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OBJECTIVES: Disorders of immune system may impact cardiovascular health; however, comprehensive study is lacking. We aimed to analyse the association of total and 20 individual immune-mediated diseases (IMDs) with risk of incident cardiovascular disease (CVD). METHODS: In this prospective cohort study, 414 495 participants (55.6% women; mean age 55.9 years) from UK Biobank with baseline assessment at 2006-10 were included. Among them, 21 784 participants had prevalent IMDs. Information on IMDs at baseline and incidence of CVDs during follow-up were recorded. Cox proportional hazard models were used to estimate the association between IMDs and CVDs risk. RESULTS: During the median follow-up of 12.1 years, there were 6506 cases of CVDs in participants with IMDs (29.9%) and 77 699 cases in those without IMDs (19.8%). After multivariable adjustment, participants with IMDs were significantly associated with an increased risk of total CVD [hazard ratio (HR) 1.57; 95% CI 1.52-1.61]. Among the 20 IMDs, 16 showed significant associations with CVD (all P < 0.0025 after Bonferroni correction), with HR ranging from 1.34 (1.16-1.54) for celiac disease to 2.75 (2.10-3.61) for SLE. Participants with any IMD exposure had a higher risk of all individual CVD events, with HR ranging from 1.34 (1.14-1.58) for cerebral hemorrhage to 1.80 (1.54-2.11) for pericardium diseases. IMD duration <5, 5-10 and >10 years was associated with 55%, 59% and 56% increased risk of total CVD, respectively. CONCLUSION: Total and individual IMDs were associated with an increased risk of overall CVDs. It is important to consider primary prevention of CVD in patients with IMD and dysregulation of immune system in the cardiovascular health.
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Doenças Cardiovasculares , Doença Celíaca , Cardiopatias , Doenças do Sistema Imunitário , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Estudos Prospectivos , Doenças do Sistema Imunitário/complicações , Doenças do Sistema Imunitário/epidemiologiaRESUMO
Evidence for reciprocal comorbidity of schizophrenia (SCZ) and body mass index (BMI) has grown in recent years. However, little is known regarding the shared genetic architecture or causality underlying the phenotypic association between SCZ and BMI. Leveraging summary statistics from the hitherto largest genome-wide association study (GWAS) on each trait, we investigated the genetic overlap and causal associations of SCZ with BMI. Our study demonstrated a genetic correlation between SCZ and BMI, and the correlation was more evident in local genomic regions. The cross-trait meta-analysis identified 27 significant SNPs shared between SCZ and BMI, most of which had the same direction of influence on both diseases. Mendelian randomization analysis showed the causal association of SCZ with BMI, but not vice versa. Combining the gene expression information, we found that the genetic correlation between SCZ and BMI is enriched in six regions of brain, led by the brain frontal cortex. Additionally, 34 functional genes and 18 specific cell types were found to have an impact on both SCZ and BMI within these regions. Taken together, our comprehensive genome-wide cross-trait analysis suggests a shared genetic basis including pleiotropic loci, tissue enrichment, and shared function genes between SCZ and BMI. This work provides novel insights into the intrinsic genetic overlap of SCZ and BMI, and highlights new opportunities and avenues for future investigation.
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Esquizofrenia , Humanos , Esquizofrenia/genética , Índice de Massa Corporal , Estudo de Associação Genômica Ampla , Encéfalo , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Predisposição Genética para Doença/genéticaRESUMO
BACKGROUND AND AIMS: To investigate the associations of ideal cardiovascular health metrics (ICVHMs) with all-cause mortality among former and current smokers compared with never smokers. METHODS AND RESULTS: A total of 378,147 participants [mean age (SD) years: 56.3 (8.1); 47.2 % men] were included from the UK Biobank cohort. The ICVHMs were combined Life's simple 7 from the American Heart Association and sleep duration time. The association was explored using COX regression models. During a median follow-up of 13.3 years, we documented 24,594 deaths. Compared with never smokers, among former smokers, the multivariable-adjusted hazard ratio (HR) for all-cause mortality was 1.82 (95%CI 1.71-1.92) for participants who had ≤2 ICVHMs and 1.03 (0.97-1.10) for participants who had ≥6 ICVHMs; among current smokers, the HRs for mortality were 2.74 (2.60-2.89) and 2.18 (1.78-2.67). The phenomenon was more pronounced among participants younger than 60 years [HR (95%CI), 1.82 (1.71-1.95) for ≤2 ICVHMs vs 1.04 (0.96-1.12) for ≥6 ICVHMs with age ≥60 years and 1.83 (1.62-2.06) vs 0.98 (0.88-1.11) with age <60 years among former smokers; 2.66 (2.49-2.85) vs 2.44 (1.84-3.24) with age ≥60 years and 2.85 (2.62-3.10) vs 1.96 (1.47-2.61) with age <60 years among current smokers]. In addition, the HR for mortality of each 1-number increment in ICVHMs was 0.87 (0.86-0.89) among former smokers and 0.91 (0.89-0.94) among current smokers. CONCLUSION: Our findings indicated the importance of adherence to have more ICVHMs in the mortality risk among former smokers, and priority of smoking cessation in current smokers. IMPLICATIONS: Studies have found that former smokers still have higher risks of lung cancer and all-cause mortality than never-smokers. The next question is whether the effects of previous or current smoking could be ameliorated by eight ideal cardiovascular health metrics (ICVHMs). We aim to explore whether ICVHMs may counteract the risk of all-cause mortality among former and current smokers. The results showed that only former smokers with ≥6 ICVHMs exhibited a comparable risk of all-cause mortality with never smokers. Furthermore, current smokers even having ≥6 ICVHMs still exhibited a higher risk of all-cause mortality compared with never smokers.
