Atopic dermatitis and food allergy are two frequently concomitant manifestations of the presence of atopy. A substantial number of studies have been published on the association of birth order and sibship size (number of siblings) with atopic dermatitis, food allergy, and atopy. The present work is the first systematic synthesis of the existing literature on this topic.Fifteen databases were searched. Screening, data extraction, and quality assessment were performed by independent pairs. Comparable numerical data were statistically synthesized using random‐effects robust variance estimation.In total, 114 studies were included out of 8819 papers obtained from database searches. Birth order ≥2 versus 1 was associated with lower risk of ever atopic dermatitis , current food allergy , and positive skin prick test (SPT) to common aeroallergens . Sibship size ≥2 versus 1 was associated with decreased risk of current atopic dermatitis , ever atopic dermatitis , and positive SPT to common aeroallergens . No putative associations were seen regarding atopy assessed through allergen‐specific immunoglobulin E with common allergens.The presence of siblings and being second‐born or later may decrease the lifetime risk of atopic dermatitis and food allergy, albeit marginally. Similar association was seen with SPT sensitization. However, significant protection was not found for IgE sensitization. The overall findings were synthesized narratively. Comparable numerical data—based on similarity in exposure, outcome, assessment methods and subject characteristics—were also synthesized statistically using meta‐analysis with random‐effects robust variance estimation (RVE).robumeta R package.forestploter R package.The meta‐analyses were performed using the correlated effects model, with small sample‐correction (to increase accuracy)sensitivity function from the robumeta R package.metafor R packagep‐values <0.05 as statistically significant.Subgroup analyses were performed where comparable data were available from ≥4 studies in ≥2 subgroups,Risk ratio (RR) was used as the measure of effect due to ease of interpretation.I‐squared (I2) statistic,τ2).https://osf.io/fp3rw/).Inter‐study heterogeneity was assessed with the squared I2 statistsquared I2 statistsquared I2 statist3The database searches yielded 17,466 records. Of these, 114 reports based on 102 studies met the full inclusion criteria , followed by cohort studies (n = 43), case‐control studies (n = 11), nested case‐control studies (n = 4), and one case‐cohort study. Most studies received a “moderate”  or “strong”  overall rating, while 16 (14%) were rated “weak”  and sibship size .Current atopic dermatitis was assessed with meta‐analysis in 22 studies for birth order and 14 studies for sibship size  and moderate for sibship size .Ever atopic dermatitis was assessed with meta‐analysis in 16 studies for birth order and seven studies for sibship size .The current food allergy was assessed with meta‐analysis in six studies for birth order  and five studies for sibship size  and sibship size . For atopy as defined through positive SPT, the pooled effect size from the 12 studies on birth order  and low for sibship size .Atopy as defined through sIgE levels above the traditional3.7p‐value of 0.04 from the Egger's regression test for atopic dermatitis by birth order indicated asymmetry  siblings was only marginally associated with lifetime risk of having atopic dermatitis, with a weaker impact on current atopic dermatitis. In contrast, the presence of older siblings was associated with a substantially decreased risk of current food allergy, albeit with only a few studies. In terms of allergic sensitization (older), siblings appeared to be marginally associated with protection against atopy to common aeroallergens assessed with SPT, but the association was not significant for atopy assessed with sIgE positivity. Because of the small number of studies in each exposure‐outcome pair, and the socioeconomic homogeneity across studies, meaningful comparison on the effect of publication year and World Bank economic classification was not possible.4.2The exhaustive search of 15 databases—with no restriction by time, language, or outcome definitions—identified a broad and comprehensive scope of relevant literature from across the world. Furthermore, the use of RVE enabled us to include correlated estimates in robust meta‐analyses, and consequently to overcome any issue of multi‐collinearity between the effect estimates. However, the included studies were largely heterogeneous in methodology and subject characteristics, thus limiting the number of comparable studies to synthesize with meta‐analysis. Similarly, the socioeconomic homogeneity, with the vast majority of studies conducted in Western countries after the turn of the millennium, did not allow for the assessment of the effect of changes in lifestyle and living conditions in recent decades on the investigated associations. The underlying data, derived from observational studies, which are prone to confounding (particularly older studies with insufficient confounder adjustment), limits causal inference.4.3To the best of our knowledge, the present work is the first systematic review and meta‐analysis synthesizing the literature on the association between birth order and sibship size with risk of atopic dermatitis, food allergy, and atopy.4.4Both the presence of siblings and being second‐born or later was associated with a marginally lower risk of atopic dermatitis. A similar strength in the association was seen between the presence of siblings and current atopic dermatitis, but the association was non‐significant in second‐born or later. As atopic dermatitis is more commonly seen in childhood (particularly early childhood) with the majority no longer experiencing symptoms in adulthood,While the protective effect of birth order above one on the current food allergy was clearer, it was also based on a relatively small set of studies. Thus, while a 23% reduction in the risk of current food allergy was seen, it is difficult to assess the robustness and generalizability of this association.The association between sibship composition and atopy was relatively similar in terms of exposure, but the association was weaker for both exposure types in relation to sIgE compared with SPT outcomes. Age may be part of the explanation in this case,All in all, the findings indicate that for the investigated outcomes, the association with sibship composition is weak, if practically meaningful at all. The causes for this may be, for example, the heterogeneity of allergic sensitization and these atopic diseases or changes in environmental factors that we were unable to account for the meta‐analyses.4.5Although a protective effect of the presence of (older) siblings was seen across all outcomes, the strength of the association varied substantially between outcomes and age groups. Thus, while our findings partly support the “hygiene hypothesis”—namely that early life cross‐infection between siblings can modulate the immune systems in such a way that the risk of allergy development is reduced5Our findings indicate that having siblings and being second‐born or later is associated with a marginal reduced risk of lifetime risk of atopic dermatitis. Likewise, a higher birth order is associated with roughly 20% lower risk of current food allergy. Allergic sensitization defined by SPT to common aeroallergens is marginally rarer in those with siblings or second‐born or later, while the association for sensitization measured using sIgE did not reach statistical significance. Atopic diseases are heterogeneous and multifactorial, so it is likely that sibship composition only plays a marginal role in the risk of these diseases.Daniil Lisik: Data curation ; Formal analysis (lead); Investigation (lead); Methodology ; Project administration (lead); Software (lead); Validation ; Visualization (lead); Writing – original draft (lead); Writing – review & editing (lead). Saliha Selin Özuygur Ermis: Data curation (supporting); Formal analysis (supporting); Investigation (supporting); Methodology (supporting); Project administration (supporting); Validation ; Writing – review & editing . Athina Ioannidou: Data curation (supporting); Investigation (supporting); Validation (supporting); Writing – review & editing (supporting). Gregorio Paolo Milani: Data curation (supporting); Investigation (supporting); Validation (supporting); Writing – review & editing (supporting). Sungkutu Nyassi: Data curation (supporting); Investigation (supporting); Validation (supporting); Writing – review & editing (supporting). Giulia Carla Immacolata Spolidoro: Data curation (supporting); Investigation (supporting); Validation (supporting); Writing – review & editing (supporting). Hannu Kankaanranta: Formal analysis (supporting); Investigation (supporting); Methodology (supporting); Supervision (supporting); Validation (supporting); Writing – review & editing (supporting). Emma Goksör: Formal analysis (supporting); Supervision (supporting); Validation (supporting); Writing – review & editing (supporting). Göran Wennergren: Formal analysis (supporting); Methodology (supporting); Supervision (supporting); Validation (supporting); Writing – review & editing (supporting). Bright Ibeabughichi Nwaru: Conceptualization (lead); Data curation (supporting); Formal analysis ; Investigation ; Methodology ; Project administration (supporting); Supervision (lead); Validation ; Visualization (supporting); Writing – original draft ; Writing – review & editing .Hannu Kankaanranta reports personal fees for lectures and consulting from AstraZeneca, Boehringer‐Ingelheim, Chiesi Pharma, GSK, MSD, Novartis, Orion Pharma and Sanofi Genzyme outside the current work. The other authors declare no conflict of interest in the context of this work.Supporting Information S1Click here for additional data file.


