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共13篇 平均IF=5.15 (2.9-7.5)更多分析
  • 2区Q1影响因子: 7.5
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    1. Multi-omic studies on the pathogenesis of Sepsis.
    期刊:Journal of translational medicine
    日期:2025-03-24
    DOI :10.1186/s12967-025-06366-w
    BACKGROUND:Sepsis is a life-threatening inflammatory condition, and its underlying genetic mechanisms are not yet fully elucidated. We applied methods such as Mendelian randomization (MR), genetic correlation analysis, and colocalization analysis to integrate multi-omics data and explore the relationship between genetically associated genes and sepsis, as well as sepsis-related mortality, with the goal of identifying key genetic factors and their potential mechanistic pathways. METHODS:To identify therapeutic targets for sepsis and sepsis-related mortality, we conducted an MR analysis on 11,643 sepsis cases and 1,896 cases of 28-day sepsis mortality from the UK Biobank cohort. The exposure data consisted of 15,944 potential druggable genes (expression quantitative trait loci, eQTL) and 4,907 plasma proteins (protein quantitative trait loci, pQTL). We then performed sensitivity analysis, SMR analysis, reverse MR analysis, genetic correlation analysis, colocalization analysis, enrichment analysis, and protein-protein interaction network analysis on the overlapping genes. Validation was conducted using 17,133 sepsis cases from FinnGen R12. Drug prediction and molecular docking were subsequently used to further assess the therapeutic potential of the identified drug targets, while PheWAS was used to evaluate potential side effects. Finally, mediation analysis was conducted to identify the mediating role of related metabolites. RESULTS:The MR analysis results identified a significant causal relationship between 24 genes and sepsis. The robustness of these causal associations was further strengthened by SMR analysis, sensitivity analysis, and reverse MR analysis. Genetic correlation analysis revealed that only two of these genes were genetically correlated with sepsis. Colocalization analysis showed that only one gene was closely associated with sepsis, while validation using the FinnGen dataset identified three genes. In the MR analysis of 28-day sepsis mortality, seven genes were found to have significant associations, with reverse MR analysis excluding one gene. The remaining genes passed sensitivity analysis, with no significant genes identified in genetic correlation and colocalization analyses. Molecular docking demonstrated excellent binding affinity between drugs and proteins with available structural data. PheWAS at the gene level did not reveal any potential side effects of the related drugs. CONCLUSIONS:The identified drug targets, associated pathways, and metabolites have enhanced our understanding of the complex relationships between genes and sepsis. These genes and metabolites can serve as effective targets for sepsis treatment, paving new pathways in this field and laying a foundation for future research.
  • 2. Role of artificial intelligence in early diagnosis and treatment of infectious diseases.
    期刊:Infectious diseases (London, England)
    日期:2024-11-14
    DOI :10.1080/23744235.2024.2425712
    Infectious diseases remain a global health challenge, necessitating innovative approaches for their early diagnosis and effective treatment. Artificial Intelligence (AI) has emerged as a transformative force in healthcare, offering promising solutions to address this challenge. This review article provides a comprehensive overview of the pivotal role AI can play in the early diagnosis and treatment of infectious diseases. It explores how AI-driven diagnostic tools, including machine learning algorithms, deep learning, and image recognition systems, enhance the accuracy and efficiency of disease detection and surveillance. Furthermore, it delves into the potential of AI to predict disease outbreaks, optimise treatment strategies, and personalise interventions based on individual patient data and how AI can be used to gear up the drug discovery and development (D3) process.The ethical considerations, challenges, and limitations associated with the integration of AI in infectious disease management are also examined. By harnessing the capabilities of AI, healthcare systems can significantly improve their preparedness, responsiveness, and outcomes in the battle against infectious diseases.
  • 2区Q1影响因子: 5.3
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    3. TRPV4 Regulates the Macrophage Metabolic Response to Limit Sepsis-induced Lung Injury.
