Non-invasive Marker Research Articles

***ECD*** maternal C-reactive protein as a predictor of neonatal sepsis

ABSTRACT Systemic bacterial infection in the newborn has a significant impact on neonatal mortality and morbidity. Non-invasive prenatal markers of risk could be useful in the prediction and prevention of neonatal sepsis. We evaluated the association of maternal third-trimester serum level of C-Reactive Protein (CRP) with neonatal sepsis in a sample of infants in the JAKids pregnancy and birth cohort study. A population-based nested case–control design was used to identify cases and controls of neonatal sepsis from the subset of infants in the JAKids study whose mothers had serum archived in the early third trimester and who were admitted to newborn intensive care. Cases were 25 neonates with neonatal sepsis identified from hospital records. Controls were a random sample of 62 sepsis-free neonates matched to cases within three gestational age strata – ≤32 weeks, 33–36 weeks, and ≥37 weeks. Mothers of neonatal sepsis cases ≥37 weeks had significantly higher mean levels of maternal CRP protein than mothers of controls (11.0 mg/dL ± 3.0 vs. 8.7 mg/dL ± 5.9; p < .05). Differences in maternal CRP were not found in sepsis cases born ≤32 weeks (9.5 mg/dL ± 4.2 vs 5.8 mg/dL ± 4.0, p = .23) nor in sepsis cases born at 33–36 weeks (9.0 mg/dL ± 3.6 vs 11.9 mg/dL ± 7.8, p = .34). Maternal third-trimester C-reactive protein levels were elevated in mothers of term-born neonates with sepsis, but not in the mothers of preterm neonates with sepsis.

Clinical performance of fecal calprotectin, lactoferrin, and hemoglobin for evaluating the disease activity of IBD and detecting colorectal tumors.

Recently, noninvasive fecal markers have been used as indicators of intestinal inflammation in patients with inflammatory bowel disease (IBD). We conducted a clinical validation study to measure fecal calprotectin (Cp), lactoferrin (Lf), and hemoglobin (Hb) levels using an all-in-one kit in patients with IBD and colorectal tumors and aimed to clarify the utility of these fecal markers. In this study, 104 patients were analyzed, including 25 patients with ulcerative colitis (UC), 20 with Crohn's disease (CD), 48 with colorectal tumors, and 13 healthy controls (HC). Of the 48 patients with colorectal tumors, 14 had invasive cancer. We validated the utility of fecal Cp, Lf, and Hb levels by simultaneously measuring fecal markers in patients with IBD and colorectal tumors. Fecal Cp and Lf had almost equivalent abilities in detecting clinical remission in patients with UC; however, fecal Cp was slightly superior to Lf. Regarding colorectal tumors, fecal Cp and Lf levels tended to be higher in patients with adenomas and colorectal cancer than in HCs. Although fecal Hb alone had the best sensitivity and specificity for detecting colorectal cancer, it had relatively low sensitivity for detecting advanced neoplasms and colorectal cancer. Fecal Cp and Lf can be used as almost equivalent biomarkers to assess the clinical activity in patients with UC. Fecal Hb is the most useful marker for screening colorectal cancer; however, adding fecal Cp and Lf may compensate for the low sensitivity of detecting for advanced colorectal tumors based on Hb alone.

Role and predictive value of microRNAs 204 and 210 in the diagnosis of pulmonary arterial hypertension and the distinction between idiopathic, systemic sclerosis, and schistosomiasis-associated pulmonary arterial hypertension

BackgroundPulmonary arterial hypertension is most of the time diagnosed late in the course of the disease and necessitates right cardiac catheterization which is an invasive and costly tool. MicroRNAs have a role in the pathogenesis of pulmonary hypertension, systemic sclerosis, and schistosomiasis and their dosages are easy and non-expensive. Therefore, determining their levels in the blood may be helpful in detecting PAH and differentiating its idiopathic form from those caused by systemic sclerosis and schistosomiasis.Purpose of the studyTo evaluate the role of microRNA (miR) 204 and miR-210 in the diagnosis of PAH and to distinguish between idiopathic PAH (IPAH), systemic sclerosis-associated PAH (SSc-PAH), and schistosomiasis-associated PAH (Sch-PAH) and to identify patients who may benefit from simple non-expensive and non-invasive methods in diagnosis of PAH.MethodsSixty patients with PAH and 30 subjects as control were enrolled in the study. PAH was diagnosed by right heart catheterization, echocardiography, and laboratory tests. Blood samples were taken from all patients for measuring miR-204 and miR-210.ResultsMiR-204 was downregulated in PAH and there was a highly significant difference between PAH and control (p = 0.003) with cut-off predictive value ≤ 0.15 µM and 70% sensitivity, 85% specificity with AUC (0.749). However, miR-204 failed to distinguish between IPAH, SSc-PAH, and Sch-PAH. MiR-210 was upregulated in PAH with a highly significant difference between PAH and control (p < 0.001) with cut-off predictive value ≥ 1.16 µM and 93.33% sensitivity, 85% specificity with AUC (0.917). MiiR-210 showed a significant difference between SSc-PAH and idiopathic PAH (P = 0.012) and between SSc-PAH and Sch-PAH (P = 0.035).ConclusionsMiR-204 and miR-210 are useful non-invasive and non-expensive markers for the diagnosis of PAH, miR-210 is an excellent predictor in the diagnosis of PAH and also miR-210 might be used to distinguish SSc-PAH from idiopathic PAH and Sch-PAH.