According to reports, maternal rheumatoid arthritis (RA) has been suggested as a possible adverse factor for developing small for gestational age (SGA) in offspring. However, some studies have also indicated a need for a more statistically significant association between the two. Understanding the relationship between maternal RA and the risk of SGA is crucial for identifying potential adverse outcomes and implementing appropriate interventions. Therefore, this study aims to elucidate the association between maternal RA and the risk of offspring developing SGA.2 test tested and estimated heterogeneity among studies. Odds ratios (ORs) with 95% CI were calculated using random or fixed effects models depending on the heterogeneity. Subgroup analyses, sensitivity analyses, and publication bias assessments were also performed.This study was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (ID: CRD42022357590). A systematic literature search was conducted to identify eligible studies up to August 2022. Quality assessment was performed according to the Newcastle-Ottawa scale. The Q test and Ip < 0.001). Sensitivity analysis showed stable results. The funnel plot of the symmetric distribution and the results of Begg’s and Egger’s tests showed no publication bias.Seven studies, including 12,323,918 participants, were included in the analysis. The results showed a statistically significant association between maternal RA and SGA (OR = 1.70, 95% CI = 1.29–2.23, Maternal RA is associated with an increased risk of SGA in offspring. However, more studies are still needed to explore the potential mechanisms underlying maternal RA and SGA association.https://www.crd.york.ac.uk/PROSPERO/, identifier [CRD42022357590]. Rheumatoid arthritis (RA)is defined as a systemic autoimmune disorder associated with a chronic inflammatory process that can damage joints and extra-articular organs, including the heart, kidneys, lungs, digestive system, eyes, skin, and nervous system , 2. The Small for gestational age (SGA) is defined as birth weight below the 10th percentile for gestational age (GA) . PerinatThis meta-analysis was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Furthermore, it was registered on the International Prospective Register of Systematic Reviews (PROSPERO). The register number was CRD42022357590.The literature was searched from inception to August 2022 in Embase, PubMed, Web of Science, Cochrane Library, and Scopus databases. A comprehensive search strategy was conducted for articles examining maternal RA and SGA in offspring. The search strategy was based on previous systematic reviews on RA and SGA. The complete retrieval strategy was finalized in discussions among three authors . The search strategy for this study consisted of three components: rheumatoid arthritis, pregnant mothers, and small for gestational age. Each component was searched using a combination of free and subject terms, and the components were combined using specific database terms. The search strategy for PubMed is shown below. It was adapted for the other databases (((((((Arthritis) OR (Rheumatoid)) OR (Rheumatoid Arthritis)) OR (Rheumatoid Nodule)) OR (Rheumatoid Vasculitis)) OR ) AND  OR )) AND .The type of study was a case–control study or cohort study.The outcome of interest was the risk in SGA.Estimates such as ratio ratios (ORs) or relative risks (RRs) with the corresponding 95% confidence intervals (CIs) were reported, or sufficient data were provided to perform the calculation.Pregnant women with no clear indication of special treatment (biologic therapy).The inclusion criteria developed for screening eligible publications were as follows:The study was not in humans, e.g., in vitro and in vivo studies.The article was in the review category.Risk estimates could not be calculated.Duplication.Exclusion criteria were as follows:Two participants (Lv Tian and Zhiyuan Zhang)extracted the data independently according to a predefined data form and then assessed the quality of the articles. If disagreements were encountered, discussions were held to reach an agreement, or a third person (Yuting Mao) was consulted regarding recommendations. Data extracted included authors’ names, year, country, study design, comparisons, total participators, OR or RR with 95% CI, quality, adjustment factors, assessment method, and age of the study participators. The quality of observational studies was assessed by the Newcastle-Ottawa scale, which has three columns: selection, comparability, and outcome/exposure. The total score is nine stars, with six or more stars for high-quality literature and 4–5 stars for moderate quality .p = 0.1 level and then based on I2 statistics: I2 < 50% of respondents indicated no significant statistical heterogeneity and therefore a fixed effects model was selected, I2 > 50% indicated statistical heterogeneity, and a random effects model was used  + (P0 × OR)], was used to perform RR to OR conversion (P0 represents the incidence of the outcome in the non-exposed group) . When muwas used , 27. Senwas used . Publicawas used , 30. p vAccording to the search strategy, the initial electronic search yielded 1872 articles, and 1,164 articles were obtained after eliminating duplicates. Seventy-eight articles were retained after reading the titles and abstracts. Finally, the full text was read through to filter the literature, and finally, seven articles were obtained for inclusion . The detThis meta-analysis included seven articles involving a total of 12,323,918 participants, published between 2006 and 2019. Of these, three were conducted in the United States, two in Canada; one was conducted in Norway, and one in Switzerland. Six of them were adjusted for confounding factors. All included studies were of high or moderate quality. p < 0.001; I2 = 89.6%; Seven studies related to the association between maternal RA and the risk of SGA in offspring were included in the overall meta-analysis . Heterogp = 0.003). Two studies conducted in Canada (p = 0.048) showed a statistically significant association between maternal RA and increased risk of SGA in offspring. A study from Norway reported an OR of 1.1 (95% CI = 0.88–1.37), and a study from Switzerland reported an OR of 13.0 (95% CI =1.68–100.91). For adjustment factors, a significant association was observed in adjusted studies . For subgroup analyses with different study qualities, the results remained unchanged [high quality  and that prolonged excessive oxidative stress and intrauterine malnutrition can lead to SGA in offspring . OxidatiIn another study, IL-10 was found to be detectable in 23.4% of RA patients and IL-6 in 76.6% of patients in late pregnancy. When IL-6 levels were high, the risk of neonatal SGA was increased, suggesting that increased levels of IL-6 are associated with neonatal SGA . In addi2 = 89.6%) of the pooled effects may reflect the significant variation in sample size. Considering the limited number of studies in our review and the high heterogeneity, more and higher quality studies are needed. Our results should be interpreted cautiously due to the limited number of included studies. Finally, our study is the absence of correlation analysis between maternal RA disease activity and the risk of neonatal SGA. Unfortunately, we could not investigate this potential association due to the need for more sufficient data in the included studies. However, we acknowledge this limitation and encourage future research to explore the relationship between maternal RA disease activity and the risk of SGA. Despite these limitations, the following strengths of this study should be acknowledged. This is the first meta-analysis to elucidate the relationship between maternal RA and the risk of SGA in offspring. In addition, sensitivity analyses showed that the meta-analysis results did not change substantially using the leave-one-out method. The results were robust, and there was no publication bias.This meta-analysis has several limitations. First, heterogeneity existed between included studies, so a random effects model was applied to combine ORs and RRs. Although subgroup analysis could explain some of the heterogeneity, sufficient data from the included original studies, such as different ethnicities of female RA patients and different rheumatoid disease characteristics , were lacking to investigate other potential sources. Second, although the sensitivity analysis results were robust and ensured the accuracy and persuasiveness of the results, the limited number of studies conducted outside of Europe and the Americas suggests the need for more data on populations of different backgrounds. The substantial heterogeneity .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.


Apolipoproteins and lipoprotein(a) are associated with various cardiometabolic diseases, including insulin resistance, diabetes mellitus, hypertension, dyslipidemia, among others. This systematic review and meta-analysis was conducted to evaluate the association of these markers with metabolic syndrome (MetS).We ran a systematic search through PubMed, Scopus, Embase, Ovid/Medline, and Web of Science on March 15, 2023. No language or date restrictions were applied. The only synthesised effect measure reported was the odds ratio (OR) with its corresponding 95% confidence interval (95% CI). We utilised the random-effects model for the quantitative synthesis.n = 150 519) with different definitions for MetS. Increased ApoB values were associated with MetS . Decreased ApoA1 values were associated with MetS . Increased values of the ApoB/ApoA1 ratio were associated with MetS . Decreased values of Lp(a) were associated with MetS .We analysed 50 studies  are associated with MetS. These findings suggest that these lipid markers may serve as potential indicators for identifying subjects at risk of developing MetS. However, further research is required to elucidate the underlying mechanisms of these associations.The online version contains supplementary material available at 10.1186/s12944-023-01860-w. Metabolic syndrome (MetS) is associated with a fivefold increase in the risk of diabetes mellitus, a twofold higher risk of cardiovascular events, and a 1.5-fold higher risk of all-cause mortality . ConsequApolipoproteins are constituents of high-density lipoproteins (HDL) and triglyceride-rich lipoproteins . Due to Circulating apolipoprotein levels reflect the number of lipoprotein particles, rather than the concentration of cholesterol . In thisIn the development of this systematic review, we adhered to guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement . A versiThe search strategy was designed using the Peer Review of Electronic Search Strategies Checklist . There wWe selected studies with the following characteristics: cohort/case–control/cross-sectional studies that evaluated the association between ApoB, ApoA1, ApoB/ApoA1 ratio and Lp (a), and MetS in adult patients (> 18 years). We excluded: duplicated studies, scoping reviews, systematic reviews, narrative reviews and conference abstracts.The studies retrieved from the systematic search were uploaded to the data