analyses by patient selection and setting, study period presented in Table We attempted analysis of studies by stage, however there was insufficient number of studies within each category to proceed. Only three studies reported stages of subclinical lung cancers diagnosed post-mortem , 27, 31.There was inadequate information provided in the studies to perform analyses looking at risk factors including smoking status.The LFK index was 4.32, with significant asymmetry , was significantly lower –12.The strengths of this review include its comprehensive search strategy, with no language barriers, and thorough evaluation of study methodology. However, there were some limitations. Firstly, this systematic review and search focused on post-mortem diagnoses of lung cancer, and as such studies which evaluated for pre-cursor lesions only were excluded. Two autopsies series which have evaluated precursor adenocarcinoma lesions are Sterner 1997  and YokoThe evidence in this review is low certainty due to the risk of bias in included studies, possible publication bias and small study effect, and the significant heterogeneity between studies. However, in the case of prevalence studies, heterogeneity may also provide confidence that the outcome is relevant to a wider population and was present in other autopsy reviews . Most stOnly five studies reported histology of subclinical lung cancers, with a pooled prevalence of 0.14%, 0.11%, 0.11%, 0.05% for NSCLC not otherwise specified, adenocarcinoma, squamous cell carcinoma (SCC), and bronchoalveolar carcinoma (BAC) respectively. This was a small cohort, with only 1840 autopsies included. Interestingly, in LDCT screening RCTs, whilst at baseline screening SCC, adenocarcinoma and BAC are more common in the LDCT screening compared with the control groups, at later time points, only adenocarcinoma and BAC remain more prevalent in the LDCT cohort , due to Whilst there were no statistically significant differences between the subgroups, there were some trends observed. The pooled prevalence based on patient selection demonstrated a lower prevalence of subclinical lung cancers in studies which recruited consecutively, compared to those which were non-consecutive. Studies from Asia (both studies were conducted in Japan) had the highest pooled prevalence compared to Europe and North America. With both Imaida 1997 and Ishii 1979 also having a low risk of bias for autopsy procedure. This may reflect the importance of race as a risk factor for lung cancer development, particularly low VDT adenocarcinoma, which may contribute to higher risks of overdiagnosis in certain populations . The preIn order to advance our understanding about the risk of overdiagnosis with lung cancer screening and the natural history of lung cancer, more information is needed. Further research is required regarding the reservoir of precursor lung lesions and high-quality, prospective studies assessing post-mortem diagnosis of subclinical lung cancer in adult populations, including those who would be eligible for lung cancer screening.This review has found that the reservoir for subclinical lung cancer is relatively small in published autopsy series, suggesting a relatively low risk of overdiagnosis with screening compared with breast, prostate and thyroid cancer. .Below is the link to the electronic supplementary material.Supplementary Material 1


The purpose of this study is to understand the conflicting results from previous studies on the association between carbohydrate intake and cardiovascular disease (CVD) by conducting a systematic review and meta-analysis to summarize the most recent scientific evidence. A systematic review used three electronic databases to gather literature on the association between carbohydrate intake and CVD. Considering the discrepancies, either fixed or random effect models were chosen to determine the effect size, and sensitivity analysis results, as well as publication bias, were also presented. The meta-analysis found that individuals with the highest carbohydrate intake had a 1.15-fold increased risk of CVD compared to those with the lowest intake . Further subgroup analysis revealed that this association was only present in Asia, with a 1.52-fold increased risk , while no associations were seen in the Americas, Europe, and Oceania. The relationship between carbohydrate intake and CVD was non-linear, with a marked escalation beyond 60% of total energy from carbohydrates. Our findings suggest that a high-carbohydrate diet may raise the risk of CVD, particularly in Asian populations. This association may be due to the higher carbohydrate consumption and genetic variations found in Asia. Cardiovascular disease (CVD) is a major public health challenge worldwide, accounting for a significant proportion of morbidity and mortality, and its prevalence is rapidly increasing, making it a critical global health concern . UnhealtDietary patterns differ between Western and Asian countries. Western countries typically consume high amounts of protein and fat from sources such as red meat and animal fat, while Asian countries tend to have a diet high in carbohydrates, specifically rice, and low in fat ,4. The aRecently, there has been a growing body of research investigating the association between carbohydrate intake and CVD risk, with some studies suggesting a significant relationship between high-carbohydrate intake and increased CVD risk in Asian populations ,12,13,14The aim of this systematic review and meta-analysis is to analyze high-quality prospective cohort studies to establish the temporal sequence between diet assessment and subsequent CVD incidence and to provide a more reliable understanding of the association between carbohydrate intake and the risk of CVD. Specifically, we aim to conduct a meta-analysis to summarize the overall findings and identify any inconsistencies in the results. Additionally, we will focus on recent studies, particularly those conducted in Asian populations, where carbohydrate intake tends to be relatively high compared to Western populations. This approach will provide valuable insights into the complex relationship between carbohydrate intake and CVD risk in different populations and inform the development of more effective prevention strategies for chronic diseases.This meta-analysis adhered to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) . An exteWe used three major electronic databases, PubMed, Scopus, and Web of Science. Our search strategy consisted of three groups of keywords related to dietary carbohydrates, CVD, and prospective cohort studies: Keyword group 1: “dietary carbohydrate”, “carbohydrate”; keyword group 2: “infarction”, “heart arrest”, “stroke”, “cardiovascular”, “heart disease”, “myocardial ischemia”, “coronary artery disease”, “coronary heart disease”, “atherosclerosis”, “hypertension”, ”acute coronary syndrome”, ”coronary bypass surgery”, ”percutaneous revascularization”, ”cerebral infarction”, ”cerebral hemorrhage”; and keyword group 3: “prospective”, “longitudinal”, “cohort”, “cohort studies”. We also manually examined the reference lists of all retrieved articles and searched for conference articles, resulting in the inclusion of one unpublished dataset. Two researchers independently conducted the searches, and any discrepancies were resolved through discussion. Our study selection criteria were based on the “participant, intervention (exposure), comparison, outcome, and study design” framework, which is outlined in The selection criteria for this systematic review and meta-analysis were designed to identify high-quality prospective cohort studies that examined the relationship between carbohydrate intake and CVD risk in adult populations. Specifically, the criteria required that studies present hazard ratio (HR) or relative risk (RR) with a 95% confidence interval (CI) for CVD or coronary heart disease (CHD) risk in relation to carbohydrate intake. Studies were excluded from the meta-analysis if they were not published in English or Korean, conducted on patients with diabetes mellitus, or presented only glycemic index, glycemic load, or carbohydrate score as dietary information when analyzing the association between carbohydrate intake and CVD outcomes. In addition, articles that were not original, including but not limited to reviews, meta-analyses, letters, and editorials, as well as non-human studies such as animal or in vivo studies, were not considered for inclusion. In the case of multiple articles using the same dataset, only the article with the most recent data or the longest follow-up period was included in order to avoid duplicative or outdated data. The selection process was rigorous and involved a detailed