Non-invasive Marker Research Articles

Dysregulated Neurofluid Coupling as a New Noninvasive Biomarker for Primary Progressive Aphasia.

Accumulation of pathological tau is one of the primary causes of Primary Progressive Aphasia (PPA). The glymphatic system is crucial for removing metabolite waste from the brain whereas impairments in glymphatic clearance in PPA are poorly understood. Thus, this study aims to investigate the role of dysregulated macroscopic cerebrospinal fluid (CSF) movement in PPA. Fifty-six PPA individuals and ninety-four healthy controls were included in our analysis after excluding those with excessive head motions during the scan. The coupling strength between blood-oxygen-level-dependent (BOLD) signals in the gray matter and CSF flow was calculated using Pearson correlation and compared between the groups. Its associations with clinical characteristics including scores from Clinical Dementia Rating (CDR), Mini-Mental State Exam, Geriatric Depression Scale and with morphological measures in the hippocampus and entorhinal cortex were examined. PPA subjects exhibited weaker global BOLD-CSF coupling compared to HCs, indicating impairments in glymphatic function in the patients (p = 0.01). In the PPA but not HC group, global BOLD-CSF coupling correlated with the CDR scores (p = 0.04) and hippocampal volume (p = 0.009). The observed decoupling between global brain activity and CSF flow and its association with symptomatology and brain structural changes in PPA converges with previous reports on the same measure in other neurodegenerative diseases. These findings support the potential role of global BOLD-CSF coupling as a noninvasive marker for glymphatic dysregulation in PPA.

Abstract 4120912: Non-Alcoholic Fatty Liver Disease is Associated with Coronary Flow Reserve Impairment: A Pilot Meta-Analysis

Background: Non-alcoholic fatty liver disease (NAFLD) is estimated to affect approximately 25% of the global population. Significant epidemiological data links NAFLD to an increased risk of coronary artery disease. Both, coronary artery disease and NAFLD are linked to underlying insulin resistance and inflammation as drivers of the disease. Coronary flow reserve parameters including coronary flow reserve velocity (CFRV), baseline diastolic peak flow velocity (DPFV), and hyperemic DPFV are non-invasive markers of coronary microvascular circulation. The existing literature contains conflicting findings for these parameters in NAFLD patients. Aim: This meta-analysis aimed to compare CFRV, baseline DPFV, and hyperemic DPFV in between NAFLD patients and healthy controls. Methods: A comprehensive systematic search was conducted on PubMed, Embase, Cochrane Library, and Google Scholar from inception until 8th May 2024 to identify relevant studies. We pooled the standardized mean differences (SMD) with the 95% confidence intervals (CI) using the inverse variance random-effects model. A p-value of less than 0.05 was considered statistically significant. Results: We included 4 studies with 1139 participants (226: NAFLD and 913: controls). The mean age in the NAFLD group was 54.55 ± 7.62 years and in the control group was 54.2 ± 7.6 years. NAFLD was associated with a significantly lower CFRV [SMD: -0.77; 95% CI: -1.19, -0.36; p<0.0002] and hyperemic DPFV [SMD: -0.73; 95% CI: -1.03, -0.44; p<0.00001] compared to the controls. NAFLD demonstrated a statistically insignificant trend towards reduction in the baseline DPFV [SMD: -0.09; 95% CI: -0.38, 0.19; p=0.52] as compared to healthy controls. Conclusion: NAFLD patients are at a higher risk of coronary microvascular dysfunction as demonstrated by reduced CFRV and hyperemic DPFV. The presence of abnormal coronary flow reserve in NAFLD patients provides insights into the higher rates of cardiovascular disease in these patients. Early aggressive targeted interventions towards impaired coronary flow reserve in NAFLD subjects may lead to improvement in clinical outcomes.

Soluble and EV-bound CD27 act as antagonistic biomarkers in patients with solid tumors undergoing immunotherapy