management software Rayyan QCRI. After removing duplicated studies, four authors  independently assessed the title/abstract of each study according to the selection criteria. Once the relevant literature was identified, two reviewers (M.A.H-C and X.L.C-T) independently assessed the full text of each article. The studies that did not comply with the entire selection criteria were excluded from the review. In case of missing information, we contacted the authors. Any discrepancies were resolved through discussion and consensus between the two reviewers.For extracting data, we employed a standardised data collection sheet created in Google Sheets©. The data were gathered independently by two authors (E.A.H-B and E.A.A-B) from each study and included the following details: title, study location, first author, publication date, study design sample size, age, sex, definition of MetS, ApoB levels(mg/dL), ApoA1 levels(mg/dL), ApoB/ApoA1 ratio levels, Lp(a) levels(mg/dL) and assay technique. For articles published in a language other than English, we proceeded to translate them using online translation tools.Two authors (J.R.U-B and E.A.A-B) independently performed the risk of bias assessment. The Newcastle–Ottawa Scale (NOS) was used for cohort and case-controls studies, whereas an adjusted version of the NOS for cross-sectional studies (NOS-CS) was applied to this type of study. A score of ≥ 7 stars was considered indicative of a low risk of bias, while a score of < 7 stars was considered indicative of a high risk of bias. To assess publication bias, we employed funnel plots and the Begg test.2 statistic to assess between-study heterogeneity, in which I2 ≥ 60% for the I2 test and a p-value < 0.05 for the Cochran's Q test indicated high heterogeneity. Subgroup analyses were conducted according to continent, sex, assay method, and MetS diagnostic criteria. In the sensitivity analysis, we excluded studies with a high risk of bias.The statistical analysis was performed in STATA 17.0 © and Review Manager v.5.4 . For all meta-analyses, we employed a random-effects model (Restricted Maximum Likelihood). All the effect measures were reported as the odds ratios (OR) with their corresponding 95% confidence intervals (CI). Any other effect measure was transformed into OR. Using Hozo's method, we converted median values and their interquartile ranges were converted into means and their corresponding standard deviations (SD) . We alsoIn the search strategy, a total of 2262 studies were identified. After removing duplicates and reviewing titles and abstracts, 153 studies met the selection criteria and advanced to the full-text reading phase. Upon reading the full text of each article, 50 studies were deemed eligible for inclusion in the qualitative synthesis and meta-analysis , 20–67. n = 10,486) did not report the sex of the included participants. Ultimately, fifty studies were included, of which 40 had a cross-sectional design, 7 were case–control studies, and 3 were cohort studies. Six studies [A total of 150 519 participants were included, of which 62 083 were female and 77 958 were male. Six studies  criteria , 10 studn = 79,661). Increased ApoB values were associated with MetS  .Twenty-nine studies assessed this association n = 79,66. Increasn = 66 189). Reduced ApoA1 values were associated with MetS  .Twenty-eight studies assessed this association n = 66 19. Reduce9%) Fig. , and stu9%) Fig. . In all 9%) Fig. , after en = 79 664). Increased values of the ApoB/ApoA1 ratio were associated with MetS  .Twenty-three studies assessed this association n = 79 66. Increas7%) Fig. , sex (Su7%) Fig. , contine7%) Fig. , and stu7%) Fig. . In all 7%) Fig. , the assn = 52 342). Decreased Lp (a) values were associated with MetS  , those using immunonephelometry to measure Lp(a) values , and those diagnosing MetS using HDM criteria  maintained a significant association with high heterogeneity. In the sensitivity analysis .Eighteen studies assessed this association n = 2 342. De2%) Fig. , MetS di2%) Fig. , contine2%) Fig. , and stu2%) Fig. . The stuNo asymmetry was found in the funnel plot , and MetS. The main findings of our investigation demonstrate evidence that high ApoB levels, low ApoA1 levels, and elevated ApoB/ApoA1 ratio are significantly associated with MetS. Despite the implementation of sensitivity analyses, our findings continue to demonstrate significant heterogeneity across the included studies.Apolipoproteins are proteins synthesised in the liver that play a crucial role in the transport and redistribution of lipids , 75. ApoThe pathophysiology of MetS involves multiple mechanisms that are not yet not fully understood. There is ongoing debate regarding the individual components of MetS, in addition to genetic and epigenetic factors, represent distinct pathologies or are interconnected within a common broader pathogenic process . RegardlIt is worth emphasising that some authors consider the ApoB/ApoA1 ratio as the most accurate marker for assessing the balance between atherogenic and anti-atherogenic lipoproteins. They argue that this ratio serves as a superior predictor of cardiovascular risk associated with cardiovascular lipoproteins than traditional lipid indices , 85. SimDespite the observed associations, the internal validity of our results is limited by their high heterogeneity, which can be attributed to inherent variations in the studies included in our study. Although sensitivity analysis was performed according to sex, diagnostic criteria for MetS, method of assessment of apolipoproteins and according to the continent in which the studies were conducted, the heterogeneity was still high, which means that other variables that can potentially affect these associations were not considered. One of these may be related to the prevalence of MetS, as it has been suggested that associations between ApoB and various cardiometabolic disorders are limited to populations with a relatively high prevalence of MetS . FurtherOur study should be interpreted considering its limitations. First, it is important to note that the high heterogeneity observed between studies did not diminish even after conducting subgroup analysis and sensitivity analysis. This implies that there is high clinical and methodological variability among these studies, so it would be desirable that future studies take into account more variables that may influence the values of these lipoproteins . Second, due to the limited information in the studies, the sensitivity, specificity and optimal cut-off point of these markers for estimating the risk of developing MetS were not determined, which would be important to evaluate in future studies. Third, since the majority of the included studies were of cross-sectional design, there is a risk of reverse causality. Despite these limitations, our study has several strengths. A large number of studies were included, resulting in a substantial number of participants, thereby ensuring adequate statistical power. Furthermore, a thorough search was conducted across multiple databases, ensuring a comprehensive inclusion of the available evidence. Likewise, subgroup analysis was performed according to assay method, MetS diagnostic criteria, continents and study design. To the best of our knowledge, this systematic review and meta-analysis represents the first comprehensive synthesis of available studies examining the association between apolipoproteins and Lp(a) levels in patients with MetS.Increased values of ApoB and ApoB/ApoA1 ratio and reduced values of ApoA1 and Lp(a) are associated with the presence of MetS. These findings suggest that these lipid markers may serve as potential indicators for identifying subjects at risk of developing MetS. However, additional studies are warranted to gain a deeper understanding of the underlying mechanisms driving these associations. In addition, further clinical research and longitudinal studies are recommended to better understand the causal relationship between these lipid markers and MetS, as well as to explore their potential utility in clinical practice for early detection and management of MetS.Additional file 1: Table S1. Search strategies. Table S2. Criteria for clinical diagnosis of metabolic syndrome used in the included studies. Table S3. Quality assessment of included studies. Figure S1. Subgroup analysis according to assay method of the association between ApoB levels and MetS. Figure S2. Subgroup analysis according to diagnostic criteria of the association between ApoB levels and MetS. Figure S3. Subgroup analysis according to sex of the association between ApoB levels and MetS. Figure S4. Subgroup analysis according to continents of the association between ApoB levels and MetS. Figure S5. Subgroup analysis according to study design of the association between ApoB levels and MetS. Figure S6. Sensitivity analysis according to risk of bias of the association between ApoB levels and MetS. Figure S7. Subgroup analysis according to assay method of the association between ApoA1 levels and MetS. Figure S8. Subgroup analysis according to diagnostic criteria of the association between ApoA1 levels and MetS. Figure S9. Subgroup analysis according to sex of the association between ApoA1 levels and MetS. Figure S10. Subgroup analysis according to continents of the association between ApoA1 levels and MetS. Figure S11. Subgroup analysis according to study design of the association between ApoA1 levels and MetS. Figure S12. Sensitivity analysis according to risk of bias of the association between ApoA1 levels and MetS. Figure S13. Subgroup analysis according to diagnostic criteria of the association between ApoB/ApoA1 ratio levels and MetS. Figure S14. Subgroup analysis according to gender of the association between ApoB/ApoA1 ratio levels and MetS. Figure S15. Subgroup analysis according to continents of the association between ApoB/ApoA1 ratio levels and MetS. Figure S16. Subgroup analysis according to study design of the association between ApoB/ApoA1 ratio levels and MetS. Figure S17. Sensitivity analysis according to risk of bias of the association between ApoB/ApoA1 ratio levels and MetS. Figure S18. Subgroup analysis according to assay method of the association between lipoprotein(a) levels and MetS. Figure S19. Subgroup analysis according to diagnostic criteria of the association between lipoprotein(a) levels and MetS. Figure S20. Subgroup analysis according to continents of the association between lipoprotein(a) levels and MetS. Figure S21. Subgroup analysis according to study design of the association between lipoprotein(a) levels and MetS. Figure S22. Sensitivity analysis according to risk of bias of the association between lipoprotein(a) levels and MetS. Figure S23. Funnel Plot of the studies that evaluated the association between ApoB and MetS. Figure S24. Funnel Plot of the studies that evaluated the association between ApoA1 and MetS. Figure S25. Funnel Plot of the studies that evaluated the association between ApoB/ApoA1 ratio and MetS. Figure S26. Funnel Plot of the studies that evaluated the association between Lipoprotein(a) and MetS.