examination of each study to ensure that it met the criteria for inclusion. By including only high-quality studies in the analysis, this systematic review and meta-analysis provide a more comprehensive and reliable understanding of the relationship between carbohydrate intake and CVD risk in different populations.Two investigators independently evaluated the quality of the selected articles using the Newcastle–Ottawa Scale (NOS) for prospective cohort studies . The NOSA meta-analysis was performed on 23 studies to determine the overall risk estimate of CVD associated with the highest intake of carbohydrates compared to the lowest intake. When a study reported results for the association between carbohydrate intake and different types or definitions of CVD-related diseases, the outcomes were defined according to the original article’s criteria and prioritized in the following order: CVD, CHD, and stroke.I2, which categorized it as low (≤25%), moderate (<25–75%), or high (≥75%) heterogeneity [For studies that reported separate results for men and women, data for each gender were analyzed separately. In cases where a study included participants from multiple countries, data from the continent where the majority of the countries belonged were used as a representative sample. The heterogeneity of effect size was evaluated using Higgin’s ogeneity . Both a A two-stage dose–response random-effects meta-regression was performed to pool the risk estimates of CVD according to carbohydrate intake from each study. The linear trend of the association between carbohydrate intake and CVD risk was tested using the Wald test, and a non-linear relationship was examined using a restricted cubic spline with carbohydrate intake ranges divided using four knots  ,23. ThisAll the participants of these studies were aged 18 and over, and the studies were conducted across various continents, including the Americas, Europe, Oceania, and Asia .et al. that focused on women and CVD was located on the left side, indicating a non-significant result. When all the results are combined, they suggest that increasing carbohydrate intake is associated with a higher risk of total CVD  and that there is moderate heterogeneity among the studies (I2 = 65.4%).I2 = 84.4%, HR/RR: 1.52, 95% CI: 1.17–1.97). These findings suggest that the impact of carbohydrate intake on CVD risk may be influenced by geographic location.The subgroup analyses conducted in this study to evaluate the impact of geographic location on the relationship between carbohydrate intake and CVD risk provide important insights . The finp for non-linearity = 0.0002).To better understand the dose–response relationship between carbohydrate intake and CVD risk, a restricted cubic splines model was employed in this study. The analysis presented in et al. study appeared to be somewhat distant from the other studies, with an overall mean of 1.15. However, this outlier did not substantially impact the overall result of the meta-analysis. In addition, the study employed a funnel plot and trim and fill analysis to test for publication bias, as shown in The sensitivity analysis conducted in this study provides important information about the robustness of the overall findings. This meta-analysis of prospective cohort studies suggests that a higher intake of carbohydrates is independently associated with an increased risk of CVD, particularly in Asian populations. Compared to those in the lowest category of carbohydrate intake, individuals in the highest category had a significantly greater risk of CVD (52%) in Asia. However, the risk was minimal in the Americas, Oceania, and Europe, and these differences were not statistically significant. A dose–response meta-analysis revealed that the risk of CVD increases dramatically in a non-linear manner when carbohydrate intake exceeds 60%. This finding has important implications for clinical practice as it highlights the potential impact of a carbohydrate-based diet on CVD risk, particularly in Asian populations and could be used as a strategy for reducing CVD.Our research findings have shed light on an intriguing observation regarding the relationship between carbohydrate consumption and CVD risk, with the association appearing to be more pronounced in Asian populations. While it is well-known that Asian populations tend to consume a diet that is high in carbohydrates ,40,41,42The effect of high-carbohydrate intake on health outcomes has been extensively studied in various populations, and recent evidence suggests that the harmful health consequences may be more pronounced in Asian populations ,7. For iThe effect of excessive carbohydrate consumption on human health is complex and can result in adverse effects on the liver’s ability to convert carbohydrates into fat and inhibit the synthesis of beneficial high-density lipoprotein cholesterol (HDL-C) ,47,48,49This study presents some intriguing findings, but there are a few limitations to consider. Firstly, the studies in the meta-analysis endeavored to control for potential confounding factors, but residual confounding may still be present. For instance, although all studies adjusted for total calorie intake, a noticeable disparity existed in the adjustment for fat intake. Considering that fat intake is an established risk factor for CVD and frequently correlates with variations in carbohydrate intake, this inconsistency might have impacted the conclusions of our meta-analysis. Moreover, the inconsistent adjustment for covarying dietary macronutrients may confound and potentially bias our results, as different macronutrients can interact with each other and have varying effects on health outcomes. Future studies should account for these interactions to provide more accurate and robust conclusions. Secondly, variations in how dietary surveys were conducted among the studies could have influenced the results. Thirdly, this study determined carbohydrate intake levels by using the proportion of total energy from carbohydrate intake based solely on calorie intake, without considering the types or quality of carbohydrates. Lastly, this meta-analysis was not preregistered on the “International Prospective Register of Systematic Reviews“, which may limit the transparency and reproducibility of our methods and results. Despite these limitations, this study has several strengths. To the best of our knowledge, this is the first systematic review and meta-analysis that summarizes the current literature on the relationship between carbohydrate intake levels and CVD, taking into consideration dietary habits by culture or geographical region. This is a significant contribution to the existing research on this topic, and the findings could be utilized to inform future research and public health interventions that consider the impact of culture and geography on dietary habits. The study’s methodology, including the search strategy and inclusion criteria, was robust and comprehensive, enhancing the study’s validity. Additionally, the study’s reliability is enhanced by the use of prospective cohort studies in the meta-analysis, which provide stronger evidence of causality compared to case-control or cross-sectional designs. Overall, the study’s strengths outweigh its limitations and highlight the need for further research to establish clear dietary guidelines that could reduce CVD risk across different populations while also taking into account cultural and geographical differences in dietary habits.In conclusion, the meta-analysis of 23 cohort studies found that high-carbohydrate intake, particularly over 60% of total energy from carbohydrates, can have adverse effects on the incidence of CVD, with a stronger association in Asians with a carbohydrate-based diet and weaker insulin sensitivity. These findings have significant implications for the ongoing efforts to reduce the incidence of CVD by providing ethnic-specific scientific evidence for prevention. However, further research is required to better understand the relationship between carbohydrate intake and CVD risk in Asian populations. It is essential to investigate the effects of high-carbohydrate diets in prospective cohort studies involving various age groups, along with a detailed analysis of types and food sources of carbohydrates. Such studies could provide a more comprehensive understanding of the mechanisms by which carbohydrate intake influences CVD risk and the potential benefits of specific dietary interventions. With this knowledge, public health interventions can be tailored to reduce the incidence of CVD and promote healthy dietary habits across diverse populations, thus enhancing global efforts to combat this significant public health challenge.