Heart rate vARiability and physical activity in inpatient treatMent of burnOut and DepressIon (HARMODI): protocol of a cross-sectional study with up to 8-week follow up

IntroductionChronic stress can cause an imbalance within the autonomic nervous system, thereby affecting cardiovascular and mental health. Physical activity (PA) may have a positive effect on the autonomic nervous system...

Neuromelanin-Sensitive MRI as Candidate Marker for Treatment Resistance in First-Episode Schizophrenia.

Markers for treatment resistance in schizophrenia are needed to reduce delays in effective treatment. Nigrostriatal hyperdopaminergic function plays a critical role in the pathology of schizophrenia, yet antipsychotic nonresponders do not show increased dopamine function. Neuromelanin-sensitive MRI (NM-MRI), which indirectly measures dopamine function in the substantia nigra, has potential as a noninvasive marker for nonresponders. Increased NM-MRI signal has been shown in psychosis, but has not yet been assessed in nonresponders. In this study, the authors investigated whether nonresponders show lower NM-MRI signal than responders. NM-MRI scans were acquired in 79 patients with first-episode psychosis and 20 matched healthy control subjects. Treatment response was assessed at a 6-month follow-up. An a priori voxel-wise analysis within the substantia nigra tested the relation between NM-MRI signal and treatment response in patients. Fifteen patients were classified as nonresponders and 47 patients as responders. Seventeen patients were excluded, primarily because of medication nonadherence or change in diagnosis. Voxel-wise analysis revealed 297 significant voxels in the ventral tier of the substantia nigra that were negatively associated with treatment response. Nonresponders and healthy control subjects had significantly lower NM-MRI signal than responders. Receiver operating characteristic curve analysis showed that NM-MRI signal separated nonresponders with areas under the curve between 0.62 and 0.85. In addition, NM-MRI signal in patients did not change over 6 months. These findings provide further evidence for dopaminergic differences between medication responders and nonresponders and support the potential of NM-MRI as a clinically applicable marker for treatment resistance in schizophrenia.

Circulating kidney injury molecule-1 (KIM-1) biomarker analysis in IMmotion010: A randomized phase 3 study of adjuvant (adj) atezolizumab (atezo) vs placebo (pbo) in patients (pts) with renal cell carcinoma (RCC) at increased risk of recurrence after resection.

4506 Background: In IMmotion010, adj atezo did not prolong investigator-assessed disease-free survival (DFS; primary endpoint) vs pbo after resection in pts with RCC (HR: 0.93, 95% CI: 0.75, 1.15; P=0.50; Pal Lancet 2023). This exploratory analysis of circulating protein biomarkers was performed to identify high-risk pts with minimal residual disease (MRD) who may show differential benefit from treatment (tx) with atezo. Methods: Pts with RCC with clear-cell or sarcomatoid component and increased recurrence risk post nephrectomy were randomized 1:1 to atezo 1200 mg or pbo IV q3w for 16 cycles or 1 year. A retrospective proteomics analysis was done with an affinity-based proximity extension assay (PEA) panel of ≈3000 analytes to identify circulating proteins with differential abundance patterns in matched serum samples (baseline vs at recurrence). A high sensitivity electrochemiluminescence (ECL) assay was then used to evaluate levels of KIM-1, a membrane glycoprotein overexpressed in clear-cell and papillary RCC, in all available baseline and post-tx serum samples. Outcomes in pts with KIM-1 high (≥86 pg/mL) vs low status at baseline were analyzed. Results: In pts with matched PEA samples (n=73), circulating KIM-1 was identified as the most significantly enriched protein at recurrence vs baseline. Of 778 pts enrolled in IMmotion010, 752 (97%) had baseline KIM-1 data (high: 300 [40%]; low: 452 [60%]). KIM-1–high status was associated with reduced DFS, and pts with KIM-1 high had better DFS with atezo vs pbo (Table). Longitudinal analysis of matched samples showed that in KIM-1–high pts, 9% (12/138) and 26% (36/141) of pts had a ≥30% increase from baseline in KIM-1 levels at Cycle 4 Day 1 with atezo vs pbo, compared with 16% (34/213) and 12% (25/207) in KIM-1-low pts, respectively. A ≥30% KIM-1 increase was associated with worse DFS in both KIM-1–high (atezo HR: 1.68, 95% CI: 0.77, 3.69; pbo HR: 3.53, 95% CI: 2.24, 5.58) and KIM-1–low (atezo HR: 3.56, 95% CI 2.21, 5.75; pbo HR: 3.22, 95% CI: 1.81, 5.70) subgroups. In pts with matched ECL samples (n=103), median KIM-1 levels were higher ( P&lt;0.001) at recurrence (172 pg/mL) than at baseline (79 pg/mL). Conclusions: In IMmotion010, high baseline serum KIM-1 levels were associated with poorer prognosis but improved clinical outcomes with atezo vs pbo. Increased post-tx KIM-1 was associated with worse DFS. These data suggest that circulating KIM-1 may be a non-invasive marker of MRD and disease recurrence and be associated with benefit from atezo in adj RCC. Further investigation of KIM-1 in adj RCC is warranted. Clinical trial information: NCT03024996 . [Table: see text]