The present meta-analysis evaluated the relationship between TNF-α polymorphisms in psoriasis cases compared to controls. The effect sizes were the 95% confidence intervals (CIs) and odds ratios (ORs). Subgroup analysis, sensitivity analyses, publication bias, trial sequential analysis (TSA), and meta-regression were performed on the initial pooled results of TNF-α polymorphisms.Four databases were searched to retrieve relevant studies reporting the distributions of rs361525, twenty-seven: rs1800629, nine: rs1799724, four: 1800630, and five: rs1799964). The pooled ORs for −238 G/A rs361525 polymorphism were 2.33 (p < 0.00001), 2.79 (p < 0.0001), 2.35 (p < 0.00001), 2.44 (p < 0.00001), and 2.45 (p < 0.00001), as well as 1.57 (p < 0.00001), 1.98 (p = 0.01), 1.61 (p < 0.00001), 1.64 (p < 0.00001), and 1.79 (p < 0.00001) for −857 C/T rs1799724 polymorphism in allelic, homozygous, heterozygous, dominant, and recessive models, respectively. Ethnicity, psoriasis type, and sample size affected the pooled results of rs361525, rs1800629, and rs1799724 polymorphisms. Based on TSA, there were just sufficient cases for −238 G/A rs361525 polymorphism in five genetic models and −857C/T rs1799724 polymorphism in allelic, heterozygous, and dominant models.Thirty-six articles with 71 studies were included in the meta-analysis  with more cases are recommended in the future.The A allele and GA and GG genotypes of −238 G/A  PsoriasThe prevalence of psoriasis varies across the world . A recenThe interaction between multiple genetic and environmental risk factors can cause psoriasis as a common inflammatory skin disease ,11 and tPsoriasis is a T lymphocyte-mediated inflammatory disease  that Th1rs361525, rs1800629, rs1799724, 1800630, and rs1799964 in psoriasis cases compared to controls with different results [TNF-α polymorphisms in psoriasis cases. One of them [rs361525, rs1800629, and rs1799724 polymorphisms, including that these polymorphisms could be associated with susceptibility to psoriasis in certain populations. Another meta-analysis [rs361525, rs1800629, rs1799724, 1800630, and rs1799964 polymorphisms that the first three polymorphisms are associated with psoriasis susceptibility. The third meta-analysis [rs1800629 polymorphism and conducted that this polymorphism was associated with psoriasis susceptibility. A fourth meta-analysis [rs361525 and rs1800629 polymorphisms, with rs361525 polymorphism having an increased risk and rs1800629 polymorphism having a protective role in psoriasis cases, and this result was confirmed by fifth meta-analysis [. A sixth meta-analysis [rs361525 and rs1800629 polymorphisms, including that these polymorphisms were associated with the risk of psoriasis.Several studies have investigated the relationship of single nucleotide polymorphism (SNP) of  results . Six met results  reported of them  searchedanalysis  until 20analysis , which ianalysis , which iTNF-α polymorphisms  and susceptibility to psoriasis in studies that followed HWE and had suitable cases.Testing for Hardy-Weinberg equilibrium (HWE) is a crucial quality control step in identifying suitable polymorphisms for genetic studies . A devia22.1TNF-α polymorphisms associated with the risk of psoriasis? .The design of the meta-analysis was performed based on preferred reporting items for systematic reviews and meta-analyses (PRISMA) protocols. Also, the population-exposure-comparators-outcomes (PECO) question was: Are 2.2The databases of Scopus, PubMed/Medline, Cochrane Library, and Web of Science until July 12, 2022, without any restrictions, were comprehensively searched. The key terms to search a database were:  and (“psoriasis” or “psoriatic”) and . Moreover, the citations of the retrieved articles in relation to the subject were examined to make sure that no study was omitted and then the titles/abstracts of all articles meeting the criteria were assessed by one author (M.S.) and then downloaded. Another author (O.E.A.) re-tested the study selection process. Differences between the results of both authors were resolved by a short conversation.2.3TNF-α polymorphisms  in psoriasis cases and controls. 3) studies included more than 100 individuals in psoriasis and control groups together. 4) studies following HWE for their controls. 5) Psoriasis cases including any subtype. 6) clinical subtypes of psoriasis (psoriasis vulgaris and psoriatic arthritis) were diagnosed based on the Moll and Wright or CASPAR criteria [Inclusion criteria: case-control or cohort studies including psoriasis cases and controls without receiving any treatment. 2) studies reporting the prevalence of alleles and genotypes of criteria ,40 or byExclusion criteria: case reports, meta-analyses, meeting abstracts, review articles, editorial articles, studies with insufficient data to calculate distributions of alleles and genotypes, studies without a control group, book chapters, and studies including psoriasis patients with other diseases were excluded.2.4Two authors (M.S. and S.S.) separately extracted the data of the articles imported in the analysis and another author (A.E.) resolved the disagreement between the authors.2.5The quality assessment of the studies was performed by one author (M.S.) using the Newcastle-Ottawa scale (NOS) that number eight was considered the maximum score, and a score of ≥7 showed a high-quality study.2.6TNF-α polymorphisms  between psoriasis cases and controls were calculated using the Review Manager 5.3 (RevMan 5.3) software. A p-value (2-sided) less than 0.05 was considered statistically significant, and Pheterogeneity less than 0.10 (I2 > 50%) identified significant heterogeneity. Due to significant heterogeneity, a random-effects model [The effect sizes, including the 95% confidence interval (CI) and odds ratio (OR), of ts model  was utilts model  was usedp-value (2-sided) of both tests were less than 0.10, it indicated the existence of the publication bias. Sensitivity analyses and publication bias were conducted using the Comprehensive Meta-Analysis version 2.0 (CMA 2.0) software.The sensitivity analyses, including “one-study-removed” and “cumulative” analyses, were conducted to evaluate the stability/consistency of pooled ORs. The publication bias degree was assessed using Egger’s test to assess the degree of asymmetry  and BeggTo report false positive or false negative results from meta-analyses , trial s33.1rs361525, 27: rs1800629, 9: rs1799724, 4: 1800630, and 5: rs1799964).Out of 1029 records recognized through databases and electronic sources, after eliminating duplicates, 670 remaining records were screened . After t3.2rs361525 polymorphism. Out of 24 articles [articles  that incrs1800629 polymorphism. Twenty-two articles [articles  includedrs1799724 polymorphism . Out of nine studies, three reported patients with psoriasis vulgaris, four psoriatic arthritis, one just psoriasis without subtype, and one generalized pustular psoriasis. Three articles [rs1800630 polymorphism . Out of four studies, three included patients with psoriatic arthritis and one included psoriasis. Four articles [rs1799964 polymorphism; included five studies that three studies were reported in Caucasians, one in Asians, and one in a mixed population. Out of five studies, two included cases with psoriasis vulgaris and three with psoriatic arthritis.articles ,26,74 inarticles ,23,25,263.3,−857 C/T, −863 C/A, and −1031 T/C polymorphisms of TNF-α have been shown in Supplementary 1 and p-value <0.00001), 2.79 , 2.35 , 2.44 , and 2.45 , as well as 1.57 , 1.98 , 1.61 , 1.64 , and 1.79  for −857 C/T rs1799724 polymorphism in allelic, homozygous, heterozygous, dominant, and recessive models, respectively. Therefore, A allele and GA and GG genotypes of −238 G/A polymorphism and T allele and TT and CT genotypes of −857 C/T polymorphism had elevated risks in psoriasis cases.Forest plots of −238 G/A,−308 G/A3.4rs361525 polymorphism including ethnicity, psoriasis type, and sample size have been identified on five genetic models in Subgroup analyses of −238 G/A rs1800629 polymorphism including ethnicity, psoriasis type, and sample size have been identified on five genetic models in Subgroup analyses of −308 G/A rs1799724 polymorphism including ethnicity, psoriasis type, and sample size have been identified on five genetic models in rs1800630 and −1031 T/C rs1799964 polymorphisms.Subgroup analyses of −857C/T 3.5rs361525,−308 G/A rs1800629,−857 C/T rs1799724 polymorphisms of TNF-α have been shown in rs361525 polymorphism; as well as on five models of −308 G/A rs1800629, and also sample size was another confounding factor on allelic and dominant models of −308 G/A rs1800629 polymorphism. Due to a low number of studies, we didn’t calculate the meta-regression analysis for −863 C/A and −1031 T/C polymorphisms.Meta-regression analyses (publication bias and sample size) of −238 G/A 3.6,−308 G/A, and −857 C/T polymorphisms of TNF-α including “one-study-removed” and “cumulative analysis” have been shown in Supplementary 2 that the results showed the stability of the pooled analyses. Due to a low number of studies, we didn’t calculate the sensitivity analysis for −863 C/A and −1031 T/C polymorphisms.The plots of sensitivity analyses for −238 G/A3.7,−308 G/A, and −857 C/T polymorphisms of TNF-α, and also Supplementary 4 shows the TSA of other models for three polymorphisms. Due to a low number of studies, we didn’t calculate the TSA for −863 C/A rs1800630 and −1031 T/C rs1799964 polymorphisms. The results showed that Z-curve crossed the RIS line for −238 G/A rs361525 polymorphism, but not for −308 G/A rs1800629 polymorphism in five genetic models. With regards to −857 C/T rs1799724 polymorphism, the RIS line was just reached by Z-curve in allelic, heterozygous, and dominant models. Therefore, there were just sufficient cases for −238 G/A rs361525 polymorphism in five genetic models and −857C/T rs1799724 polymorphism in allelic, heterozygous, and dominant models.3.8,−308 G/A, and −857 C/T polymorphisms of TNF-α have been shown in Supplementary 3. The p-values of Egger’s/Begg’s tests were 0.855/0.707, 0.970/0.216, 0.652/0.842, 0.840/0.912, and 0.935/0.248 for −238 G/A rs361525 polymorphism; 0.474/0.631, 0.545/0.804, 0.573/0.545, 0.491/0.491, and 0.510/0.869 for −308 G/A rs1800629 polymorphism; and 0.272/0.404, 0.823/0.834, 0.364/0.297, 0.324/0.404, and 0.755/0.676 for −857 C/T rs1799724 polymorphism in allelic, homozygous, heterozygous, dominant, and recessive models, respectively. There was no publication bias for the pooled results of three polymorphisms. The due to low numbers of studies, we didn’t calculate the publication bias for −863 C/A and −1031 T/C polymorphisms.Funnel plots of −238 G/A4rs361525 polymorphism, as well as T allele and TT and CT genotypes of −857 C/T rs1799724 polymorphism were associated with elevated risks in psoriasis cases. There was no association between −308 G/A, −863 C/A, and −1031 T/C polymorphisms and the risk of psoriasis. Ethnicity, psoriasis type, and sample size were effective factors in the pooled results of −238 G/A, −308 G/A, and −857 C/T polymorphisms. The number of cases was not sufficient for the pooled analysis of −308 G/A polymorphism.The main results of the meta-analysis recommended that A allele and GA and GG genotypes of −238 G/A TNF-α polymorphisms were associated with psoriasis risk. The meta-analysis of Zhu et al. [Psoriasis is in a state of oxidative stress  and its u et al.  reportedu et