Glucocorticoids and sepsis and 28-day mortality of sepsis: a Mendelian randomization study

Glucocorticoids and sepsis and 28-day mortality of sepsis: a Mendelian randomization study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Glucocorticoids and sepsis and 28-day mortality of sepsis: a Mendelian randomization study Jingxian Huang, Yubo Xie, Huageng Huang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4805652/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Whether glucocorticoids are beneficial in sepsis and related deaths has been controversial, and the exact causal relationship is unclear. This study used Mendelian randomization to investigate the causal relationships between glucocorticoids and sepsis and 28-day mortality of sepsis. Methods: We obtained SNPs (p-value < 5 × 10-8) strongly associated with the exposure factor glucocorticoids (n=5440) from a genome-wide association study (GWAS) with glucocorticoids as the exposure factor and sepsis and 28-day mortality from sepsis as the outcome factor. Causality studies were conducted using variance weighted inverse methods supplemented with MR Egger, weighted median and weighted mode and MR simple mode analyses. The results were analyzed for heterogeneity and tested for horizontal multiplicity, leave-one-out sensitivity tests were performed and ORs were calculated for the results. Results: A total of 26 qualified SNPs were ultimately selected as proxies for glucocorticoids. The results of the random effects from IVW revealed that glucocorticoids had no causal effect on sepsis(OR=0.989, 95% CI 0.895-1.093, P=0.833, se=0.051), 28-day mortality of sepsis(OR=0.921, 95% CI 0.768-1.104, P=0.375, se=0.093). These results were confirmed using the MR-Egger, weighted median, simple model, and weighted models. Conclusions: In a two-sample Mendelian randomization analysis, no strong evidence was found to support a causal effect of glucocorticoids on sepsis, sepsis 28-day mortality, from a genetic perspective. Glucocorticoids Sepsis 28-day mortality of sepsis Mendelian randomization Single nucleotide polymorphisms Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction Sepsis is a complex, dysfunctional host response to infection, that is usually accompanied by acute organ dysfunction and high mortality [ 1 ]. A Global Burden of Disease report revealed that 48.9 million cases of sepsis were reported globally in 2017, with a mortality rate of 22.5%, accounting for nearly 20% of all global deaths [ 2 , 3 ], and posing significant global health challenges. Treatment of sepsis is currently based on a combination of antibiotics, organ support and protection, and fluid resuscitation, for which glucocorticoid therapy is still controversial. Glucocorticoids modulate the immune response to infection and enhance cardiovascular stability and organ protection, which has been used routinely in the treatment of sepsis since the 1950s and were routinely used in the treatment of septic patients [ 4 ]. Large randomized controlled studies have shown that low-dose glucocorticoids reduce mortality in patients with sepsis [ 5 , 6 ]. However, large trials and meta-analyses in the late 1980s demonstrated that high-dose glucocorticoid therapy (30 mg/kg methylprednisone or equivalent) regimens not only failed to benefit septic patients in terms of mortality or disease [ 5 , 7 ], but were also detrimental [ 8 ], therefore, the use of high-dose glucocorticoids in the treatment of septic shock is no longer popular. The use of glucocorticoids in the treatment of sepsis remains controversial. The causal relationship between the use of glucocorticoids and sepsis and sepsis mortality is unclear and more direct evidence is needed. Mendelian randomization (MR) is an observational design that uses single nucleotide polymorphisms (SNPs) reliably associated with an exposure to estimate the causal effect of the exposure (glucocorticoids) on the outcome (sepsis and 28-day mortality of sepsis) [ 9 ]. Humans are randomly "assigned" their genotype at conception [ 10 , 11 ], thus, MR is less susceptible to confounding than other observational designs [ 12 ]。Due to the limitations of randomized controlled studies and retrospective studies, such as potential confounders and selection bias, it is difficult to draw consistent conclusions about the association of glucocorticoids with the development of sepsis and 28-day mortality of sepsis; therefore, we performed a two-sample MR analysis using pooled statistical data from the GWAS to assess the causal effect of glucocorticoids on the development of sepsis and the 28-day mortality of sepsis risk. 2. Materials and methods 2.1. Research design This was a two-sample Mendelian randomization study to screen for SNPs strongly associated with exposure factors from the GWAS, which was intended to satisfy three main hypotheses: (1) they should be robustly associated with the exposure; (2) they should not be associated with potential confounders of the exposure-outcome association; and (3) they should not influence the outcome by any variable other than the exposure [ 13 ]. 2.2. Ethics statement All of the datasets employed in our study were large-scale public GWAS summary data. Ethical approval and consent to participate were acquired from all original studies. The flowchart of the process is illustrated in Fig. 1 . 2.3 Data sources Exposure data glucocorticoids and outcome data sepsis and 28-day mortality of sepsis GWAS data were obtained from the IEU Open GWAS project ( https://gwas.mrcieu.ac.uk/ ). Different populations may lead to biased estimates, and we restricted the genetic background of populations in the MR study to individuals of European origin [ 14 ].Glucocorticoid GWAS ID: ebi-a-GCST90019000, from the most recent GWAS pooled data, is a collection of 220 in-depth phenotypic GWAS performed by BioBank Japan (BBJ), which included 108 phenotypes that had never been GWASed in East Asian populations; then, the corresponding phenotypes were GWASed in the United Kingdom Biobank (UKB) and GWAS of the corresponding phenotypes were performed in FinnGen, and the most recent GWAS pooled data were meta-analyzed across populations. Selections from this database included 205,700 Europeans (17,352 cases and 188,348 controls) and 14,256,400 SNPs [ 15 ].Sepsis GWAS ID: ieu-b-4980, established by the UK Biobanking Consortium, contains 486,484 Europeans (11,643 cases, 474,841 controls) and 12,243,539 SNPs. 28-day mortality of sepsis GWAS ID: ieu-b-5086, established by the UK Biobanking Consortium. The dataset included 486,484 Europeans (1896 cases, 484588 controls) and 12,243,487 SNPs, as shown in Table 1 . 2.4 Selection of Instrumental Variables All genetic variants that achieved genome-wide significance were selected as instrumental variables (IVs), with the correlation setting a p-value cutoff of 5 × 10 − 8 . To ensure that the variants were independent, SNPs with high linkage disequilibrium (r 2 > 0.001,clump window < 10000 kb) were excluded, thus ensuring their independence. We used these carefully selected SNPs as the final genetic IVs for subsequent MR analysis. 2.5 Statistical analyses First, the inverse variance weighted (IVW) method was chosen as the main two-sample MR analysis method to estimate causal effects [ 16 ]. MR Egger regression, weighted median and weighted mode methods, and MR-simple-mode were used to infer causality; to test the robustness of the results, Cochran's Q test was performed via the IVW method to assess the heterogeneity among SNPs. Significant horizontal pleiotropy was assessed by MR-Egger intercept. Additionally, Leave-one-out analysis was used to test whether the MR results were driven by specific SNPs. Finally, scatter plots, forest plots and funnel plots were drawn. A p-value less than 0.05 indicated statistical significance in all the sensitivity analysis methods. All the statistical analyses were performed via the "TwoSampleMR" package in R software [ 17 ]. 3. Results After strict adherence to the criteria of IVs selection, a total of 26 qualified SNPs were ultimately selected as proxies for glucocorticoids use in the present study (Table 2 , Table 3 ). 3.1 Causal effect of glucocorticoids on sepsis According to the results of the main MR method, glucocorticoids had no etiological effect on sepsis in IVW [OR = 0.989, 95% CI 0.895–1.093, P = 0.833, standard error (SE) = 0.051, Table 4 ]. The results were validated in other complementary methods, MR-Egger (OR = 0.914, 95% CI 0.672–1.243, P = 0.572, se = 0.157), weighted median (OR = 0.986, 95% CI 0.878–1.106, P = 0.806, se = 0.059), the simple model (OR = 1.075, 95% CI 0.870–1.327, P = 0.510, se = 0.108), and the weighted model (OR = 1.038, 95% CI 0.865–1.246, P = 0.691, se = 0.093, Table 4 ). A scatterplot of the causal associations between glucocorticoids and sepsis is shown in Fig. 2 a. The forest map is shown in Fig. 3 a. 3.2 Causal effect of glucocorticoids on 28-day mortality of sepsis Similarly, no significant causal effect was identified between glucocorticoids and 28-day mortality of sepsis, as estimated by the following five two-sample MR analysis methods (IVW OR = 0.921, 95% CI 0.768–1.104, P = 0.375, se = 0.093; MR-Egger OR = 0.805, 95% CI 0.460–1.410, P = 0.456, se = 0.286; weighted median OR = 0.855, 95% CI 0.665–1.098, P = 0.220, se = 0.128; simple model OR = 0.842, 95% CI 0.561–1.263, P = 0.413, se = 0.207; weighted model OR = 0.831, 95% CI 0.583–1.184, P = 0.316, se = 0.181, Table 5 ). A scatterplot of the causal relationships between glucocorticoids and 28-day mortality of sepsis is shown in Fig. 2 b. The forest map is shown in Fig. 3 b. 3.5 Sensitivity analyses The detailed results of MR-Egger intercept analysis, heterogeneity tests by IVW, and heterogeneity tests by MR-Egger are shown in Table 1 .According to the results of the leave-one-out cross-validation test, we did not detect any potentially influential or problematic SNPs(Fig. 4 ).As shown in the funnel plots (Supplementary Fig. 5), no potential horizontal pleiotropy was discovered. On the basis of the consistency of the results estimated by the five different MR analytical approaches, no strong evidence was found to support a causal effect of glucocorticoids on sepsis and 28-day mortality of sepsis. Table 1 The characteristics of the SNPs of both glucocorticoids and sepsis and 28-day mortality of sepsis. Table 2 Associations of individual single nucleotide polymorphisms (SNPs) (used as Mendelian randomization instruments) with Glucocorticoids and Sepsis Traits Population Sample Size Number of SNPs ID Glucocorticoids European 205,700 14,256,400 ebi-a-GCST90019000 Sepsis European 486,484 12,243,539 ieu-b-4980 28-day mortality of sepsis European 486,484 12,243,487 ieu-b-5086 SNP Allele a chromosome Position Glucocorticoids(exposure) Sepsis(outcome) β b se P β b se P rs1011082 C/T 17 38068514 0.060 0.009 1.41E-11 0.014 0.014 0.316 rs10519067 A/G 15 61068347 -0.091 0.012 2.76E-15 0.016 0.020 0.445 rs10905284 A/C 10 8115362 -0.048 0.009 2.72E-08 -0.025 0.014 0.068 rs12123821 T/C 1 152179152 0.153 0.026 5.89E-09 -0.002 0.032 0.960 rs12413578 T/C 10 9049253 -0.171 0.018 4.85E-21 -0.024 0.022 0.280 rs13019081 C/A 2 102950822 0.073 0.009 2.84E-17 -0.032 0.014 0.022 rs1391371 T/A 6 32603798 0.123 0.010 1.19E-37 -0.005 0.017 0.778 rs1504215 A/G 6 91006227 -0.087 0.012 1.11E-13 0.019 0.014 0.182 rs1689510 C/G 12 56396768 0.073 0.010 4.67E-14 -0.045 0.014 0.002 rs1881457 C/A 5 131992809 0.065 0.011 1.10E-09 0.011 0.018 0.526 rs1898671 T/C 5 110408002 0.100 0.011 7.85E-20 0.012 0.014 0.417 rs2370615 T/C 8 81290387 -0.076 0.012 3.56E-11 -0.007 0.014 0.611 rs2395005 A/G 6 31412652 0.068 0.009 1.04E-14 -0.001 0.014 0.936 rs2671657 A/G 17 47473616 -0.053 0.009 1.40E-08 -0.001 0.014 0.938 rs2949661 T/C 1 167424924 -0.072 0.010 7.14E-12 0.018 0.014 0.199 rs3024575 T/C 16 27358132 0.049 0.009 1.84E-08 -0.022 0.014 0.120 rs34290285 A/G 2 242698640 -0.113 0.011 3.43E-26 0.006 0.016 0.699 rs35441874 A/T 16 11213021 -0.069 0.011 1.28E-09 0.000 0.016 0.998 rs36132266 T/G 14 69266023 -0.048 0.009 2.38E-08 -0.013 0.014 0.349 rs4335039 A/T 7 20581949 -0.053 0.009 3.67E-09 -0.014 0.014 0.328 rs4491851 A/G 3 33083985 0.060 0.010 1.82E-09 0.024 0.014 0.087 rs72743461 A/C 15 67441750 0.089 0.012 1.83E-13 -0.004 0.016 0.808 rs7717955 T/C 5 35862841 -0.057 0.010 7.64E-09 -0.010 0.015 0.497 rs78496075 G/A 6 32608967 -0.101 0.014 7.66E-13 -0.077 0.029 0.008 rs7936312 T/G 11 76293726 0.100 0.011 1.10E-18 0.022 0.014 0.111 rs992969 G/A 9 6209697 -0.131 0.012 7.98E-27 0.033 0.016 0.036 a. Alleles are shown as other alleles/effect alleles b. Effect sizes for the effect allele a. Alleles are shown as other alleles/effect alleles b. Effect sizes for the effect allele Table 3 Associations of individual single nucleotide polymorphisms (SNPs) (used as Mendelian randomization instruments) with Glucocorticoids and 28-day mortality of sepsis SNP Allele a chromosome Position Glucocorticoids(exposure) Sepsis(outcome) β b se P β b se P rs1011082 C/T 17 38068514 0.06 0.009 1.41E-11 -0.025 0.033 0.448 rs10519067 A/G 15 61068347 -0.091 0.012 2.76E-15 -0.01 0.050 0.847 rs10905284 A/C 10 8115362 -0.048 0.009 2.72E-08 -0.063 0.034 0.062 rs12123821 T/C 1 152179152 0.153 0.026 5.89E-09 -0.133 0.079 0.090 rs12413578 T/C 10 9049253 -0.171 0.018 4.85E-21 -0.115 0.054 0.035 rs13019081 C/A 2 102950822 0.073 0.009 2.84E-17 -0.048 0.034 0.163 rs1391371 T/A 6 32603798 0.123 0.010 1.19E-37 -0.017 0.042 0.688 rs1504215 A/G 6 91006227 -0.087 0.012 1.11E-13 0.019 0.035 0.584 rs1689510 C/G 12 56396768 0.073 0.010 4.67E-14 -0.058 0.035 0.096 rs1881457 C/A 5 131992809 0.065 0.011 1.1E-09 -0.01 0.044 0.818 rs1898671 T/C 5 110408002 0.100 0.011 7.85E-20 -0.01 0.035 0.776 rs2370615 T/C 8 81290387 -0.076 0.012 3.56E-11 0.003 0.034 0.934 rs2395005 A/G 6 31412652 0.068 0.009 1.04E-14 0.019 0.033 0.577 rs2671657 A/G 17 47473616 -0.053 0.009 1.4E-08 -0.07 0.034 0.038 rs2949661 T/C 1 167424924 -0.072 0.010 7.14E-12 0.022 0.034 0.511 rs3024575 T/C 16 27358132 0.049 0.009 1.84E-08 0.017 0.034 0.630 rs34290285 A/G 2 242698640 -0.113 0.011 3.43E-26 0.023 0.038 0.550 rs35441874 A/T 16 11213021 -0.069 0.011 1.28E-09 0.015 0.039 0.695 rs36132266 T/G 14 69266023 -0.048 0.009 2.38E-08 0.041 0.034 0.220 rs4335039 A/T 7 20581949 -0.053 0.009 3.67E-09 0.004 0.034 0.918 rs4491851 A/G 3 33083985 0.060 0.010 1.82E-09 -0.001 0.034 0.973 rs72743461 A/C 15 67441750 0.089 0.012 1.83E-13 -0.032 0.039 0.421 rs7717955 T/C 5 35862841 -0.057 0.010 7.64E-09 -0.034 0.037 0.363 rs78496075 G/A 6 32608967 -0.101 0.014 7.66E-13 -0.058 0.072 0.421 rs7936312 T/G 11 76293726 0.100 0.011 1.1E-18 -0.016 0.033 0.642 rs992969 G/A 9 6209697 -0.131 0.012 7.98E-27 0.038 0.038 0.326 Table 4 Results of Mendelian randomization (MR) analysis and sensitivity analysis for the effect of glucocorticoids on Sepsis Method p OR 95%CI Inverse variance weighted 0.833 0.989 0.895–1.093 MR Egger 0.572 0.914 0.672–1.243 Weighted median 0.806 0.986 0.878–1.106 Simple mode 0.510 1.075 0.870–1.327 Weighted mode 0.691 1.038 0.865–1.246 Table 5 Results of Mendelian randomization (MR) analysis and sensitivity analysis for the effect of glucocorticoids on Sepsis (28-day mortality of sepsis) Method p OR 95%CI Inverse variance weighted 0.375 0.921 0.768–1.104 MR Egger 0.456 0.805 0.460–1.410 Weighted median 0.220 0.855 0.665–1.098 Simple mode 0.413 0.842 0.561–1.263 Weighted mode 0.316 0.831 0.583–1.184 Table 6 The results of sensitivity analyses. Exposure Outcome MR-Egger intercept analysis Heterogeneity tests by IVW Heterogeneity tests by MR-Egger Intercept p -value Cochran’s Q p -value Cochran’s Q p -value Glucocorticoids Sepsis 0.007 0.598 47.609 0.004 47.049 0.003 Glucocorticoids Sepsis (28 day death) 0.012 0.623 26.496 0.382 26.225 0.342 p < 0.05 was considered significant in sensitivity analyses 4. Discussion The results of our study indicate that glucocorticoids are not causally related to sepsis and 28-day mortality of sepsis. Sepsis is defined as the invasion of a host by microorganisms, persistent of infection, a dysregulated host response to inflammation, excessive inflammation and immunosuppression leading to organ dysfunction followed by organ failure [ 18 ], with mortality rates ranging from 30–45% in hospitalized patients with this disease [ 19 , 20 ]. Glucocorticoids have been used as adjunctive therapies for sepsis since the mid-20th century because they modulate the host immune response to infection [ 21 ],and enhance the cardiovascular response to exogenous catecholamines [ 22 ], Studies have confirmed that glucocorticoids reduce mortality in septic patients [ 4 ], and are beneficial for survival [ 23 ]. In the early 1990s, researchers concluded that septic patients with dysregulation of the thalamic-pituitary-adrenal axis and relative adrenal insufficiency required supplemental exogenous low-dose glucocorticoid therapy [ 24 ].Low-dose glucocorticoids increase the vascular smooth muscle response to vasopressor agents [ 25 , 26 ], have anti-inflammatory effects, are minimally immunosuppressive, improve innate immunity in patients with infectious shock, and may even reverse endothelial activation and sepsis-associated coagulation disorders [ 26 ], which may reduce death in patients with infectious shock [ 6 , 27 ]. However, whether glucocorticoids are beneficial in the treatment of sepsis has been controversial. Large randomized controlled trials have shown no significant difference in 28-day mortality between patients treated with corticosteroids and those treated with placebo (mortality rates of 39.2% and 36.1%, respectively) [ 28 ] ,similarly, there was no significant correlation with a reduction in long-term mortality (90 days to 1 year) in adults with sepsis or infectious shock [ 29 ]. High-dose glucocorticoids may even increase mortality in patients with infectious shock [ 8 ]. The debate over whether the use of glucocorticosteroids in sepsis treatment has a survival benefit centers on high or low dose glucocorticoids. High-dose glucocorticoid therapy is defined as treatment with greater than 30 mg/kg methylprednisone or equivalent, and low-dose glucocorticoid therapy is defined as treatment with less than 500 mg hydrocortisone or equivalent [ 30 ]. Low-dose glucocorticoid therapy has shown beneficial effects in reducing mortality in septic patients [ 4 , 23 ]. Whether glucocorticoids for sepsis treatment have a survival benefit is the subject of another debate: the timing of administration. Two cohort studies evaluating the relationship between the timing of GC administration and survival benefit reported that early treatment with glucocorticoids reduced mortality [ 31 , 32 ].The reason for this is the emergence of glucocorticoid resistance after sepsis, and reduced glucocorticoid receptor response is correlated with disease severity and mortality in sepsis [ 33 ]. One possible mechanism is the development of the glucocorticoid resistance axis during sepsis-hyperlactatemia, and the overexpression of vascular endothelial growth factor can lead to secondary infections and death [ 34 ]. The 2021 guidelines for the Sepsis Survivors' Campaign recommend the use of hydrocortisone in patients with infectious shock and a persistent need for vasopressor therapy, with adults receiving a dose of 200 mg/day via intravenous injection or continuous infusion of 50 mg [ 35 ]. The SSC guidelines recommend the use of corticosteroids 4 hours after the initiation of pressure-boosting drugs in patients with infectious shock, and suggest that the earliest time to start the use of [ 36 ], within 24 hours of shock is reasonable [ 37 ]. 2024 Focus Update: "It is recommended that high-dose/short-term corticosteroids (> 400 mg/d hydrocortisone) not be used". Hydrocortisone(400 mg/d)was administerd for < 3 d to adult patients with infectious shock for the same period of time (strong recommendation, moderate certainty) [ 38 ]. To summarize, another area of research involves the dose, and start time of glucocorticoid therapy. Randomized controlled trials are conducted at a given time point or period, but Mendelian randomization estimates the effect of lifetime differences in exposure levels. Thus, Mendelian randomization may not be the best approach if the association between the genetic tool and the exposure of interest changes throughout the life course, or if the exposure has an effect on the outcome of interest at a critical time. In addition, genetically determined changes in exposure levels are usually small and are thought to be consistent across populations, whereas interventions have a greater effect when evaluated in randomized controlled trials. For all these reasons, extrapolating beyond modest genetic effects from Mendelian randomization analyses may be invalid [ 39 ]. This study has certain limitations. First, the analysis focused on a European population, in our study, we did not verify whether a causal effect existed in other populations. Further studies validating the causality among other ethnic groups are needed. Second, the number of variants used for analysis was relatively small. 5. Conclusion This MR analysis provided no evidence of a causal association between glucocorticoids and sepsis and 28-day mortality of sepsis. However,further studies,such as clinical trials and basic experiments,are needed to elucidate the pathogenesis and treatment of sepsis. Declarations Conflict of Interest 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. Author Contributions Jingxian Huang: Data curation, Investigation, Methodology, Software, Validation, Visualization,Writing – original draft.Yubo Xie: Conceptualization, Investigation, Methodology, Supervision, Funding acquisition,Writing – review & editing. Huageng Huang: Investigation, Methodology, Supervision, Writing – review & editing. Funding 1. Guangxi Key Research and Development Program (No. AB24010066) 2. Guangxi Clinical Research Center for Anesthesiology (No. GK AD22035214) 3. Special Fund of Neurotoxicity of General Anesthetics and Its Prevention and Treatment Innovation Team of the First Affiliated Hospital of Guangxi Medical University (No. YYZS2022001) References Cecconi M, Evans L, Levy M et al. Sepsis and septic shock. lancet 2018, 392(10141):75–87. Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet. 2020;395(10219):200–11. Gavelli FA-OX, Castello LM, Avanzi GC. Management of sepsis and septic shock in the emergency department. Intern Emerg Med. 2021;16(6):1649–61. Wagner Hn IL Jr, Lasagna L, et al. The effect of hydrocortisone upon the course of pneumococcal pneumonia treated with penicillin. Bull Johns Hopkins Hosp. 1956;98(3):197–215. Bone Rc FC Jr, Clemmer Tp, et al. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med. 1987;317(11):653–8. Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018;378(9):809–18. VASSCS G. Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. N Engl J Med. 1987;317(11):659–65. Cronin L, Cook Dj Fau - Carlet J, Carlet J, Fau - Heyland DK, et al. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit Care Med. 1995;23(8):1430–9. Sanderson E. Multivariable Mendelian Randomization and Mediation. Cold Spring Harb Perspect Med. 2021;11(2):a038984. Sheehan NA, Meng S, Fau - Didelez V, Didelez V. Mendelian randomization: a tool for assessing causality in observational epidemiology. Methods Mol Biol. 2011;713:153–66. He W, Castiblanco J, Fau - Walter EA, Walter Ea Fau -, Okulicz JF, et al. Mendelian randomization: potential use of genetics to enable causal inferences regarding HIV-associated biomarkers and outcomes. Curr Opin HIV AIDS. 2010;5(6):545–59. Smith GD, Ebrahim S. Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003;32(1):1–22. Bowden JA-O, Holmes MV. Meta-analysis and Mendelian randomization: A review. Res Synth Methods. 2019;10(4):486–96. Burgess SA-O, Labrecque JA. Mendelian randomization with a binary exposure variable: interpretation and presentation of causal estimates. Eur J Epidemiol. 2018;33(10):947–52. Sakaue SA-O, Kanai MA-O, Tanigawa YA-OX, et al. A cross-population atlas of genetic associations for 220 human phenotypes. Nat Genet. 2021;53(10):1415–24. Auton A, Fau - Brooks LD et al. Brooks Ld Fau - Durbin RM, Durbin Rm Fau - Garrison EP : A global reference for human genetic variation. Nature 2015, 526(7571):68–74. Walker VA-OX, Davies NA-O, Hemani GA-O, et al. Using the MR-Base platform to investigate risk factors and drug targets for thousands of phenotypes. Wellcome Open Res. 2019;4:113. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801–10. Fleischmann C, Scherag A, Adhikari NK, et al. Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. Am J Respir Crit Care Med. 2016;193(3):259–72. Walkey AJ, Lagu T, Fau - Lindenauer PK, Lindenauer PK. Trends in sepsis and infection sources in the United States. A population-based study. Ann Am Thorac Soc. 2015;12(2):216–20. Annane D. Glucocorticoids in the treatment of severe sepsis and septic shock. Glucocorticoids Treat severe sepsis septic shock. 2005;11(5):449–53. Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med. 1995;332(20):1351–62. Annane D, Sébille V, Fau - Charpentier C, Charpentier C, Fau - Bollaert P-E, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288(7):862–71. Schneider Aj Fau -, Voerman HJ, Voerman HJ. Abrupt hemodynamic improvement in late septic shock with physiological doses of glucocorticoids. Intensive Care Med. 1991;17(7):436–7. Marik PE, Pastores Sm Fau - Annane D, Annane D, Fau - Meduri GU, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008;36(6):1937–49. Annane D, Bellissant E, Fau - Bollaert P-E, Bollaert Pe Fau -, Briegel J, et al. Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA. 2009;301(22):2362–75. Fang F, Zhang Y, Tang J, et al. Association of Corticosteroid Treatment With Outcomes in Adult Patients With Sepsis: A Systematic Review and Meta-analysis. JAMA Intern Med. 2019;179(2):213–23. Sprung CL, Annane D, Fau - Keh D, Keh D, Fau - Moreno R, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358(2):111–24. Fujii TA-O, Salanti G, Belletti A, et al. Effect of adjunctive vitamin C, glucocorticoids, and vitamin B1 on longer-term mortality in adults with sepsis or septic shock: a systematic review and a component network meta-analysis. Intensive Care Med. 2022;48(1):16–24. Volbeda M, Wetterslev J, Fau - Gluud C, Gluud C, Fau - Zijlstra JG, et al. Glucocorticosteroids for sepsis: systematic review with meta-analysis and trial sequential analysis. Intensive Care Med. 2015;41(7):1220–34. Katsenos CS et al. Antonopoulou An Fau - Apostolidou EN, Apostolidou En Fau - Ioakeimidou A : Early administration of hydrocortisone replacement after the advent of septic shock: impact on survival and immune response*. Crit Care Med 2014, 42(7). Park HY, Suh Gy Fau - Song J-U, Song Ju Fau -, Yoo H, et al. Early initiation of low-dose corticosteroid therapy in the management of septic shock: a retrospective observational study. Crit Care. 2012;16(1):R3. Cohen J, Pretorius Cj Fau - Ungerer JPJ, Ungerer Jp Fau -, Cardinal J et al. Glucocorticoid Sensitivity Is Highly Variable in Critically Ill Patients With Septic Shock and Is Associated With Disease Severity. Crit Care Med 2016, 44(6):1034–1041. Aziz M, Wang P. Glucocorticoid resistance and hyperlactatemia: A tag team to worsen sepsis. Cell Metab. 2021;33(9):1717–8. Evans LA-O, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47(11):1181–247. Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11):e1063–143. Ammar MA-O, Ammar AA, Wieruszewski PM, et al. Timing of vasoactive agents and corticosteroid initiation in septic shock. Ann Intensive Care. 2022;12(1):47. Chaudhuri D, Nei AM, Rochwerg B, et al. 2024 Focused Update: Guidelines on Use of Corticosteroids in Sepsis, Acute Respiratory Distress Syndrome, and Community-Acquired Pneumonia. Crit Care Med. 2024;52(5):e219–33. Burgess S, Butterworth A, Fau - Malarstig A, Malarstig A, Fau - Thompson SG, et al. Use of Mendelian randomization to assess potential benefit of clinical intervention. BMJ. 2012;345:e7325. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4805652","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":337147332,"identity":"bca772aa-fd89-4233-918c-555cab4448f3","order_by":0,"name":"Jingxian Huang","email":"","orcid":"","institution":"The First Affiliated Hospital of Guangxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jingxian","middleName":"","lastName":"Huang","suffix":""},{"id":337147333,"identity":"c849308d-60b7-44a2-beeb-c913170ff1ad","order_by":1,"name":"Yubo Xie","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAt0lEQVRIiWNgGAWjYFACHgYJMM3e2PjwAwlaDID04WZjCdK0SKS3CfAQo8HgRu7BGx9q/siZz3zYBtRsJ6fbQECL5Iy8ZMsZxwyMZW4ntj0oYEg2NjtAQAu/RI6ZNG+DQeIM6cR2AwmGA4nbCGlhg2uRPNgmwUOMFoQtEoxEapHseQfyi7GxBE8iMJANiPCLwXFwiMnJSbAff/jwQ4WdHEEtDAIJKCYQUg4C/AQNHQWjYBSMghEPAPK8PRtJ7wY2AAAAAElFTkSuQmCC","orcid":"","institution":"The First Affiliated Hospital of Guangxi Medical University","correspondingAuthor":true,"prefix":"","firstName":"Yubo","middleName":"","lastName":"Xie","suffix":""},{"id":337147334,"identity":"f0eaf698-524f-4153-b018-8f3fccefbec4","order_by":2,"name":"Huageng Huang","email":"","orcid":"","institution":"Nanning Second People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Huageng","middleName":"","lastName":"Huang","suffix":""}],"badges":[],"createdAt":"2024-07-26 06:06:44","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4805652/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4805652/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":63390823,"identity":"29ba4175-4277-49b6-a255-fa16ee18dbea","added_by":"auto","created_at":"2024-08-27 15:36:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":32141,"visible":true,"origin":"","legend":"\u003cp\u003eThe flowchart of our study. GWAS=genome-wide association study,MR=Mendelian randomization,SNP=single nucleotide\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4805652/v1/da9c3e318634cf8cae945910.png"},{"id":63390822,"identity":"c7b4a16a-a46b-467d-9211-3cbbef26d954","added_by":"auto","created_at":"2024-08-27 15:36:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":33469,"visible":true,"origin":"","legend":"\u003cp\u003eMendelian randomized regression scatter plots of glucocorticoids (exposure) and sepsis and 28-day mortality of sepsis. (a) Glucocorticoids and sepsis. (b) Glucocorticoids and 28-day mortality of sepsis.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4805652/v1/8ba2724e67ee74ae589d0a89.png"},{"id":63391330,"identity":"f0720749-afd4-4b2c-a2d9-326c25884b59","added_by":"auto","created_at":"2024-08-27 15:44:00","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":44553,"visible":true,"origin":"","legend":"\u003cp\u003eForest plots of single nucleotide polymorphism (SNP) ratio estimates and Mendelian randomization estimates for the set of instrumental variables used to analyze glucocorticoids (exposure) and sepsis, and 28-day mortality of sepsis (outcome) (using Egger and inverse variance weighted (IVW) models). (a) Glucocorticoids and sepsis. (b) Glucocorticoids versus 28-day mortality of sepsis. Solid line indicates 95% CI.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4805652/v1/f741f0a488b1d0b3650ab9ff.png"},{"id":63391331,"identity":"71778117-0d6b-4cbd-a4ea-8cd95456d5d8","added_by":"auto","created_at":"2024-08-27 15:44:00","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":41954,"visible":true,"origin":"","legend":"\u003cp\u003eGlucocorticoids (exposure) and sepsis, 28-day mortality of sepsis (outcome) Leave-one-out analysis. (a) Glucocorticoids and sepsis. (b) Glucocorticoids and 28-day mortality of sepsis.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4805652/v1/e7cb02f887ad9842ccb888b6.png"},{"id":63390826,"identity":"904fb1ed-721a-4056-a0a8-3ac837771f25","added_by":"auto","created_at":"2024-08-27 15:36:00","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":15452,"visible":true,"origin":"","legend":"\u003cp\u003eMendelian randomized regression funnel plots of glucocorticoids (exposure) and sepsis and 28-day mortality of sepsis. (a) Glucocorticoids and sepsis. (b) Glucocorticoids and 28-day mortality of sepsis.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4805652/v1/7352353b7b04e65dfe0503c8.png"},{"id":77667133,"identity":"6858fb7a-1569-435c-9e2e-37c40b5281aa","added_by":"auto","created_at":"2025-03-04 06:17:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1270838,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4805652/v1/20385c9f-11f0-4bdc-a764-fc784619c04f.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Glucocorticoids and sepsis and 28-day mortality of sepsis: a Mendelian randomization study","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eSepsis is a complex, dysfunctional host response to infection, that is usually accompanied by acute organ dysfunction and high mortality [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. A Global Burden of Disease report revealed that 48.9\u0026nbsp;million cases of sepsis were reported globally in 2017, with a mortality rate of 22.5%, accounting for nearly 20% of all global deaths [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], and posing significant global health challenges. Treatment of sepsis is currently based on a combination of antibiotics, organ support and protection, and fluid resuscitation, for which glucocorticoid therapy is still controversial.