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Fumantes , Abandono do Hábito de Fumar , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Fatores de Risco , Estudos Prospectivos , Fumar/efeitos adversosRESUMO
AIMS: To evaluate the association of cardiovascular health (CVH), measured by Life's Essential 8 score, with the risk of premature mortality and to determine the patterns of CVH-related differences in life expectancy among people with and without type 2 diabetes (T2D). MATERIALS AND METHODS: This prospective study included 309,789 participants (age 56.6 ± 8.1 years; 46% men) enroled in the UK Biobank. The Life's Essential 8 composite measure consists of four health behaviours (diet, physical activity, nicotine exposure, and sleep) and four health factors (BMI, non-HDL cholesterol, blood glucose, and blood pressure), and the maximum CVH score was 100 points. CVH was categorised into low, moderate, and high groups. Premature death was defined as death before the age of 75. Cox proportional hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated, and life expectancy was estimated. RESULTS: During a median follow-up of 12.7 years, 13,683 cases of premature death were documented. Compared to participants with low CVH, the multivariable HRs (95% CIs) of premature death were 0.59 (0.56-0.62) and 0.42 (0.39-0.45) for the moderate and high CVH groups, respectively. This association was stronger in participants with T2D compared with those without T2D. At the age of 50 years, compared to low CVH groups, high CVH was associated with a gain of 9.79 (9.70-9.87) and 5.58 (5.48-5.67) additional life years for men with and without T2D, respectively. The corresponding life gain for women with and without T2D was 24.21 (24.13-24.27) and 10.18 (10.10-10.27), respectively. CONCLUSIONS: Maintaining an ideal Life's Essential 8 score may provide more benefits for people with T2D than for those without T2D, including a lower risk of premature death and an increased lifespan.
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Masculino , Humanos , Feminino , Estados Unidos , Pessoa de Meia-Idade , Estudos Prospectivos , Mortalidade Prematura , Diabetes Mellitus Tipo 2/complicações , Risco , Dieta , Fatores de Risco , Pressão SanguíneaRESUMO
BACKGROUND: Septic shock is characterized by an uncontrolled inflammatory response and microcirculatory dysfunction. There is currently no specific agent for treating septic shock. Anisodamine is an agent extracted from traditional Chinese medicine with potent anti-inflammatory effects. However, its clinical effectiveness remains largely unknown. METHODS: In a multicentre, open-label trial, we randomly assigned adults with septic shock to receive either usual care or anisodamine (0.1-0.5 mg per kilogram of body weight per hour), with the anisodamine doses adjusted by clinicians in accordance with the patients' shock status. The primary end point was death on hospital discharge. The secondary end points were ventilator-free days at 28 days, vasopressor-free days at 28 days, serum lactate and sequential organ failure assessment (SOFA) score from days 0 to 6. The differences in the primary and secondary outcomes were compared between the treatment and usual care groups with the χ2 test, Student's t test or rank-sum test, as appropriate. The false discovery rate was controlled for multiple testing. RESULTS: Of the 469 patients screened, 355 were assigned to receive the trial drug and were included in the analyses-181 patients received anisodamine, and 174 were in the usual care group. We found no difference between the usual care and anisodamine groups in hospital mortality (36% vs. 30%; p = 0.348), or ventilator-free days (median [Q1, Q3], 24.4 [5.9, 28] vs. 26.0 [8.5, 28]; p = 0.411). The serum lactate levels were significantly lower in the treated group than in the usual care group after day 3. Patients in the treated group were less likely to receive vasopressors than those in the usual care group (OR [95% CI] 0.84 [0.50, 0.93] for day 5 and 0.66 [0.37, 0.95] for day 6). CONCLUSIONS: There is no evidence that anisodamine can reduce hospital mortality among critically ill adults with septic shock treated in the intensive care unit. Trial registration ClinicalTrials.gov ( NCT02442440 ; Registered on 13 April 2015).