Pegozafermin Added to Background GLP-1 Therapy Led to Greater Improvement in Non-invasive Markers of Liver Fat, Injury and Fibrosis as well as Glycemic Control in NASH Patients with F2/F3 Fibrosis at 24 weeks: A Posthoc Analysis from ENLIVEN

Pegozafermin Added to Background GLP-1 Therapy Led to Greater Improvement in Non-invasive Markers of Liver Fat, Injury and Fibrosis as well as Glycemic Control in NASH Patients with F2/F3 Fibrosis at 24 weeks: A Posthoc Analysis from ENLIVEN

Proteomic analysis of serum extracellular vesicles reveals Fibulin-3 as a new marker predicting liver-related events in MASLD.

There is a need for novel noninvasive markers for metabolic dysfunction-associated steatotic liver disease (MASLD) to stratify patients at high risk for liver-related events including liver cancer and decompensation. In the present study, we used proteomic analysis of proteins in extracellular vesicles (EVs) to identify new biomarkers that change with fibrosis progression and can predict the development of liver-related events. We analyzed serum EVs from 50 patients with MASLD assessed for liver fibrosis by biopsy and identified proteins that altered with advanced fibrosis. A further evaluation was conducted on another cohort of 463 patients with MASLD with biopsy. Eight candidate proteins were identified by proteomic analysis of serum EVs. Among them, serum levels of Fibulin-3, Fibulin-1, and Ficolin 1 correlated with their EV levels. In addition, serum Fibulin-3 and serum Fibulin-1 levels changed significantly with advanced fibrosis. Using another cohort with biopsy, we found that the serum Fibulin-3 concentration was significantly greater in those with advanced fibrosis but that the serum Fibulin-1 concentration was not significantly different. Multivariate Cox proportional hazards analysis revealed that a higher Fibrosis-4 (FIB-4) index and higher serum Fibulin-3 concentration were independent risk factors for liver-related events. When the cutoff value for the serum Fibulin-3 concentration was 6.0µg/mL according to the Youden index of AUROCs, patients with high serum Fibulin-3 significantly more frequently developed liver-related events than did other patients. Validation using another cohort of 226 patients with clinically diagnosed MASLD confirmed that high serum Fibulin-3 levels are associated with a greater frequency of liver-related events. Serum Fibulin-3 was identified as a biomarker for predicting liver-related events in patients with MASLD.

Inflammatory markers as diagnostic and precision nutrition tools for metabolic dysfunction-associated steatotic liver disease: Results from the Fatty Liver in Obesity trial

