Low Risk Score Research Articles

Outdoor worker knowledge of ticks and Lyme disease in Québec.

Lyme disease is a well-known occupational risk across North America caused by exposure to Borrelia burgdorferi via blacklegged ticks (Ixodes scapularis). As the geographic range of B. burgdorferi advances with the increasing distribution of blacklegged ticks, more outdoor workers are at risk of contracting Lyme disease. In this study, we examined the demography and personal perceptions of outdoor workers within one framework to better determine the overall risk for those working outdoors. We analysed outdoor worker knowledge of ticks and of behaviours that can prevent tick bites and Lyme disease. We then compared these risk perceptions of individuals across age, sex, education, and industry, as well as time spent outdoors. We tested the hypothesis that the risk perception of an individual and their knowledge of Lyme disease transmission was dependent on their demographics, experience in their job, and the region in which they spend time outdoors. We estimated a knowledge-based risk score based on individuals' answers to a questionnaire on risk perception given to voluntary participants who work outdoors. Those who had higher risk scores were more at risk. We found that knowledge-based risk scores were correlated with geographic risk levels and with the number of hours per day spent outdoors. Those who work longer hours and who work in areas with mid-level risk had higher risk scores. Those who spend more time outdoors recreationally had lower risk scores. Further examination and acknowledgment of the reasoning behind why these factors are affecting workers' risks must be considered to recognize that it is not necessarily demographics or geographically high-risk areas that affect an individual's risk. Workers' knowledge of these risks is affected by several variables that should be taken into consideration when implementing safety measures and awareness programs.

Association between CHA2DS2-VASc score and left atrial function by speckle tracking echocardiography in patients with sinus rhythm

Abstract Background The CHA2DS2-VASc score is a scoring system that was first used for the risk assessment of cerebrovascular or thromboembolic events in patients with atrial fibrillation (AF). The factors that constitute the CHA2DS2-VASc scoring system can all individually have an impact on LA function. The application of this scoring system can also be applied to patients without AF. The LA structural remodeling and/or functional impairment play a part in the pathogenesis and development of AF and independent of rhythm, may result in atrial hemostasis and confer a prothrombotic diathesis, resulting in thromboembolic stroke. Speckle- tracking echocardiography (STE) makes it possible to measure LA function with relatively high accuracy and at the very early stage even in the absence of LA enlargement. Purpose The aim of our study was to assess the left atrial function in patients with sinus rhythm with different CHA2DS2-VASc scores (low, moderate and high) by speckle tracking echocardiography and to identify the association between them. Methods This study was conducted using prospectively collected data (1st May, 2022 to 30th October 2022) from patients with sinus rhythm and different CHA2DS2-VASc scores (50 Low risk score patients (1 for females and 0 for males), 50 moderate risk score patients (2 for females and 1 for males) and 50 high risk score patients (≥3 for females and ≥2 for males) After obtaining an informed consent, all volunteers underwent thorough history taking, 12 lead ECG and conventional transthoracic echocardiography and speckle-tracking echocardiography. Results LA strain during the reservoir (LASr) and conduit phases (LAScd) were statistically significantly lower in the high-risk score group (33.2 ± 7.1 and 20.3 ± 5.7) than the moderate-risk score group (36.9 ± 6.1 and 23.5 ± 4.8, p = 0.005 and 0.003 respectively) and low -risk score group (40.6 ± 5.6 and 26.9 ± 3.9, p < 0.001). In addition, LASr and LAScd were statistically significantly lower in moderate- risk score group (36.9 ± 6.1 and 23.5 ± 4.8) than the low -risk score group (40.6 ± 5.6 and 26.9 ± 3.9 ,p=0.007 and 0.001 respectively). Conclusion Higher CHA2DS2-VASc scores were associated with decreased LA strain during the reservoir and conduit phases as markers of LA function with relatively high accuracy and at the very early stage even in the absence of LA enlargement.

High ABCD2-score after transient ischemic attack is associated with a two-fold higher stroke-rate during long-term follow-up

Abstract Background The ABCD2-score is a validated risk score used to estimate the short-term risk of stroke after transient ischemic attack (TIA). However, "real-world" contemporary data on the long-term risk of stroke after TIA according to ABCD2-score are needed in order to guide preventive strategies. Purpose To determine the long-term risk of stroke after TIA according to modified ABCD2-score (high-risk (≥4 points) versus low-risk (<4 points)). Methods Patients aged ≥18 years with first-time TIA were included from the Danish Stroke Registry (2014-2020). The study population was stratified in high-risk (≥4 points) and low-risk (<4 points) ABCD2-score group. We utilized a modified ABCD2-score consisting of the following parameters: age ≥60 years, hypertension, clinical features, and diabetes. The 3-year risk of ischemic stroke and all-cause mortality was compared between the high-risk and low-risk group using the Aalen-Johansen and Kaplan-Meier estimator. A cox regression model was also conducted. Results In total, 21,433 patients with first-time TIA were included; 1,281 (6.0%) in the high-risk and 20,152 (94.0%) in the low-risk group. Patients in the high-risk group were older (77.5 years [interquartile range [IQR] 70.8-84.1] versus 70.3 years [IQR 60.1-78.2]), more often females (52.2% versus 46.6%) (p <0.001), more comorbid and received more medication compared with the low-risk group at baseline. The 3-year cumulative incidence of stroke was 6.0% [95% CI: 4.6-7.5] in the high-risk group and 4.2% [95% CI: 3.9-4.5] in the low-risk group, and the unadjusted hazard ratio (HR) was 1.6 (95% CI 1.2 – 2.0) (Figure 1). The cumulative incidence of all-cause mortality within three-years after TIA was 28.9% [95% CI: 26.1-31.7] in the high-risk group and 10.3% [95% CI: 9.9-10.8] in the low-risk group. The unadjusted HR was 3.2 (95% CI 2.8 – 3.6). Conclusions Patients with high-risk ABCD2-scores had an almost two-fold higher associated long-term stroke-rate compared to those with low-risk scores. Trials focusing on preventive measures, including evidence-based antithrombotic strategies, especially for the high-risk group are warranted.