BackgroundThe major breakthrough in cancer therapy with immune checkpoint inhibitors (ICIs) has highlighted the important role of immune checkpoints in antitumoral immunity. However, most patients do not achieve durable responses, making biomarker research in this setting essential. CD27 is a well known costimulatory molecule, however the impact of its soluble form in ICI is poorly investigated. Therefore, we aimed at testing circulating concentrations of soluble CD27 (sCD27) and CD27 bound to extracellular vesicles (EVs) as potential biomarkers to predict response and overall survival (OS) in patients undergoing ICI.MethodsSerum and plasma levels of sCD27 were assessed by immunoassay in three patient cohorts (n = 187) with advanced solid malignancies including longitudinal samples (n = 126): a training (n = 84, 210 specimens, Aachen ICI) and validation cohort (n = 70, 70 specimens, Hamburg ICI), both treated with ICI therapy, and a second independent validation cohort (n = 33, 33 specimens, Hamburg non-ICI) undergoing systemic therapy without any ICI. In a subset (n = 36, 36 baseline and 108 longitudinal specimens), EV-bound CD27 from serum was measured, while EV characterization studies were conducted on a fourth cohort (n = 45).ResultsIn the Aachen and Hamburg ICI cohorts, patients with lower circulating sCD27 levels before and during ICI therapy had a significantly longer progression-free survival (PFS) and OS compared to patients with higher levels, a finding that was confirmed by multivariate analysis (MVA) (Aachen ICI: pPFS = 0.012, pOS = 0.001; Hamburg ICI: pPFS = 0.040, pOS = 0.004) and after randomly splitting both cohorts into training and validation. This phenomenon was not observed in the Hamburg non-ICI cohort, providing a rationale for the predictive biomarker role of sCD27 in immune checkpoint blockade. Remarkably, EV-bound CD27 baseline levels and dynamics during ICI therapy also emerged as potent predictive biomarkers, acting however antagonistically to soluble sCD27, i.e. higher levels were associated with PFS and OS benefit. Combining both molecules (“multi-CD27” score) enhanced the predictive ability (HRPFS: 17.21 with p < 0.001, HROS: 6.47 with p = 0.011).ConclusionSoluble and EV-bound CD27 appear to have opposing immunomodulatory functions and may represent easily measurable, non-invasive prognostic markers to predict response and survival in patients undergoing ICI therapy.

Association analysis of gut microbiota with LDL-C metabolism and microbial pathogenicity in colorectal cancer patients

BackgroundColorectal cancer (CRC) is the most common gastrointestinal malignancy worldwide, with obesity-induced lipid metabolism disorders playing a crucial role in its progression. A complex connection exists between gut microbiota and the development of intestinal tumors through the microbiota metabolite pathway. Metabolic disorders frequently alter the gut microbiome, impairing immune and cellular functions and hastening cancer progression.MethodsThis study thoroughly examined the gut microbiota through 16S rRNA sequencing of fecal samples from 181 CRC patients, integrating preoperative Low-density lipoprotein cholesterol (LDL-C) levels and RNA sequencing data. The study includes a comparison of microbial diversity, differential microbiological analysis, exploration of the associations between microbiota, tumor microenvironment immune cells, and immune genes, enrichment analysis of potential biological functions of microbe-related host genes, and the prediction of LDL-C status through microorganisms.ResultsThe analysis revealed that differences in α and β diversity indices of intestinal microbiota in CRC patients were not statistically significant across different LDL-C metabolic states. Patients exhibited varying LDL-C metabolic conditions, leading to a bifurcation of their gut microbiota into two distinct clusters. Patients with LDL-C metabolic irregularities had higher concentrations of twelve gut microbiota, which were linked to various immune cells and immune-related genes, influencing tumor immunity. Under normal LDL-C metabolic conditions, the protective microorganism Anaerostipes_caccae was significantly negatively correlated with the GO Biological Process pathway involved in the negative regulation of the unfolded protein response in the endoplasmic reticulum. Both XGBoost and MLP models, developed using differential gut microbiota, could forecast LDL-C levels in CRC patients biologically.ConclusionsThe intestinal microbiota in CRC patients influences the LDL-C metabolic status. With elevated LDL-C levels, gut microbiota can regulate the function of immune cells and gene expression within the tumor microenvironment, affecting cancer-related pathways and promoting CRC progression. LDL-C and its associated gut microbiota could provide non-invasive markers for clinical evaluation and treatment of CRC patients.

A Simple Test Ratio APRI (AST to Platelet Ratio Index) as a Useful Tool for Cirrhosis: A Study from Bir Hospital, Nepal

Background Liver cirrhosis is a leading cause of morbidity and mortality worldwide, including Nepal. Liver biopsy, the gold standard for fibrosis assessment, is invasive and carries risks. The Aspartate Aminotransferase to Platelet Ratio Index (APRI) offers a non-invasive, cost-effective alternative. However, data on its utility in Nepalese populations are limited.  Objective To evaluate the diagnostic performance of APRI as a non-invasive marker of cirrhosis in Nepalese patients, determining its sensitivity, specificity, and predictive values.  Methods This cross-sectional study enrolled 58 cirrhotic patients and 58 healthy controls at Bir Hospital from April 2019 to January 2020. Clinical examinations, laboratory tests, and ultrasonography were performed. APRI with a cut-off of 0.5 was evaluated using SPSS version 23, applying chi-square and ANOVA tests.  Results Among 116 participants, APRI at a 0.5 cut-off demonstrated 88.3% sensitivity, 82.5% specificity, 90.1% positive predictive value, and 70.2% negative predictive value (p = 0.002, 95% CI).  Conclusion APRI is a reliable non-invasive tool for diagnosing liver fibrosis in cirrhotic patients, offering high sensitivity and specificity. It is practical for bedside use, especially in resource-limited settings.