Background & AimsMetabolic dysfunction-associated steatotic liver disease (MASLD) is a growing public health concern. The disease is silent, and its diagnosis is often delayed. Inflammatory markers constitute an interesting tool to act as subrogate, non-invasive markers. This study aimed to evaluate the changes of inflammatory markers throughout a two-year dietary intervention in subjects presenting MASLD, to determine which of the markers are suitable to predict the disease, and act as a customizing tool for MASLD´s dietary treatment. MethodsNinety-eight subjects with MASLD and forty-five controls from the Fatty Liver in Obesity (FLiO) Study were analyzed. MASLD was diagnosed and graded by ultrasound. The MASLD subjects were randomly assigned to two different dietary strategies, the American Heart Association (AHA diet) or a dietary strategy based on the Mediterranean pattern, which was specially designed for the study (FLiO diet), and then followed for two years. Hepatic status was additionally assessed through Magnetic Resonance Imaging (MRI), elastography, and determination of transaminases. Results & DiscussionInflammatory markers improved throughout the intervention in the MASLD subjects and managed to reach similar levels to controls, especially at 6 and 12 months. Additionally, leptin, adiponectin, M30, and LECT2 managed to significantly diagnose the disease at all time marks of the intervention, making them candidates for subrogate non-invasive markers of the disease. Moreover, baseline chemerin, leptin, LECT2, and M65 were used to build a predictive score to achieve greater weight loss, and therefore, which strategy could be more useful for MASLD ´s treatment. The predictive score was significantly able assign a specific diet to 55% of the study participants, meaning that the remaining 45% could achieve the same amount of weight loss following either diet equally. ConclusionInflammatory markers constitute a potential non-invasive tool to be used in MASLD screening and could also constitute an interesting tool for MASLD’s treatment customization, being able to predict the effectiveness of a dietary strategy based on the initial inflammatory state of each subject. Trial registrationwww.clinicaltrials.gov (NCT03183193).

Interatrial block and abnormal P-wave electrocardiographic parameters as non-invasive predictors of atrial fibrillation

Aim. To identify noninvasive markers of atrial electrical dysfunction and risk of nonvalvular atrial fibrillation (AF) and to develop a predictive mathematical model to estimate the AF risk based on electrocardiographic (ECG) P-wave parameters during sinus rhythm.Methods. The study included 211 patients with cardiovascular pathology (aged median 62 [52; 71] years, 67.8% male, NYHA heart failure class I-III). All patients (follow-up median 45 [26; 67] months) underwent a complex of studies: 12-lead ECG, echocardiography, 24-hour ECG monitoring. Based on surface ECG data during sinus rhythm, parameters of atrial electrical activation were assessed such as Morphology, Voltage and P waves duration (MVP) according to integral analysis by MVP score.Results. During 3.7-year period, 44 (20.8%) patients experienced new-onset sustained AF and 12 (5.69%) patients developed ischemic stroke. As a result of ROC analysis and univariate Cox regression, independent predictors of AF were identified: P-wave prolongation in the DII lead, 3rd degree or advanced interatrial block (aIAB), an increase P-wave terminal force in lead V1 (PTFV1), low-voltage P-wave in the DI lead and сalculated level of abnormal P-wave ≥3 points on the MVP score. Data from multivariate Cox proportional hazards regression analysis confirmed the prognostic significance for three independent predictors of AF: aIAB (hazard ratio (HR) 5.92; 95% confidence interval (CI) [2.48-4.12]; p=0.0001); PTFV1 (HR 1.14; 95% CI [1.04-1.24], p=0.003); low-voltage P-wave in lead DI &lt;0.1 mV (HR 1.03; 95% CI [1.02-1.05]; p=0.0001); and as a result a mathematical model was created to predict AF risk (-2LL =258; χ2=105; p=0.0001). Predictors such as PTFV1 (HR 1.41; 95% CI [1.17-1.72], p=0.0001) and MVP score of abnormal P-waves (HR 1.85; 95% CI [1.27-1.72] 2.70], p=0.001) were associated with a high risk of stroke according to Cox regression model (-2LL= 62.5; χ2=38.4; p &lt;0.001).Conclusion. Complex of ECG markers of atrial electrical dysfunction such as aIAB, PTFV1, level MVP score of abnormal P-wave and low P-wave voltage allows identifying patients at high risk of AF and ischemic stroke.

Correlation of Systemic Inflammatory Index and Neutrophil Platelet Ratio with Intracranial Haemorrhage and Mortality After Endovascular Treatment Due to Acute Ischaemic Stroke

Many studies in recent years have shown that systemic and local inflammatory responses following various diseases are important markers of tissue damage. We aimed to investigate the correlation of systemic inflamatory index and neutrophil platelet ratio with intracranial haemorrhage and mortality in patients undergoing endovascular treatment due to ischaemic stroke. Between 2022 and 2024, patients who hospitalised in the Antalya Training and Research Hospital Neurology intensive care unit after endovascular treatment were screened. Patients over 18 years of age with a door-needle time of less than 24 hours and who underwent endovascular treatment for successful internal carotid artery ICA, MCA, and basilar artery occlusion due to acute ischaemic stroke were included in the study. A total of 133 patients were included. intracranial haemorrhage was observed in 59 (44.4%) patients, and exitus developed in 38 (28.6%) patients. There was a correlation between the development of intracranial haemorrhage and systemic inflamatory index and neutrophil platelet ratio. A statistically significant difference was observed between the neutrophil platelet ratio and systemic inflamatory index median values according to mortality status, and neutrophil platelet ratio values were higher in patients who developed exitus. In conclusion, our findings indicate the correlation of systemic inflamatory index and neutrophil platelet ratio independently with intracranial haemorrhage and mortality in patients with endovascular treatment. These noninvasive and cost-effective inflammatory markers may constitute a good biomarker for intracranial haemorrhage and mortality after endovascular treatment. In order to confirm these findings, prospective studies with a larger population of patients are needed.