Validation of the HCM Risk-SCD model in patients with hypertrophic cardiomyopathy and future perspectives

Abstract Background/Introduction The fact that hypertrophic cardiomyopathy (HCM) is associated with sudden cardiac death (SCD) due to malignant ventricular arrhythmias underlies its clinical importance (1). SCD in patients with HCM is often an unpredictable event, occurring without previous warning signs or symptoms, and is most common in the young middle-aged group (2). The greatest dilemma in the management of HCM patients is to identify the high-risk population for SCD. The HCM risk- SCD model provides a useful convenience in determining the risk of SCD in patients with HCM even though some patients with low-risk scores still remain at risk of SCD (3). These results have increased the interest in additional strategies to improve the existing risk model. Purpose Hence, the aim of our study was to assess the performance of HCM Risk-SCD in a large series of consecutive patients with HCM who had been followed up in a tertiary centre. Methods The study population consisted of 389 consecutive HCM patients who had been followed up between 2004 and 2021. Demographic and clinical characteristics estimated 5-year risk using the HCM Risk-SCD model were compiled and survival data were collected during follow-up. Patients were divided into 2 groups according to their long-term survival and HCM risk-SCD scores of these two groups were compared. Results The long-term mortality was observed in 47 patients out of 389 patients in the mean follow-up of 55.5 ± 12.7 months. The mean HCM Risk-SCD of surviving patients was significantly lower than that of non-survivors (1.8% vs. 3.0%, p<0.001). The HCM Risk-SCD score was above 6% in 9 (2.6%) survivors and 9 (19.1%) non-survivors (p<0.001). Considering the Kaplan-Meier curve based on the 6% HCM Risk-SCD score, patients at ≥6% risk also had a significantly higher long-term risk of death compared to those with <6% (log-rank test value: 33.72, p<0.001) (Figure 1). The ROC curve based on the HCM Risk-SCD score had 61% sensitivity and 61% specificity for risk for 2.0%, 38% sensitivity and 99% specificity for ≥4%, 17% sensitivity and 99% specificity for ≥6% (Figure 2). Conclusion(s) In conclusion, the current study demonstrates that the HCM risk-SCD model, while easily calculable and clinically useful, does not reliably identify a significant subset of patients with HCM who will potentially be at lifetime risk of SCD. Identifying patients with hypertrophic cardiomyopathy at high risk for SCD who deserve ICD therapy is a critical management priority. A new risk algorithm that can detect the SCD risk of HCM patients with higher sensitivity is needed.Figure 1Figure 2

Cuproptosis-related lncRNAs emerge as a novel signature for predicting prognosis in prostate carcinoma and functional experimental validation

BackgroundProstate cancer (PCa) is one of the most common malignancies of the urinary system. Cuproptosis, a newly discovered form of cell death. The relationship between cuproptosis-related long non-coding RNAs (ClncRNAs) related to PCa and prognosis remains unclear. This study aimed to explore the clinical significance of novel ClncRNAs in the prognostic assessment of PCa.MethodsClncRNAs and differentially expressed mRNAs linked to these ClncRNAs were identified using Pearson’s correlation and differential expression analyses. A prognostic signature (risk score) comprising three ClncRNAs was established based on multivariable Cox regression analysis. The predictive performance of this ClncRNAs signature was validated using receiver operating characteristic curves and nomograms. Finally, further in vitro cell experiments were conducted for validation, including quantitative polymerase chain reaction (qPCR), western blot (WB), cell proliferation assays, cell migration assays, cell invasion assays, apoptosis, and cell cycle analysis.ResultsWe constructed a prognostic signature of ClncRNAs for PCa comprising three key differentially expressed ClncRNAs(AC010896-1, AC016394-2, and SNHG9). Multivariable Cox regression analysis indicated that clinical staging and risk scores of the ClncRNAs signature were independent prognostic factors for PCa. Compared to other clinical features, the ClncRNAs signature exhibited higher diagnostic efficiency and performed well in predicting the 1-, 3-, and 5-year progression-free intervals (PFIs) for PCa. Notably, in terms of immune activity, PCa patients with high-risk scores exhibited higher tumor mutational burden (TMB) levels, while their Tumor Immune Dysfunction and Exclusion (TIDE) scores were lower than those of PCa patients with low-risk scores. Additionally, in vitro cellular functional experiments, we knocked down SNHG9 that is the most significantly differentially expressed ClncRNA among the three key ClncRNAs. SNHG9 knockdown resulted in a significant increase in G1 phase cells and a decrease in S and G2 phases, indicating inhibition of DNA synthesis and cell cycle progression. Colony formation assays showed reduced clonogenic ability, with fewer and smaller colonies. Western blot analysis revealed the upregulation of the key cuproptosis-related mRNAs FDX1 and DLST. These findings suggested that SNHG9 promotes PCa cell proliferation, migration, and invasion.ConclusionBuilding on the three ClncRNAs, we identified a novel prognostic signature of PCa. The ClncRNA SNHG9 can promote PCa cell proliferation, migration, and invasion.