FLG variants in both European and Asian populations and AD risk, while synthesis of the available data revealed novel loci mapped to IL18 and TGFB1 genes in Europeans and IL12RB1 and MIF in Asians that have not yet been identified by genome-wide association studies. Our findings provide comprehensive evidence for AD risk loci in cases of both European and Asian ancestries, validating previous associations as well as revealing novel loci that could imply previously unexplored biological pathways.Atopic dermatitis (AD) has been extensively investigated for genetic associations utilizing both candidate gene approaches and genome-wide scans. Here, we comprehensively evaluated the available literature to determine the association of candidate genes in AD to gain additional insight into the etiopathogenesis of the disease. We systematically screened all studies that explored the association between polymorphisms and AD risks in cases of European and Asian ancestry and synthesized the available evidence through a random-effects meta-analysis. We identified 99 studies that met our inclusion/exclusion criteria that examined 17 candidate loci in Europeans and 14 candidate genes in Asians. We confirmed the significant associations between  H) 2 cell-like inflammatory pattern in the skin [FLG) gene, including the rs558269137 (2282del4) and rs61816761 (R501X) [IL4 rs2243248 [IL13 rs1800925 [H2-related interleukins (ILs), with the major examples of the IL4 and IL13 that have been further targeted by modern therapeutic approaches [Atopic dermatitis (AD) is a common, chronic inflammatory cutaneous disease characterized by the development of recurrent eczematous lesions and intense itching . AD affethe skin . Specifis1800925  SNPs, reproaches .n = 116,863, ncases = 21,399) has identified 31 genetic variants that account for less than 20% of the general heritability [ncases = 2639) [Accumulating evidence from genome-wide association studies (GWASs) in participants of European ancestry (tability . Contras = 2639) . However = 2639)  limit th = 2639) ,111,112.To address this issue, we assessed the inter-individual variability present in the genetic predisposition of AD, incorporating a conservative random-effects meta-analysis (REM) approach to synthesize the evidence derived from available studies and thus unveil putative risk loci associated with the disease onset in participants of European ,64,65,66We conducted a systematic literature search to identify studies that examined the inter-individual genetic variability in patients with AD. Searches in the Medline database (through PubMed) using keywords referring to the association  of genetic variants  with the AD trait  from inception to 18 September 2022. Screening was performed by two independent authors in a standardized manner, following relevant titles and abstract reading before full-text reviewing. We considered all case-control candidate-gene studies that examined the genetic predisposition of atopic dermatitis through targeted genotyping, regardless of the age of onset and the allergic disease spectrum that includes hay fever, rhinitis and asthma. Studies included in our analysis were published in peer-reviewed journals in the English language; variants incorporated in our meta-analysis should be investigated by at least two eligible studies. We excluded case reports, abstracts, animal studies, duplicate reported data and reports that did not provide the appropriate data for the calculation of effect size and confidence intervals.Two authors extracted concurrently and independently the eligible studies and extracted the appropriate data; discrepancies were resolved through re-examination of the respective publications until consensus was reached. Data extracted from the eligible studies referred to the first author, publication year, total sample size and the reported genotypes for further effect size computations.https://ldlink.nci.nih.gov/?tab=ldpop; accessed on 15 November 2022). R-squared values greater than 0.9 highlighted SNPs in high LD and were therefore considered as a single locus in the meta-analysis.Odds Ratios (ORs), along with their 95% Confidence Intervals (95% Cis), were calculated for the allelic model of inheritance. To avoid the parallel assessment of non-independent SNPs in the same locus, we measured linkage disequilibrium (LD) using the LDpop tool provided by the National Institutes of Health  and quantified via the I2 metric, with 0% < I2 < 25% reporting small, 25% < I2 < 50% reporting moderate, 50% < I2 < 75% reporting high and I2 > 75% reporting very high heterogeneity. The predominant role of the FLG variants in the AD predisposition led us to further evaluate their combined effect due to their similar biological effects. To explore the inter-study variability, we employed the Harbord’s modified test, a robust statistical analysis for the assessment of small-study effects in each meta-analysis. All statistical analyses were performed with the Stata 13.1 software . The metan plugin was incorporated for our REMs, while the metabias plugin was utilized for the Harbord’s modified test. Statistical significance threshold was set at p-value ≤ 0.05, while the p-value < 0.1 threshold was used for the Harbord’s modified test.We calculated OR and 95% CI for each respective heritance pattern by synthesizing the available study-specific evidence through the random-effects model. The presence of heterogeneity was assessed with the Cochran’s Q test , TLR2 [n = 7, 7%), IL10 [n = 7, 7%), 11q13.5 [n = 5, 5%), IL13 [n = 4, 4%), IL4 [n = 3, 3%), HRNR [n = 3, 3%) and IL6 [n = 3, 3%) loci, while evidence for possible association for relevant genes were examined by a total of two studies [FLG [n = 18, 18%), IL4 [n = 7, 7%) and SPINK5 [n = 4, 4%) genes, with the rest of the explored loci assessed by two or three studies [Selected characteristics of the available literature are provided in FLG ,38,39,40%), TLR2 ,45,46,47%), IL10 ,52,53,54 11q13.5 ,56,57 (n%), IL13 ,49,52,584%), IL4 ,51 (n = %), HRNR ,56,59 , IL4 ,89,90,91d SPINK5 ,92,93,94 studies ,111,112 FLG loss-of-function (LOF) variants and increased AD risk from a total of 27 studies, incorporating 17,759 participants. Specifically, both FLG rs558269137 (OR (95% CI): 0.26 (0.20–0.34); I2 = 70.4%) and FLG rs61816761 (OR (95% CI): 0.27 (0.20–0.36); I2 = 67.8%) common alleles were associated with reduced AD risk from a total of 25 studies showing, however, a high heterogeneity , FLG rs150597413  and FLG rs397507563  SNPs yielded significant associations with higher risk of developing AD (OR (95% CI): 0.27 (0.18–0.40); I2 = 5.9%; OR (95% CI): 0.32 (0.21–0.50); I2 = 0.0%; OR (95% CI): 0.14 (0.03–0.69); I2 = 0.0%)  .FLG locus in the disease onset, as well as the similar, trans-acting biological mechanism of the above variants [2 = 68.7%; OR (95% CI): 0.33 (0.17–0.63); I2 = 36.8%; OR (95% CI): 0.23 (0.15–0.36); I2 = 81.0%) highlighting thus the contribution of the FLG locus in the disease predisposition, nevertheless reporting a high heterogeneity metric : 0.61 (0.29–1.30); I2 = 30.7%). Similarly, the synthesis of evidence from three studies evaluating the TLR2 rs4696480 SNP in 741 participants failed to establish a significant association with the risk of developing AD (OR (95% CI): 0.81 (0.62–1.06); I2 = 40.2%)  .TLR2 locus, our meta-analysis did not detect significant associations between the IL10 rs1800896 variant and AD predisposition (OR (95% CI): 1.06 (0.89–1.27); I2 = 29.6%), using data from seven studies with 1703 participants (IL10 rs1800871 and IL10 rs1800872 SNP were found in high LD SNPs (r2 > 0.9) and were consequently assessed as a single genotype; we did not observe significant associations between these variants and disease risk from a total of three studies : 1.08 (0.72–1.64); I2 = 76.7%) (Comparably to the icipants . Notably= 76.7%) .2 = 0.0%) : 0.78 (0.71–0.85); I = 0.0%) .IL13 rs1800925 SNP (n = 931); synthesis of the available data depicted the association of the common rs1800925 SNP with reduced AD risk (OR (95% CI): 0.60 (0.48–0.75); I2 = 0.0%) (Our systematic search identified four studies examining the  = 0.0%) .IL4 rs2243248 was significantly associated with a higher risk of developing AD, including data from two studies with a total of 503 participants (OR (95% CI): 2.67 (1.53–4.65); I2 = 0.0%). Contrastingly, the IL4 rs2243250, assessed in three studies (n = 639) did not yield a significant outcome (OR (95% CI): 0.81 (0.59–1.13); I2 = 3.5%). Two studies further assessed SNPs mapped to the IL18  and TGFB1  genes, providing significant associations with the exception of the TGFB1 rs1800470 variant  were found in high LD and were therefore considered together during data synthesis; the meta-analysis from three studies (n = 1432) assessing these variants did not demonstrate significant association between the common allele and AD risk (OR (95% CI): 1.08 (0.89–1.31); I2 = 16.7%). Similarly, the HRNR rs877776 common allele was not associated with disease onset from a total of three studies incorporating 2158 participants (OR (95%CI): 0.91 (0.62–1.34); I2 = 72.9%). Additional investigation of putative risk loci through meta-analysis in two studies, including VDR rs2228570, rs7975232, VDR rs1544410 and rs731236 (r2 > 0.9), IL1B rs16944, IL1B rs1143634, TNF rs1800629, TNF rs361525, SPINK5 rs2303067, IL4RA rs1801275, TLR4 rs4986790 and rs4986791 (r2 > 0.9) and GSTP1 rs1695, gave null results : 0.32; (0.25–0.42); I2 = 0.0%). As far as FLG rs121909626  and FLG rs761212672  SNPs are concerned, both yielded significant associations with higher eczema risk (OR (95% CI): 0.19 (0.11–0.34); I2 = 0.0%; OR (95% CI): 0.14 (0.04–0.44); I2 = 0.0%). Our REM highlighted two additional FLG variants  associated with increased AD risk (OR (95% CI): 0.23 (0.06–0.89); I2 = 0.0%; OR (95% CI): 0.14 (0.07–0.27); I2 = 0.0%). Notably, the FLG rs558269137 variant was further associated in participants of Asian ancestry from a total of two studies including 1382 cases (OR (95% CI): 0.43 (0.24–0.79); I2 = 0.0%)  .FLG variants and increased AD risk in both Europeans and Asians, several variants, including FLG rs61816761 , FLG rs146466242 , FLG rs772851618  and FLG rs11584340 , failed to provide significant signals (OR (95% CI): 0.45 (0.11–1.74); I2 = 0.0%; OR (95% CI): 0.54 (0.21–1.38); I2 = 1.7%; OR (95% CI): 2.39 (0.54–10.53); I2 = 0.0%; OR (95% CI): 0.80 (0.44–1.47); I2 = 86.5%)  .2 = 0.0%) ; CG incorporated 877 participants from three studies and yielded a significant association (OR (95% CI): 0.11 (0.06–0.19); I = 0.0%) .IL4 gene  were found in high LD (r2 > 0.9) and were thus examined together from a total of seven studies (n = 2454). Our REM did not demonstrate a significant association (OR (95% CI): 0.97 (0.64–1.48); I2 = 88.0%) (Two variants mapped to the = 88.0%) .IL4 variants, two SPINK5 variants  were found in high LD (r2 > 0.9) and were thus examined together from a total of three studies (n = 1280). However, we found that the above locus was significantly associated with AD risk (OR (95% CI): 1.26 (1.06–1.48); I2 = 0.0%). Relevant, independent variants mapped to the SPINK5 gene yielded additional significant signals, with the examples of SPINK5 rs2303070 : 0.65 (0.51–0.83); I2 = 0.0%) and SPINK5 rs2303065 ; I2 = 0.0%). Nevertheless, data synthesis from four studies (n = 930) regarding the SPINK5 rs2303064 SNP showed no evidence for an association with AD predisposition in the Asian population (OR (95% CI): 0.97 (0.79–1.19); I2 = 0.0%) (Comparably to  = 0.0%) .IL10 rs1800896, IL10 rs1800871 rs1800872 (r2 > 0.9), IL4RA rs1801275, IL4RA rs1805010 and IL13 rs20541, while two studies assessed the IL13 rs1800925 in AD Asians. Our REM gave null results in all above cases . Our meta-analysis yielded statistically significant associations in both cases (OR (95% CI): 0.80 (0.66–0.96); I2 = 0.0%; OR (95% CI): 0.79 (0.65–0.95); I2 = 0.0%) (IL9 rs31563 (n = 1391) and MIF rs755622 (n = 649) SNPs provided significant associations with AD risk (OR (95% CI): 1.32 (1.07–1.64); I2 = 0.0%; OR (95% CI): 0.65 (0.49–0.86); I2 = 0.0%) (Considering the  = 0.0%) . In addi = 0.0%) .IL5RA (rs334809), TNF (rs1800629), FCER1A (rs2427837) and TARC (431C > T) genes, generating non-significant results (IL18 rs187238 was not associated with AD risk in the Asian population (OR (95% CI): 1.52 (0.96–2.42); I2 = 0.0%)  .FLG rs150597413 , TLR2 rs4696480 , 11q13.5 rs7927894  and TLR4 rs4986790, rs4986791  in European cases  and FLG rs772851618  in Asians (Harbord’s modified test identified small-study effect biases in six cases. Specifically, we found a small-study effect bias in the REM of an cases , while sn Asians .IL18 and TGFB1 genes in Europeans (IL12RB1 and MIF loci in AD predisposition in Asians was additionally characterized through our analysis, revealing results not previously reported by genome-wide scans (Here, we performed a systematic review and meta-analysis of all available evidence considering the genetic predisposition to AD in participants of both European and Asian ancestry. Despite the expanding list of risk loci identified through genome-wide scans in AD, our REM shed light upon new risk loci mapped to the uropeans , while tde scans . We thusFLG locus in disease susceptibility, as LOF mutations disrupt the production of the filaggrin protein in the stratum corneum. The impaired barrier function facilitates a loss of water and pH increase, as well as the entry of irritants and allergens, contributing to the onset and exacerbation of allergic reactions [FLG in maintaining skin homeostasis and its relevance in AD [FLG rs558269137 and rs61816761 in European population was also observed in a prior meta-analysis of FLG polymorphisms in AD [IL4 and IL13, represents a prominent risk locus implicated in the pathogenesis of the disease and has been extensively linked with AD through several GWAS-derived variants. Here, we identified the IL13 rs1800925 SNP, a regulatory variant that enhances the activity of the IL13 promoter in human Th2 lymphocytes, thereby augmenting the risk of allergic disorders [IL4 and IL13 signaling [IL4 rs2243248 SNP, where our REM reported the protective effect of the minor rs2243248 G allele in AD risk, similar to asthma [SPINK5 nonsynonymous variants that disrupt the function of serine protease inhibitors in the integrity of the epidermal barrier, as well as the IL9 rs31563 variant that exhibits a regulatory role in IL9 expression, a cytokine known to contribute to B cell isotype switching from IgM to IgE synthesis [Several of our findings have been previously discovered by GWASs in both participants of European and Asian ancestries. In particular, the present meta-analysis confirms the pivotal role of the eactions . The conce in AD . The prems in AD , which cms in AD . We furtisorders . Remarkaisorders , a maligisorders , an antiignaling . Anotherynthesis .IL18 rs187238 polymorphism and AD risk in European cases (IL18 promoter region, supports the modulation of the binding affinity of transcription factors and thus participates in the dysregulated Th2 response [TGFB1 rs1800471 missense variant (Despite the prominence of GWAS outcomes as the gold standard in genetic association studies, there are still certain risk loci that have not been yet identified. We further report four novel loci, two belonging to Europeans  and two an cases ; this varesponse . Our sec variant  that sigIL12RB1 rs393548 and rs436857 variants were significantly associated with AD risk in Asians (IL12RB1 receptor subunit is involved in the modulation of the IL12-dependent inhibition of IgE synthesis and Th2 cell function. Consequently, a potential decrease of the IL12RB1 expression perturbs the above inhibitory activity [MIF rs755622 C allele and increased AD susceptibility (MIF expression levels [MIF holds a significant role in the development of AD-related immune dysregulation through the induction of a type 2 immune response, as well as through fostering the recruitment of eosinophils in the cutaneous inflammation [In addition, the promoter n Asians ; the IL1activity , thus letibility ; the rarn levels . Studiesammation .However, our study displays some constraints. Despite the assessment of small-study effect bias through the Harbord’s modified test and the identification of six significant cases, the majority of studies included in our synthesis incorporated a relatively small sample size and are thus susceptible to biases . In addiIn conclusion, we conducted a systematic review and meta-analysis of all available data regarding the genetic predisposition to AD in participants of both European and Asian ancestry. We report four novel risk loci that have not been previously shown by GWAS, partially contributing to the elucidation of the genetic architecture of the disease. By exploring data from both ethnic groups, our study endeavors to provide a broader understanding and enhance the applicability of our findings across diverse populations. High-throughput investigation of putative risk loci in AD ,123 coul