\u003c/p\u003e \u003cp\u003eGlucocorticoids modulate the immune response to infection and enhance cardiovascular stability and organ protection, which has been used routinely in the treatment of sepsis since the 1950s and were routinely used in the treatment of septic patients [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Large randomized controlled studies have shown that low-dose glucocorticoids reduce mortality in patients with sepsis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, large trials and meta-analyses in the late 1980s demonstrated that high-dose glucocorticoid therapy (30 mg/kg methylprednisone or equivalent) regimens not only failed to benefit septic patients in terms of mortality or disease [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], but were also detrimental [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], therefore, the use of high-dose glucocorticoids in the treatment of septic shock is no longer popular. The use of glucocorticoids in the treatment of sepsis remains controversial. The causal relationship between the use of glucocorticoids and sepsis and sepsis mortality is unclear and more direct evidence is needed.\u003c/p\u003e \u003cp\u003eMendelian randomization (MR) is an observational design that uses single nucleotide polymorphisms (SNPs) reliably associated with an exposure to estimate the causal effect of the exposure (glucocorticoids) on the outcome (sepsis and 28-day mortality of sepsis) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Humans are randomly \"assigned\" their genotype at conception [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], thus, MR is less susceptible to confounding than other observational designs [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]。Due to the limitations of randomized controlled studies and retrospective studies, such as potential confounders and selection bias, it is difficult to draw consistent conclusions about the association of glucocorticoids with the development of sepsis and 28-day mortality of sepsis; therefore, we performed a two-sample MR analysis using pooled statistical data from the GWAS to assess the causal effect of glucocorticoids on the development of sepsis and the 28-day mortality of sepsis risk.\u003c/p\u003e"},{"header":"2. Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Research design\u003c/h2\u003e \u003cp\u003eThis was a two-sample Mendelian randomization study to screen for SNPs strongly associated with exposure factors from the GWAS, which was intended to satisfy three main hypotheses: (1) they should be robustly associated with the exposure; (2) they should not be associated with potential confounders of the exposure-outcome association; and (3) they should not influence the outcome by any variable other than the exposure [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Ethics statement\u003c/h2\u003e \u003cp\u003eAll of the datasets employed in our study were large-scale public GWAS summary data. Ethical approval and consent to participate were acquired from all original studies. The flowchart of the process is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Data sources\u003c/h2\u003e \u003cp\u003eExposure data glucocorticoids and outcome data sepsis and 28-day mortality of sepsis GWAS data were obtained from the IEU Open GWAS project (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gwas.mrcieu.ac.uk/\u003c/span\u003e\u003cspan address=\"https://gwas.mrcieu.ac.uk/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Different populations may lead to biased estimates, and we restricted the genetic background of populations in the MR study to individuals of European origin [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].Glucocorticoid GWAS ID: ebi-a-GCST90019000, from the most recent GWAS pooled data, is a collection of 220 in-depth phenotypic GWAS performed by BioBank Japan (BBJ), which included 108 phenotypes that had never been GWASed in East Asian populations; then, the corresponding phenotypes were GWASed in the United Kingdom Biobank (UKB) and GWAS of the corresponding phenotypes were performed in FinnGen, and the most recent GWAS pooled data were meta-analyzed across populations. Selections from this database included 205,700 Europeans (17,352 cases and 188,348 controls) and 14,256,400 SNPs [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].Sepsis GWAS ID: ieu-b-4980, established by the UK Biobanking Consortium, contains 486,484 Europeans (11,643 cases, 474,841 controls) and 12,243,539 SNPs. 28-day mortality of sepsis GWAS ID: ieu-b-5086, established by the UK Biobanking Consortium. The dataset included 486,484 Europeans (1896 cases, 484588 controls) and 12,243,487 SNPs, as shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Selection of Instrumental Variables\u003c/h2\u003e \u003cp\u003eAll genetic variants that achieved genome-wide significance were selected as instrumental variables (IVs), with the correlation setting a p-value cutoff of 5 \u0026times; 10\u003csup\u003e\u0026minus;\u0026thinsp;8\u003c/sup\u003e. To ensure that the variants were independent, SNPs with high linkage disequilibrium (r\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.001,clump window\u0026thinsp;\u0026lt;\u0026thinsp;10000 kb) were excluded, thus ensuring their independence. We used these carefully selected SNPs as the final genetic IVs for subsequent MR analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Statistical analyses\u003c/h2\u003e \u003cp\u003eFirst, the inverse variance weighted (IVW) method was chosen as the main two-sample MR analysis method to estimate causal effects [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. MR Egger regression, weighted median and weighted mode methods, and MR-simple-mode were used to infer causality; to test the robustness of the results, Cochran's Q test was performed via the IVW method to assess the heterogeneity among SNPs. Significant horizontal pleiotropy was assessed by MR-Egger intercept. Additionally, Leave-one-out analysis was used to test whether the MR results were driven by specific SNPs. Finally, scatter plots, forest plots and funnel plots were drawn. A p-value less than 0.05 indicated statistical significance in all the sensitivity analysis methods. All the statistical analyses were performed via the \"TwoSampleMR\" package in R software [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eAfter strict adherence to the criteria of IVs selection, a total of 26 qualified SNPs were ultimately selected as proxies for glucocorticoids use in the present study (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Causal effect of glucocorticoids on sepsis\u003c/h2\u003e \u003cp\u003eAccording to the results of the main MR method, glucocorticoids had no etiological effect on sepsis in IVW [OR\u0026thinsp;=\u0026thinsp;0.989, 95% CI 0.895\u0026ndash;1.093, P\u0026thinsp;=\u0026thinsp;0.833, standard error (SE)\u0026thinsp;=\u0026thinsp;0.051, Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e]. The results were validated in other complementary methods, MR-Egger (OR\u0026thinsp;=\u0026thinsp;0.914, 95% CI 0.672\u0026ndash;1.243, P\u0026thinsp;=\u0026thinsp;0.572, se\u0026thinsp;=\u0026thinsp;0.157), weighted median (OR\u0026thinsp;=\u0026thinsp;0.986, 95% CI 0.878\u0026ndash;1.106, P\u0026thinsp;=\u0026thinsp;0.806, se\u0026thinsp;=\u0026thinsp;0.059), the simple model (OR\u0026thinsp;=\u0026thinsp;1.075, 95% CI 0.870\u0026ndash;1.327, P\u0026thinsp;=\u0026thinsp;0.510, se\u0026thinsp;=\u0026thinsp;0.108), and the weighted model (OR\u0026thinsp;=\u0026thinsp;1.038, 95% CI 0.865\u0026ndash;1.246, P\u0026thinsp;=\u0026thinsp;0.691, se\u0026thinsp;=\u0026thinsp;0.093, Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). A scatterplot of the causal associations between glucocorticoids and sepsis is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea. The forest map is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Causal effect of glucocorticoids on 28-day mortality of sepsis\u003c/h2\u003e \u003cp\u003eSimilarly, no significant causal effect was identified between glucocorticoids and 28-day mortality of sepsis, as estimated by the following five two-sample MR analysis methods (IVW OR\u0026thinsp;=\u0026thinsp;0.921, 95% CI 0.768\u0026ndash;1.104, P\u0026thinsp;=\u0026thinsp;0.375, se\u0026thinsp;=\u0026thinsp;0.093; MR-Egger OR\u0026thinsp;=\u0026thinsp;0.805, 95% CI 0.460\u0026ndash;1.410, P\u0026thinsp;=\u0026thinsp;0.456, se\u0026thinsp;=\u0026thinsp;0.286; weighted median OR\u0026thinsp;=\u0026thinsp;0.855, 95% CI 0.665\u0026ndash;1.098, P\u0026thinsp;=\u0026thinsp;0.220, se\u0026thinsp;=\u0026thinsp;0.128; simple model OR\u0026thinsp;=\u0026thinsp;0.842, 95% CI 0.561\u0026ndash;1.263, P\u0026thinsp;=\u0026thinsp;0.413, se\u0026thinsp;=\u0026thinsp;0.207; weighted model OR\u0026thinsp;=\u0026thinsp;0.831, 95% CI 0.583\u0026ndash;1.184, P\u0026thinsp;=\u0026thinsp;0.316, se\u0026thinsp;=\u0026thinsp;0.181, Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). A scatterplot of the causal relationships between glucocorticoids and 28-day mortality of sepsis is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb. The forest map is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Sensitivity analyses\u003c/h2\u003e \u003cp\u003eThe detailed results of MR-Egger intercept analysis, heterogeneity tests by IVW, and heterogeneity tests by MR-Egger are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.According to the results of the leave-one-out cross-validation test, we did not detect any potentially influential or problematic SNPs(Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).As shown in the funnel plots (Supplementary Fig.\u0026nbsp;5), no potential horizontal pleiotropy was discovered.