Correlation of fractional exhaled nitric oxide (FeNO) and clinical outcomes in patients with chronic obstructive pulmonary disease: A prospective cohort study

BackgroundFractional exhaled nitric oxide (FeNO) is an acceptable and noninvasive marker for defining eosinophilic airway inflammation. Further study is necessary to clarify the role of FeNO in patients with chronic obstructive pulmonary disease (COPD). This study aimed to determine the association between FeNO levels and clinical outcomes. MethodsA prospective observational study was conducted at Songklanagarind Hospital from October 2020 to November 2022. FeNO testing and spirometry were performed at the initial visit and 12-month follow-up. Exacerbation, hospitalization, lung function decline, and all-cause mortality were analyzed to determine the association between FeNO levels and clinical outcomes. ResultsA total of 60 patients with COPD were enrolled, 88.3 % of whom were male, with a mean age of 71.3 ± 9.5 years. There were 18 patients (30 %) in the high FeNO group (≥25 ppb) and 42 patients (70 %) in the low (<25 ppb) FeNO group. The mean blood eosinophil count (BEC) was significantly higher in the high FeNO group (p < 0.001). After a 12-month follow-up period, high FeNO group had higher exacerbation events (HR of 1.26, 95 % confidence interval (CI), 1.10–1.97, p= 0.025). Hospitalization and mortality rates were significantly higher in the high FeNO group. Regardless of the inhaled corticosteroids used, patients with high BEC and FeNO levels tended to have a greater risk of exacerbation. ConclusionIn patients with COPD, FeNO levels are strongly correlated with BEC. Poor clinical outcomes were reported in patients with high FeNO levels. FeNO may be a useful biomarker for predicting clinical outcomes in patients with COPD.

ECG screening and Sudden Cardiac Death prevention in endurance athletes

Abstract Introduction Sudden cardiac death (SCD) is the leading cause of mortality in athletes during sport activity. Identifying non-invasive and repeatable risk markers during annual athletes screening remains a crucial goal for the scientific community for the prevention of cardiovascular disease. The ECG, exercise test and spirometry are part of the annual screening program in the sport population over 40 years of age. The Heart Rate Variability (HRV) has been shown to be an independent predictor of mortality in populations with CV disease, but its relationship with SCD has been little explored in those at low risk, including athletes. This study aims to use a 5 minute ECG screening in a specific population of athletes practicing endurance sports and evaluate its clinical repercussions. Aims The primary aim of the study is to assess whether morphological and spectral ECG analysis in endurance athletes by the 5-minute 'mini Holter ECG' can add information to the annual screening for the prevention of CV diseases and SCD. Materials The study population were selected from Endurance Marathon athletes. A control group was also collected for comparison. The 5 minutes ECG was recorded at rest with the Kardia Mobile 6L™ device that use three electrodes, which allows 6 leads recording. HRV indices were obtained using the Kubios software. A morphological analysis was performed and the HRV parameters were analyzed in the time and frequency domains. Results A total of 554 subjects (220 athletes-334 controls, 325 male-229 women) were analyzed. A higher incidence of sinus arrhythmias, LAFB, 1stdegree AVB, J point/ST-segment abnormalities in athletes compared to controls was observed. Athletes had a significantly shorter QTc than the control group (394.87±30.55 ms vs. 407.01±29.09 ms), suggestive of greater protection from malignant ventricular arrhythmias. The HRV PNS (-0.73±1.25 vs -0.21±1.45) and SNS (1.71±1.91 vs 0.58 ± 1.43) indices were also higher and lower in the athlete group than in the control group, suggestive for higher vagal tone. Given the absence of a normality range of standard HRV parameters in the athlete population, values in the normal range of the 5th to 95th percentile were extrapolated in the whole population for the main HRV parameters. The project, therefore, is to evaluate patients with HRV values higher or lower than 5-95 percentile to identify those deserving further clinical investigations and closer follow-up for suspected increased risk of CV disease and SCD. Conclusions The 5-minute cardiac Holter, combining a more accurate analysis in terms of morphology and arrhythmias than the 12-lead ECG, allows a greater number of static and dynamic alterations to be detected; moreover, the analysis of HRV could provide even more information, such that it could be considered as a complementary tool during the examination and FUP of athletes. Further long-term prospective studies are needed to correlate alterations in HRV and clinical events.