    期刊:American journal of respiratory cell and molecular biology
    日期:2024-06-01
    DOI :10.1165/rcmb.2023-0456OC
    Sepsis is a systemic inflammatory response that requires effective macrophage metabolic functions to resolve ongoing inflammation. Previous work showed that the mechanosensitive cation channel, transient receptor potential vanilloid 4 (TRPV4), mediates macrophage phagocytosis and cytokine production in response to lung infection. Here, we show that TRPV4 regulates glycolysis in a stiffness-dependent manner by augmenting macrophage glucose uptake by GLUT1. In addition, TRPV4 is required for LPS-induced phagolysosome maturation in a GLUT1-dependent manner. In a cecal slurry mouse model of sepsis, TRPV4 regulates sepsis-induced glycolysis as measured by BAL fluid (BALF) lactate and sepsis-induced lung injury as measured by BALF total protein and lung compliance. TRPV4 is necessary for bacterial clearance in the peritoneum to limit sepsis-induced lung injury. It is interesting that BALF lactate is increased in patients with sepsis compared with healthy control participants, supporting the relevance of lung cell glycolysis to human sepsis. These data show that macrophage TRPV4 is required for glucose uptake through GLUT1 for effective phagolysosome maturation to limit sepsis-induced lung injury. Our work presents TRPV4 as a potential target to protect the lung from injury in sepsis.
  • 3区Q1影响因子: 2.9
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    4. Validation of SeptiCyte RAPID to Discriminate Sepsis from Non-Infectious Systemic Inflammation.
    期刊:Journal of clinical medicine
    日期:2024-02-20
    DOI :10.3390/jcm13051194
    (1) SeptiCyte RAPID is a molecular test for discriminating sepsis from non-infectious systemic inflammation, and for estimating sepsis probabilities. The objective of this study was the clinical validation of SeptiCyte RAPID, based on testing retrospectively banked and prospectively collected patient samples. (2) The cartridge-based SeptiCyte RAPID test accepts a PAXgene blood RNA sample and provides sample-to-answer processing in ~1 h. The test output (SeptiScore, range 0-15) falls into four interpretation bands, with higher scores indicating higher probabilities of sepsis. Retrospective (N = 356) and prospective (N = 63) samples were tested from adult patients in ICU who either had the systemic inflammatory response syndrome (SIRS), or were suspected of having/diagnosed with sepsis. Patients were clinically evaluated by a panel of three expert physicians blinded to the SeptiCyte test results. Results were interpreted under either the Sepsis-2 or Sepsis-3 framework. (3) Under the Sepsis-2 framework, SeptiCyte RAPID performance for the combined retrospective and prospective cohorts had Areas Under the ROC Curve (AUCs) ranging from 0.82 to 0.85, a negative predictive value of 0.91 (sensitivity 0.94) for SeptiScore Band 1 (score range 0.1-5.0; lowest risk of sepsis), and a positive predictive value of 0.81 (specificity 0.90) for SeptiScore Band 4 (score range 7.4-15; highest risk of sepsis). Performance estimates for the prospective cohort ranged from AUC 0.86-0.95. For physician-adjudicated sepsis cases that were blood culture (+) or blood, urine culture (+)(+), 43/48 (90%) of SeptiCyte scores fell in Bands 3 or 4. In multivariable analysis with up to 14 additional clinical variables, SeptiScore was the most important variable for sepsis diagnosis. A comparable performance was obtained for the majority of patients reanalyzed under the Sepsis-3 definition, although a subgroup of 16 patients was identified that was called septic under Sepsis-2 but not under Sepsis-3. (4) This study validates SeptiCyte RAPID for estimating sepsis probability, under both the Sepsis-2 and Sepsis-3 frameworks, for hospitalized patients on their first day of ICU admission.
  • 1区Q1影响因子: 5
    5. Early Physician Gestalt Versus Usual Screening Tools for the Prediction of Sepsis in Critically Ill Emergency Patients.