Biomarkers of polyunsaturated fatty acids and cardiovascular risk factors and events in healthy Asian populations: a systematic review.

The associations between circulating polyunsaturated fatty acids (PUFAs) and cardiovascular risk factors and events in healthy Asian populations have been less examined robustly compared to Western populations. This systematic review aimed to summarise current evidence on the associations between n-3 and n-6 PUFAs biomarkers and cardiovascular risk factors and events in healthy Asian populations. PubMed, Embase, Web of Science and Cochrane Library were searched for observational studies from January 2010 until August 2024. Twenty-three studies were eligible, which covered six Asian countries and included events(n=7), traditional risk factors such as blood pressure and lipids(n=4), physical signs such as arterial stiffness(n=4), non-traditional lipid markers(n=1), markers of inflammation(n=4), markers of thrombosis(n=2), and non-invasive imaging-based markers such as carotid intima media thickness(n=5). Biological sample type included plasma(n=6), serum(n=14) and erythrocyte(n=3). Higher circulating total n-3 PUFAs appeared to be associated with lower hypertension risk and specifically eicosapentaenoic acid and docosahexaenoic acid to be associated with lower myocardial infarction risk, reduction in triglycerides and inflammation. Higher circulating linoleic acid was associated with improved lipid profiles and lower inflammation. Limited evidence led to inconclusive associations between circulating n-6 PUFAs biomarkers and cardiovascular disease events and blood pressure. No consistent associations with arterial stiffness, obesity, thrombosis and imaging-based biomarkers were observed for circulating PUFAs biomarkers in Asian populations. Limited studies exist for each outcome, hence results should be interpreted with caution. More high quality and prospective studies in Asian populations are warranted. Several recommendations such as sample size justification and reporting of non-respondents rate are proposed for future studies.

Ferric carboxymaltose reduces the burden of arrhythmic events in heart failure with reduced ejection fraction: the role of the non-invasive arrhythmic biomarkers

BackgroundTreating iron deficiency (ID) with ferric carboxymaltose (FCM) in patients with heart failure with reduced ejection fraction (HFrEF) enhances morbidity, quality of life (QoL), and exercise capacity. MethodsThis single center, prospective follow-up study aims to assess FCM's impact on arrhythmic events and non-invasive markers in HFrEF patients with cardiac implantable electronic devices (CIEDs) and ID. Symptomatic HFrEF patients with ID and CIEDs scheduled for IV FCM were followed for 12-months. Arrhythmic activity was evaluated from CIEDs and non-invasive markers from Holter recordings pre- and post-FCM. Ventricular tachycardia/ventricular fibrillation (VT/VF) episodes, non-sustained VT (nsVT), late potentials (LPs), Microvolt T-wave alternans (MTWA), heart rate variability, turbulence (HRT) QTc, and premature ventricular contractions (PVCs, number and Lown and Wolf classification) were assessed. Left ventricular EF (LVEF), global longitudinal strain (LV GLS), QoL (KCCQ, EQ-5D-5L), six-minute walking distance (6MWD), peak oxygen consumption, and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels were also recorded. ResultsNinety-six patients in optimal medical treatment participated (median age 71.9 [12.3] years, 83% male). Post-FCM treatment, VT/VF (P=0.043) and nsVT (P<0.001) frequency decreased significantly. The Lown and Wolf classification improved (P=0.002) and predicted VT/VF episodes better than other markers (AUC 0.737, P=.001). MTWA, LPs and HRT improved statistically significantly post-FCM. Hospitalization rates and NT-proBNP levels decreased, while LVEF, LV GLS, 6MWD, QoL and peak VO2 improved statistically significantly (P<0.001). ConclusionsOur study provides real-world evidence that IV FCM led to statistically significant reduction in ventricular arrhythmic episodes, as well as an improvement in non-invasive arrhythmic markers.

Prognostic Significance of Right Atrial Volume and Interval Changes in Patients with Idiopathic Pulmonary Arterial Hypertension

Idiopathic pulmonary arterial hypertension (IPAH) is a severe condition characterized by a poor prognosis, rapid deterioration, and high mortality in the absence of lung transplantation. However, non-invasive prognostic markers in assessing IPAH remain uncertain. We aimed to investigate the prognostic significance of chest CT and alterations in heart contours on chest radiography (CXR) in predicting adverse outcomes in IPAH patients. A retrospective study analyzed medical records of IPAH patients who underwent right heart catheterization and chest CT at a tertiary center between 2001 and 2023. Clinical, hemodynamic, and CT findings, and changes (Δ) in heart contours on CXR were assessed. Adverse events were defined as IPAH-related death or lung transplantation. Cox regression models evaluated the predictive power of these parameters. In 80 patients with IPAH (mean age 42.6 years; 75% females), the 3- and 5-year survival rates were 65.8% and 55.1%, respectively. Adverse events were associated with a history of cardiac arrest (Hazard ratio [HR], 11.67, p=0.02), mean pulmonary artery pressure (HR, 1.04, p=0.001), creatinine (HR, 4.12, p<0.001), 6-min walk distance (HR, 0.997, p=0.03), CT-derived right atrial (RA) volume index (HR, 1.01, p=0.02), and ΔRA contour on CXR (HR, 1.27, p<0.001). Combined clinical, CT, and CXR findings showed a 3-year event-free survival predictive accuracy of 82.2% (95% CI, 69.8-94.7), outperforming clinical factors alone. Rapid increases in RA contour on CXR and CT-derived RA volume index were associated with adverse outcomes in IPAH. Assessing these parameters may be helpful in identifying patients who require proactive treatments.