Pericoronary adipose tissue computed tomography attenuation (PCAT) as a marker of premature CVD in asymptomatic people living with HIV (PLWH) without traditional risk factors: H-ART to heart study

Abstract Background Controversy exists regarding the contribution of HIV, ART or traditional risk factors to CVD risk in PLWH. The H-ART to Heart study investigates the prevalence of subclinical CVD in asymptomatic PLWH without cardiovascular risk factors compared to negative controls(-). Vascular inflammation inhibits local adipogenesis in pericoronary adipose tissue (PCAT) and thus can be detected on coronary computed tomography angiography (CTCA) as an increase in CT attenuation of PCAT surrounding the proximal right coronary artery (RCA). Methods This cross-sectional study compared PLWH aged 35-55yrs (diagnosed >10 yrs, on ART) to matched controls. Included were Caucasian men who have sex with men(MSM) and Black African/Caribbean women (BW) with traditional risk factors excluded (hypertension, hyperlipidaemia, diabetes, kidney disease, smoking, depression, inflammatory conditions, etc.). Detailed vitals, 10 year CVD risk calculation (Q-RISK 3) were recorded. CTCA were performed with novel analysis using PCAT to assess for coronary inflammation (Figure 1.) Results 98 participants were recruited (49M; 51 PLWH). Mean Q Risk 3 (10yr CVD risk - %) was low across the groups (HIV+MSM 4.65±2.1, HIV-MSM 3.88±2.7;p=0.29; HIV+BW 2.03±1.3, HIV-BW 1.38±0.98 p=0.66). 79 participants (42 PLWH; 37 controls) completed a CTCA with only 2 PLWH having clinically significant disease (CAD-RAD 3+ ie. >50% luminal stenosis) and none in the control group. (p=0.49) The CT scans of 69 patients were assessed for peri-coronary adipose tissue (PCAT) density, 2 were ruled out due to a small non-dominant RCA. The PCAT density of PLWH was higher than that of the controls (-71.2±27.6 vs -75.5±30.3 P=<0.05). Multivariate linear regression demonstrated that HIV status was an independent predictor of coronary inflammation (p=0.037) after adjusting for age, gender and BMI. Conclusion PWLH without traditional CV risk factors did not have significant evidence of more clinically relevant stenosis than controls on CTCA. However PCAT demonstrated a higher signal of coronary inflammation, despite stable disease, compliance with ART and low CVD risk scores. PLWH remain at risk of CV disease, this study supports the rationale for early preventative strategies for CVD prevention in PLWH.PCAT showing HIV inflammation Vs Control

Novel CMR-assessed right ventricular-pulmonary artery coupling index independently associates with exercise capacity and clinical risk in pulmonary arterial hypertension

Abstract Background We defined a novel noninvasive right ventricle (RV)–pulmonary artery (PA) coupling index as the ratio of cardiovascular magnetic resonance (CMR)-assessed RV direct flow (RVDF) and PA pulse wave velocity (PWV), and investigated its associations with exercise capacity and clinical risk in pulmonary arterial hypertension (PAH). Method 43 PAH patients (mean age 46±12 years, M:F 7:36) and 60 healthy volunteers (mean age 46±13 years, M:F 11:48) underwent CMR and cardiopulmonary exercise test (CPET) within one week. From cine CMR, RV ejection fraction (EF) and RV end-diastolic volume (RVEDV) were calculated using volumetric analysis; and tricuspid annular plane systolic excursion (TAPSE), feature tracking. PAPWV was the ratio of early systolic DPA flow and DPA area measured from instantaneous phase and magnitude through plane 2D flow CMR images across the pulmonary trunk, respectively. RVDF was the 4D flow CMR-assessed blood volume entering and exiting the RV in one cardiac cycle, indexed to RVEDV. RV-PA coupling was RVDF/PAPWV. Based on CPET-assessed peak oxygen consumption (PVO2), all 103 participants were stratified into two groups: PVO2>15 ml/kg/min; and PVO2≤15 ml/kg/min. Based on the REVEAL (Registry to Evaluate Early and Long-term PAH Disease Management) 2.0 score, the 43 PAH patients were stratified into low risk (score ≤6) and intermediate to high risk (score >6) groups. Results RVDF/PAPWV was significantly lower in PAH vs. controls (7.9 vs. 20.4 %/(m/s), P<0.001); and in PAH patients with intermediate to high risk vs. low risk (4.6 vs. 9.4 %/(m/s), P=0.001). On multivariable analyses, RVDF/PAPWV was an independent predictor of PVO2≤15 ml/kg/min (=0.302, P=0.001) among all participants, and of REVEAL 2.0 score >6 (=0.621, P=0.009) among PAH patients. Compared to RVEF and TAPSE, RVDF/PAPWV had numerically higher discrimination (p values non-significant based on Delong test) for PVO2≤15 ml/kg/min (AUC=0.914 vs. 0.872, 0.843); and among PAH patients, REVEAL 2.0 score >6 (AUC=0.851 vs. 0.723 and 0.728) (Figure). Conclusion CMR-derived noninvasive RVDF/PAPWV independently associates with exercise capacity and PAH clinical risk, supporting its utility as an imaging marker of disease progression and therapeutic response.