\u003c/p\u003e \u003cp\u003eOn the basis of the consistency of the results estimated by the five different MR analytical approaches, no strong evidence was found to support a causal effect of glucocorticoids on sepsis and 28-day mortality of sepsis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe characteristics of the SNPs of both glucocorticoids and sepsis and 28-day mortality of sepsis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e Associations of individual single nucleotide polymorphisms (SNPs) (used as Mendelian randomization instruments) with Glucocorticoids and Sepsis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTraits\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePopulation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSample Size\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNumber of SNPs\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eID\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlucocorticoids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEuropean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e205,700\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14,256,400\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eebi-a-GCST90019000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSepsis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEuropean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e486,484\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12,243,539\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eieu-b-4980\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e28-day mortality of sepsis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEuropean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e486,484\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12,243,487\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eieu-b-5086\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSNP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAllele\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003echromosome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePosition\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eGlucocorticoids(exposure)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e \u003cp\u003eSepsis(outcome)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eβ\u003c/em\u003e\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ese\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003eβ\u003c/em\u003e\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003ese\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1011082\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC/T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e38068514\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.060\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.41E-11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.316\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers10519067\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA/G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e61068347\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.091\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.76E-15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.445\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers10905284\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA/C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8115362\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.048\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.72E-08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.068\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers12123821\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT/C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e152179152\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.153\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.026\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.89E-09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.960\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers12413578\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT/C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9049253\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.171\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.85E-21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.280\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers13019081\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e102950822\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.073\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.84E-17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1391371\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e32603798\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.123\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.19E-37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.778\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1504215\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA/G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e91006227\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.087\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.11E-13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.182\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1689510\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC/G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e56396768\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.073\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.67E-14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.045\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1881457\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e131992809\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.065\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.10E-09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.526\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1898671\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT/C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e110408002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.85E-20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.417\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers2370615\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT/C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e81290387\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.076\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.56E-11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.611\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers2395005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA/G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e31412652\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.068\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.04E-14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.936\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers2671657\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA/G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e47473616\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.053\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.40E-08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.938\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers2949661\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT/C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e167424924\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.072\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.14E-12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.199\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers3024575\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT/C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e27358132\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.049\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.84E-08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.120\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers34290285\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA/G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e242698640\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.113\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.43E-26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.699\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers35441874\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA/T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11213021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.069\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.28E-09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.998\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers36132266\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT/G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e69266023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.048\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.38E-08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.349\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers4335039\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA/T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20581949\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.053\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.67E-09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.328\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers4491851\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA/G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e33083985\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.060\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.82E-09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.087\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers72743461\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA/C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e67441750\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.089\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.83E-13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.808\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers7717955\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT/C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e35862841\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.057\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.64E-09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.497\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers78496075\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e32608967\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.66E-13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.077\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.029\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers7936312\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT/G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e76293726\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.10E-18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.111\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers992969\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6209697\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.131\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.98E-27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ea. Alleles are shown as other alleles/effect alleles\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eb. Effect sizes for the effect allele\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ea. Alleles are shown as other alleles/effect alleles\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eb. Effect sizes for the effect allele\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e Associations of individual single nucleotide polymorphisms (SNPs) (used as Mendelian randomization instruments) with Glucocorticoids and 28-day mortality of sepsis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSNP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAllele\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003echromosome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePosition\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eGlucocorticoids(exposure)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e \u003cp\u003eSepsis(outcome)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eβ\u003c/em\u003e\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ese\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003eβ\u003c/em\u003e\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003ese\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1011082\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC/T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e38068514\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.41E-11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.448\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers10519067\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA/G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e61068347\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.091\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.76E-15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.050\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.847\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers10905284\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA/C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8115362\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.048\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.72E-08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.063\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.062\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers12123821\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT/C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e152179152\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.153\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.026\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.89E-09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.133\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.079\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.090\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers12413578\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT/C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9049253\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.171\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.85E-21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.115\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.054\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.035\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers13019081\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e102950822\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.073\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.84E-17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.048\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.163\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1391371\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e32603798\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.123\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.19E-37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.042\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.688\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1504215\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA/G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e91006227\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.087\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.11E-13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.035\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.584\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1689510\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC/G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e56396768\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.073\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.67E-14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.058\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.035\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.096\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1881457\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e131992809\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.065\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.1E-09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.044\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.818\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers1898671\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT/C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e110408002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.85E-20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.035\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.776\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers2370615\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT/C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e81290387\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.076\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.56E-11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.934\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers2395005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA/G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e31412652\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.068\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.04E-14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.577\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers2671657\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA/G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e47473616\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.053\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.4E-08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.038\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers2949661\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT/C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e167424924\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.072\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.14E-12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.511\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers3024575\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT/C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e27358132\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.049\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.84E-08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.630\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers34290285\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA/G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e242698640\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.113\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.43E-26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.038\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.550\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers35441874\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA/T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11213021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.069\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.28E-09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.039\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.695\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers36132266\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT/G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e69266023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.048\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.38E-08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.041\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.220\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers4335039\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA/T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20581949\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.053\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.67E-09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.918\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers4491851\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA/G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e33083985\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.060\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.82E-09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.973\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers72743461\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA/C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e67441750\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.089\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.83E-13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.039\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.421\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers7717955\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT/C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e35862841\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.057\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.64E-09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.037\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.363\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers78496075\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e32608967\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.66E-13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.058\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.072\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.421\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers7936312\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eT/G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e76293726\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.1E-18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.642\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ers992969\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6209697\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.131\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.98E-27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.038\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.038\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e0.326\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eResults of Mendelian randomization (MR) analysis and sensitivity analysis for the effect of glucocorticoids on Sepsis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMethod\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e95%CI\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInverse variance