al.  confirmers361525 polymorphism [rs1799724 polymorphism was significantly related to psoriasis in Caucasians and the present meta-analysis confirmed it, but the result was in contrast with the result of the meta-analysis of Zhu and his colleagues [rs1799724 polymorphism was related to psoriatic arthritis risk that the present meta-analysis identified that this polymorphism was associated with both psoriasis vulgaris and psoriatic arthritis. In addition, the polymorphisms of −308 G/A, −863 C/A, and −1031 T/C were not related to the psoriasis susceptibility, as well as the present meta-analysis confirmed it.All meta-analyses reporting −238 G/A morphism  recommenmorphism , reportelleagues . Zhu et lleagues  in theirThe accurate mechanism of ethnic disparity is unclear, but studying variations in genetic base and social agents across different people may be important . EthnicaTNF-α polymorphisms in two types of psoriasis (psoriasis vulgaris and psoriatic arthritis) that these results can suggest stronger heritability in a number of psoriasis types [, and −857 C/T polymorphisms and psoriasis risk can be related to psoriasis type.The relationship between types of polymorphisms and the risk of psoriasis is related to psoriasis type ,78 incluis types . As wellIn this study, publication year, HWE, ethnicity, psoriasis type, and sample size could be probable confounding factors in the results. One way to reduce these effects would be the researchers to conduct additional studies including the controls without a deviation of HWE across diverse ethnic groups, each study focusing on a specific subtype of psoriasis., and −857 C/T polymorphisms.It is important to note that the meta-analysis had two important limitations: firstly, only published studies were included in the analysis; secondly, there was low representation of certain polymorphisms in terms of the number of studies and individuals. Nonetheless, the strengths of the meta-analysis include high-quality scores in the studies, lack of publication bias, and the stability of results for −238 G/A,−308 G/A5, −863 C/A, and −1031 T/C polymorphisms and the susceptibility to psoriasis. The −238 G/A,−308 G/A, and −857 C/T polymorphisms are playing the roles in psoriasis risk in an ethnicity-, psoriasis type, and sample size-related manner. A number of polymorphisms included low studies and individuals and therefore, well-designed studies (with no deviation from HWE in controls) with more are recommended in the future.The meta-analysis recommended that the A allele and GA and GG genotypes of −238 G/A polymorphism, as well as the T allele and TT and CT genotypes of −857 C/T polymorphism were related to increased risks in psoriasis cases. There was no relationship between −308 G/ASepehr Sadafi: Conceived and designed the experiments; Contributed reagents, materials, analysis tools or data.Ali Ebrahimi: Contributed reagents, materials, analysis tools or data.Masoud Sadeghi: Performed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data.Omid Emami Aleagha: Contributed reagents, materials, analysis tools or data; Wrote the paper.Data included in article/supp. material/referenced in article.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper


Medical device-related pressure injury (MDRPI) in intensive care unit (ICU) patients is a serious issue. We aimed to evaluate the risk factors for MDRPI associated with ICU patients through systematic review and meta-analysis, and provide insights into the clinical prevention of MDRPI.We searched PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), WanFang Database, and China BioMedical Literature Database (CBM) (from inception to January 2023) for studies that identified risk factors of MDRPI in ICU patients. In order to avoid the omission of relevant literature, we performed a secondary search of the above database on February 15, 2023. Meta-analysis was performed using Revman 5.3.Fifteen studies involving 4850 participants were selected to analyze risk factors for MDRPI in ICU patients. While conducting a meta-analysis, we used sensitivity analysis to ensure the reliability of the results for cases with significant heterogeneity among studies. When the source of heterogeneity cannot be determined, we only described the risk factor. The risk factors for MDRPI in ICU patients were elder age , diabetes mellitus , edema , lower Braden scale score , higher SOFA score , higher APACHE II score , longer usage time of medical devices , use of vasoconstrictors , surgery , prone position , and prone position ventilation . Furthermore, we found that ICU patients who used subglottic suction catheters had a higher risk of MDRPI, whereas ICU patients with higher hemoglobin and serum albumin levels had a lower risk of MDRPI.This study reported the risk factors for MDRPI in ICU patients. A comprehensive analysis of these risk factors will help to prevent and optimize interventions, thereby minimizing the occurrence of MDRPI. Pressure injury (PI) is a local injury to the skin and/or subcutaneous tissue caused by pressure or a combination of shear forces. It usually occurs at bone protuberances, but may also be associated with medical devices or other objects . Patientet al.  OR "pressure ulcer" [Title/Abstract] OR "pressure injury" [Title/Abstract] OR "stress ulcer" [Title/Abstract] OR "stress injury" [Title/Abstract]) AND ("intensive care units" [Mesh] OR "intensive care units" [Title/Abstract] OR "ICU" [Title/Abstract]).The language used in the search was not restricted. For the literature search, we combined subject words and free words. Simultaneously, we conducted a supplementary search using the snowball method. In order to avoid the omission of relevant literature, we performed a secondary search of the above database on February 15, 2023.The inclusion criteria: (1) Published case-control studies, cohort studies, and cross-sectional studies; (2) Participants were ≥18 years old, and the occurrence of PI was related to the medical device used; (3) Relevant data can be obtained, either directly or after calculation; (3) The OR (95%) of risk factors was reported or can be calculated.The exclusion criteria: (1) Meeting abstracts, review papers, case reports, qualitative studies, and letters; (2) Unable to obtain the full text; (3) Unable to get the data required for meta-analysis; (4) Duplicate publications; (5) Animal experiments; (6) Evaluation of research with low literature quality.The quality of a cohort study and case-control study was evaluated using the Newcastle-Ottawa scale (NOS), which included selection , comparability , exposure/outcome evaluation . The total score on the scale was 9. When the total score was ≤ 3, the study was rated as low quality, 4–6 as medium quality, and ≥ 7 as high quality . The croTwo researchers conducted literature screening and data extraction respectively. The items for data extraction mainly included first authors, publication year, study design, type of MDRPI, sociodemographic data, sample size, risk factors, detailed information on methodology, etc. In case of disagreement, it should be resolved through discussion.2) test and I2 statistics. When P > 0.1 and I2 < 50%, the fixed effect model was used for meta-analysis. For P < 0.1 and I2 ≥ 50%, sensitivity analysis was carried out by subgroup analysis, changing the effect model or leave-one-out method. When the source of heterogeneity could not determine, descriptive analysis was used. The results of pooled OR (95%CI) were illustrated using forest plots. A funnel plot was used to evaluate publication bias. Statistical significance was set at P value < 0.05.Revman 5.3 software was used for meta-analysis. The heterogeneity test among studies was examined using Cochran’s Q , Korea (n = 2), and Turkey (n = 1). The cohort study included eight articles of medium or high quality. The case-control study included one high-quality article. The cross-sectional study consisted of six articles of medium quality. A total of 4,850 subjects were included in the study, with a sample size ranging from 156 to 912. The average/median age of the included participants ranged from 53.88 to 68.1 years. Age. Four studies  . A meta-analysis using a fixed effect model showed that ICU patients with diabetes were more likely to develop MDRPI  , and changing the effect model revealed substantial differences in results. Therefore, only descriptive analysis was conducted. Both studies showed that higher hemoglobin levels are protective factors against MDRPI in ICU patients. studies , 37 haveSerum albumin. Three studies  . Meta-analysis using a fixed effect model showed that the lower the total Braden scale score, the greater the risk of MDRPI in ICU patients  , and only descriptive analysis was used. Qin et al. . There was significant heterogeneity between the studies of Zhou . studies , 33, 36  studies , 25 exam 0.0001] . Two stuSequential organ failure assessment (SOFA). Two studies  . Thus, a meta-analysis using a random effect model shows that the higher the APACHE II score, the greater the risk of MDRPI in ICU patients  , confirmed by subgroup analysis and the leave-one-out method. After changing the effect model, no significant difference was observed in the pooled OR results. A meta-analysis using a random effect model showed that the longer the medical device was used, the higher the risk of MDRPI in ICU patients  . After changing the effect model, the results of the meta-analysis have significantly changed; thus, only descriptive analysis has been conducted. Both studies found that ICU patients who used subglottic suction catheters had a higher risk of MDRPI. studies , 36 repoThe use of vasoconstrictors. Five studies  . Based on a meta-analysis using a fixed effect model, surgery significantly increased the risk of MDRPI in ICU patients  . A meta-analysis using a fixed effect model showed that ICU patients in prone positions had a higher risk of MDRPI  . A meta-analysis using a fixed effect model showed that ICU patients using prone ventilation had a greater risk of MDRPI   The number of included literature on some risk factors is small, and the reliability of research results needs to be further improved; (2) Most of the original studies included did not distinguish between MDR-S PI and MDR-MM PI; thus, mixed calculations can only be performed during meta-analysis; (3) Some of the studies included all stages of MDRPI, while others included only one or several stages of MDRPI. However, no subgroup analysis was conducted due to the small number of literature included in this study.This study systematically evaluated the risk factors for MDRPI, which included demographic data, disease data, device factors, and treatment factors. The results of this study showed that age, diabetes, hemoglobin, serum albumin, edema, Braden scale score, SOFA score, APACHE II score, usage time of medical devices, use of a subglottic suction catheter, vasoconstrictors, surgery, position, and prone position ventilation might be related to the occurrence of MDRPI in ICU patients. A comprehensive analysis of these risk factors will help to prevent and optimize interventions, thereby minimizing the occurrence of MDRPI. However, there is still a lack of data in this area, and more high-quality research is recommended in the future to verify the relevant results.S1 Checklist(DOCX)Click here for additional data file.S1 Data(DOCX)Click here for additional data file.