ICG-r15 predicts esophageal varices in compensated liver cirrhosis: a noninvasive approach

ObjectiveThe aim of our study was to evaluate the indocyanine green (ICG) retention test as a noninvasive marker of esophageal varices(EV).MethodsThe clinical data of patients diagnosed with compensated liver cirrhosis in Tianjin Second People’s Hospital between January 2018 and January 2021 were analysed with SPSS 23.0.ResultA total of 144 patients (88 M/56 F, 51.7 ± 11.06 years) were enrolled. The ICG retention at 15 min(ICG-r15), PVD, TBIL, Cholinesterase(CHE), AST to ALT ratio(ARR), APRI, splenic area, Lok index, Park index and liver stiffness measurement in the absent or small EV group were lower than those in the medium or large EV group, while the ICG disappareance rate(ICG-K), Effective hepatic blood flow(EHBF), ALB, PLT, and Platelet to Spleen Diameter Ratio(PSDR) were higher, and the differences were significant (P < 0.05). ICG-r15, splenic area, APRI and PLT were independent predictors for medium or large esophageal varices (OR = 1.115, 1.025, 0.281, and 0.987, respectively,P < 0.05). The predictive value of ICG-r15 for medium or large varices was 17.95%, the specificity was 0.849, and the sensitivity was 0.662, the AUROC was 0.815. The cut-off value of PLT for M/L EV was 113.5, and the specificity and sensitivity were 0.616 and 0.887, the AUROC was 0.759. The AUROC of ICG-r15 combined with PLT was 0.866, which was more superior than others.ConclusionAlthough we are far from the replacement of endoscopy, ICG-r15 combined with PLT seems to be able to identify patients with medium or large EV in patients with compensated liver cirrhosis.

Prognostic Value of Neutrophil-to-Eosinophil Ratio (NER) in Cancer: A Systematic Review and Meta-Analysis.

The identification of reliable prognostic biomarkers is crucial for optimizing cancer treatment strategies, especially in the era of personalized medicine. This systematic review and meta-analysis evaluate the prognostic significance of the neutrophil-to-eosinophil ratio (NER) in various cancer types, with a focus on its association with overall survival (OS) and progression-free survival (PFS). We conducted a systematic literature search across PubMed, Scopus, and Web of Science databases for studies published up to 28 July 2024. We performed the meta-analyses with the generic inverse variance method with a random effects model and reported hazard ratios (HR) with 95% confidence intervals (CI). The comprehensive literature search identified 10 studies comprising 2351 patients. Pooled analyses demonstrated that elevated pretreatment NER levels were significantly correlated with poorer OS (HR: 1.74, 95% CI: 1.28-2.36, p < 0.001) and PFS (HR: 1.53, 95% CI: 1.21-1.95, p < 0.001). Subgroup analyses confirmed a consistent adverse association between high NER and OS across various tumor types and geographic locations, although results from studies conducted in the Far East did not reach statistical significance. This meta-analysis demonstrates that elevated NER is associated with poorer OS and PFS in cancer patients, suggesting its potential utility as a non-invasive prognostic marker. Further validation in large, prospective studies is warranted to establish NER's role in guiding personalized treatment strategies across diverse oncologic contexts.

Role of Obeticholic Acid, a Farnesoid X Receptor Agonist, in Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis.

Background. Obeticholic acid (OCA) has emerged as a promising drug in the management of nonalcoholic fatty liver disease (NAFLD). This meta-analysis aimed to analyse the therapeutic effect of OCA on NAFLD. Methods. Randomized controlled trials (RCTs) involving patients with NAFLD receiving OCA in the intervention arm and placebo in the control arm were searched throughout the electronic databases. The primary outcomes were changes in non-invasive markers of hepatic fibrosis and liver histology. The secondary outcomes included changes in liver enzymes, metabolic parameters from baseline and adverse events (AEs). Results. Four RCTs involving 1,278 subjects met the inclusion criteria. Over 6 weeks to 18 months of clinical use, OCA outperformed placebo in resolving definite nonalcoholic steatohepatitis (odds ratio [OR] 1.60, 95% confidence interval [CI] [1.04-2.48], p=0.03) and improving fibrosis (OR 2.23, 95% CI [1.56-3.20], p<0.0001), hepatocellular ballooning (OR 1.83, 95% CI [1.35-2.47], p<0.0001) and lobular inflammation (OR 1.62, 95% CI [1.13-2.32], p=0.009). OCA did not improve the enhanced liver fibrosis score and steatosis better than placebo, and demonstrated superior efficacy compared with the placebo in reducing serum alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase levels. Although a favourable effect of OCA over placebo was seen in body-weight reduction, the OCA use was associated with adverse changes in lipid parameters. Except for the greater risk of pruritus and constipation, the AE profile was comparable between the OCA and placebo groups. Conclusions. OCA has a favourable efficacy in improving liver histology and liver enzymes. However, the worsening of lipid parameters and other AEs with the OCA use warrants further investigation.