Sugar-sweetened beverage (SSB) intake is associated with an increased risk of cardiometabolic diseases. However, evidence regarding associations of artificially sweetened beverages (ASBs) and fruit juices with cardiometabolic diseases is mixed. In this study, we aimed to investigate the association between the SSB, ASB and fruit juice consumption with the incidence of cardiometabolic conditions and mortality.Relevant prospective studies were identified by searching PubMed, Web of Science, Embase, and Cochrane Library until December 2022 without language restrictions. The pooled relative risk (RR) and 95% confidence intervals (CIs) were estimated for the association of SSBs, ASBs, and fruit juices with the risk of type 2 diabetes (T2D), cardiovascular disease (CVD), and mortality by using random-effect models.p < 0.05). A dose-response meta-analysis showed monotonic associations between SSB intake and hypertension, T2D, coronary heart disease (CHD), stroke and mortality, and the linear association was only significant between ASB consumption and hypertension risk. Higher SSB and ASB consumptions were associated with a greater risk of developing cardiometabolic diseases and mortality. Fruit juice intake was associated with a higher risk of T2D.A total of 72 articles were included in this meta-analysis study. Significantly positive associations were observed between the consumption of individual beverages and T2D risk . Moreover, our findings showed that intakes of SSBs and ASBs were significantly associated with risk of hypertension, stroke, and all-cause mortality (RR ranging from 1.08 to 1.54; all Therefore, our findings suggest that neither ASBs nor fruit juices could be considered as healthier beverages alternative to SSBs for achieving improved health.Systematic Review Registration: [PROSPERO], identifier [No. CRD42022307003]. The health effects of beverages especially sugar sweetened beverages (SSBs), have received widespread attention from the scientific community and general public over the past decades. Despite public health measures to limit and reduce the consumption of added sugars by introducing sugar tax on SSBs in several countries, SSBs still remain a major source of added sugars . The mosAccording to Dietary Guidelines for Americans 2020–2025, everyone can benefit from shifting food and beverage choices to better support healthy dietary patterns . Some tyThus, to better illustrate the conflicting results of the previous studies, a dose–response meta-analysis of prospective cohort studies was conducted to comprehensively evaluate the association between the consumption of SSBs, ASBs as well as fruit juices and the risk of cardiometabolic diseases and mortality.PROSPERO  guidelines  and recoA systematic search of PubMed, EMBASE, Web of Science, and Cochrane Library was performed to identify relevant articles up to December 2022 without language restriction by using MeSH terms and free-text terms . ReferenStudies meeting the following criteria were eligible for inclusion:  the studThe following information was extracted from each study by three independent authors : the first author, year of publication, geographical location, duration of the follow-up, cohort name, number of participants and cases, age, gender, beverage intake categories, method of dietary assessment, methods of outcome ascertainment, type and number of cases or deaths, covariates adjusted in the multivariable analysis, and the RRs with 95% CIs for each category of beverage. If studies provided more than one estimate, the RRs fully adjusted for confounding factors were extracted for analysis.Study quality was assessed by the same three authors according to the Newcastle–Ottawa quality assessment scale . StudiesTo estimate the credibility of evidence for the association between drinks and risk of cardiometabolic diseases, the NutriGrade scoring system was used . The cal2I statistic (with I2 < 50% being low and I2 > 50% being apparent heterogeneity) was used to measure the magnitude of between-study heterogeneity. Meta-regression and subgroup analyses were conducted according to sex , geographical locations , follow-up year (< 10 years or ≥ 10 years), assessment method , body mass index  as well as the study quality (high or medium). There were relatively too few studies on the associations of fruit juice and hypertension/CHD/stroke/mortality and the association of ASBs and CHD/stroke to conduct meaningful subgroup analyses, thus, no further stratified analyses were conducted.The combined risk estimates across studies were calculated by using random-effect models for the associations of SSBs, ASBs, and fruit juices with hypertension, T2D, CVD and mortality . The I2 We assessed the potential dose–response meta-analyses between the categories of beverage consumption and the chronic diseases mentioned above by using restricted cubic splines with three knots located at 10, 50, and 90th percentiles of the distribution, which was proposed by Greenland and Longnecker  and OrsiIf the extreme category of one study was open-ended, it is assumed that its width was the same as that of the adjacent category , 29. Forp < 0.10 level of significance  24 records were excluded because they were meta-analyses or systematic reviews; (2) 16 records were excluded because they were case-cohort studies or case control studies; (3) 13 records were excluded because they were cross-sectional studies; (4) 45 records were excluded because the endpoint or exposure was not relevant to the purpose of the present study. Finally, 72 records  were included in the final analysis  32–82)..32–82).n = 70), physical activity (n = 70), age (n = 68), body mass index (n = 64), and alcohol drinking (n = 58). The quality scores of the studies were shown in The main characteristics of the selected studies are presented in Pheterogeneity < 0.001; I2 = 69.2%; n = 17; Pheterogeneity < 0.001; I2 = 92.7%; n = 10; Pheterogeneity = 0.59; I2 = 0.0%; n = 6; SSB: 1.20, 95% CI: 1.15, 1.25; Pnonlinearity = 0.06; RRASB: 1.11, 95% CI: 1.05, 1.18; Pnonlinearity = 0.09; Pnonlinearity = 0.001; A total of 20 studies with a total of 70,674 T2D cases in 1,246,307 participants investigated the associations between beverage consumption and T2D risk, including 17 studies of SSBs, 10 studies of ASBs, and 6 studies of fruit juices . The oven = 10), 23,757 cases of CHD (n = 8), and 15,830 cases due to stroke (n = 9) in 1,395,468 participants were included in the present study  and 28,615 cases of mortality from CVD (n = 10) in 3,013,817 participants were included in the analyses of beverages and mortality , Begg’s test , or the visual inspection of the funnel plot (p = 0.001). Six missing studies were imputed by using the trim-and-fill method and the magnitude of the pooled effect size incorporating these hypothetical studies was weaker than the original risk estimate, however, remained to be statistically significant ; Nutrition Science Research Foundation of BY-HEALTH (TY0181101); New-star Plan of Science and Technology of Shaanxi Province (2015LJXX-07); and the Fundamental Research Funds for the Central Universities . The funders of the study had no role in the study design, implementation, analysis, decision to publish, or reparation of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Acute kidney injury (AKI) is a complex clinical syndrome of hospitalization that may be affected by undernutrition and metabolic changes. The aim of this meta-analysis was to systematically assess the association between malnutrition and the risk of prevalent AKI.  We searched PubMed, Embase, Ovid MEDLINE, Web of Science, and Chinese databases  from database inception until May 1, 2023, for studies evaluating the association of malnutrition with the risk of AKI. Summary odds ratios (ORs) were estimated using a random-effects model.  We identified 17 observational studies, which included 273,315 individuals. Compared with patients with normal nutritional status, those with malnutrition had a 125% increased risk of prevalent AKI . Malnutrition was also significantly associated with prevalent AKI across all subgroups when subgroup analyses were performed on covariates such as region, study design, age, sample size, malnutrition assessment method, patient characteristics, covariate adjustment degree, and risk of bias. Meta-regression models demonstrated no significant differences in AKI risk between patients with malnutrition and without malnutrition.  