    期刊:Annals of emergency medicine
    日期:2024-03-25
    DOI :10.1016/j.annemergmed.2024.02.009
    STUDY OBJECTIVE:Compare physician gestalt to existing screening tools for identifying sepsis in the initial minutes of presentation when time-sensitive treatments must be initiated. METHODS:This prospective observational study conducted with consecutive encounter sampling took place in the emergency department (ED) of an academic, urban, safety net hospital between September 2020 and May 2022. The study population included ED patients who were critically ill, excluding traumas, transfers, and self-evident diagnoses. Emergency physician gestalt was measured using a visual analog scale (VAS) from 0 to 100 at 15 and 60 minutes after patient arrival. The primary outcome was an explicit sepsis hospital discharge diagnosis. Clinical data were recorded for up to 3 hours to compare Systemic Inflammatory Response Syndrome (SIRS), Sequential Organ Failure Assessment (SOFA), quick SOFA (qSOFA), Modified Early Warning Score (MEWS), and a logistic regression machine learning model using Least Absolute Shrinkage and Selection Operator (LASSO) for variable selection. The screening tools were compared using receiver operating characteristic analysis and area under the curve calculation (AUC). RESULTS:A total of 2,484 patient-physician encounters involving 59 attending physicians were analyzed. Two hundred seventy-five patients (11%) received an explicit sepsis discharge diagnosis. When limited to available data at 15 minutes, initial VAS (AUC 0.90; 95% confidence interval [CI] 0.88, 0.92) outperformed all tools including LASSO (0.84; 95% CI 0.82 to 0.87), qSOFA (0.67; 95% CI 0.64 to 0.71), SIRS (0.67; 95% 0.64 to 0.70), SOFA (0.67; 95% CI 0.63 to 0.70), and MEWS (0.66; 95% CI 0.64 to 0.69). Expanding to data available at 60 minutes did not meaningfully change results. CONCLUSION:Among adults presenting to an ED with an undifferentiated critical illness, physician gestalt in the first 15 minutes of the encounter outperformed other screening methods in identifying sepsis.
  • 2区Q1影响因子: 4.3
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    6. Proposal and Validation of a Clinically Relevant Modification of the Japanese Association for Acute Medicine Disseminated Intravascular Coagulation Diagnostic Criteria for Sepsis.
    期刊:Thrombosis and haemostasis
    日期:2024-05-10
    DOI :10.1055/s-0044-1786808
    BACKGROUND: Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) criteria were launched nearly 20 years ago. Following the revised conceptual definition of sepsis and subsequent omission of systemic inflammatory response syndrome (SIRS) score from the latest sepsis diagnostic criteria, we omitted the SIRS score and proposed a modified version of JAAM DIC criteria, the JAAM-2 DIC criteria. OBJECTIVES: To validate and compare performance between new JAAM-2 DIC criteria and conventional JAAM DIC criteria for sepsis. METHODS: We used three datasets containing adult sepsis patients from a multicenter nationwide Japanese cohort study (J-septic DIC, FORECAST, and SPICE-ICU registries). JAAM-2 DIC criteria omitted the SIRS score and set the cutoff value at ≥3 points. Receiver operating characteristic (ROC) analyses were performed between the two DIC criteria to evaluate prognostic value. Associations between in-hospital mortality and anticoagulant therapy according to DIC status were analyzed using propensity score weighting to compare significance of the criteria in determining introduction of anticoagulants against sepsis. RESULTS: Final study cohorts of the datasets included 2,154, 1,065, and 608 sepsis patients, respectively. ROC analysis revealed that curves for both JAAM and JAAM-2 DIC criteria as predictors of in-hospital mortality were almost consistent. Survival curves for the anticoagulant and control groups in the propensity score-weighted prediction model diagnosed using the two criteria were also almost entirely consistent. CONCLUSION: JAAM-2 DIC criteria were equivalent to JAAM DIC criteria regarding prognostic and diagnostic values for initiating anticoagulation. The newly proposed JAAM-2 DIC criteria could be potentially alternative criteria for sepsis management.
  • 2区Q1影响因子: 5.6
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    7. Single-cell landscape of immunological responses in elderly patients with sepsis.