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Choque Séptico , Alcaloides de Solanáceas , Estado Terminal , Humanos , Choque Séptico/tratamento farmacológico , Alcaloides de Solanáceas/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Kidney dysfunction is linked to nonalcoholic fatty liver disease (NAFLD) progression including fibrosis, steatosis, or inflammation. We aimed to explore whether lower levels of estimated glomerular filtration rate (eGFR) was associated with increased probability of liver fibrosis. METHODS: Two thousand six hundred eighty-nine subjects enrolled from Shanghai, China, were included in this study. NAFLD fibrosis score (NFS) was used to risk stratify NAFLD patients for fibrosis. eGFR was used to assess kidney function. The association of eGFR level with elevated NFS, and thus high risk of fibrosis, was analysed by linear regression and multinomial logistic regression. The predictive power of eGFR was evaluated via receiver operating characteristic (ROC) curve. RESULTS: A negative association was found between eGFR and NFS (B = -0.21, 95% CI, -0.37 to -0.04, P = .016). As eGFR quartiles decreased, the prevalence of probable fibrosis increased after adjusting for age, sex, current smoking, waist circumference, duration of diabetes, HbA1c , hypertension, dyslipidaemia, and homeostasis model assessment index of insulin resistance (HOMA-IR) (Q4: reference; Q3: 1.49, 95% CI, 0.82-2.71; Q2: 1.88, 95% CI, 0.97-3.67; Q1: 2.70, 95% CI, 1.36-5.37, Pfor trend = .002, 1SD increment: 0.73, 95% CI, 0.58-0.92). The eGFR level can be an effective indicator in differentiating patients with probable presence of fibrosis from those without (AUROC: 0.71, cut-off point: 92.78 mL/min/1.73 m2 , P < .001). CONCLUSIONS: Lower levels of eGFR were associated with higher NFS and thus greater risk of presence of fibrosis in patients with NAFLD and T2DM. Individuals with NAFLD and diabetes should carefully monitor eGFR and receive regular urinalysis, especially when advanced fibrosis is suspected.
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Diabetes Mellitus Tipo 2/complicações , Taxa de Filtração Glomerular , Cirrose Hepática/etiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Insuficiência Renal Crônica/etiologia , Índice de Gravidade de Doença , Idoso , Biomarcadores/análise , Glicemia/análise , China/epidemiologia , Feminino , Seguimentos , Humanos , Cirrose Hepática/epidemiologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/patologia , Fatores de RiscoRESUMO
The rapidly progressing of coronavirus disease 2019 (COVID-19) pandemic has become a global concern. This meta-analysis aimed at evaluating the efficacy and safety of current option of therapies for severe acute respiratory syndrome (SARS), Middle Eastern respiratory syndrome (MERS) besides COVID-19, in an attempt to identify promising therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected patients. We searched PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and WANFANG DATA for randomized controlled trials (RCTs), prospective cohort, and retrospective cohort studies that evaluated therapies (hydroxychloroquine, lopinavir/ritonavir-based therapy, and ribavirin-based therapy, etc.) for SARS, MERS, and COVID-19. The primary outcomes were mortality, virological eradication and clinical improvement, and secondary outcomes were improvement of symptoms and chest radiography results, incidence of acute respiratory disease syndrome (ARDS), utilization of mechanical ventilation, and adverse events (AEs). Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effects models, and the quality of evidence was appraised using GRADEpro. Eighteen articles (5 RCTs, 2 prospective cohort studies, and 11 retrospective cohort studies) involving 4,941 patients were included. Compared with control treatment, anti-coronary virus interventions significantly reduced mortality (RR 0.65, 95% CI 0.44-0.96; I2 = 81.3%), remarkably ameliorate clinical improvement (RR 1.52, 95% CI 1.05-2.19) and radiographical improvement (RR 1.62, 95% CI 1.11-2.36, I2 = 11.0 %), without manifesting clear effect on virological eradication, incidence of ARDS, intubation, and AEs. Subgroup analyses demonstrated that the combination of ribavirin and corticosteroids remarkably decreased mortality (RR 0.43, 95% CI 0.27-0.68). The lopinavir/ritonavir-based combination showed superior virological eradication and radiographical improvement with reduced rate of ARDS. Likewise, hydroxychloroquine improved radiographical result. For safety, ribavirin could induce more bradycardia, anemia and transaminitis. Meanwhile, hydroxychloroquine could increase AEs rate especially diarrhea. Overall, the quality of evidence on most outcomes were very low. In conclusion, although we could not draw a clear conclusion for the recommendation of potential therapies for COVID-19 considering the very low quality of evidence and wide heterogeneity of interventions and indications, our results may help clinicians to comprehensively understand the advantages and drawbacks of each anti-coronavirus agents on efficacy and safety profiles. Lopinavir/ritonavir combinations might observe better virological eradication capability than other anti-coronavirus agents. Conversely, ribavirin might cause more safety concerns especially bradycardia. Thus, large RCTs objectively assessing the efficacy of antiviral therapies for SARS-CoV-2 infections should be conducted with high priority.