Our results suggest that malnutrition may be a potential target for AKI prevention. However, well-designed studies with ethnically or geographically diverse populations are needed to evaluate strategies and interventions to prevent or slow the development and progression of AKI in malnourished individuals. Acute kidney injury (AKI) is a complex clinical syndrome caused by a range of factors in various clinical settings and is characterized by a sudden but often reversible decline in the estimated glomerular filtration rate (eGFR) and the resultant accumulation of metabolic waste products . AnnuallMalnutrition is defined as a physical state of imbalanced nutrition that is significantly associated with increased length of stay, complication rates, healthcare costs, and mortality in hospitalized patients , 5. A reEmerging evidence has suggested that malnutrition is a predictor of AKI. A retrospective study of 46,549 Chinese inpatients demonstrated that a malnutrition level ≥3, as assessed using the nutritional risk screening 2002 (NRS-2002), was strongly associated with prevalent AKI . AnotherWe reported our meta-analysis review in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines  PRISMA , and theWe searched for potential publications in PubMed, Embase, Ovid MEDLINE, Web of Science, and Chinese databases  from database inception until May 1, 2023. The search terms were “acute kidney injury,” “acute renal injury,” “AKI,” “malnutrition,” “nutritional deficiency,” “nutritional deficiencies,” “undernutrition,” “malnutrition” and “Nutritional Risk Index,” “Geriatric Nutritional Risk Index,” “Subjective Global Assessment,” “Mini Nutritional Assessment-Screening Form,” “Malnutrition Universal Screening Tool,” “Nutritional Risk Screening 2002,” and “Prognostic nutritional index.” The details are shown in the Supplementary All articles retrieved using our search strategies were assessed by screening titles and abstracts. Study selection was conducted by two authors independently. In cases of disagreement on the inclusion or exclusion of studies, consensus was reached through discussion with a third author.The inclusion criteria were observational studies, studies investigating the association between malnutrition and AKI risk, studies on populations of any sex or ethnicity, and studies with a clear diagnosis of malnutrition and AKI. Animal studies, non-English-language studies, and study types such as review, conference, letter, case report, and comments were excluded.Data were independently extracted from the included studies by two authors. Any disagreement was resolved by consensus between the two authors. The following data were extracted from the included studies: year of publication, country, participant characteristics, sample size, malnutrition assessment tools, adjusted variables, and study quality. Disagreements between the two authors were resolved through discussion until consensus was reached.In the evaluation of potential biases within the selected studies, two independent reviewers utilized the Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool . The ROBQ statistic and I2. Both of these tools helped us quantify the extent of variability in effect estimates due to heterogeneity rather than chance. We capitalized on both fixed- and random-effects models, depending on the level of heterogeneity. In instances of significant heterogeneity, the preference was given to the random-effects model. More specifically, we employed the Der Simonian and Laird method within the context of the random-effects model. This method considers the variance of the effect sizes across the studies, providing a more accurate computation of weights for meta-analysis. This approach thereby offers a more reliable estimate of the overall effect size, enhancing the credibility of our findings. Moreover, to identify potential sources of heterogeneity, we conducted subgroup and meta-regression analyses. We delineated subgroups based on various factors, including region, malnutrition assessment method, participant demographics, sample size, the degree of covariate adjustment, and study quality. This comprehensive analysis enabled us to delve deeper into the influence of these factors on our results. In addition, to evaluate whether the overall estimate depended on a single study, we conducted a sensitivity analysis by removing any of the included studies. Moreover, we used funnel plots to visualize the publication bias of the study data and further used Egger's test to objectively assess potential publication bias.For data analysis, we used the “metaprop” function in the “meta” package of R (version 4.1.3). To enable accurate calculation and input of effect sizes and thus ensure the reliability of our results, we used the “metagen” function. In our research, we dealt with dichotomous data, for which we calculated the odds ratios (ORs) and their corresponding 95% confidence intervals (CIs). In addition, to evaluate the heterogeneity among the studies, we utilized the chi-squared test for Cochran's A flowchart of the literature selection process is presented in The characteristics of the included studies are summarized in Utilizing the ROBINS-I instrument for evaluation, it was discerned that four studies presented a moderate overall risk of bias. Eleven studies were identified as having a serious overall risk of bias. In addition, two studies were found to show a serious overall risk of bias. Supplementary I2 = 97.0% and P < 0.01 and that the included studies were derived from multiple study settings and their populations, relevant effect values were pooled using a random-effects model . Given their combined ts model .P=0.88), study design (standard error (SE) = 0.44, P=0019), sample size , mean or median patient age , malnutrition assessment method , patient characteristics , adjusted/unadjusted confounders , or risk of bias   .t = 0.16 and P=0.87, suggesting that the included studies had no publication bias  [P=0.021) [According to the subgroup analysis, the source of heterogeneity is partly explained by the differences in patient characteristics. Eleven studies explored the association of malnutrition with the risk of CA-AKI among patients undergoing CAG or PCI. CA-AKI is a common phenomenon in patients following contemporary PCI and is characterized by an abrupt decline in eGFR after intravascular administration of iodinated contrast media. Studies reported that CA-AKI had an incidence of 6%–18% in patients undergoing PCI –46 and tP=0.003) . AnotherP=0.021) . Thus, mAnother important source of heterogeneity can be partly explained by the differences in malnutrition assessment methods. To date, there is a lack of unified and standard measurement tools for malnutrition; thus, the prevalence of malnutrition varies when different measurement tools are used. Fortunately, the results from the subgroup analysis showed that malnutrition was associated with an increased risk of AKI across all groups of assessment tools for malnutrition. The NRS-2002 score, developed by the European Society for Clinical Nutrition and Metabolism, has been widely used in clinical malnutrition screening in various diseases, including CKD. The parameters of the NRS-2002 score, such as decreased body mass index and intensive care admission, were also significantly associated with the occurrence of AKI , 50. In P=0.019). This could be attributable to the fundamental differences in methodology between these two types of study design. In cohort studies, participants are followed over time, and data about them is collected at regular intervals, allowing for the observation of changes and the development of outcomes over time. In contrast, cross-sectional studies provide a snapshot of a population at a specific point in time, which could lead to different findings and interpretations [In our meta-analysis, the source of heterogeneity was investigated through regression analysis. Intriguingly, our findings indicate that study design could potentially be a notable source of heterogeneity. Specifically, there was a significant difference between cohort studies and cross-sectional studies (SE = 0.44, etations , 53. ThiOur meta-analysis has some limitations that are strictly inherent to the design of the eligible studies. First, our meta-analysis could not prove causality between malnutrition and the risk of AKI because of the observational design of the included studies. Second, heterogeneity was high in the pooled analyses, and the meta-regression analysis failed to define the source of heterogeneity, which may have affected the reliability of our results. Third, the included studies were mostly conducted in China and Turkey, and there was a significant publication bias in the funnel plot, which may have weakened our ability to evaluate the strength of the association between malnutrition and the risk of prevalent AKI in other countries. Fortunately, the significant association between malnutrition and the risk of prevalent AKI has also been confirmed in several studies conducted in America and Korea , 48, 49.In conclusion, the results of the present meta-analysis provide evidence that malnutrition is significantly associated with an increased AKI prevalence. Our findings suggest that malnutrition may be a potential target for AKI prevention. However, well-designed studies with ethnically or geographically diverse populations are needed to evaluate strategies and interventions to prevent or slow the development and progression of AKI in malnourished individuals.