The role of fecal matrix metalloprotease-9 as a non-invasive marker in diagnosis and assessment of clinical activity in inflammatory bowel disease patients

BackgroundInflammatory bowel disease is characterized by chronic and relapsing inflammation of the gastrointestinal tract, including two prominent forms: Crohn’s disease and ulcerative colitis. Determining diagnostic biomarkers for predicting disease activity and treatment response remains a challenging aspect.Aim of the workThe purpose of our research was to compare fecal CP and fecal MMP-9, two non-invasive biomarkers for inflammatory bowel disease (IBD), and to find out how fecal MMP-9 levels relate to disease activity by looking at how they relate to clinical, endoscopic, and histologic scores of disease activity.Patients and methodsThis study was performed on 80 subjects divided into 3 groups: group A: 30 patients with Crohn’s disease evidenced by endoscopy ileocolonoscopy, upper GI endoscopy, and tissue biopsy (15 patients with active disease and 15 patients in remission). Group B: 30 patients with ulcerative colitis disease evidenced by colonoscopy and tissue biopsy (15 patients with active disease and 15 patients in remission). Group C: 20 age-matched and sex-matched healthy controls. All participants underwent a thorough history review, comprehensive physical examination, complete laboratory tests, and C-reactive protein measurements. A quantitative enzyme-linked immunosorbent assay was used to determine the levels of fecal matrix metalloproteinase MMP 9 for both the patients and the controls. Ulcerative colitis was evaluated using the Mayo score, Montreal classification, and the Riley histological score. Additionally, Crohn’s disease was assessed with the Crohn’s Disease Activity Index, the Simple Endoscopic Score for Crohn’s Disease, and the D’Haens histological score.ResultsComparing fecal MMP-9 with fecal calprotectin (FC), we found that fecal MMP-9 was superior to FC in differentiating active Crohn’s disease from inactive Crohn’s disease, although there was no significant difference between FC and MMP-9 (P-value = 0.561). However, in ulcerative colitis, FC was superior to MMP-9 in distinguishing active UC from inactive UC, but again, there was no significant difference between FC and MMP-9 (P-value = 0.0731).In both the ulcerative colitis and Crohn’s disease groups, fecal MMP-9 could discriminate between patients in remission and those with active disease. Fecal matrix metalloproteinase-9 (MMP-9) was discovered to be a significant marker for assessing the clinical activity of both Crohn’s disease (CD) and ulcerative colitis (UC), with an AUC of 0.998 for CD and 0.991 for UC. Fecal MMP-9 demonstrated great sensitivity (93.33%), specificity (100%), positive predictive value (PPV) of 100%, and negative predictive value (NPV) of 93.7% (with a P-value < 0.001) using cutoff values of > 0.34 ng/mL for CD and > 0.36 ng/mL for UC. There was a strong positive correlation between fecal MMP-9 and endoscopic and clinical scores of disease activity.ConclusionFecal MMP-9 has emerged as a promising biomarker for evaluating the clinical activity of both Crohn’s disease and ulcerative colitis. It demonstrated superior diagnostic performance compared to fecal calprotectin in distinguishing active from inactive disease, especially in Crohn’s disease. Although fecal calprotectin outperformed MMP-9 in identifying active ulcerative colitis, the differences between the two markers were not statistically significant, suggesting that they may complement each other in clinical practice. Furthermore, fecal MMP-9 is capable of assessing the activity of endoscopically visible inflammatory bowel disease (IBD), which could help reduce the need for invasive endoscopic procedures.