Pre-discharge prediction of long-term prognosis in patients after ST-segment elevation myocardial infarction - the ValAMI-P risk score

Abstract Background Despite contemporary management of ST-segment elevation myocardial infarction (STEMI) patients, cardiovascular death (CV death) and re-admission for acute heart failure (aHF) are frequent complications during follow-up. Several clinical, electrocardiographic, and echocardiographic variables have been identified as risk factors of major adverse cardiovascular events (MACE) in this setting. We aim to study the usefulness of a risk score using universally available clinical, electrocardiographic, and echocardiographic variables at discharge to stratify the risk of MACE during follow-up. Methods We prospectively included 712 patients treated with primary percutaneous coronary intervention after STEMI. We registered clinical, ECG and echocardiography-derived pre-discharge data. Left ventricular ejection fraction (LVEF) was categorized according to current recommendations. The primary endpoint was time to first MACE, defined as CV death or aHF, whichever occurred first. We created a risk score (ValAMI-P) including variables independently associated with MACE in multivariable analysis. Patients were classified in three groups (low, intermediate, and high risk) according to the ValAMI-P score. Results Mean age was 60±12 years, most patients (78.5%) were male, and smoking was the most prevalent risk factor (54.4%). During an 8.1-year median follow-up, 154 MACE (21.6%) were registered. In multivariable analysis, age (HR 1.03 [1.01-1.05], p=0.001), previous hypertension (HR 1.49 [1.04-2.12], p=0.029), GRACE score (HR 1.01 [1.01-1.02], p<0.001), mildly reduced LVEF (41-49%; HR 1.92 [1.18-3.11], p=0.008), reduced LVEF (≤40%; HR 5.2 [3.53-7.65], p<0.001) and the number of leads with Q-wave and residual ST-segment elevation at pre-discharge ECG (Q-STE; HR 1.13 [1.03-1.25], p=0.013) associated with long-term MACE. After classification according to the ValAMI-P risk score, patients with intermediate (8-13 points) and high (≥14 points) score depicted an increased risk of MACE (31% and 50%, respectively) compared to patients with low ValAMI-P risk score (≤7 points; 13%; p<0.001 for all comparisons). Conclusions The ValAMI-P risk score, which comprises widely available clinical, ECG and echocardiographic variables at discharge, can identify patients at increased long-term risk of MACE after STEMI.ValAMI-P risk score after STEMI

Comparison of risk factors and mortality in veterans with HIV and those without HIV suffering first major acute cardiovascular events.

Previous studies have demonstrated that people with HIV have an increased atherosclerotic plaque vulnerability, making them more susceptible to severe cardiovascular complications. This study aimed to examine the clinical characteristics of people with HIV in comparison to people without HIV admitted to Veterans Health Administration (VHA) with their first major acute cardiovascular events (MACE) and compare their total mortality. We used national VHA data to extract data of those admitted to VHA hospitals with MACE defined as acute myocardial infarction (AMI), acute cerebrovascular accident (CVA) or cardiac arrest during the fiscal years 2003-2021. The hazard ratio (HR) of mortality for people with HIV versus people without HIV was estimated using Cox proportional hazard regression analysis. Out of 280 311 veterans, 2510 people with HIV and 277 801 people without HIV had their first MACE during the study period. People with HIV were younger, more likely to be African American, had a lower prevalence of diabetes mellitus and hypertension, similar total cholesterol levels and a lower mean 10-year cardiovascular risk score (25.4 in people with HIV vs. 28.7 in people without HIV). Among MACE components, people with HIV had a higher proportion of CVA (27% vs. 21.3%, p < 0.001) and cardiac arrest (13.0% vs. 8.4%, p < 0.001) but a lower incidence of AMI (62.4% vs. 72.5%, p < 0.001) than people without HIV. Additionally, people with HIV had a higher risk of total mortality (adjusted HR: 2.05, 95% confidence interval: 1.90-2.22) compared with people without HIV. People with HIV experience MACE at younger ages despite lower cardiovascular risks and similar baseline cholesterol and blood pressure levels. People with HIV had higher mortality and a higher risk of having ventricular fibrillation arrest and stroke as their first MACE.