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Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Antivirais/efeitos adversos , Betacoronavirus/efeitos dos fármacos , COVID-19 , Humanos , Pandemias , SARS-CoV-2RESUMO
BACKGROUND: Probiotics could prevent Pseudomonas aeruginosa colonization in lower respiratory tract (LRT) and reduced P. aeruginosa ventilator-associated pneumonia (VAP) rate. Recent studies also suggested that probiotics could improve lung inflammation in mice infected with P. aeruginosa. It seems that microbiota regulation may be a potential therapy for P. aeruginosa VAP patients. However, we know less about the LRT microbial composition and its correlation with prognosis in P. aeruginosa VAP patients. This study aimed to characterize LRT microbiota in P. aeruginosa VAP patients and explore the relationship between microbiota and patient prognosis. METHODS: Deep endotracheal secretions were sampled from subjects via intubation. Communities were identified by 16S ribosomal RNA gene sequencing. The relationship between microbiota and the prognosis of P. aeruginosa VAP patients were evaluated. Clinical pulmonary infection score and the survival of intensive care unit were both the indicators of patient prognosis. RESULTS: In this study, the LRT microbial composition of P. aeruginosa VAP patients was significantly different from non-infected intubation patients, and showed significant individual differences, forming two clusters. According to the predominant phylum of each cluster, these two clusters were named Pro cluster and Fir-Bac cluster respectively. Patients from Pro cluster were dominated by Proteobacteria (adj.P < 0.001), while those from Fir-Bac cluster were dominated by Firmicutes, and Bacteroidetes (both adj.P < 0.001). These two varied clusters (Pro and Fir-Bac cluster) were associated with the patients' primary disease (χ2-test, P < 0.0001). The primary disease of the Pro cluster mainly included gastrointestinal disease (63%), and the Fir-Bac cluster was predominantly respiratory disease (89%). During the two-week dynamic observation period, despite the use of antibiotics, the dominant genera and Shannon diversity of the LRT microbiota did not change significantly in patients with P. aeruginosa VAP. In prognostic analysis, we found a significant negative correlation between Lactobacillus and clinical pulmonary infection score on the day of diagnosis (P = 0.014); but we found no significant difference of microbial composition between survivors and non-survivors. CONCLUSIONS: LRT microbial composition was diversified among P. aeruginosa VAP patients, forming two clusters which were associated with the primary diseases of the patients.
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Pneumonia Associada à Ventilação Mecânica/diagnóstico , Pneumonia Associada à Ventilação Mecânica/microbiologia , Infecções por Pseudomonas/diagnóstico , Pseudomonas aeruginosa/isolamento & purificação , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Unidades de Terapia Intensiva/tendências , Masculino , Pessoa de Meia-Idade , Pneumonia Associada à Ventilação Mecânica/epidemiologia , Estudos Prospectivos , Infecções por Pseudomonas/epidemiologia , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/epidemiologiaRESUMO
Objective. To investigate the effect of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in serum, bronchoalveolar lavage fluid (BALF), endotracheal aspiration (ETA), and exhaled breath condensate (EBC) samples as early biomarkers for the diagnosis of ventilator-associated pneumonia (VAP) in patients with ischemic stroke. Methods. One hundred and thirty-two patients with clinically suspected VAP were enrolled in this study. Bronchoscopy was performed on the day of clinically suspected VAP. sTREM-1 levels in serum, BALF, ETA, and EBC were measured. VAP was diagnosed by quantitative cultures of BALF (≥104 cfu/mL). Results. VAP was confirmed in 76 (57.58%) cases. Patients with VAP showed significantly higher sTREM-1 in BALF [32.35 (IQR, 30.08-41.72) versus 18.92 (11.89-31.72)] pg/mL and in EBC [1.57 (IQR, 1.02-2.61) versus 0.41 (0.19-1.61)] pg/mL than patients without VAP. The area under the curve was 0.813 (p < 0.001). The optimum cut-off value for sTREM-1 in BALF was 23.61 pg/mL, yielding sensitivity and specificity of 85.5% and 73.1%. sTREM-1 in BALF had excellent correlation with that in EBC (R2 = 0.78, p < 0.05). Conclusions. sTREM-1 in EBC and BALF had good diagnostic performance in differentiating patients with and without VAP.