#521 Increasing levels of aortic peak wave velocity along with prolonged higher CaxP product is associated with mortality in peritoneal dialysis

Abstract Background and Aims Valvular calcification is concordant with vascular calcification and develops faster in end-stage renal disease patients than in the average population. There are contradictory reports about the pathophysiology and the predictive value of valvular calcification regarding mortality in this patient population. Aortic peak wave velocity (Vmax) measurement is a non-invasive and reliable marker for the diagnosis of valve calcification. Our study analyzes cardiovascular risk prediction effect of increasing levels of Vmax at different time points in peritoneal dialysis (PD) patients. Method We conducted a retrospective, single-center study of incident PD patients under follow-up between January 1992 and January 2023 in our clinic. Demographics, laboratory, and echocardiographic findings were obtained from medical records. Patients without a baseline echocardiography were excluded. ΔVmax is defined as the last Vmax minus baseline Vmax levels. The patients were divided into two subgroups: Vmax-stable and Vmax-increased. Results The baseline demographics, laboratory, and clinical characteristics, including daily elemental calcium and calcitriol usage, were similar between Vmax-stable and Vmax-increased groups. Baseline calcium (Ca), phosphate (P), and annual CaXP levels were significantly higher in Vmax-increased group [p = 0.01, p = 0.02, and (F(1,27) = 10.415, p = 0.003), respectively]. Cardiovascular mortality was 9.8% in Vmax-stable group and 26.8% in Vmax-increased group (p = 0.02). Conclusion During a follow-up of 20 years, increasing Vmax values were associated with higher CaxP levels in PD patients. Increased Vmax levels, along with higher CaxP levels, are associated with cardiovascular mortality. Even without clinical manifestations, Vmax follow-up is a non-invasive, easily accessible method and might identify the high-risk group regarding cardiovascular mortality in the PD population.

#2908 Renal progenitor cells an early non-invasive biomarker of silent kidney injury in Fabry disease

Abstract Background and Aims Fabry's disease (FD), a hereditary condition, is linked to the X chromosome due to a mutation in the gene encoding alpha-galactosidase A (alpha-GalA). This mutation results in a defect in the metabolism of glycosphingolipids, leading to the deposition of globotriaosylceramide (GB3) primarily in organs such as the heart, kidneys, and nervous system. Renal injury can affect any level of the structure, with the podocytes being the most commonly affected due to their low regeneration and high contact with GB3. This leads to proteinuria, and if it exceeds 0.5 g, it is associated with a rapid deterioration of renal function. Renal assessment is carried out through blood analysis, proteinuria measurement, ultrasound, and the gold standard, renal biopsy. However, there is a growing trend towards less invasive biomarkers such as lysoGB3 titration in blood and urine, podocyturia, or renal progenitor cells (RPCs) in renal biopsy material or cell culture. RPCs possess self-renewal, clonogenicity, and multidifferentiation properties, contributing to cellular remodeling. They express specific markers like CD133/CD24 and CD106 in the parietal epithelium of Bowman's capsule. It is known that GB3 expresses CD77. The proliferative response of RPCs can become dysregulated, leading to detachment and elimination in the urine. The aim of the study was to demonstrate the presence of renal progenitor cells (RPCs) in urine as a non-invasive early marker for detecting renal damage in patients with Fabry's disease (FD) and to establish a correlation between RPC presence, GB3 deposition, and their potential association with the degree of renal injury. Method It is an open observational, case-control, single-center study on the urine of patients with Fabry's disease (FD) considered as cases, patients without a history considered as healthy controls, and patients with non-FD renal disease such as Gittelman syndrome or another biopsy-proven cause as positive controls. Renal progenitor cells (RPCs) were isolated using specific markers and flow cytometry, correlating these findings with renal function and albuminuria. Results A total of 75 recent urine samples were processed, corresponding to 59 patients: 16 with Fabry's disease (FD), 11 with Gittelman syndrome, 10 with chronic kidney disease (CKD), and 22 healthy controls. The samples were divided for sediment and microalbuminuria analysis, and separately for the isolation of renal progenitor cells (RPCs). The classification and quantification of the isolated cell types were performed, establishing positivity points using compensation panels with CD3 lymphocyte markers. This was followed by the identification of RPCs through positivity for CD133+/CD24+, CD106+, and CD106– markers. Once RPCs were identified, GB3 marking was carried out using CD77+. Differences were observed among the analyzed patient groups. In healthy controls, there was minimal or no presence of renal progenitor cells (RPCs), except in two patients where isolation was repeated in three different samples, maintaining positivity. Subsequent diagnoses revealed bilateral lithiasis and previously unknown hypertension in these cases. Patients with Gittelman syndrome showed a higher quantity of RPCs compared to healthy controls, but with P &amp;gt; .05. However, clear RPCs positivity was evident in patients with Fabry's disease (FD) and chronic kidney disease (CKD) confirmed by biopsy, with P &amp;lt; .05. Additionally, differences in the number of RPCs were noted based on the degree of renal disease when correlated with the presence of proteinuria &amp;lt; 0.5 g and &amp;gt; 0.5 g, with P &amp;lt; .05. Conclusion With these results, we can conclude that renal progenitor cells (RPCs) may serve as an early biomarker for silent renal injury of various etiologies. Furthermore, if we perform labeling with CD77, we can attribute it to the deposition of GB3 in Fabry's disease (FD).