Integration of ubiquitination-related genes in predictive signatures for prognosis and immunotherapy response in sarcoma.

Ubiquitination is one of the most prevalent and complex post-translational modifications of proteins in eukaryotes, playing a critical role in regulating various physiological and pathological processes. Targeting ubiquitination pathways, either through inhibition or activation, holds promise as a novel therapeutic approach for cancer treatment. However, the expression patterns, prognostic significance, and underlying mechanisms of ubiquitination-related genes (URGs) in sarcoma (SARC) remain unclear. We analyzed URG expression patterns and prognostic implications in TCGA-SARC using public databases, identifying DEGs related to ubiquitination among SARC molecular subtypes. Functional enrichment analysis elucidated their biological significance. Prognostic signatures were developed using LASSO-Cox regression, and a predictive nomogram was constructed. External validation was performed using GEO datasets and clinical tissue samples. The association between URG risk scores and various clinical parameters, immune response, drug sensitivity, and RNA modification regulators was investigated. Integration of data from multiple sources and RT-qPCR confirmed upregulated expression of prognostic URGs in SARC. Single-cell RNA sequencing data analyzed URG distribution across immune cell types. Prediction analysis identified potential target genes of microRNAs and long non-coding RNAs. We identified five valuable genes (CALR, CASP3, BCL10, PSMD7, PSMD10) and constructed a prognostic model, simultaneously identifying two URG-related subtypes in SARC. The UEGs between subtypes in SARC are mainly enriched in pathways such as Cell cycle, focal adhesion, and ECM-receptor interaction. Analysis of URG risk scores reveals that patients with a low-risk score have better prognoses compared to those with high-risk scores. There is a significant correlation between DRG riskscore and clinical features, immune therapy response, drug sensitivity, and genes related to pan-RNA epigenetic modifications. High-risk SARC patients were identified as potential beneficiaries of immune checkpoint inhibitor therapy. We established regulatory axes in SARC, including CALR/hsa-miR-29c-3p/LINC00943, CASP3/hsa-miR-143-3p/LINC00944, and MIR503HG. RT-qPCR data further confirmed the upregulation of prognostic URGs in SARC. Finally, we validated the prognostic model's excellent predictive performance in predicting outcomes for SARC patients. We discovered a significant correlation between aberrant expression of URGs and prognosis in SARC patients, identifying a prognostic model related to ubiquitination. This model provides a basis for individualized treatment and immunotherapy decisions for SARC patients.

Unlocking the Potential of Disulfidptosis-Related LncRNAs in Lung Adenocarcinoma: A Promising Prognostic LncRNA Model for Survival and Immunotherapy Prediction.

Disulfidptosis was stimulated in high SLC7A11 expression cells starving to glucose. We attempted to identify disulfidptosis-related lncRNAs (DRLs), built a prognostic model to predict survival, and analyzed the tumor microenvironment. The TCGA database was utilized to procure the pertinent data. By utilizing both Cox regression and the least absolute shrinkage and selection operator (LASSO) method, a risk model based on DRLs was formulated for prognostic evaluation. The ability of survival prediction was validated by multiple approaches. The biological functions were screened through GO, KEGG, and GSEA. Various methods were employed to evaluate the tumor immune environment, which included ESTIMATE, tumor mutation burden (TMB) score, CIBERSORT algorithm, and tumor immune dysfunction and exclusion (TIDE) score. Ninety-one DRLs were recognized, and lncRNA AC092718.4, AL365181.2, AL606489.1, EMSLR, and ENTPD3-AS1 were involved in the risk model. The GEO database was used to verify the influence of these lncRNAs on survival. The following analyses showed that survival could be predicted excellently by the DRLs risk model. The results of enrichment analyses pointed toward the involvement of the cell cycle and IgA production pathways. In the low-risk patient group, there was a notable surge in stromal, immune, and ESTIMATE scores, while the TMB scores took a tumble. Conversely, the high-risk patient group displayed a converse trend. Notably, the group of patients with lower risk scores and higher TMB scores showed the most favorable survival outcomes, underscoring the importance of considering both risk score and TMB in predicting the response to immune checkpoint blockade therapy. Furthermore, patients classified as high-risk might display resistance to both chemotherapy and targeted therapy. Cellular biological experiments proved that lncRNA AC092718.4 promoted invasion, migration, and proliferation abilities invitro. These results provided valuable insights into the role of DRLs in LUAD and presented a possible effective treatment approach for LUAD. We developed a disulfidptosis-related risk model with 5 lncRNAs that enables survival prediciton for LUAD patients and aids cilinical decisions by forecasting the TME, TMB, and drug sensitivity, making it a valuable tool for outcomes prediction.

Predictive MINT Pathologic Risk Score for Adjuvant Chemotherapy in Resected Cholangiocarcinoma: A Propensity Score-Matched Multicenter Study in Thailand.