    期刊:Immunity & ageing : I & A
    日期:2024-06-22
    DOI :10.1186/s12979-024-00446-z
    Sepsis is a dysregulated host response to severe infections, and immune dysfunction plays a crucial role in its pathogenesis. Elderly patients, a special population influenced by immunosenescence, are more susceptible to sepsis and have a worse prognosis. However, the immunopathogenic mechanisms underlying sepsis in elderly patients remain unclear. Here, we performed single-cell RNA sequencing of peripheral blood samples from young and old subjects and patients with sepsis. By exploring the transcriptional profiles of immune cells, we analyzed immune cell compositions, phenotype shifts, expression heterogeneities, and intercellular communication. In elderly patients with sepsis, innate immune cells (e.g., monocytes and DCs) exhibit decreased antigen presentation, presenting an overactive inflammatory and senescent phenotype. However, the immunophenotype of T cells shifted to characterize effector, memory, and exhaustion. Moreover, we identified strong interferon-γ responses of T cells in both aging and sepsis groups and a deranged inflammaging status in elderly sepsis patients. Tregs in elderly patients with sepsis showed increased abundance and enhanced immunosuppressive effects. In addition, metabolism-associated pathways were upregulated in T cells in elderly patients with sepsis, and the lysine metabolism pathway was enriched in Tregs. Cell-cell interaction analysis showed that the expression profile of ligand-receptor pairs was probably associated with aggravated immune dysfunction in elderly patients with sepsis. A novel HLA-KIR interaction was observed between Tregs and CD8 + T cells. These findings illustrate the immunological hallmarks of sepsis in elderly patients, and highlight that immunosuppressive and metabolic regulatory pathways may undergo important alterations in elderly patients with sepsis.
  • 1区Q1影响因子: 6.9
    8. Serum 25-hydroxyvitamin D concentrations, vitamin D receptor polymorphisms, and risk of infections among individuals with type 2 diabetes: a prospective cohort study.
    期刊:The American journal of clinical nutrition
    日期:2024-06-22
    DOI :10.1016/j.ajcnut.2024.06.007
    BACKGROUND:Evidence on the association between serum 25-hydroxyvitamin D [25(OH)D] and infections among patients with type 2 diabetes (T2D), a group susceptible to vitamin D deficiency and infections, is limited. OBJECTIVES:We aimed to examine this association in individuals with T2D, and to evaluate whether genetic variants in vitamin D receptor (VDR) would modify this association. METHODS:This study included 19,851 participants with T2D from United Kingdom Biobank. Infections were identified by linkage to hospital inpatient and death registers. Negative binomial regression models were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs), with adjustment of potential confounders. RESULTS:In patients with T2D, the incidence rate of infections was 29.3/1000 person-y. Compared with those with 25(OH)D of 50.0-74.9 nmol/L, the multivariable-adjusted IRRs and 95% CIs of total infections, pneumonia, gastrointestinal infections, and sepsis were 1.44 (1.31, 1.59), 1.49 (1.27, 1.75), 1.47 (1.22, 1.78), and 1.41 (1.14, 1.73), respectively, in patients with 25(OH)D <25.0 nmol/L. Nonlinear inverse associations between 25(OH)D concentrations and the risks of total infections (P-overall < 0.001; P-nonlinear = 0.002) and gastrointestinal infections (P-overall < 0.001; P-nonlinear = 0.040) were observed, with a threshold effect at ∼50.0 nmol/L. The vitamin D-infection association was not modified by genetic variants in VDR (all P-interaction > 0.050). CONCLUSIONS:In patients with T2D, lower serum 25(OH)D concentration (<50 nmol/L) was associated with higher risks of infections, regardless of genetic variants in VDR. Notably, nonlinear inverse associations between 25(OH)D concentrations and the risks of infections were found, with a threshold effect at ∼50.0 nmol/L. These findings highlighted the importance of maintaining adequate vitamin D in reducing the risk of infections in patients with T2D.
  • 2区Q1影响因子: 5.4
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    9. Isaridin E Protects against Sepsis by Inhibiting Von Willebrand Factor-Induced Endothelial Hyperpermeability and Platelet-Endothelium Interaction.
    期刊:Marine drugs
    日期:2024-06-16
    DOI :10.3390/md22060283
    Endothelial hyperpermeability is pivotal in sepsis-associated multi-organ dysfunction. Increased von Willebrand factor (vWF) plasma levels, stemming from activated platelets and endothelium injury during sepsis, can bind to integrin αvβ3, exacerbating endothelial permeability. Hence, targeting this pathway presents a potential therapeutic avenue for sepsis. Recently, we identified isaridin E (ISE), a marine-derived fungal cyclohexadepsipeptide, as a promising antiplatelet and antithrombotic agent with a low bleeding risk. ISE's influence on septic mortality and sepsis-induced lung injury in a mouse model of sepsis, induced by caecal ligation and puncture, is investigated in this study. ISE dose-dependently improved survival rates, mitigating lung injury, thrombocytopenia, pulmonary endothelial permeability, and vascular inflammation in the mouse model. ISE markedly curtailed vWF release from activated platelets in septic mice by suppressing vesicle-associated membrane protein 8 and soluble N-ethylmaleide-sensitive factor attachment protein 23 overexpression. Moreover, ISE inhibited healthy human platelet adhesion to cultured lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs), thereby significantly decreasing vWF secretion and endothelial hyperpermeability. Using cilengitide, a selective integrin αvβ3 inhibitor, it was found that ISE can improve endothelial hyperpermeability by inhibiting vWF binding to αvβ3. Activation of the integrin αvβ3-FAK/Src pathway likely underlies vWF-induced endothelial dysfunction in sepsis. In conclusion, ISE protects against sepsis by inhibiting endothelial hyperpermeability and platelet-endothelium interactions.