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Artrite Reumatoide/complicações , Azetidinas/efeitos adversos , Criptococose/induzido quimicamente , Cryptococcus neoformans/isolamento & purificação , Pneumonia/microbiologia , Purinas/efeitos adversos , Pirazóis/efeitos adversos , Sulfonamidas/efeitos adversos , Idoso , Humanos , Masculino , Pneumonia/induzido quimicamenteAssuntos
Líquido da Lavagem Broncoalveolar/microbiologia , Ureia/análise , Adulto , Idoso , Lavagem Broncoalveolar/métodos , Lavagem Broncoalveolar/estatística & dados numéricos , Líquido da Lavagem Broncoalveolar/química , Broncoscopia/métodos , Broncoscopia/estatística & dados numéricos , Feminino , Humanos , Unidades de Terapia Intensiva/organização & administração , Masculino , Pessoa de Meia-Idade , Ureia/metabolismoRESUMO
Pulmonary strongyloidiasis is a rare infection in patients with autoimmune diseases, and immunosuppression can lead to the development of hyperinfection syndrome with a high mortality rate. We present a case of a 78-year-old male with previous idiopathic inflammatory myopathy (IIM) with interstitial lung disease. He developed hyperinfection syndrome and respiratory failure, and diagnostic metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage fluid (BALF) confirmed the presence of Strongyloides stercoralis. After treatment with ivermectin, the patient's symptoms improved. Therefore, adequate screening and prophylactic treatment are needed for people at risk of immunosuppression, which can reduce the occurrence of the devastating S. stercoralis hyperinfection syndrome. It also highlights mNGS as a highly accurate test for the detection of difficult to atypical pathogens.
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Background: Type 1 diabetes mellitus (T1DM) is frequently associated with various infections, including mycoses; however, the direct link between T1DM and fungal infections remains under-researched. This study utilizes a Mendelian randomization (MR) approach to investigate the potential causal relationship between T1DM and mycoses. Methods: Genetic variants associated with T1DM were sourced from the European Bioinformatics Institute database, while those related to fungal infections such as candidiasis, pneumocystosis, and aspergillosis were obtained from the Finngen database, focusing on European populations. The primary analysis was conducted using the inverse variance weighted (IVW) method, with additional insight from Mendelian randomization Egger regression (MR-Egger). Extensive sensitivity analyses assessed the robustness, diversity, and potential horizontal pleiotropy of our findings. Multivariable Mendelian randomization (MVMR) was employed to adjust for confounders, using both MVMR-IVW and MVMR-Egger to evaluate heterogeneity and pleiotropy. Results: Genetically, the odds of developing candidiasis increased by 5% in individuals with T1DM, as determined by the IVW method (OR = 1.05; 95% CI 1.02-1.07, p = 0.0001), with a Bonferroni-adjusted p-value of 0.008. Sensitivity analyses indicated no significant issues with heterogeneity or pleiotropy. Adjustments for confounders such as body mass index, glycated hemoglobin levels, and white blood cell counts further supported these findings (OR = 1.08; 95% CI:1.03-1.13, p = 0.0006). Additional adjustments for immune cell counts, including CD4 and CD8 T cells and natural killer cells, also demonstrated significant results (OR = 1.04; 95% CI: 1.02-1.06, p = 0.0002). No causal associations were found between T1DM and other fungal infections like aspergillosis or pneumocystosis. Conclusion: This MR study suggests a genetic predisposition for increased susceptibility to candidiasis in individuals with T1DM. However, no causal links were established between T1DM and other mycoses, including aspergillosis and pneumocystosis.