This study aims to clarify the benefit of adjuvant chemotherapy (AC) in resectable cholangiocarcinoma (CCA) and develop a predictive risk score for treatment selection. Patients with resected CCA undergoing curative surgery, with or without AC, were identified from three centers in Thailand. Patients with R2 resection and 30 days postoperative death were excluded. Using the largest center as the discovery cohort, we generated propensity score matching (PSM). A predictive model for overall survival (OS) was identified, and a predictive risk score was developed from the PSM discovery cohort, classifying patients into high- and low-risk groups. The proposed risk score was validated in the other two centers. In the discovery cohort, 493 patients were identified. After PSM, 328 patients were categorized into surgery (n = 164) and surgery + AC (n = 164) groups. The baseline characteristics in the PSM discovery cohort were well-balanced. In the validation cohort (n = 83), patients with positive lymph node 1 received AC more frequently than those under observation (47% v 18%; P = .02). A MINT pathologic risk score was developed from multivariate analysis for OS. The score includes margin, perineural invasion, pathologic nodal status, and pathologic tumor size. In the PSM discovery cohort, for the low-risk score group, the surgery group had significantly longer OS compared with the surgery + AC group (49.4 v 31.5 months; hazard ratio [HR], 1.78 [95% CI, 1.11 to 2.86]; P = .016). Conversely, for the high-risk score group, the surgery + AC group had better OS than the surgery group (18.8 v 8 months; HR, 0.60 [95% CI, 0.46 to 0.79]; P < .001). The results were comparable in the validation cohort. Patients with resected CCA with a high-risk MINT pathologic risk score were likely to benefit from AC, whereas those with a low-risk score were not. Further validation in a larger prospective cohort is warranted.

Comprehensive analysis of prognostic and immunological role of basement membrane-related genes in soft tissue sarcoma.

Soft tissue sarcoma (STS) represents highly multifarious malignant tumors that often occur in adolescents and have a poor prognosis. The basement membrane, as an ancient cellular matrix, was recently proven to play a vital role in developing abundant tumors. The relationship between basement membrane-related genes and STS remains unknown. Consensus clustering was employed to identify subgroups related to differentially expressed basement membrane-related genes. Cox and least absolute shrinkage and selection operator regression analyses were utilized to construct this novel signature. Then, we established a nomogram and calibration curve, including the risk score and available clinical characteristics. Finally, we carried out functional enrichment analysis and immune microenvironment analysis to investigate enriched pathways and the tumor immune microenvironment related to the novel signature. A prognostic predictive signature consisting of eight basement membrane-related genes was established. Kaplan-Meier survival curves demonstrated that the patients in the high-risk group had a poor prognosis. Independent analysis illustrated that this risk model could be an independent prognostic predictor. We validated the accuracy of our signature in the validation data set. In addition, gene set enrichment analysis and immune microenvironment analysis showed that patients with low-risk scores were enriched in some pathways associated with immunity. Finally, in vitro experiments showed significantly differential expression levels of these signature genes in STS cells and PSAT1 could promote the malignant behavior of STS. The novel signature is a promising prognostic predictor for STS. The present study may improve the prognosis and enhance individualized treatment for STS in the future.

Circulating ketone bodies, genetic susceptibility, with left atrial structure, function and atrial fibrillation: A prospective study from UK Biobank

BackgroundKetone bodies (KB) are important cardiac metabolic energy source. Metabolic remodeling has been recently pointed to play an important role in the pathological process of atrial fibrillation (AF). ObjectiveTo evaluate the associations between circulating KB levels with incident AF risk in the general population. MethodsWe studied 237,163 participants (mean age, 56.5 years; 55% women) from the UK Biobank who were free of AF at baseline and had data about circulating β-hydroxybutyrate (β-OHB), acetoacetate, and acetone. The associations between KB with new-onset AF were evaluated by Cox regression in the general population and across three genetic risk groups [low, moderate, and high polygenic risk score of AF]. ResultsDuring a median follow-up of 14.8 years, 16,638 (7.0%) participants developed AF. There was a U-shaped association between total KB and β-OHB with incident AF, with nadirs at 60.6 and 40.8 μmol/L, respectively (P non-linear <0.05), whereas a positive association between acetoacetate and acetone with AF was observed (P overall <0.001, P non-linear >0.05). Consistently, a U-shaped association was observed between total KB and β-OHB with left atrial (LA) volume parameters, including LA maximum volume (LAVmax), LA minimum volume (LAVmin), and their body surface area-indexed counterparts, and an inverted U-shaped association was observed for LA ejection fraction (all P non-linear <0.05). The association between KB with AF was greater among individuals with low genetic risk (Pinteraction <0.05), while the highest AF risk was for those at high genetic risk with high KB levels. Significant mediation effects of inflammatory markers on the associations between KB and AF were identified. ConclusionsThere was a U-shaped association between circulating total KB and β-OHB with incident AF, as well as a positive association between acetoacetate and acetone level with AF risk in the general population.

Mitochondrial-related genes as prognostic and metastatic markers in breast cancer: insights from comprehensive analysis and clinical models.