weighted\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0.833\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.989\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.895\u0026ndash;1.093\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMR Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0.572\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.914\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.672\u0026ndash;1.243\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeighted median\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0.806\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.986\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.878\u0026ndash;1.106\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSimple mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0.510\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.075\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.870\u0026ndash;1.327\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeighted mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0.691\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.038\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.865\u0026ndash;1.246\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eResults of Mendelian randomization (MR) analysis and sensitivity analysis for the effect of glucocorticoids on Sepsis (28-day mortality of sepsis)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMethod\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e95%CI\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInverse variance weighted\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0.375\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.921\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.768\u0026ndash;1.104\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMR Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0.456\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.805\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.460\u0026ndash;1.410\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeighted median\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0.220\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.855\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.665\u0026ndash;1.098\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSimple mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0.413\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.842\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.561\u0026ndash;1.263\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeighted mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0.316\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.831\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.583\u0026ndash;1.184\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe results of sensitivity analyses.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eExposure\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eMR-Egger intercept analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eHeterogeneity tests by IVW\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eHeterogeneity tests by MR-Egger\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIntercept\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCochran\u0026rsquo;s Q\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCochran\u0026rsquo;s Q\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlucocorticoids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSepsis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.598\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e47.609\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e47.049\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlucocorticoids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSepsis (28 day death)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.623\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e26.496\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.382\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e26.225\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.342\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant in sensitivity analyses\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThe results of our study indicate that glucocorticoids are not causally related to sepsis and 28-day mortality of sepsis.\u003c/p\u003e \u003cp\u003eSepsis is defined as the invasion of a host by microorganisms, persistent of infection, a dysregulated host response to inflammation, excessive inflammation and immunosuppression leading to organ dysfunction followed by organ failure [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], with mortality rates ranging from 30\u0026ndash;45% in hospitalized patients with this disease [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Glucocorticoids have been used as adjunctive therapies for sepsis since the mid-20th century because they modulate the host immune response to infection [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e],and enhance the cardiovascular response to exogenous catecholamines [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], Studies have confirmed that glucocorticoids reduce mortality in septic patients [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], and are beneficial for survival [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In the early 1990s, researchers concluded that septic patients with dysregulation of the thalamic-pituitary-adrenal axis and relative adrenal insufficiency required supplemental exogenous low-dose glucocorticoid therapy [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].Low-dose glucocorticoids increase the vascular smooth muscle response to vasopressor agents [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], have anti-inflammatory effects, are minimally immunosuppressive, improve innate immunity in patients with infectious shock, and may even reverse endothelial activation and sepsis-associated coagulation disorders [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], which may reduce death in patients with infectious shock [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. However, whether glucocorticoids are beneficial in the treatment of sepsis has been controversial. Large randomized controlled trials have shown no significant difference in 28-day mortality between patients treated with corticosteroids and those treated with placebo (mortality rates of 39.2% and 36.1%, respectively) [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] ,similarly, there was no significant correlation with a reduction in long-term mortality (90 days to 1 year) in adults with sepsis or infectious shock [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. High-dose glucocorticoids may even increase mortality in patients with infectious shock [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The debate over whether the use of glucocorticosteroids in sepsis treatment has a survival benefit centers on high or low dose glucocorticoids. High-dose glucocorticoid therapy is defined as treatment with greater than 30 mg/kg methylprednisone or equivalent, and low-dose glucocorticoid therapy is defined as treatment with less than 500 mg hydrocortisone or equivalent [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Low-dose glucocorticoid therapy has shown beneficial effects in reducing mortality in septic patients [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Whether glucocorticoids for sepsis treatment have a survival benefit is the subject of another debate: the timing of administration. Two cohort studies evaluating the relationship between the timing of GC administration and survival benefit reported that early treatment with glucocorticoids reduced mortality [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].The reason for this is the emergence of glucocorticoid resistance after sepsis, and reduced glucocorticoid receptor response is correlated with disease severity and mortality in sepsis [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. One possible mechanism is the development of the glucocorticoid resistance axis during sepsis-hyperlactatemia, and the overexpression of vascular endothelial growth factor can lead to secondary infections and death [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. The 2021 guidelines for the Sepsis Survivors' Campaign recommend the use of hydrocortisone in patients with infectious shock and a persistent need for vasopressor therapy, with adults receiving a dose of 200 mg/day via intravenous injection or continuous infusion of 50 mg [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. The SSC guidelines recommend the use of corticosteroids 4 hours after the initiation of pressure-boosting drugs in patients with infectious shock, and suggest that the earliest time to start the use of [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], within 24 hours of shock is reasonable [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. 2024 Focus Update: \"It is recommended that high-dose/short-term corticosteroids (\u0026gt;\u0026thinsp;400 mg/d hydrocortisone) not be used\". Hydrocortisone(400 mg/d)was administerd for \u0026lt;\u0026thinsp;3 d to adult patients with infectious shock for the same period of time (strong recommendation, moderate certainty) [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo summarize, another area of research involves the dose, and start time of glucocorticoid therapy. Randomized controlled trials are conducted at a given time point or period, but Mendelian randomization estimates the effect of lifetime differences in exposure levels. Thus, Mendelian randomization may not be the best approach if the association between the genetic tool and the exposure of interest changes throughout the life course, or if the exposure has an effect on the outcome of interest at a critical time. In addition, genetically determined changes in exposure levels are usually small and are thought to be consistent across populations, whereas interventions have a greater effect when evaluated in randomized controlled trials. For all these reasons, extrapolating beyond modest genetic effects from Mendelian randomization analyses may be invalid [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study has certain limitations. First, the analysis focused on a European population, in our study, we did not verify whether a causal effect existed in other populations. Further studies validating the causality among other ethnic groups are needed. Second, the number of variants used for analysis was relatively small.