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OBJECTIVE: Antibiotic utilization stands as the strongest modifiable determinant for Clostridioides difficile infection (CDI). However, previous studies have relied on aggregated antibiotic categories, leaving prescribers without detailed comparative risk information for individual antibiotics. The objective of this study was to estimate the risk of CDI comprehensively across specific antibiotics. METHODS: Two methodologies were integrated to access and rank the risk of CDI associated with individual antibiotics or classes. Initially, a network comparison was conducted by analysing data from randomized controlled trials (RCTs). Subsequently, a real-world disproportionality analysis using the Food and Drug Adverse Event Reporting System (FAERS) database complemented and enriched the findings from RCTs. RESULTS: The network comparison, encompassing 61 RCTs with 25,931 patients, revealed that exposure to cefepime [odds ratio (OR) 2.56, 95% confidence interval (CI) 1.20-5.44; P=0.02] and imipenem/cilastatin (OR 3.86, 95% CI 1.61-9.29; P=0.003) exhibited higher frequencies of CDI compared with piperacillin/tazobactam. No significant differences were observed between the carbapenems, albeit a trend indicating higher incidence of CDI with imipenem/cilastatin compared with meropenem (OR 3.89, 95% CI 0.94-16.09). In the FAERS disproportionality analysis, nearly all antibiotics displayed associations with CDI, and CDI risk signals often clustered within the majority of antibiotic classes. Among these, lincomycin demonstrated the strongest association (OR 112.17, 95% CI 51.68-243.43). Additionally, oral third-generation cephalosporins tended to exhibit higher CDI risk signals than other antibiotics. CONCLUSIONS: The findings unveiled substantial diversity in the risk of CDI, both within and between antibiotic classes, providing valuable guidance for clinicians in antibiotic prescription decisions and for initiatives aimed at antibiotic stewardship.
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OBJECTIVE: To integrate an enhanced molecular diagnostic technique to develop and validate a machine-learning model for diagnosing sepsis. METHODS: We prospectively enrolled patients suspected of sepsis from August 2021 to August 2023. Various feature selection algorithms and machine learning models were used to develop the model. The best classifier was selected using 5-fold cross validation set and then was applied to assess the performance of the model in the testing set. Additionally, we employed the Shapley Additive exPlanations (SHAP) method to illustrate the effects of the features. RESULTS: We established an optimized mNGS assay and proposed using the copies of microbe-specific cell-free DNA per milliliter of plasma (CPM) as the detection signal to evaluate the real burden, with strong precision and high accuracy. In total, 237 patients were eligible for participation, which were randomly assigned to either the training set (70 %, n = 165) or the testing set (30 %, n = 72). The random forest classifier achieved accuracy, AUC and F1 scores of 0.830, 0.918 and 0.856, respectively, outperforming other machine learning models in the training set. Our model demonstrated clinical interpretability and achieved good prediction performance in differentiating between bacterial sepsis and non-sepsis, with an AUC value of 0.85 and an average precision of 0.91 in the testing set. Based on the SHAP value, the top nine features of the model were PCT, CPM, CRP, ALB, SBPmin, RRmax, CREA, PLT and HRmax. CONCLUSION: We demonstrated the potential of machine-learning approaches for predicting bacterial sepsis based on optimized mcfDNA sequencing assay accurately.
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Ácidos Nucleicos Livres , Aprendizado de Máquina , Sepse , Humanos , Sepse/diagnóstico , Sepse/microbiologia , Masculino , Feminino , Pessoa de Meia-Idade , Ácidos Nucleicos Livres/sangue , Idoso , Análise de Sequência de DNA , Estudos ProspectivosRESUMO
BACKGROUND: Metagenomic Next-Generation Sequencing (mNGS) is a rapid, non-culture-based, high-throughput technique for pathogen diagnosis. Despite its numerous advantages, only a few studies have investigated its use in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: We conducted a retrospective analysis of 404 mNGS tests performed on 264 patients after allo-HSCT. The tests were divided into three groups (Phase A, B, C) based on the time spent hospitalized post-transplantation, and we evaluated the analytical performance of mNGS in comparison with conventional microbiological tests (CMT), while also analyzing its clinical utility for clinical impacts. RESULTS: Metagenomic sequencing demonstrated a significantly higher rate of positive microbiological findings as compared to CMT (334/404 (82.7 %) vs. 159/404 (39.4 %), respectively, P < 0.001). The detection rates by both mNGS and CMT varied across the three-phase (mNGS: A-60/89 (67.4 %), B-147/158 (93.0 %), C-125/157 (79.6 %), respectively, P < 0.001; CMT: A-21/89 (23.6 %), B-79/158 (50.0 %), C-59/157 (37.6 %), respectively, P < 0.001). The infection sites and types of pathogens were also different across the three phases. Compared to non-GVHD cases, mNGS detected more Aspergillus spp. and Mucorales in GVHD patients (Aspergillus: 12/102 (11.8 %) vs. 8/158 (5.1 %), respectively, P = 0.048; Mucorales: 6/102 (5.9 %) vs. 2/158 (1.3 %), respectively, P = 0.035). Forty-five (181/404) percent of mNGS tests yielded a positive impact on the clinical diagnosis, while 24.3 % (98/404) of tests benefited the patients in antimicrobial treatment. CONCLUSION: mNGS is an indispensable diagnostic tool in identifying pathogens and optimizing antibiotic therapy for hematological patients receiving allo-HSCT.