Comparison of Non-invasive Biochemical Fibrosis Markers According to Obesity-Based Metabolic Profile in Chronic Liver Disease with Chronic Hepatitis B Etiology

Aim: The aim of this study is to investigate the impact of obesity on fibrosis by comparing fibrosis markers between obese and non-obese patients with Chronic Hepatitis B (CHB). Material and Method: A total of 172 CHB (50.6±9.4 mean aged) patients were included in this retrospective study. The patients were divided into two groups: Obese (n=72) and Non-obese (n=100). Inclusion criteria were those diagnosed with chronic hepatitis B and ≤ 50 IU/mL or undetectable HBV-DNA, and exclusion criteria were other chronic diseases other than CHB and pregnancy. The height, body weight, and waist circumferences were measured. BMI ≥30 kg/m2 was classified as the obese group. Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma-glutamyl transferase, albumin, bilirubin, and prothrombin time were analyzed. Fibrosis-4 score (FIB-4) was calculated with the formula Age x AST / platelet count x √(ALT), and AST-Platelet Ratio Index (APRI) was calculated with the formula [AST/AST (upper limit of normal)]/ platelet count. Results: AST levels were significantly higher in obese patients (p

Predictive brain activity related to auditory information is associated with performance in speech comprehension tasks in noisy environments.

Understanding speech in noisy environments is challenging even for individuals with normal hearing, and it poses a significant challenge for those with hearing impairments or listening difficulties. There are limitations associated with the current methods of evaluating speech comprehension in such environments, especially in individuals with peripheral hearing impairments. According to the predictive coding model, speech comprehension is an active inference process that integrates sensory information through the interaction of bottom-up and top-down processing. Therefore, in this study, we aimed to examine the role of prediction in speech comprehension using an electrophysiological marker of anticipation: stimulus-preceding negativity (SPN). We measured SPN amplitude in young adults with normal hearing during a time-estimation task with auditory feedback under both quiet and noisy conditions. The results showed that SPN amplitude significantly increased in noisy environments. Moreover, individual differences in SPN amplitude correlated with performance in a speech-in-noise test. The increase in SPN amplitude was interpreted as reflecting the increased requirement for attentional resources for accurate prediction of speech information. These findings suggest that SPN could serve as a noninvasive neural marker for assessing individual differences in top-down processing involved in speech comprehension in noisy environments.

A direct comparison of non-invasive blood markers of liver fibrosis as associates of cardiovascular risk. The Athens cardiometabolic registry

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is associated with increased risk of cardiovascular disease (CVD). This risk increases further with advanced liver fibrosis. To date, non-invasive tests (NIT) for liver fibrosis risk have not been established as diagnostic or prognostic biomarkers of CVD. Purpose The purpose of the study was to compare NIT of liver fibrosis with respect to their associations with vascular injury and cardiovascular (CV) events. Methods Individuals without clinically overt CVD and patients with CVD (total n=1,692), consecutively recruited in the Athens Cardiometabolic Registry, were analysed in this study. We retrospectively evaluated the association of NIT (i.e. Fibrosis-4 index (FIB-4), NAFLD Fibrosis score (NFS), BARD score) with indices of subclinical arterial injury (i.e. carotid wall thickness and atherosclerotic plaque for subclinical atherosclerosis, pulse wave velocity (PWV), for arterial stiffness) and the incidence of CV events. Patients were followed-up for CV events for a median time of 39 months. Results Elevated FIB-4 (&amp;gt;2.67) was associated with vascular damage [adjusted odds ratio (aOR)=2.97, 95% confidence intervals (CI)= 1.71-5.78 for maximal wall thickness (maxWT) and aOR=4.58, 95% CI=2.44-8.60 for PWV] across the entire study population, including those with or without clinically overt CVD. NFS&amp;gt; 0.675 showed similar associations but lacked significant correlation with arterial stiffness in coronary artery disease patients. FIB-4&amp;gt; 2.67 and BARD&amp;gt; 2 were associated with increased risk of the composite endpoint of CV death, acute myocardial infarction, or coronary revascularization [adjusted hazard ratio, (aHR)=2.00, 95% CI= 1.12-3.55 and aHR=3.36, 95% CI=1.03-11.0 for FIB-4 (n=842) and BARD (n=887) respectively]. FIB-4 and BARD as continuous variables confered incremental prognostic value compared to European Systematic Coronary Risk Evaluation 2 (SCORE2). Conclusion In a population with a wide range of cardiometabolic risk, FIB-4 was associated with both markers of atherosclerotic disease and arterial stiffness as well as with adverse CV events. These data support further investigation of FIB-4 as a biomarker of CV risk.

Can the presence of aortic or coronary artery calcifications in the standard of care baseline CT or PET-CT scan of patients with Hodgkin or non-Hodgkin lymphoma be used as a predictor of MACE?