#1861 Association of the polymorphisms of the angiotensin converting enzyme and FRMD3 genes in the development of diabetic kidney disease

Abstract Background and Aims Individual genetic biomarkers, called single nucleotide polymorphisms (SNPs), have been proposed that could represent potential non-invasive markers for the early diagnosis of diabetic kidney disease (DKD), in addition to their association with a characteristic phenotype. Aim To determine the association of polymorphisms of the Angiotensin Converting Enzyme and FRMD3 genes with the risk of developing ERD in patients with type 2 diabetes. Method Case-control study, comparative, observational, ambispective and cross-sectional, in which men and women, over 18 years of age with T2D with and without ERD and healthy patients, who underwent DNA extraction, participated. genomic and subsequent genotyping, and detection of SNPs by mass spectrometry. Results A total of 400 patients participated, 199 men and 201 women, within which they were divided into three groups: 100 patients with type 2 diabetes and ERD confirmed by renal biopsy, 100 patients with type 2 diabetes without ERD and 200 healthy controls. A total of 3 polymorphisms of the ACE and FRMD3 genes were studied. Among the polymorphisms analyzed in the logistic regression, rs179975 CA (OR, 6.2; 95% CI: 1.15-7.48, p = 0.03), rs1888747 GA (OR, 6.6; 95% CI: 4.60-8.45, p = 0.002) and rs10868025 resulted. CG (OR, 4.1; 95% CI: 2.40-5.60, p = 0.002) Table 1. Conclusion Our study demonstrated the association of well-established genetic variants of the ACE and FRMD3 gene polymorphisms with the presence of ERD, showing that these SNPs, specifically rs179975 CA, rs1888747 GA and rs10868025 GC, may represent important genetic markers in the development of ERD and could be a predisposing factor due to the high frequency and strength of association that were observed in our studied population, this being the first study in Latin America.

Management of Portal Hypertension in the Older Patient.

Aging is a process of physiological slowing, reduced regenerative capacity and inability to maintain cellular homeostasis. World Health Organisation declared the commencement of population aging globally, largely attributed to improvement in the healthcare system with early diagnosis and effective clinical management. Liver ages similar to other organs, with reduction in size and blood flow. In this review we aim to evaluate the effect of aging in liver disease. Aging causes dysregulation of major carbohydrate, fat and protein metabolism in the liver. Age is a major risk factor for liver fibrosis accelerated by sinusoidal endothelial dysfunction and immunological disharmony. Age plays a major role in patients with liver cirrhosis and influence outcomes in patients with portal hypertension. Transient elastography may be an useful tool in the assessment of portal hypertension. Hepatic structural distortion, increased vascular resistance, state of chronic inflammation, associated comorbidities, lack of physiological reserve in the older population may aggravate portal hypertension in patients with liver cirrhosis and may result in pronounced variceal bleed. Cut-offs for other non-invasive markers of fibrosis may differ in the elderly population. Non-selective beta blockers initiated at lower dose followed by escalation are the first line of therapy in elderly patients with cirrhosis and portal hypertension, unless contraindicated. Acute variceal bleed in the elderly cirrhotic patients can be life threatening and may cause rapid exsanguination due to poor reserve and associated comorbidities. Vasoactive drugs may be associated with more adverse reactions. Early endoscopy may be warranted in the elderly patients with acute variceal bleed. Role of TIPS in the elderly cirrhotics discussed. Management of portal hypertension in the older population may pose significant challenges to the treating clinician.