Breast cancer (BC) constitutes a significant peril to global women's health. Contemporary research progressively suggests that mitochondrial dysfunction plays a pivotal role in both the inception and advancement of BC. However, investigations delving into the correlation between mitochondrial-related genes (MRGs) and the prognosis and metastasis of BC are still infrequent. Utilizing data from the TCGA database, we employed the "limma" R package for differential expression analysis. Subsequently, both univariate and multivariate Cox regression analyses were executed, alongside LASSO Cox regression analysis, to pinpoint prognostic MRGs and to further develop the prognostic model. External validation (GSE88770 merged GSE425680) and internal validation were further conducted. Our investigation delved into a broad spectrum of analyses that included functional enrichment, metabolic and immune characteristics, immunotherapy response prediction, intratumor heterogeneity (ITH), mutation, tumor mutational burden (TMB), microsatellite instability (MSI), cellular stemness, single-cell, and drug sensitivity analysis. We validated the protein and mRNA expressions of prognostic MRGs in tissues and cell lines through immunohistochemistry and qRT-PCR. Moreover, leveraging the GSE102484 dataset, we conducted differential gene expression analysis to identify MRGs related to metastasis, subsequently developing metastasis models via 10 distinct machine-learning algorithms and then selecting the best-performing model. The division between training and validation cohorts was set at 70% and 30%, respectively. A prognostic model was constructed by 9 prognostic MRGs, which were DCTPP1, FEZ1, KMO, NME3, CCR7, ISOC2, STAR, COMTD1, and ESR2. Patients within the high-risk group experienced more adverse outcomes than their counterparts in the low-risk group. The ROC curves and constructed nomogram showed that the model exhibited an excellent ability to predict overall survival (OS) for patients and the risk score was identified as an independent prognostic factor. The functional enrichment analysis showed a strong correlation between metabolic progression and MRGs. Additional research revealed that the discrepancies in outcomes between the two risk categories may be attributed to a variety of metabolic and immune characteristics, as well as differences in intratumor heterogeneity (ITH), tumor mutational burden (TMB), and cancer stemness indices. ITH, TIDE, and IPS analyses suggested that patients possessing a low-risk score may exhibit enhanced responsiveness to immunotherapy. Additionally, distant metastasis models were established by PDK4, NRF1, DCAF8, CHPT1, MARS2 and NAMPT. Among these, the XGBoost model showed the best predicting ability. In conclusion, MRGs significantly influence the prognosis and metastasis of BC. The development of dual clinical prediction models offers crucial insights for tailored and precise therapeutic strategies, and paves the way for exploring new avenues in understanding the pathogenesis of BC.

Identification of prognostic biomarkers in neuroblastoma using WGCNA and multi-omics analysis

BackgroundNeuroblastoma (NB) is one of the most frequent parenchymal tumors among children, with a high degree of heterogeneity and wide variation in clinical presentation. Despite significant therapeutic advances in recent years, long-term survival in high-risk patients remains low, emphasizing the urgent need to find new biomarkers and construct reliable prognostic models.MethodsIn this study, data from neuroblastoma samples in the ArrayExpress database were utilized to identify key gene modules and pivotal genes associated with NB prognosis by weighted gene co-expression network analysis (WGCNA). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis was performed using the DAVID database. Based on these hub genes, survival prognosis models were constructed and validated on an independent validation set in the Gene Expression Omnibus (GEO) database. Differences in biological functions and immune microenvironments and the sensitivity to pharmacological and immunotherapeutic treatments of patients in the high- and low-risk groups were examined by gene set enrichment analysis (GSEA) and immune infiltration analysis.ResultsWGCNA identified 14 gene modules and screened the module with the highest relevance to the International Neuroblastoma Staging System (INSS), containing 60 pivotal genes. GO and KEGG analyses demonstrated that these pivotal genes were mainly implicated in biological processes and signaling pathways including DNA replication, cell division, mitotic cell cycle, and cell cycle. Based on Lasso regression and COX regression analysis, a prognostic model containing DHFR, GMPS and E2F3 was constructed, and the RiskScore was significantly correlated with the 1-, 3- and 5-year survival of the patients. GSEA and immune infiltration analyses revealed significant differences in the levels of cell cycle-related pathways and immune cell infiltration between the high and low RiskScore groups. In particular, patients in the high-risk group are less likely to benefit from immunotherapy and may be better suited for treatment with drugs such as Oxaliplatin and Alpelisib.ConclusionThis research systematically identified biomarkers related to NB prognosis and developed a reliable prognostic model applying WGCNA and multiple bioinformatics methods. The model has important application value in predicting patients’ prognosis, evaluating drug sensitivity and immunotherapy effect, and provides new ideas and directions for precise treatment of neuroblastoma.