Abstract Background Major adverse cardiovascular events (MACE), commonly defined as acute myocardial infarction, acute coronary syndrome/ischemic heart disease requiring revascularization, stroke, and heart failure, represent a significant cause of mortality among patients with cancer. With increased rates of both cancer and cancer survivorship, the identification of new predictive markers for the development of MACE in this population is crucial for implementing effective preventive and risk-mitigation strategies. Purpose To determine whether the presence of calcifications in the coronary arteries (CAC) or aorta (CA) of lymphoma patients, as reported in standard-of-care PET-CT (Positron Emission Tomography-Computed Tomography) or chest CT (Computed Tomography) scan, can predict the occurrence of MACE. Methods A Retrospective analysis was conducted on a cohort of patients diagnosed with Hodgkin or non-Hodgkin lymphoma and treated with anthracycline-based chemotherapy. Patients were diagnosed from January 1, 2013, and followed through to June 30, 2023. The reference point for the study was the radiologist’s report of the PET-CT or chest CT conducted before the initiation of anthracycline therapy. Patients who did not undergo a PET-CT or CT before the start of treatment, and/or developed MACE before treatment initiation were excluded. Univariate and multivariate adjusted Cox regression models were employed to assess whether the presence of CA and CAC was associated with the development of MACE. Associations with outcomes were evaluated using the Kaplan-Meier method and Cox regression. Results 326 patients were included with a mean age of 55 years (range: 52-60), predominantly male 201 (61%) and white 314 (96%), CAC was reported in 75 patients (23%) and CA in 18 (6%). In the univariate regression model, a statistically significant association was found between the presence of both CA and CAC with the risk of MACE. CAC showed a stronger association with the development of MACE than CA (HR: 3.7 [1-7.9], p=0.0005 vs HR: 2.9 [1- 8.5], p=0.050). In multivariable analysis CAC emerged as the strongest predictor of MACE (HR: 2.9 [1.3 – 6.4], p=0.01), after accounting for hypertension, diabetes, dyslipidemia, and GFR &amp;lt;60 (Table 1), while the association with CA attenuated (HR: 2.01 [0.7-6.5], p=0.2010) and was no longer significant (Table 2). Conclusion CAC in the standard-of-care PET/-CT scans was a predictor of MACE in lymphoma patients treated with anthracyclines, while the association with CA weakened in multivariable analyses and was likely underpowered given the small number of patients with CA. If replicated, this finding warrants closer surveillance of this group of patients and can be considered as a non-invasive cardiovascular risk marker.

Left atrial volumetric-mechanical coupling index as a marker of subclinical primary heart involvement in systemic sclerosis

Abstract Background Primary heart involvement in systemic sclerosis (SSc) is a common yet often clinically silent marker of poor prognosis. Up to 80% of patients have histopathological evidence of heart involvement, highlighting the need for better screening and diagnostic methods. N-terminal pro-brain natriuretic peptide (NTproBNP), a well-established cardiac biomarker, is often increased in patients with SSc, but with a not fully understood mechanism. Meanwhile, left atrial volumetric-mechanical coupling index (LACI), a new echocardiographic parameter, has been shown to predict cardiovascular outcomes in heart failure patients and the general population, but it has not been studied in SSc. Purpose To identify new echocardiographic parameters, particularly related to left atrial volume and function, as markers of increased NTproBNP in SSc patients without overt heart involvement. Methods Consecutive SSc patients without overt heart disease referred for routine cardiac screening underwent 2D and 3D transthoracic echocardiography, including atrial and ventricular strain analysis. LACI was calculated by both 2D and 3D echocardiography as the ratio between the left atrial volume index and the tissue-Doppler-imaging septal a’ velocity. Patients with significant structural and functional changes suggestive of systolic or diastolic dysfunction or pulmonary hypertension, and those with impaired global left ventricular strain were excluded. Logistic regression, Pearson correlation coefficients, and area under the receiver-operating characteristic curve (AUC) are used to analyze the association and predictive power of LACI for elevated NTproBNP. Results A total of 36 SSc patients (55±10 years old; 34 (94%) women; mean disease duration 14±11 years) were included. Sixteen (44.4%) had diffuse cutaneous involvement (dcSSc). Seventeen (47%) patients had increased NTproBNP levels (i.e. &amp;gt;125 pg/mL). Among all tested variables, 3D LACI had the best correlation with NTproBNP values (r = 0.63, p&amp;lt;0.001). A 3D LACI of &amp;gt;2 associated with NTproBNP of &amp;gt;125 pg/mL (odds ratio 7.33 [95%CI 1.38-38.8]; p=0.01) and predicted these increased values with a sensitivity of 76.9% and a specificity of 81.2% (AUC 0.78). NTproBNP was also correlated with 2D LACI (r=0.55, p&amp;lt;0.001), peak left atrial longitudinal strain (r=-0.42, p=0.01), and left atrial contraction strain (r=0.48, p=0.005). Compared to patients with limited cutaneous involvement, those with dcSSc had higher NTproBNP values (250±139.6 vs 107.2±110.9 pg/mL, p=0.001), higher 3D LACI values (2.6±0.9 vs 1.9±0.5, p=0.02), with similar left atrial and ventricular strain parameters. Conclusion Left atrial volumetric-mechanical coupling index assessed by 3D echocardiography is significantly associated with and predictive of elevated NTproBNP levels in SSc patients without overt heart disease and may be a potentially useful non-invasive marker for screening for early subclinical heart involvement in SSc patients.