To investigate the efficacy and postoperative clinical adverse events of coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) for chronic kidney disease (CKD) study participants combined with coronary artery disease (CAD).All randomized controlled trials (RCTs) that focus on the therapeutic effect evaluation of CABG and PCI and their effect on postoperative clinical adverse events as well as main adverse cardiovascular and cerebrovascular events (MACCEs) in CKD study participants with CAD were screened from the following databases, including CNKI, CBM, Wan Fang, VIP, Embase, PubMed, as well as Cochrane library clinical controlled trials. The study was conducted under the PRISMA 2020 criteria. Data were extracted, and quality control was evaluated from the modified Jadad rating scale. Meta-analysis was then undertaken through STATA 16.0 software.A total of 5 RCTs were obtained, including 1198 patients. Study participants were subdivided into two groups, including the PCI group (n = 604) and the CABG group (n = 594). Meta-analysis of clinical adverse events results showed that the long-term survival results of CAD patients with CKD who underwent PCI were worsened compared to CABG, such as long-term MACCEs  and the long-term repeated revascularization . Also, cardiac death , as well as cerebrovascular accident  in CABG group was significantly lower than that in PCI group.This meta-analysis showed that CABG provided a better therapeutic effect than PCI in CKD patients with CAD when considering long-term prognosis. However, more prospective RCTs are needed to define the proper revascularization strategy for CAD patients with CKD. Chronic kidney disease (CKD) generally has a worse prognosis after invasive procedures such as PCI or CABG than patients with healthy renal function. Coronary artery disease (CAD) is the main factor of death induced by cardiovascular events in CKD study participation . CAD patRecent studies have revealed that for CAD patients with CKD, timely diagnosis and early PCI or CABG have a lower mortality rate than drug therapy , 6. PrevThe 2018 European Society of Cardiology/ European Association for Cardio-Thoracic Surgery (ESC/EACTS) Guidelines recommend CABG over PCI in patients with moderate to severe CKD with multi-vessel disease . SimilarThe published studies using PCI and CABG outcome data in CKD study participants with CAD were systematically reviewed in accordance with the Preferred Reporting Project (PRISMA) Guidelines for Systematic Review and Meta-analysis . As of FThe studies where quantitative raw data can be obtained or the risk ratio (RR) can be calculated were included. If the study patient groups overlap, select a study with a larger sample size. Studies that meet the following criteria are included:  ComparisStandardized data tables were utilized to extract information. The following data related to the study, patients, and outcomes were extracted: author, year of publication, design of experiment, sample in time, sample size, age, gender, average follow-up period, eGFR value, smoking, diabetes, hypertension, hyperlipidemia, history of myocardial infarction as well as unstable angina history, history of peripheral vascular disease, myocardial involvement lesion blood vessel, main not conscience for all-cause death, MACCEs, cardiogenic death, MI, repeated revascularization, as well as cerebrovascular accident. The RoB2 scale was utilized to evaluate the quality of the study by two independent authors .2. CAD is defined as the presence of stenosis of ≥ 50% in the left main or ≥ 70% in any other epicardial coronary artery. The MI definition follows the 4th Universal definition of MI, like most papers currently [In CKD, the diagnostic standard was estimated as glomerular filtration rate (eGFR) < 60 mL/min/1.73 murrently . OutcomeP < 0.05. The I² statistic was utilized to check the heterogeneity of the study. I2 values of 25–50%, 50–75%, as well as > 75%, were low, medium as well as high heterogeneity [2 < 50% and the random-effects model is utilized in the statistical analysis if I2 > 50%. When heterogeneity was high, sensitivity analysis was implemented after the exclusion of studies one by one. In order to evaluate the latent impact of publication bias, funnel plot asymmetry tests were conducted.Statistical analysis was conducted using STATA 16.0 software. RR as well as the corresponding 95% confidence interval (CI) are analyzed. Statistically significant was defined as ogeneity , respectOur pre-designated literature search identified 465 articles. After reviewing the title and abstract, 65 citations were reviewed in detail. However, we excluded 55 studies due to the inconformity of the designated inclusion criteria. A total of 5 trials were eligible for inclusion Fig. . All theThe quality evaluation process of the five included studies was assessed in accordance with the modified Jadad scale. Finally, based on the evaluation results of 3 researchers, there were three high-quality and two low-quality articles. The quality evaluation form according to the RoB2 scale  is shown in Fig. b.Five research analyzed the long-term all-cause death events. The long-term mortality risk of participants who underwent CABG was slightly lower than that of the participants who underwent PCI , without significant heterogeneity I²=23.6%). The result is represented in Fig. .6%. The a. However, after the analysis of the subgroup was limited to the short-term risk of MACCEs, it showed different results. There were no significant differences in short-term risk of MACCEs between the participants who underwent CABG and PCI , with significant heterogeneity (I²=85.5%).Four studies reported long-term MACCEs. Due to the high heterogeneity , the random-effects model was applied for analysis. The combined results show that the long-term risk of MACCEs in CABG is lower than that of PCI , which is represented in Fig. 2 = 46.5%; Fig. Three studies reported long-term cardiac death. Based on the pooled analysis results of these three studies based on a fixed-effect model, the long-term cardiac mortality rate of patients receiving CABG was significantly lower than that of patients receiving PCI ; using a fixed-effect model, the results shown in Fig. Five included studies reported long-term myocardial infarction and the results showed low heterogeneity . Therefore, the fixed-effect model was utilized. The long-term risk of repeated revascularization of participants who underwent PCI was higher than that of participants who underwent CABG . When the subgroup analysis referred to the short-term risk of repeated revascularization, it showed different results. There were no significant differences in short-term risk of repeated revascularization between the participants with who underwent CABG and PCI , without heterogeneity (I2 = 0.0%).Four studies reported repeated revascularization without heterogeneity ; therefore, the fixed-effects model was utilized. The results indicated that the risk of long-term cerebrovascular accidents of participants who underwent PCI was significantly higher than that of participants who underwent CABG  reported that compared with PCI, CABG is associated with lower long-term mortality, MI, and repeated revascularization risk, and these results are consistent with our meta-analysis . The hetOur study found that PCI was significantly less effective than CABG in terms of repeated revascularization and cardiovascular mortality endpoints. Several possible reasons can be analyzed: (1) CKD is often secondary to diabetes , 25, andA meta-analysis that included 2 RCTs and 15 retrospective experiments reported that contrary to our findings, the incidence of short-term all-cause death of CABG is higher than PCI . At the The novelty of this study is that we included all randomized controlled experiments. However, our research has several restrictions. Firstly, the amount of people participating in the research is still limited. Secondly, the SYNTAX scale tool is a specific instrument introduced by the Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) trial, which was utilized to assess the severity as well as the progression of CAD. Because of the lack of SYNTAX scale data in the majority of the research involved, the analysis of subgroups according to different SYNTAX score ranges were unfinished. Thirdly, a previous study has shown that patients undergoing peritoneal dialysis have a decreased incidence of hemorrhagic stroke than patients undergoing hemodialysis . NeverthThus, in accordance with the long-term follow-up results, CABG is still better than PCI for CAD patients with CKD. However, further large-sample RCT experiments are still needed to confirm the short-term MACCEs risk of PCI and CABG.