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Transplante de Células-Tronco Hematopoéticas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Estudos Retrospectivos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Metagenômica , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: To compare the research hotspots of infections with the Delta and Omicron variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the coronavirus disease 2019 (COVID-19) pandemic and to identify future research trends. METHODS: Studies about Delta and Omicron variant infections published over the last 3 years were retrieved from the Web of Science (WoS) database. A comparative bibliometric analysis was conducted through machine learning and visualization tools, including VOSviewer, Bibliographic Item Co-Occurrence Matrix Builder, and Graphical Clustering Toolkit. Research hotspots and trends in the field were analyzed, and the contributions and collaborations of countries, institutions, and authors were documented. A cross-sectional analysis of the relevant studies registered at ClinicalTrials.gov was also performed to clarify the direction of future research. RESULTS: A total of 1,787 articles distributed in 107 countries and 374 publications from 77 countries focused on the Delta and Omicron variants were included in our bibliometric analysis. The top five productive countries in both variants were the USA, China, the UK, India, and Germany. In 5,999 and 1,107 keywords identified from articles on the Delta and Omicron, the top two frequent keywords were the same: "COVID-19" (occurrence: 713, total link strength: 1,525 in Delta; occurrence: 137, total link strength: 354 in Omicron), followed by "SARS-CoV-2" (occurrence: 553, total link strength: 1,478 in Delta; occurrences 132, total link strength: 395 in Omicron). Five theme clusters from articles on Delta variant were identified: transmission, molecular structure, activation mode, epidemiology, and co-infection. While other three theme clusters were recognized for the Omicron variant: vaccine, human immune response, and infection control. Meanwhile, 21 interventional studies had been registered up to April 2022, most of which aimed to evaluate the immunogenicity and safety of different kinds of vaccines in various populations. CONCLUSIONS: Publications and clinical trials related to COVID-19 increased annually. As the first comparative bibliometric analysis for Delta and Omicron variants, we noticed that the relevant research trends have shifted from vaccine development to infection control and management of complications. The ongoing clinical studies will verify the safety and efficacy of promising drugs.
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BACKGROUND: Life's Simple 7, the former construct of cardiovascular health (CVH) has been used to evaluate adverse non-communicable chronic diseases (NCDs). However, some flaws have been recognized in recent years and Life's Essential 8 has been established. In this study, we aimed to analyze the association between CVH defined by Life's Essential 8 and risk of 44 common NCDs and further estimate the population attributable fractions (PAFs) of low-moderate CVH scores in the 44 NCDs. METHODS: In the UK Biobank, 170,726 participants free of 44 common NCDs at baseline were included. The Life's Essential 8 composite measure consists of four health behaviours (diet, physical activity, nicotine exposure, and sleep) and four health factors (body mass index, non-high density lipoprotein cholesterol, blood glucose, and blood pressure), and the maximum CVH score was 100 points. CVH score was categorized into low, moderate, and high groups. Participants were followed up for 44 NCDs diagnosis across 10 human system disorders according to the International Classification of Diseases 10th edition (ICD-10) code using linkage to national health records until 2022. Cox proportional hazard models were used in this study. The hazard ratios (HRs) and PAFs of 44 NCDs associated with CVH score were examined. RESULTS: During the median follow-up of 10.85 years, 58,889 incident NCD cases were documented. Significant linear dose-response associations were found between higher CVH score and lower risk of 25 (56.8%) of 44 NCDs. Low-moderate CVH (<80 points) score accounted for the largest proportion of incident cases in diabetes (PAF: 80.3%), followed by gout (59.6%), sleep disorder (55.6%), chronic liver disease (45.9%), chronic kidney disease (40.9%), ischemic heart disease (40.8%), chronic obstructive pulmonary disease (40.0%), endometrium cancer (35.8%), lung cancer (34.0%), and heart failure (34.0%) as the top 10. Among the eight modifiable factors, overweight/obesity explained the largest number of cases of incident NCDs in endocrine, nutritional, and metabolic diseases (35.4%), digestive system disorders (21.4%), mental and behavioral disorders (12.6%), and cancer (10.3%); however the PAF of ideal sleep duration ranked first in nervous system (27.5%) and neuropsychiatric disorders (9.9%). CONCLUSIONS: Improving CVH score based on Life's Essential 8 may lower risk of 25 common NCDs. Among CVH metrics, normal weight may especially important to prevent new cases of metabolic diseases, NCDs in digestive system and mental and behavioral disorders, and cancer.