Diagnostic role of the fibrosis-4 index and nonalcoholic fatty liver disease fibrosis score as a noninvasive tool for liver fibrosis scoring.

Nonalcoholic fatty liver disease (NAFLD) is characterized by liver fibrosis, which serves as a crucial indicator of its progression and prognosis. Owing to the limitations of biopsy, which is the gold standard for measuring liver fibrosis, a reliable and noninvasive marker is required. We evaluated the diagnostic role of the fibrosis-4 (FIB-4) index and nonalcoholic fatty liver disease fibrosis score (NFS) in patients with NAFLD with varying severities of liver fibrosis. The FIB-4 index and NFS were calculated using laboratory data from 121 patients who underwent liver biopsies between January 2022 and December 2023. The results were compared with those of the Scheuer scoring system for liver biopsies (F0, F1 + F2, and F3 + F4) to determine the sensitivity and specificity of the FIB-4 index and the liver disease fibrosis score in detecting and staging liver fibrosis. Twenty-one patients had advanced fibrosis (F3-F4), and 100 had minimal or mild fibrosis (F0-F2). The degree of liver fibrosis increased with decreased albumin, alanine aminotransferase and platelet count levels, and increasing age. Receiver operating characteristic curve analysis for the FIB-4 index and NFS revealed that the areas under the curve for the FIB-4 index and NFS were 0.895 (95% confidence interval: 0.836-0.954) and 0.882 (95% confidence interval: 0.813-0.952), respectively. The FIB-4 indices showed 95.24% sensitivity at a cutoff point of 1.30, and 85% specificity at a cutoff point of 2.67, while the NFS indices showed 95.24% sensitivity at -1.455 cutoff point and 95% specificity at a cutoff point of 0.676. The FIB-4 index and NFS may replace biopsy for the detection of fibrosis in patients with NAFLD.

Functional Three-Dimensional Zeolitic Imidazolate Framework with an Ordered Macroporous Structure for the Isolation of Extracellular Vesicles.

Extracellular vesicles (EVs) and their cargoes are increasingly being recognized as noninvasive diagnostic markers, necessitating the isolation of EVs from complex biological samples. Herein, a distearoyl phospholipid ethanolamine-functionalized single-crystal ordered macroporous three-dimensional zeolitic imidazolate framework (SOM-ZIF-8-DSPE) was developed, which combines the surface charge interaction of ZIF-8 with the synergistic effect of DSPE insertion into the phospholipid membrane of EVs to improve the isolating selectivity of EV capture. The materials have porous structures larger than 300 nm in diameter, providing enough space and active sites to trap EVs. Benefiting from this feature, the entire isolation process takes only 10 min and is well compatible with the subsequent analysis of RNA in EVs. Consequently, 10 upregulated miRNA of plasma EVs in the primary colorectal cancer (pCRC) patients is found over the healthy donors, and 6 upregulated miRNA of plasma EVs in the metastatic colorectal cancer (mCRC) patients over pCRC patients. These findings suggest that the isolation of EV-based SOM-ZIF-8-DSPE is a promising strategy to identify biomarkers for disease diagnosis, such as miRNAs in plasma EVs for the early detection of CRC.

Single‑center, retrospective, evaluator‑blinded, pilot and pivotal clinical trials: Assessing the mirCaP Kit (hsv2‑miR‑H9/hsa‑miR‑3659) as a diagnostic marker for prostate cancer in patients with PSA levels in the gray zone.

Prostate-specific antigen (PSA) remains a key biomarker for the diagnosis and monitoring of prostate cancer (PCa). For patients within the 'PSA gray zone', the positive predictive value (PPV) of PSA for PCa detection by biopsy is estimated to be between 30 and 42%. In the present study, a single-center, retrospective, evaluator-blinded, pilot and pivotal clinical trial was performed to assess the clinical performance of the mirCaP kit (Urotech, Inc.), which measures the herpes simplex virus 2-microRNA (miR)-H9/hsa-miR-3659 ratio, with respect to helping physicians make appropriate decisions regarding further assessment of patients with PSA levels within this gray zone. For the patients in the initial clinical trial group who were in the PSA gray zone, the sensitivity, specificity, accuracy, PPV and negative predictive value (NPV) of the mirCaP kit were 94.29, 77.50, 85.33, 78.57 and 93.94%, respectively. For those in the pivotal clinical trial, these values were 94.50, 82.73, 87.90, 81.10 and 95.04%, respectively. These results suggest that the mirCaP kit may be an effective non-invasive diagnostic marker for PCa in patients with PSA levels in the gray zone. Thus, the mirCaP kit is a promising tool that can help physicians make a decision regarding the need for prostate biopsy in these patients. Of note, the NPV of >90% indicates that the mirCaP kit could prevent unnecessary prostate biopsies in >90% of these cases.