Objectives: To investigate the performance of the END-PAC model in predicting pancreatic cancer risk in individuals with new-onset diabetes (NOD). Methods: The PRISMA statement standards were followed to conduct a systematic review. All studies investigating the performance of the END-PAC model in predicting pancreatic cancer risk in individuals with NOD were included. Two-by-two tables, coupled forest plots and summary receiver operating characteristic plots were constructed using the number of true positives, false negatives, true negatives and false positives. Diagnostic random effects models were used to estimate summary sensitivity and specificity points. Results: A total of 26,752 individuals from four studies were included. The median follow-up was 3 years and the pooled risk of pancreatic cancer was 0.8% (95% CI 0.6–1.0%). END-PAC score ≥ 3, which classifies the patients as high risk, was associated with better predictive performance (sensitivity: 55.8% (43.9–67%); specificity: 82.0% (76.4–86.5%)) in comparison with END-PAC score 1–2 (sensitivity: 22.2% (16.6–29.2%); specificity: 69.9% (67.3–72.4%)) and END-PAC score < 1 (sensitivity: 18.0% (12.8–24.6%); specificity: 50.9% (48.6–53.2%)) which classify the patients as intermediate and low risk, respectively. The evidence quality was judged to be moderate to high. Conclusions: END-PAC is a promising model for predicting pancreatic cancer risk in individuals with NOD. The score ≥3 should be considered as optimum cut-off value. More studies are needed to assess whether it could improve early pancreatic cancer detection rate, pancreatic cancer re-section rate, and pancreatic cancer treatment outcomes. Pancreatic cancer is the fourth leading cause of cancer-related deaths in most developed countries including the European Union , with a Several modifiable and non-modifiable risk factors are associated with pancreatic cancer such as smoking, alcohol, obesity and diet, as well as increasing age, gender, genetics and family history . New-onsPredictive models using different clinical features have been developed over the years. The Enriching New-Onset Diabetes for Pancreatic Cancer (END-PAC) model, developed by Sharma et al. , was ablUltimately there is a strong need for a validated screening tool to predict which patients have a high risk of developing pancreatic cancer. Given the promising performance of the END-PAC model, we were encouraged to conduct a systematic review of the literature to assess its accuracy in predicting the risk of pancreatic cancer in patients with NOD.The predefined protocol and design of this study were compliant with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement standards .Study design of interest. All retrospective or prospective observational studies (cohort or case-control studies) and randomised controlled trials investigating the predictive value of the END-PAC model in determining pancreatic cancer risk in individuals with NOD were considered eligible. Case reports, correspondences, letters, review articles, systematic reviews and meta-analyses were excluded.Population of interest. All patients aged above 50 with new-onset diabetes were considered eligible for inclusion.Predictive Model of interest. The Enriching New-Onset Diabetes for Pancreatic Cancer (END-PAC) model as defined by Sharma et al.  software . We evaluated the statistical heterogeneity by calculating IWe performed subgroup analyses based on the patients who were classed as high risk (END-PAC score ≥ 3), intermediate risk (END-PAC score 1–2), and low risk (END-PAC score < 1) by the END-PAC model.We performed sensitivity analyses based on the studies that were associated with low risk of bias and low applicability concerns based on the QUADAS-2 tool. Moreover, we planned to evaluate the effect of each study on overall results and heterogeneity by removing one study at a time.The search of the literature yielded 98 articles; 92 studies were excluded due to irrelevance. After full text review, two more articles were excluded because they did not evaluate the END-PAC model. Consequently, four studies ,8,9,12 cThe risk of bias and applicability concerns summary and graph based on the QUADAS-2 criteria are demonstrated in High risk (END-PAC score ≥ 3). Four studies including 26,752 patients evaluated the accuracy of the END-PAC model in patients classed as high-risk patients (END-PAC score ≥ 3) by the model. END-PAC score ≥ 3 was associated with 121 true positives, 5127 false positives, 21,410 true negatives and 94 false negatives. The visual assessment of the coupled forest plots of the estimated sensitivities and specificities suggested moderate between-study heterogeneity (2 = 59%) and pooled specificity of 82.0%  (ogeneity . END-PAC2 = 99%) . Visual 2 = 99%) .Intermediate risk (END-PAC score 1–2). Three studies including 20,451 patients evaluated the accuracy of the END-PAC model in patients classed as intermediate-risk patients (END-PAC score 1–2) by the model. END-PAC score 1–2 was associated with 32 true positives, 5814 false positives, 14,470 true negatives and 130 false negatives. The visual assessment of the coupled forest plots of the estimated sensitivities and specificities suggested moderate between-study heterogeneity (2 = 0%) and pooled specificity of 69.9%  (ogeneity . END-PAC2 = 91%) . Visual 2 = 91%) . Low risk (END-PAC score < 1). Three studies including 20,451 patients evaluated the accuracy of the END-PAC model in patients classed as low-risk patients (END-PAC score < 1) by the model. END-PAC score < 1 was associated with 29 true positives, 10,092 false positives, 10,192 true negatives and 138 false negatives. The visual assessment of the coupled forest plots of the estimated sensitivities and specificities suggested moderate between-study heterogeneity (2 = 0%) and pooled specificity of 50.9%  (ogeneity . END-PAC2 = 86%) . Visual 2 = 86%) .The sensitivity analyses based on the studies with low risk of bias and low applicability concerns showed consistency of the results. Moreover, the overall results and heterogeneity remained unchanged after removing one study at a time.We conducted a systematic review and meta-analysis to investigate the performance of the END-PAC model in predicting pancreatic cancer risk in individuals with NOD. Analysis of 26,752 individuals from four studies suggested that END-PAC score ≥ 3 (high risk) is an optimum cut-off value for the model with promising sensitivity, specificity and accuracy in predicting the risk of pancreatic cancer; however, END-PAC score 1–2 (intermediate risk) and END-PAC score < 1 (low risk) were associated with suboptimal predictive performance. The clinical between-study heterogeneity was low and statistical between-study heterogeneity was moderate. The quality of the available evidence was judged to be moderate to high based on QUADAS-2 criteria.Our study is the first systematic review and meta-analysis analysing the accuracy of the END-PAC model, which was first developed by Sharma et al.  and lateThe END-PAC model uses a patient’s age at diagnosis, change in body weight and change in fasting plasma glucose . It is oThe END-PAC model was designed to be part of a multi-step process for pancreatic cancer screening and highlights that patients with END-PAC score of 3 or above should undergo further imaging such as CT scan, MRI or endoscopic ultrasound. Schwartz et al.  found thThe strengths of the current study include the following: (1) relatively large sample size in terms of the number of included patients; (2) similar baseline characteristics of the included studies; (3) low clinical between-study heterogeneity; and (4) moderate-to-high quality of evidence. We acknowledge there are limitations with the current study: (1) only four available studies on the topic of interest; (2) moderate statistical between-study heterogeneity; (3) publication bias could not be assessed because the number of included studies did not reach the minimum of 10; and (4) the retrospective nature of included studies, with the inevitable risk of selection bias.END-PAC is a promising model for predicting pancreatic cancer risk in individuals with NOD. A score ≥ 3 should be considered as the optimum cut-off value. More studies are needed to assess whether it could improve early pancreatic cancer detection rate, pancreatic cancer resection rate and pancreatic cancer treatment outcomes.


The number of cancer survivors is growing rapidly; however, specific lifestyle recommendations for these patients are still sparse, including dietary approaches. Thus, the aim of the present systematic review and meta-analysis was to examine the associations between adherence to diet-quality indices and dietary patterns on overall mortality, cancer-specific mortality, and cancer recurrence among cancer survivors. The literature search was conducted in PubMed and Web of Science between 18 May 2016 and 22 May 2022 with no language restrictions. Thirty-nine studies were included for quantitative analysis, providing data from 77,412 participants. Adherence to both diet-quality indices and a healthy/prudent dietary pattern was inversely associated with overall mortality  and with cancer-specific mortality . These associations could be observed following assessment of dietary patterns either pre- and/or postdiagnosis. For unhealthy/western dietary patterns, high adherence was associated with overall mortality . Although the certainty of evidence was rated as low, we conclude that there are no reservations against high adherence to healthy dietary patterns or indices in cancer survivors. With respect to causes of mortality, cancer is either number one or two in 112 countries for people under the age of 70 years. In 2020, global cancer incidence was estimated at 19.3 million cases and cancer mortality at 10 million deaths. Moreover, a 47% increase in new cancer cases is expected by 2040, resulting in 28.4 million new people affected [The systematic analyses of the Global Burden of Disease Study Group showed that in 2019, 44.4% of cancer deaths and 42% of cancer disability-adjusted life-years (DALYs) worldwide are attributable to modifiable risk factors. Dietary risks constitute the second most common risk factor causing 6.0% of deaths and 5.6% of DALYs, respectively . To datehttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42015023684 (accessed on 12 June 2023); no. CRD42015023684). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, PRISMA for abstract [The protocol of the previous version of this systematic review and meta-analysis has been registered in the PROSPERO International Prospective Register of Systematic Reviews , between 18 May 2016 and 22 May 2022, with no language restrictions on 23 May 2022. The search strategies were adapted from Schwedhelm et al.  and are In addition, a hand search of references from selected articles was performed to identify other eligible studies as well as systematic reviews and meta-analyses. Eligible studies selected by Schwedhelm et al.  were incThe evaluation of eligible studies was conducted by two authors (A.T. and G.H.), and any uncertainties were resolved by discussion with the third author (L.S.). After manually removing duplicates, studies were included in the systematic review and meta-analysis if they met the following criteria): (1) cohort study (prospective and retrospective); (2) diagnosed with primary cancer/survivor of any type of cancer ; (3) use of a priori-based diet-quality indices (such as the Mediterranean diet (MED), Dietary Approach to Stop Hypertension (DASH), Healthy Eating Index (HEI), and WCRF/American Institute for Cancer Research (AICR) dietary guidelines adherence score (ACS)); (4) use of dietary patterns assessed by principal component analysis ; (5) overall mortality and/or cancer-specific mortality and/or cancer recurrence reported as relative risk (RR) or hazard ratio (HR) with the corresponding 95% confidence interval (CI); and (6) study population restricted to adults only (≥18 years). PICOS criteria for eligible studies are given in For quantitative analysis, studies using the same cohort were screened for cancer type, same indices/patterns, and pre- or postdiagnosis diet assessment. In case of overlapping data, the study that provided more information was selected to avoid duplication of data. Studies with the same cohort but different diagnosed cancer types were included in the quantitative analysis. The same applied to studies with the same cohort but different indices or different times of dietary assessment (prediagnosis or postdiagnosis).Data extraction from the included studies was carried out as follows: (1) name of the first author and year of publication; (2) country; (3) cohort name; (4) types of outcome ; (5) sample size of the population; (6) mean follow-up duration in years; (7) sex of participants; (8) mean age of participants at diagnosis in years; (9) tumor characteristics; (10) assessment of recurrence; (11) exposure assessment and timeframe; (12) components of score and score range; 13) adjustment factors; and (14) multivariate-adjusted risk estimates (RR or HR with the corresponding 95% CI) comparing highest vs. lowest category. If a study provided more than one multivariate-adjusted model, the model with the most adjusted variables was selected. Furthermore, when combining outcomes, e.g., mortality and cancer progression, risk estimates were not extracted. All studies previously selected by Schwedhelm et al. [ adjustmeAn adjusted version of the Cochrane Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool was used to evaluate the risk of bias in each study.  It inclugradepro.org (accessed on 12 June 2023)).The certainty of evidence for diet quality indices, healthy/prudent dietary patterns, unhealthy/western dietary patterns in association with overall mortality, cancer-specific mortality, and cancer recurrence was evaluated using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach . The GRAThe meta-analysis was conducted by pooling the most multivariable-adjusted risk estimates (RR or HR) of the highest compared with the lowest category of dietary adherence using a random-effects model with the Der Simonian-Laird method . The uncI2). As recommended by Higgins et al., an I2 of 25% was considered as low heterogeneity, an I2 of 50% as moderate heterogeneity, and an I2 of 75% as high heterogeneity [Heterogeneity was estimated using the Cochrane Q test and the inconsistency test  was used in eleven studies, alternate Healthy Eating Index (aHEI) in seven studies, MED or an adapted version like the alternate Mediterranean Diet (aMED) in fourteen studies, DASH in nine studies, ACS in four studies, and WCRF in three studies. The Recommended Food Score and healthful Plant-based Diet were each used in two studies, and the Chinese Healthy Eating Index, Chinese Food Pagoda (2007 and 2016), Australian Dietary Guideline Index, Dutch Healthy Diet Index, and Diet Quality Index-Revised were each used in one study. Fifteen of the included studies investigated diet quality using dietary patterns obtained by principal component analysis. Both a healthy/prudent dietary pattern and an unhealthy/western dietary pattern were derived from 14 studies, with 13 studies examining both.Overall mortality was reported in 36 studies. Two studies ,28 did nTwenty-six of the included studies were conducted in the United States. Seven studies were conducted in European countries: three from Germany, two from Italy, one from Portugal, and one from the Netherlands. One cohort study was conducted in Australia, one was conducted in Canada, and three studies were conducted in China.The potential risk of bias was assessed using an adjusted version of the ROBINS-I tool. Synthesized risk ratios of all analyses with at least three studies included are shown in The certainty of evidence for the major outcomes is summarized in With respect to breast cancer, adherence to diet-quality indices was inversely associated with overall mortality , which was still the case following post-diagnostic assessments only . Adherence to an unhealthy/western dietary pattern was associated with overall mortality in breast cancer survivors . Regarding colorectal cancer survivors, inverse associations with overall mortality were found following adherence to high-quality diets , and this observation could still be made when only postdiagnosis assessments were considered  . In addiInverse associations with overall mortality following assessments of dietary indices were found for HEI , aHEI , MED , and DASH . Comparable results could be obtained considering only postdiagnostic dietary analyses: HEI , aHEI , MED , and DASH  . For canTo test for small study effects and publication bias, funnel plots were used and analyzed for symmetry/asymmetry. Funnel plots were created for thirteen analyses with ten or more studies included and are presented in The purpose of this updated systematic review and meta-analysis was to investigate the associations of adherence (now including postdiagnosis adherence) to dietary indices and dietary patterns on mortality and cancer recurrence among cancer survivors. Furthermore, cancer-specific mortality was examined for the first time in this update. In summary, 21 new studies were added to the quantitative analysis, resulting in a total of 39 studies providing data on 77,412 patients.Higher adherence to diet-quality indices and healthy/prudent dietary patterns showed an inverse association with overall mortality among cancer survivors, whereas unhealthy/western dietary patterns were associated with an increase. In breast and colorectal cancer survivors, diet-quality indices were also inversely associated with the risk of overall mortality, which is in line with findings of previous meta-analyses ,66. SimiWith respect to diet-quality indices, an inverse association with overall mortality risk was observed for higher adherence to the HEI, AHEI, MED, and DASH. These data confirm the results of meta-analyses by Morze et al. ,68. In aOverall, diet-quality indices, as well as dietary patterns with beneficial associations, can differ with respect to specific characteristics, but analyses of the same cohorts with different dietary indices showed moderate to strong correlations between them . LikewisFruits and vegetables are food groups with a high density of nutrients such as dietary fiber, selenium, and vitamins A, C, and E, as well as with high amounts of phytochemicals, such as carotenoids, flavonoids, phenols, isothiocyanates, dithiolthiones, glucosinolates and indoles, allium compounds, plant sterols, limonene, and protease inhibitors. All of these agents are potential anticarcinogens due to their ability to have antioxidative effects, induce detoxification enzymes, bind carcinogens, inhibit nitrosamine formation, alter hormone metabolism, suppress proliferation, and others . Foods hCarcinogenic N-nitroso compounds are an exogenous component of processed meat but can be formed endogenously as well due to the high heme-iron content of red meat. Moreover, the heating of meat at high temperatures yields carcinogenic heterocyclic amines and polycyclic aromatic hydrocarbons. Taken together, there is strong evidence for a correlation between high consumption of red and processed meat and increased risk for colorectal cancer . The samThe interpretation of the results of this systematic review should be conducted considering its limitations. Different attempts were made to keep these limitations as small as possible using various state-of-the-art tools. In cohort studies, the interpretation of causality is limited, and bias is more likely when compared to randomized controlled trials. Therefore, the ROBINS-I tool was used to assess the risk of bias in each included study, resulting in 18 studies with a moderate risk of bias, 18 studies with a high risk of bias, and 3 studies with insufficient information to assess the risk of bias correctly. It should be noted that randomized controlled trials are difficult to conduct over a long follow-up period. In addition, the timing of dietary assessment and follow-up varied among the included studies. To reduce the risk of bias due to confounding, the most adjusted HRs were chosen, and almost all included studies reported HR adjusted for sex, age, and smoking, but the majority of studies did not adjust for cancer stage and treatment. However, several studies excluded people who died within 1 year of cancer diagnosis or performed a sensitivity analysis regarding this outcome, with no changes in findings. The majority of the included studies assessed the diet at only one time point. Therefore, if a change in diet occurred after the dietary assessment, it is not included in the results. Nevertheless, changes in overall diet sometimes occur after a cancer diagnosis, but the current evidence suggests that these changes are small ,92,93,94Apart from its limitations, this systematic review has several strengths as well. Two databases were searched without language restriction yielding 41 studies in the systematic review and 39 studies in the meta-analysis. Accordingly, data from an overall high number of participants could be synthesized. This study focused on cancer survivors, who represent an increasing number of patients with a special interest in the topic of this study, which is shared by organizations and authorities working in this field of research. A prominent example is the Global Cancer Update Programme of the WCRF continuously reviewing the long-term effects of lifestyle factors  following diagnosis of colorectal and prostate cancer, with an already published Update Report for breast cancer survivors . The preIn the present study, a high-quality diet, as defined by adherence to various dietary quality indices, was inversely associated with the risk of overall mortality and cancer-specific mortality among cancer survivors, even when dietary adherence starts after diagnosis. Considering specific cancer sites, this relationship was also found in breast and colorectal cancer survivors with respect to overall mortality. The individual diet-quality indices HEI, aHEI, MED, and DASH demonstrated beneficial associations on overall mortality, while detrimental associations on this outcome were found following an unhealthy/western dietary pattern before and/or after diagnosis. Regarding cancer-specific mortality other than breast and colorectal cancer or recurrence among cancer survivors in general, the available data are not robust enough to draw any conclusions. Since no detrimental associations could be observed, there are no reservations against adherence to healthy dietary patterns or indices in cancer survivors.