A novel proteomic prognostic signature characterizes the immune landscape and predicts nasopharyngeal carcinoma prognosis

BackgroundNasopharyngeal carcinoma (NPC) is a highly diverse and aggressive cancer type, leading to varying prognoses and responses to immunotherapy. This study aims to develop a protein-based signature that provides new insights into assessing the prognosis and immunotherapeutic response in NPC patients. Methods and ResultsWe obtained transcriptomic and proteomic data for NPC from TCGA and CPTAC databases, respectively. Differentially expressed proteins with prognostic significance were identified using limma combined with uniCox analysis. A prognostic protein signature was created utilizing the LASSO algorithm. Receiver operating characteristic (ROC) curve analysis along with Kaplan-Meier survival analysis was conducted to assess the predictive accuracy of this signature. To evaluate immune infiltration levels among patients categorized by high or low risk scores (RPscores), we employed ssGSEA and ESTIMATE methods, while TIDE was used to forecast responses to immunotherapy. Our research pinpointed four critical prognostic proteins: CdSTA, AGR3, DUSP14, and LRRC17, allowing us to compute risk scores (RPscores). Kaplan-Meier curves demonstrated that individuals in the low-risk category exhibited better survival rates. Furthermore, RPscore effectively predicted overall survival across both training and testing cohorts. The ssGSEA results indicated that RPscore is linked with an immune-suppressive microenvironment correlating with diminished immune responses. Notably, DUSP14 showed significant upregulation in NPC cases; its role in promoting cell invasion and metastasis was confirmed through in vitro studies. ConclusionWe have established a robust protein-related signature capable of accurately forecasting prognosis as well as immunotherapy outcomes for NPC patients. Moreover, DUSP14 emerged as a potential therapeutic target due to its strong association with patient prognosis in nasopharyngeal carcinoma.

Is my fishing gear impacting the habitat? An impact assessment in four fisheries in the Northwest Mexican Pacific

The impacts of fishing activities on habitats for commercially important species may, directly and indirectly, influence species and associated communities. These effects include those on target species, bycatch species, habitats, etc. In this study, the impact of small-scale fisheries on habitats was evaluated in four fishing communities from the Northwest Mexican Pacific. The species and size selectivity of several fishing gear were evaluated, and the spatial distribution of catches was studied to assess the impacts of fishing gear using a Consequence Spatial Analysis (CSA). Our results showed that in finfish fisheries from Guaymas and Isla Natividad, the catch of the target species represents more than 75% of the total catch and in El Rosario, the catch represents less than 50%. We assessed 42 habitat types in four communities, which were qualified with low-risk scores. The fishing gears used to target commercial species are selective to optimal sizes above their maturity size. The results contribute to improving management in data-poor fisheries by evaluating the impacts of fishing on habitats and discussing their relevance for implementation.

Integrating amyloid imaging and genetics for early risk stratification of Alzheimer's disease.

Alzheimer's disease (AD) initiates years prior to symptoms, underscoring the importance of early detection. While amyloid accumulation starts early, individuals with substantial amyloid burden may remain cognitively normal, implying that amyloid alone is not sufficient for early risk assessment. Given the genetic susceptibility of AD, a multi-factorial pseudotime approach was proposed to integrate amyloid imaging and genotype data for estimating a risk score. Validation involved association with cognitive decline and survival analysis across risk-stratified groups, focusing on patients with mild cognitive impairment (MCI). Our risk score outperformed amyloid composite standardized uptake value ratio in correlation with cognitive scores. MCI subjects with lower pseudotime risk score showed substantial delayed onset of AD and slower cognitive decline. Moreover, pseudotime risk score demonstrated strong capability in risk stratification within traditionally defined subgroups such as early MCI, apolipoprotein E (APOE) ε4+ MCI, APOE ε4- MCI, and amyloid+ MCI. Our risk score holds great potential to improve the precision of early risk assessment. Accurate early risk assessment is critical for the success of clinical trials. A new risk score was built from integrating amyloid imaging and genetic data. Our risk score demonstrated improved capability in early risk stratification.

Life's Essential 8, genetic susceptibility, and risk of incident pancreatic cancer: A prospective cohort study.

The association between the American Heart Association (AHA) Life's Essential 8 (LE8) and the risk of pancreatic cancer (PC) remains unclear. Our goal was to assess the relationships between LE8, genetic susceptibility, and PC risk. This cohort consisted of 234,102 participants from the UK Biobank. The components of LE8 include diet, nicotine exposure, sleep, physical activity, blood glucose, body mass index, blood lipids, and blood pressure. LE8 is classified into three categories: low cardiovascular health (CVH), moderate CVH, and high CVH. Measurements were made using Cox proportional risk models to estimate impact of associations between LE8, genetic susceptibility, and incidence of PC in participants. Compared to participants with low LE8 scores, those with moderate and high LE8 scores had a 53% (HR, 0.47; 95% CI, 0.39-0.57) and 70% (HR, 0.30; 95% CI, 0.22-0.41) lower risk of developing PC, respectively. Interestingly, among individuals with high genetic risk, high LE8 scores were associated with greater benefits (HR, 0.24; 95% CI, 0.15-0.40), whereas the protective effect was weaker among those with low genetic risk (HR, 0.40; 95% CI, 0.21-0.75). Participants with a high LE8 score and a low polygenic risk score (PRS) had the lowest risk of PC (HR, 0.19; 95% CI: 0.11-0.33). Furthermore, we observed a significant additive interaction between LE8 and PRS. A higher LE8 score is associated with a lower risk of PC, especially for participants with a high PRS. These findings have important implications for participants most genetically predisposed to PC and for targeted strategies for PC prevention.