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Introduction: Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are both chronic multisystem diseases that cause tremendous health burdens worldwide. Previous epidemiological studies have found a bidirectional relationship between these two diseases; however, their causality remains largely unknown. We aim to examine the causal relationship between NAFLD and T2DM. Methods: The observational analysis included 2,099 participants from the SPECT-China study and 502,414 participants from the UK Biobank. Logistic regression and Cox regression models were used to examine the bidirectional association between NAFLD and T2DM. Two-sample Mendelian randomization (MR) analyses were conducted to investigate the causal effects of the two diseases using summary statistics of genome-wide association studies from the UK Biobank for T2DM and the FinnGen study for NAFLD. Results: During the follow-up, 129 T2DM cases and 263 NAFLD cases were observed in the SPECT-China study, and 30,274 T2DM cases and 4,896 NAFLD cases occurred in the UK Biobank cohort. Baseline NAFLD was associated with an increased risk of incident T2DM in both studies (SPECT-China: OR: 1.74 (95% confidence interval (CI): 1.12-2.70); UK Biobank: HR: 2.16 (95% CI: 1.82-2.56)), while baseline T2DM was associated with incident NAFLD in the UK Biobank study only (HR: 1.58). Bidirectional MR analysis showed that genetically determined NAFLD was significantly associated with an increased risk of T2DM (OR: 1.003 (95% CI: 1.002-1.004, p< 0.001)); however, there was no evidence of an association between genetically determined T2DM and NAFLD (OR: 28.1 (95% CI: 0.7-1,143.0)). Conclusions: Our study suggested the causal effect of NAFLD on T2DM development. The lack of a causal association between T2DM and NAFLD warrants further verification.
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Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Humanos , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/genética , China/epidemiologiaRESUMO
BACKGROUND: Plasma cell-free DNA Next-Generation Sequencing has been used as a non-invasive and comprehensive method for the etiological diagnosis of infectious diseases. However, only a handful of studies have described the real-world utility of this technique in patients with hematological disorders, a cohort of patients that are distinctive due to neutropenia and weakened immune functions. METHODS: We retrospectively analyzed the results of plasma cell-free DNA sequencing performed on 184 and 163 specimens collected from hematological patients suspected of infections with (Group I) or without (Group II) neutropenia, respectively. The diagnostic performance and the clinical impact of plasma sequencing were comparatively evaluated to conventional microbiological tests and a composite reference standard (conventional tests combined with the clinical assessment). RESULTS: The overall positive detection rate of plasma cell-free DNA sequencing was significantly higher than that of conventional microbiological tests (72.6% vs.31.4%, P < 0.001). The positive rate of conventional microbiological tests in Group I was lower than that in Group II (25.5% vs. 38.0%, P = 0.012). Combining plasma sequencing with conventional tests yielded a positive detection rate of 75.0% and 74.8% for these two groups, respectively. Using the composite reference standard, the sensitivity and specificity of plasma sequencing were 89.1% and 65.1%, respectively. The proportions of the positive impact of cell-free DNA sequencing results in the Group I were higher than in the Group II in terms of both diagnosis and treatment (diagnosis: 54.3% vs. 40.5%, P = 0.013; treatment: 45.7% vs.30.7%, P = 0.004). A total of 73 patients (21.0%) benefited from plasma sequencing through adjustment of the antibiotic regimen. CONCLUSIONS: The diagnostic yield of conventional microbiological tests was low in patients with neutropenia. Combining conventional tests with plasma cell-free DNA sequencing significantly improved the detection rate for pathogens and optimized antibiotic treatment. Our findings on the clinical impact warrant confirmation through larger, multicenter, randomized controlled trials. Moreover, the cost-effectiveness of this testing strategy remains unknown and requires further exploration.