Subgroup analysis found differences according to the continent of origin of the study, the follow-up length, and the sample size . CAP is a significant risk factor for all major CVD events including ACS, stroke, and mortality. However, these findings should be taken with caution due to the substantial heterogeneity and the possible publication bias.One-third of adult inpatients with community-acquired pneumonia (CAP) develop acute coronary syndrome (ACS), stroke, heart failure (HF), arrhythmias, or die. The evidence linking CAP to cardiovascular disease (CVD) events is contradictory. We aimed to systematically review the role of CAP as a CVD risk factor. We registered the protocol (CRD42022352910) and searched for six databases from inception to 31 December 2022. We included 13 observational studies, 276,109 participants, 18,298 first ACS events, 12,421 first stroke events, 119 arrhythmic events, 75 episodes of new onset or worsening HF, 3379 deaths, and 218 incident CVD events. CAP increased the odds of ACS , stroke , mortality , and all CVD events . Heterogeneity was significant (I Community-acquired pneumonia (CAP) and cardiovascular disease (CVD) events are the leading causes of morbidity and mortality globally ,2,3,4,5.There seems to exist a bidirectional relationship between pneumonia and CVD . On one However, the evidence linking CAP to cardiovascular complications is contradictory and not substantial. Most published studies included a single cohort without an adequate control group. Additionally, only two meta-analyses published in full text have included some of these studies ,13. TherWe conducted this systematic review following the recommendations of the Cochrane Handbook for Systematic Reviews , PRISMA The articles found were analyzed using the terms of the PECO strategy and the inclusion and exclusion criteria. In addition, relevant data from each paper were extracted and recorded in a spreadsheet: the name of authors, year and country of publication, type of study, number of patients, number of events, the measure of association, and adjusted confounders.2 statistic. Heterogeneity was significant , then we used a random effects model. We carried out sensitivity and subgroup analyses. The risk of bias was assessed using the Newcastle–Ottawa Scale (NOS) tool [In the meta-analysis, we pooled the adjusted odds ratios (OR), risk ratios (RR), or hazard ratios (HR) with 95% confidence intervals (95% CI) using the generic inverse variance method. Forest plots represented the quantitative synthesis. Heterogeneity among studies was assessed with Cochran’s Q test and Higgins IOS) tool  and publWe defined “all CVD events” as a composite of first ACS or first stroke event, new or worsening episodes of heart failure, arrhythmia , and death. Incident CVD event was defined as a composite of ACS, stroke, and fatal CHD . For stuWe collected a total of 12,796 in the primary and 31 in the secondary search. After eliminating duplicates, 83 publications were evaluated for their titles and abstracts. Subsequently, 40 articles were analyzed in full text, of which 13 papers (nine cohort and four case-control studies) were selected for qualitative and quantitative assessment . We only2 = 97%, p < 0.001). The sensitivity analysis—with outliers excluded—did not significantly affect the overall estimate. In the subgroup analysis, we found statistically significant differences according to the continent of origin of the study , the length of follow-up , and the sample size . Conversely, we did not find statistically significant differences between subgroups according to the study design   A–G. Due All of the studies included had a low risk of bias . HoweverThis systematic review and meta-analysis shows that CAP significantly increases the odds of developing ACS , stroke , mortality , and all CVD events—a composite of first ACS event, first stroke event, new or worsening episodes of heart failure, arrhythmia , and death  A–E. ThesCorrales-Medina et al. performed a meta-analysis to determine the incidence of major cardiac complications in CAP patients. They searched Medline, Scopus, and EMBASE for observational studies of adults with CAP reporting the following: overall cardiac complications, incident HF, ACS, or incident cardiac arrhythmias occurring within 30 days of CAP diagnosis. They found 25 articles that met the eligibility and minimum quality criteria. Seventeen articles (68%) reported cohorts of CAP inpatients. In this group, the pooled incidence rates for overall cardiac complications , incident HF , ACS , and incident cardiac arrhythmias  were 17.7% , 5.3% (95% CI 3.2–8.6), and 4.7% (95% CI 2.4–8.9), respectively. One article reported cardiac complications in CAP outpatients, four in low-risk (not severely ill) inpatients, and three in high-risk inpatients. The incidences for all outcomes except the overall cardiac complications were lower in the two former groups and higher in the latter. One additional study reported on CAP outpatients and low-risk inpatients without discriminating between these groups. Twelve studies (48%) asserted the evaluation of cardiac complications in their methods, but only six (24%) defined them. Only three studies, all examining ACS, carried out risk factor analysis for these events. No study analyzed the association between cardiac complications and other medical complications or their impact on other CAP outcomes. Nevertheless, the authors concluded that major cardiac complications occur in a substantial proportion of patients with CAP .Tralhão et al. undertook a meta-analysis to report the incidence of overall complications, ACS, new or worsening HF, new or worsening arrhythmias, and acute stroke as well as short-term mortality outcomes. In addition, they reviewed the interplay between the two conditions (pneumonia and CVD complications). They included 39 observational studies involving 92,188 patients, divided by setting (inpatients versus outpatients) and clinical severity (low risk versus high risk). They reported that the overall cardiac complications occurred in 13.9%, ACS in 4.5%, HF in 9.2%, arrhythmias in 7.2%, and stroke in 0.71% of the pooled inpatients. Furthermore, the meta-regression analysis suggested that overall and individual cardiac complication incidence decreased. After adjusting for confounders, cardiovascular events after CAP independently increased the risk for short-term mortality (range of OR: 1.39–5.49). The authors’ findings highlighted the need for effective, large, trial-based, preventive, and therapeutic interventions in this patient population [Baskaran et al. performed a meta-analysis, searching for observational studies to summarize the literature on the incidence of ACS in adults with CAP. They looked for Medline and Embase and reported that 103 studies met the inclusion criteria. The authors included 26 studies , most of them of good quality. This meta-analysis showed that the pooled incidence of ACS in-hospital and 30 days after CAP was 3.2%  and 3.5% , respectively. Sensitivity analysis excluding studies with selected cohorts  showed a higher pooled incidence for in-hospital ACS  but unchanged for 30-day incidence. These researchers concluded that their meta-analysis showed a small but significant risk of ACS in patients with CAP. This study was published in 2020 only in abstract form .It is worth noting that most of the primary studies published to date and included in these three previous meta-analyses ,13,79 haThe pathophysiologic mechanisms by which pneumonia can trigger CVD are probably diverse and involve several ways: (1) systemic and coronary artery inflammation increases cardiovascular risk; (2) infection and inflammation promote platelet activation and thrombosis; (3) changes in nitric oxide (NO) synthase and cyclooxygenase (COX) lead to endothelial dysfunction; (4) pneumonia impairs myocardial contractility, oxygen demand, and delivery; and additionally (5), the microorganisms may have a direct effect on cardiovascular risk ,87,88,89To the best of our knowledge, this is the first “non-proportional” meta-analysis on CAP and CVD that reports ORs instead of proportions as a measure of effect size. A proportional meta-analysis is a data synthesis method that allows one to calculate a pooled, overall proportion from several individual proportions for a certain event instead of estimating an effect size, as conducted in a “traditional meta-analysis” ,91. ThatFurthermore, the appropriateness of conducting a proportional meta-analysis is controversial, as the individual studies contributing to such a meta-analysis commonly have been conducted in different contexts. These studies’ prevalence and cumulative incidence estimates reflect unique population characteristics . This meThis work has some limitations. (1) Although we performed subgroup analysis according to the continent of origin, the type of study design, the sample size, and the length of follow-up, we could not perform subgroup analyses according to other important variables such as age, sex, treatment setting, clinical severity, and timing after CAP because of the lack of data. (2) It is possible that a meta-regression analysis could further explain the origin of the heterogeneity, although we did not perform this analysis due to limited data. (3) We cannot rule out a possible publication bias against negative studies that did not find a significant association between CAP and CVD complications. (4) The fact that the different continent of origin explains the heterogeneity found could reflect the different forms of diagnosis, treatment, and prognosis, both for pneumonia and cardiovascular complications in each of these countries.Overall, if the heterogeneity is high, the conclusions of the meta-analysis may be less generalizable. Nevertheless, this does not necessarily mean that the results are incorrect or do not have clinical importance. Instead, it is crucial to interpret the meta-analysis results considering the heterogeneity and possible explanations for the differences between the studies included ,95,96,97We highlight some of the strengths of our work: (1) Our search strategy was thorough and complete; (2) we included the odds ratios instead of proportion as the effect measure; consequently, this is the first “traditional” meta-analysis, instead of proportional meta-analysis on this topic; (3) we included primary studies that specifically examined the association between pneumonia and CVD complications; (4) we excluded studies that reported a single cohort without a control group; and (5) we only included studies that reported the adjusted effect sizes. Therefore, our results are more robust than any other meta-analysis reported before.In conclusion, our study shows that pneumonia should be considered as a new risk factor for cardiovascular complications. Furthermore, our findings support the hypothesis that inflammation triggered by acute and chronic infections such as pneumonia is crucial in the pathogenesis of atherosclerosis and cardiovascular complications. However, this conclusion should be taken with caution due to the limitations of our study.