  • 2区Q1影响因子: 5.9
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    10. Peripheral PD-1NK cells could predict the 28-day mortality in sepsis patients.
    期刊:Frontiers in immunology
    日期:2024-06-17
    DOI :10.3389/fimmu.2024.1426064
    Background:Unbalanced inflammatory response is a critical feature of sepsis, a life-threatening condition with significant global health burdens. Immune dysfunction, particularly that involving different immune cells in peripheral blood, plays a crucial pathophysiological role and shows early warning signs in sepsis. The objective is to explore the relationship between sepsis and immune subpopulations in peripheral blood, and to identify patients with a higher risk of 28-day mortality based on immunological subtypes with machine-learning (ML) model. Methods:Patients were enrolled according to the sepsis-3 criteria in this retrospective observational study, along with age- and sex-matched healthy controls (HCs). Data on clinical characteristics, laboratory tests, and lymphocyte immunophenotyping were collected. XGBoost and k-means clustering as ML approaches, were employed to analyze the immune profiles and stratify septic patients based on their immunological subtypes. Cox regression survival analysis was used to identify potential biomarkers and to assess their association with 28-day mortality. The accuracy of biomarkers for mortality was determined by the area under the receiver operating characteristic (ROC) curve (AUC) analysis. Results:The study enrolled 100 septic patients and 89 HCs, revealing distinct lymphocyte profiles between the two groups. The XGBoost model discriminated sepsis from HCs with an area under the receiver operating characteristic curve of 1.0 and 0.99 in the training and testing set, respectively. Within the model, the top three highest important contributions were the percentage of CD38CD8T cells, PD-1NK cells, HLA-DRCD8T cells. Two clusters of peripheral immunophenotyping of septic patients by k-means clustering were conducted. Cluster 1 featured higher proportions of PD1 NK cells, while cluster 2 featured higher proportions of naïve CD4T cells. Furthermore, the level of PD-1NK cells was significantly higher in the non-survivors than the survivors (15.1% vs 8.6%, <0.01). Moreover, the levels of PD1 NK cells combined with SOFA score showed good performance in predicting the 28-day mortality in sepsis (AUC=0.91,95%CI 0.82-0.99), which is superior to PD1 NK cells only(AUC=0.69, sensitivity 0.74, specificity 0.64, cut-off value of 11.25%). In the multivariate Cox regression, high expression of PD1 NK cells proportion was related to 28-day mortality (aHR=1.34, 95%CI 1.19 to 1.50; <0.001). Conclusion:The study provides novel insights into the association between PD1NK cell profiles and prognosis of sepsis. Peripheral immunophenotyping could potentially stratify the septic patients and identify those with a high risk of 28-day mortality.
  • 3区Q1影响因子: 4.6
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    11. Exploring the relationship between life course adiposity and sepsis: insights from a two-sample Mendelian randomization analysis.