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThis MR analysis provided no evidence of a causal association between glucocorticoids and sepsis and 28-day mortality of sepsis. However,further studies,such as clinical trials and basic experiments,are needed to elucidate the pathogenesis and treatment of sepsis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJingxian Huang: Data curation, Investigation, Methodology, Software, Validation, Visualization,Writing \u0026ndash; original draft.Yubo Xie: Conceptualization, Investigation, Methodology, Supervision, Funding acquisition,Writing \u0026ndash; review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003eHuageng Huang: Investigation, Methodology, Supervision, Writing \u0026ndash; review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1. Guangxi Key Research and Development Program (No. AB24010066)\u003c/p\u003e\n\u003cp\u003e2. Guangxi Clinical Research Center for Anesthesiology (No. GK AD22035214)\u003c/p\u003e\n\u003cp\u003e3. Special Fund of Neurotoxicity of General Anesthetics and Its Prevention and Treatment Innovation Team of the First Affiliated Hospital of Guangxi Medical University (No. YYZS2022001)\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCecconi M, Evans L, Levy M et al. Sepsis and septic shock. \u003cem\u003elancet\u003c/em\u003e 2018, 392(10141):75\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990\u0026ndash;2017: analysis for the Global Burden of Disease Study. Lancet. 2020;395(10219):200\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGavelli FA-OX, Castello LM, Avanzi GC. Management of sepsis and septic shock in the emergency department. Intern Emerg Med. 2021;16(6):1649\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWagner Hn IL Jr, Lasagna L, et al. The effect of hydrocortisone upon the course of pneumococcal pneumonia treated with penicillin. Bull Johns Hopkins Hosp. 1956;98(3):197\u0026ndash;215.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBone Rc FC Jr, Clemmer Tp, et al. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med. 1987;317(11):653\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAnnane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018;378(9):809\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVASSCS G. Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. N Engl J Med. 1987;317(11):659\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCronin L, Cook Dj Fau - Carlet J, Carlet J, Fau - Heyland DK, et al. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit Care Med. 1995;23(8):1430\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSanderson E. Multivariable Mendelian Randomization and Mediation. Cold Spring Harb Perspect Med. 2021;11(2):a038984.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSheehan NA, Meng S, Fau - Didelez V, Didelez V. Mendelian randomization: a tool for assessing causality in observational epidemiology. Methods Mol Biol. 2011;713:153\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHe W, Castiblanco J, Fau - Walter EA, Walter Ea Fau -, Okulicz JF, et al. Mendelian randomization: potential use of genetics to enable causal inferences regarding HIV-associated biomarkers and outcomes. Curr Opin HIV AIDS. 2010;5(6):545\u0026ndash;59.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmith GD, Ebrahim S. Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003;32(1):1\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBowden JA-O, Holmes MV. Meta-analysis and Mendelian randomization: A review. Res Synth Methods. 2019;10(4):486\u0026ndash;96.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBurgess SA-O, Labrecque JA. Mendelian randomization with a binary exposure variable: interpretation and presentation of causal estimates. Eur J Epidemiol. 2018;33(10):947\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSakaue SA-O, Kanai MA-O, Tanigawa YA-OX, et al. A cross-population atlas of genetic associations for 220 human phenotypes. Nat Genet. 2021;53(10):1415\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAuton A, Fau - Brooks LD et al. Brooks Ld Fau - Durbin RM, Durbin Rm Fau - Garrison EP : A global reference for human genetic variation. \u003cem\u003eNature\u003c/em\u003e 2015, 526(7571):68\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWalker VA-OX, Davies NA-O, Hemani GA-O, et al. Using the MR-Base platform to investigate risk factors and drug targets for thousands of phenotypes. Wellcome Open Res. 2019;4:113.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSinger M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFleischmann C, Scherag A, Adhikari NK, et al. Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. Am J Respir Crit Care Med. 2016;193(3):259\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWalkey AJ, Lagu T, Fau - Lindenauer PK, Lindenauer PK. Trends in sepsis and infection sources in the United States. A population-based study. Ann Am Thorac Soc. 2015;12(2):216\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAnnane D. Glucocorticoids in the treatment of severe sepsis and septic shock. Glucocorticoids Treat severe sepsis septic shock. 2005;11(5):449\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med. 1995;332(20):1351\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAnnane D, S\u0026eacute;bille V, Fau - Charpentier C, Charpentier C, Fau - Bollaert P-E, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288(7):862\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchneider Aj Fau -, Voerman HJ, Voerman HJ. Abrupt hemodynamic improvement in late septic shock with physiological doses of glucocorticoids. Intensive Care Med. 1991;17(7):436\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarik PE, Pastores Sm Fau - Annane D, Annane D, Fau - Meduri GU, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008;36(6):1937\u0026ndash;49.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAnnane D, Bellissant E, Fau - Bollaert P-E, Bollaert Pe Fau -, Briegel J, et al. Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA. 2009;301(22):2362\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFang F, Zhang Y, Tang J, et al. Association of Corticosteroid Treatment With Outcomes in Adult Patients With Sepsis: A Systematic Review and Meta-analysis. JAMA Intern Med. 2019;179(2):213\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSprung CL, Annane D, Fau - Keh D, Keh D, Fau - Moreno R, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358(2):111\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFujii TA-O, Salanti G, Belletti A, et al. Effect of adjunctive vitamin C, glucocorticoids, and vitamin B1 on longer-term mortality in adults with sepsis or septic shock: a systematic review and a component network meta-analysis. Intensive Care Med. 2022;48(1):16\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVolbeda M, Wetterslev J, Fau - Gluud C, Gluud C, Fau - Zijlstra JG, et al. Glucocorticosteroids for sepsis: systematic review with meta-analysis and trial sequential analysis. Intensive Care Med. 2015;41(7):1220\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKatsenos CS et al. Antonopoulou An Fau - Apostolidou EN, Apostolidou En Fau - Ioakeimidou A : Early administration of hydrocortisone replacement after the advent of septic shock: impact on survival and immune response*. \u003cem\u003eCrit Care Med\u003c/em\u003e 2014, 42(7).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePark HY, Suh Gy Fau - Song J-U, Song Ju Fau -, Yoo H, et al. Early initiation of low-dose corticosteroid therapy in the management of septic shock: a retrospective observational study. Crit Care. 2012;16(1):R3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCohen J, Pretorius Cj Fau - Ungerer JPJ, Ungerer Jp Fau -, Cardinal J et al. Glucocorticoid Sensitivity Is Highly Variable in Critically Ill Patients With Septic Shock and Is Associated With Disease Severity. \u003cem\u003eCrit Care Med\u003c/em\u003e 2016, 44(6):1034\u0026ndash;1041.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAziz M, Wang P. Glucocorticoid resistance and hyperlactatemia: A tag team to worsen sepsis. Cell Metab. 2021;33(9):1717\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEvans LA-O, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47(11):1181\u0026ndash;247.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEvans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11):e1063\u0026ndash;143.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmmar MA-O, Ammar AA, Wieruszewski PM, et al. Timing of vasoactive agents and corticosteroid initiation in septic shock. Ann Intensive Care. 2022;12(1):47.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChaudhuri D, Nei AM, Rochwerg B, et al. 2024 Focused Update: Guidelines on Use of Corticosteroids in Sepsis, Acute Respiratory Distress Syndrome, and Community-Acquired Pneumonia. Crit Care Med. 2024;52(5):e219\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBurgess S, Butterworth A, Fau - Malarstig A, Malarstig A, Fau - Thompson SG, et al. Use of Mendelian randomization to assess potential benefit of clinical intervention. BMJ. 2012;345:e7325.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Glucocorticoids, Sepsis,28-day mortality of sepsis, Mendelian randomization, Single nucleotide polymorphisms","lastPublishedDoi":"10.21203/rs.3.rs-4805652/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4805652/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Background: Whether glucocorticoids are beneficial in sepsis and related deaths has been controversial, and the exact causal relationship is unclear. This study used Mendelian randomization to investigate the causal relationships between glucocorticoids and sepsis and 28-day mortality of sepsis.\nMethods: We obtained SNPs (p-value \u003c 5 × 10-8) strongly associated with the exposure factor glucocorticoids (n=5440) from a genome-wide association study (GWAS) with glucocorticoids as the exposure factor and sepsis and 28-day mortality from sepsis as the outcome factor. Causality studies were conducted using variance weighted inverse methods supplemented with MR Egger, weighted median and weighted mode and MR simple mode analyses. The results were analyzed for heterogeneity and tested for horizontal multiplicity, leave-one-out sensitivity tests were performed and ORs were calculated for the results.\nResults: A total of 26 qualified SNPs were ultimately selected as proxies for glucocorticoids. The results of the random effects from IVW revealed that glucocorticoids had no causal effect on sepsis(OR=0.989, 95% CI 0.895-1.093, P=0.833, se=0.051), 28-day mortality of sepsis(OR=0.921, 95% CI 0.768-1.104, P=0.375, se=0.093). These results were confirmed using the MR-Egger, weighted median, simple model, and weighted models.\nConclusions: In a two-sample Mendelian randomization analysis, no strong evidence was found to support a causal effect of glucocorticoids on sepsis, sepsis 28-day mortality, from a genetic perspective.","manuscriptTitle":"Glucocorticoids and sepsis and 28-day mortality of sepsis: a Mendelian randomization study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-27 15:35:55","doi":"10.21203/rs.3.rs-4805652/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6c94279a-fc83-4f7d-bc3f-b4d1869b62ff","owner":[],"postedDate":"August 27th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-03-04T06:09:00+00:00","versionOfRecord":[],"versionCreatedAt":"2024-08-27 15:35:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4805652","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4805652","identity":"rs-4805652","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}