Evidence on the association between the risk of new-onset osteoporosis and oral anticoagulants remains controversial. We aimed to compare the risk of osteoporosis associated with the use of direct oral anticoagulants (DOACs) with that associated with warfarin use.Studies published up to 15 March 2023 that investigated the association between the use of DOACs and warfarin and the incidence of osteoporosis were identified by online searches in PubMed, Embase, the Cochrane Library, and Web of Science conducted by two independent investigators. Random-effects or fixed-effect models were employed to synthesize hazard ratios (HRs)/relative ratios (RRs) with 95% confidence intervals (CIs) for estimating the risk of osteoporosis correlated with DOAC and warfarin prescriptions (PROSPERO No. CRD42023401199).p < 0.001, I2: 85.1%). Subanalyses revealed that rivaroxaban was associated with a lower risk of osteoporosis than both warfarin and dabigatran. In addition, DOACs were associated with a lower risk of developing osteoporosis than warfarin in both male and female patients, in patients with atrial fibrillation (AF), and in patients who underwent therapy for > 365 days.Our meta-analysis ultimately included four studies involving 74,338 patients. The results suggested that DOAC use was associated with a significantly lower incidence of new-onset osteoporosis than warfarin use (pooled HR: 0.71, 95% CI: 0.57 to 0.88, DOAC users experienced a lower incidence of osteoporosis than warfarin users. This study may give us insight into safe anticoagulation strategies for patients who are at high risk of developing osteoporosis.https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023401199. Warfarin, a vitamin K antagonist, is a traditional oral anticoagulant that has been used in many situations for the prevention or treatment of thromboembolic diseases or events. Warfarin can produce an anticoagulant effect by inhibiting the γ-carboxylation of coagulation factors II, VII, IX, and X . StudiesAs oral anticoagulants are commonly prescribed for older patients who are vulnerable to thromboembolic events, the possible risks of osteoporosis constitute a vital clinical issue. Therefore, we conducted a meta-analysis to determine the correlation of DOACs vs. warfarin with the risk of osteoporosis by pooling the data from the included observational studies. These studies may indicate preferable anticoagulation strategies for patients at high risk of developing osteoporosis.https://www.crd.york.ac.uk/PROSPERO/; CRD42023401199).The meta-analysis and systematic review were carried out in accordance with the PRISMA guidelines  and the Two investigators (YML and XPX) searched PubMed, Embase, Web of Science, and the Cochrane Library databases for eligible studies published before 15 March 2023. The search items included “osteoporosis”, “bone mineral density”, “direct oral anticoagulant”, “non-vitamin K antagonist”, “vitamin K antagonist”, and “warfarin”. The detailed search strategies are presented in Studies were included if they fulfilled the following inclusion criteria: (1) patients had been prescribed a DOAC or warfarin for the first time; (2) the study aimed to evaluate the association between the risk of developing osteoporosis and DOAC use compared with warfarin use; (3) the study provided sufficient data to pool the results, such as hazard ratios (HRs) or relative risks (RRs) with 95% confidence intervals (CIs); and (4) the study design was an observational study. Patients who initiated osteoporosis medication were also considered to have osteoporosis. The exclusion criteria were as follows: (1) duplicate reports; (2) case reports, editorials, reviews, and meta-analyses; and (3) animal or molecular biology studies.Two investigators (YML and XPX) independently screened the articles by the titles and abstracts. Subsequently, the full texts were obtained to identify eligible studies. Disagreements were resolved by extensive discussion or consultation when necessary.The data were extracted using a standardized table. The collected data included the first author, year of publication, region, number of patients, study period, study participants, and study outcomes. For outcome data, the HRs or RRs with 95% CIs were extracted to synthesize the results. Two investigators (YML and XPX) independently conducted the extraction process. Discrepancies were resolved by discussion. Consultation with a third reviewer (TCY) was sought when necessary. Furthermore, we evaluated the quality of the included observational studies using the Newcastle–Ottawa Scale (NOS) . StudiesI2 statistic. Values of p < 0.05 and I2 > 50% indicated significant heterogeneity across the included studies. Subsequently, random-effects models were employed to pool the results of HRs or RRs and corresponding 95% CIs for osteoporosis when heterogeneity was statistically significant. Fixed-effect models were used when heterogeneity was not statistically significant. Furthermore, we conducted subgroup meta-analyses based on individual DOACs, comparisons among each DOAC, gender, duration of therapy, and patients with AF or an unspecified condition. In addition, sensitivity analyses were performed to test whether or not the included studies had a high risk of bias and to examine the robustness of the results by removing individual studies. Publication bias was assessed using a funnel plot, Begg’s rank correlation, and Egger’s weighted regression methods. A two-tailed p < 0.05 was considered statistically significant. All analyses were conducted using STATA software, version 12.0 .For the primary analysis, the risk of developing osteoporosis in DOAC users was compared with that in warfarin users. HRs or RRs with corresponding 95% CIs were collected to calculate pooled outcomes. Pooled HRs/RRs were presented for estimation in this meta-analysis. Heterogeneity was assessed by using the Q statistic and the The database search identified 1,046 potentially relevant articles –19, 28. . However, there was no significant difference in the risk of osteoporosis associated with apixaban and dabigatran compared with that associated with warfarin . In AF patients, neither dabigatran nor rivaroxaban use was significantly associated with the risk of developing osteoporosis compared with apixaban , or Egger’s test (p = 0.53).After removing one study at a time in the sensitivity analyses, the risk of new-onset osteoporosis for DOAC users vs. warfarin users appeared to be stable and robust (I2: 85.1%). In addition, the subanalyses for each DOAC vs. warfarin revealed that rivaroxaban use was associated with a significantly lower risk of new-onset osteoporosis than warfarin and dabigatran use. In addition, DOACs tended to be associated with a lower risk of new-onset osteoporosis than warfarin in both male and female patients and in patients with non-valvular AF. Among patients treated for more than 365 days, the association between DOAC use and a lower incidence of osteoporosis appeared to be stronger than that between warfarin use and a lower incidence of osteoporosis.This meta-analysis based on four observational studies indicated that patients prescribed DOACs were at a significantly lower risk of experiencing new-onset osteoporosis than those prescribed warfarin. This meta-analysis was based on significant heterogeneity  were seen in patients on anticoagulants than in those not on anticoagulants, which was more pronounced with warfarin use than DOACs. This conclusion was inconsistent with the findings of a study of two retrospective cohorts conducted by Bezabhe et al. . In addiThis meta-analysis has several strengths. First, we included observational studies that involved a large number of participants and compared the risk of developing osteoporosis in patients receiving DOACs with that in those receiving warfarin based on pooled data. In addition, we analyzed the risk of osteoporosis associated with each DOAC compared with that associated with warfarin. Second, the studies included in this meta-analysis had a relatively long study duration for the emergence of osteoporosis.This meta-analysis has several limitations. First, due to unmeasured confounders, observational studies are prone to bias. Although sophisticated analysis methods, such as propensity score matching, were employed in the included studies, unmeasured confounders remained. Second, the included observational studies were based on routinely collected electronic health records that were not designed to study osteoporosis, which may have resulted in misclassification bias in the outcomes. For example, BMD data were not available for baseline characteristics in all studies. Finally, a high degree of heterogeneity exists in this meta-analysis, which may limit the findings. Our subanalyses indicated that an individual DOAC could potentially contribute to heterogeneity. Therefore, our results cannot completely determine causality in the association between DOACs or warfarin and the risk of osteoporosis, and this conclusion should be interpreted with caution.This meta-analysis demonstrated that new DOAC users experienced a lower incidence of osteoporosis than warfarin users. Among all the oral anticoagulants, rivaroxaban was associated with a lower risk of osteoporosis than both warfarin and dabigatran. In addition, DOAC use was significantly associated with a lower risk of osteoporosis than warfarin use in both male and female patients, and in patients with non-valvular AF. Further randomized controlled trials are needed to determine the comparative risk of osteoporosis for different DOACs and warfarin to provide safe anticoagulation options for patients with risk factors for osteoporosis.The original contributions presented in the study are included in the article/YL designed the study, conducted statistical analysis of the data, and drafted the manuscript. XX, SB, QZ, QS, and YS contributed to the writing and discussed the manuscript. TY provided critical suggestions and contributed significantly to the revision of the manuscript. All authors contributed to the article and approved the submitted version.


Finding factors that are causally related to both risk of Parkinson's and/or progression of Parkinson's disease (PD) are of considerable interest. This could help in finding new treatments or the repurposing of existing treatments from other diseases as well as assist in counseling of recently diagnosed patients. One factor that has been of interest for many years in the epidemiology of PD is Diabetes.Systematic reviews and meta-analyses are methods that are used to summarize the evidence across many publications. Zhong and Wang present a systematic review and meta-analysis of the association between diabetes, prediabetes and risk, disease progression of Parkinson's  on patients within the Tracking Parkinson's cohort. The first, published in 2016, was a cross-sectional study of only the baseline data comparing the severity of motor and cognitive disease in those with and without different vascular risk factors one of which was DM  and another looks at the association between DM and cognitive decline . There are three issues with these meta-analyses.Double counting: the results from the Athauda and Malek papers are presented as two individual studies. However since they come from the same cohort they are clearly not independent and the Tracking Parkinson's cohort will be given a greater weighting in the meta-analysis than it should have.Different effect estimates: in the meta-analysis of DM and motor progression of PD, they incorrectly combine absolute and relative effect estimates where one is from a cross-sectional analysis and the other from a longitudinal analysis. The result they report from the Malek paper, 3.65 (95% CI: 1.07 to 6.22), is an adjusted mean difference from a linear regression of baseline MDS-UPDRS III total scores. Whilst the result they report from the Athauda paper, 1.55 (95% CI: 1.07 to 2.23) is an adjusted hazard ratio from a Cox regression model where substantial gait impairment was the outcome (defined as score > 3 in MDS-UPDRS III question 10). These statistics are clearly not comparable and are also both incorrectly labeled as Risk Ratios in the forest plot.Binary vs. ordinal outcomes: in their meta-analysis of DM and cognitive decline they again combine two different effect estimates where one is from a cross-sectional analysis and the other from a longitudinal analysis. In the Malek paper, the effect estimate of 1.52 (95% CI: 0.89 to 2.58) is an adjusted odds ratio from a ordinal logistic regression where Normal Cognition, Mild Cognitive Impairment (MCI) and Dementia  at baseline was the outcome (defined using the MoCA and MDS-UPDRS I question 1). Hence this is the impact of DM in moving up one category on the ordinal scale. Whilst the result they report from the Athauda paper, 1.74 (95% CI: 1.19 to 2.55), is an adjusted hazard ratio from a Cox regression model for a binary outcome of MCI (defined using the MoCA and MDS-UPDRS I question 1). These statistics are clearly not comparable and are also both incorrectly labeled as Risk Ratios in the forest plot. Also, it should be noted that slightly different cut-points were used in these two papers to define MCI using the MoCA and we have planned research that is going to consider the optimal cut-point comparing sensitivity and specificity.Given that the authors have made mistakes in reporting from our two papers it is possible that there have been some mis-representations of other papers that have been cited. We would recommend that they carefully consider the other papers that have been included in the meta-analyses and submit an erratum with the revised results.ML: manuscript writing. YB-S, DA, NM, and DG: manuscript revision. All authors have read and approved the final version of the manuscript.