    期刊:Frontiers in endocrinology
    日期:2024-06-14
    DOI :10.3389/fendo.2024.1413690
    Objectives:The relationship between adiposity and sepsis has received increasing attention. This study aims to explore the causal relationship between life course adiposity and the sepsis incidence. Methods:Mendelian randomization (MR) method was employed in this study. Instrumental variants were obtained from genome-wide association studies for life course adiposity, including birth weight, childhood body mass index (BMI), childhood obesity, adult BMI, waist circumference, visceral adiposity, and body fat percentage. A meta-analysis of genome-wide association studies for sepsis including 10,154 cases and 454,764 controls was used in this study. MR analyses were performed using inverse variance weighted, MR Egger regression, weighted median, weighted mode, and simple mode. Instrumental variables were identified as significant single nucleotide polymorphisms at the genome-wide significance level ( < 5×10). The sensitivity analysis was conducted to assess the reliability of the MR estimates. Results:Analysis using the MR analysis of inverse variance weighted method revealed that genetic predisposition to increased childhood BMI ( = 1.29, = 0.003), childhood obesity ( = 1.07, = 0.034), adult BMI ( = 1.38, < 0.001), adult waist circumference ( = 1.01, = 0.028), and adult visceral adiposity ( = 1.53, < 0.001) predicted a higher risk of sepsis. Sensitivity analysis did not identify any bias in the MR results. Conclusion:The results demonstrated that adiposity in childhood and adults had causal effects on sepsis incidence. However, more well-designed studies are still needed to validate their association.
  • 3区Q2影响因子: 3.9
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    12. The beneficial effects of Rosuvastatin in inhibiting inflammation in sepsis.
    期刊:Aging
    日期:2024-06-14
    DOI :10.18632/aging.205937
    Microbial infection-induced sepsis causes excessive inflammatory response and multiple organ failure. An effective strategy for the treatment of sepsis-related syndromes is still needed. Rosuvastatin, a typical β-hydroxy β-methylglutaryl-CoA reductase inhibitor licensed for reducing the levels of low-density lipoprotein cholesterol in patients with hyperlipidemia, has displayed anti-inflammatory capacity in different types of organs and tissues. However, its effects on the development of sepsis are less reported. Here, we found that the administration of Rosuvastatin reduced the mortality of sepsis mice and prevented body temperature loss. Additionally, it inhibited the production of inflammatory cytokines such as tumor necrosis factor (TNF-α), Interleukin-6 (IL-6), interleukin-1β (IL-1β), and migration inhibitory factor (MIF) in peritoneal lavage supernatants of animals. The increased number of mononuclear cells in the peritoneum of sepsis mice was reduced by Rosuvastatin. Interestingly, it ameliorated lung inflammation and improved the hepatic and renal function in the sepsis animals. Further experiments show that Rosuvastatin inhibited lipopolysaccharide (LPS)-induced production of proinflammatory cytokines in RAW 264.7 macrophages by preventing the activation of nuclear factor kappa-B (NF-κB). Our findings demonstrate that the administration of Rosuvastatin hampered organ dysfunction and mitigated inflammation in a relevant model of sepsis.
  • 3区Q2影响因子: 3.4
    13. Hospital-treated infectious diseases, genetic susceptibility and risk of type 2 diabetes: A population-based longitudinal study.
    期刊:Diabetes & metabolic syndrome
    日期:2024-06-15
    DOI :10.1016/j.dsx.2024.103063
    BACKGROUND:The longitudinal association between infectious diseases and the risk of type 2 diabetes (T2D) remains unclear. METHODS:Based on the UK Biobank, the prospective cohort study included a total of 396,080 participants without diabetes at baseline. We determined the types and sites of infectious diseases and incident T2D using the International Classification of Diseases 10th Revision codes (ICD-10). Time-varying Cox proportional hazard model was used to assess the association. Infection burden was defined as the number of infection episodes over time and the number of co-occurring infections. Genetic risk score (GRS) for T2D consisted of 424 single nucleotide polymorphisms. RESULTS:During a median of 9.04 [IQR, 8.3-9.7] years of follow-up, hospital-treated infectious diseases were associated with a greater risk of T2D (adjusted HR [aHR] 1.54 [95 % CI 1.46-1.61]), with risk difference per 10,000 individuals equal to 154.1 [95 % CI 140.7-168.2]. The heightened risk persisted after 5 years following the index infection. Bacterial infection with sepsis had the strongest risk of T2D (aHR 2.95 [95 % CI 2.53-3.44]) among different infection types. For site-specific analysis, bloodstream infections posed the greatest risk (3.01 [95 % CI 2.60-3.48]). A dose-response association was observed between infection burden and T2D risk within each GRS tertile (p-trend <0.001). High genetic risk and infection synergistically increased the T2D risk. CONCLUSION:Infectious diseases were associated with an increased risk of subsequent T2D. The risk showed specificity according to types, sites, severity of infection and the period since infection occurred. A potential accumulative effect of infection was revealed.
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