Long non-coding RNA TUG1 is down-regulated in Friedreich’s ataxia

Abstract Friedreich's Ataxia (FRDA) is a neurodegenerative disorder caused by reduced frataxin (FXN) levels. It leads to motor and sensory impairments and has a median life expectancy of around 35 years. As the most common inherited form of ataxia, FRDA lacks reliable, non-invasive biomarkers, prolonging and inflating the cost of clinical trials. This study proposes TUG1, a long non-coding RNA, as a promising blood-based biomarker for FRDA, which is known to regulate various cellular processes. In a previous study using a frataxin knockdown mouse model, we observed several hallmark FRDA symptoms. Building on this, we hypothesized that a dual-source approach—comparing the data from peripheral blood samples from FRDA patients with tissue samples from affected areas in FRDA knockdown mice, tissues usually unattainable from patients—would effectively identify robust biomarkers. A comprehensive reanalysis was conducted on gene expression data from 183 age- and sex-matched peripheral blood samples of FRDA patients, carriers, and controls, and 192 tissue datasets from FRDA knockdown mice. Blood and tissue samples underwent RNA isolation and quantitative reverse transcription PCR, and frataxin knockdown was confirmed through ELISA. Tug1 RNA interaction was explored via RNA pull-down assays. Validation was performed in serum samples on an independent set of 45 controls and 45 FRDA patients, and in blood samples from 66 heterozygous carriers and 72 FRDA patients. Tug1 and Slc40a1 emerged as potential blood-based biomarkers, confirmed in the FRDA knockdown mouse model (One-way ANOVA, p ≤ 0.05). Tug1 was consistently downregulated after Fxn knockdown and correlated strongly with Fxn levels (R2 = 0.71 during depletion, R2 = 0.74 during rescue). Slc40a1 showed a similar but tissue-specific pattern. Further validation of Tug1's downstream targets strengthened its biomarker candidacy. In additional human samples, TUG1 levels were significantly downregulated in both whole blood and serum of FRDA patients compared to controls (Wilcoxon signed-rank test, p &amp;lt; 0.05). Regression analyses revealed a negative correlation between TUG1 fold-change and disease onset (p &amp;lt; 0.0037), and positive correlations with disease duration and Functional Disability Stage score (p &amp;lt; 0.04). This suggests that elevated TUG1 levels correlate with earlier onset and more severe cases. This study identifies TUG1 as a potential blood-based biomarker for FRDA, showing consistent expression variance in human and mouse tissues related to disease severity and key FRDA pathways. It correlates with frataxin levels, indicating its promise as an early, non-invasive marker. TUG1 holds potential for FRDA monitoring and therapeutic development, meriting additional research.

Genomic characterization and risk stratification of esophageal squamous dysplasia.

The majority of esophageal squamous dysplasia (ESD) patients progress slowly, while a subset of patients can undergo recurrence rapidly or progress to invasive cancer even after proper treatment. However, the molecular mechanisms underlying these clinical observations are still largely unknown. By sequencing the genomic data of 160 clinical samples from 49 tumor-free ESD patients and 88 esophageal squamous cell carcinoma (ESCC) patients, wedemonstrated lower somatic mutation and copy number alteration (CNA) burden in ESD compared with ESCC. Cross-species screening and functional assays identified ACSM5 as a novel driver gene for ESD progression. Furthermore, we revealed that miR-4292 promoted ESD progression and could serve as a non-invasive diagnostic marker for ESD. These findings largely expanded our understanding of ESD genetics and tumorigenesis, which possessed promising significance for improving early diagnosis, reducing overtreatment, and identifying high-risk ESD patients.

Biomarkers of Airway Disease, Barrett's and Underdiagnosed Reflux Noninvasively (BAD-BURN): a Case-Control Observational Study Protocol.

Particulate matter exposure (PM) is a cause of aerodigestive disease globally. The destruction of the World Trade Center (WTC) exposed fifirst responders and inhabitants of New York City to WTC-PM and caused obstructive airways disease (OAD), gastroesophageal Refux disease (GERD) and Barrett's Esophagus (BE). GERD not only diminishes health-related quality of life but also gives rise to complications that extend beyond the scope of BE. GERD can incite or exacerbate allergies, sinusitis, bronchitis, and asthma. Disease features of the aerodigestive axis can overlap, often necessitating more invasive diagnostic testing and treatment modalities. This presents a need to develop novel non-invasive biomarkers of GERD, BE, airway hyperreactivity (AHR), treatment efficacy, and severity of symptoms. Our observational case-cohort study will leverage the longitudinally phenotyped Fire Department of New York (FDNY)-WTC exposed cohort to identify Biomarkers of Airway Disease, Barrett's and Underdiagnosed Refux Noninvasively (BAD-BURN). Our study population consists of n = 4,192 individuals from which we have randomly selected a sub-cohort control group (n = 837). We will then recruit subgroups of i. AHR only ii. GERD only iii. BE iv. GERD/BE and AHR overlap or v. No GERD or AHR, from the sub-cohort control group. We will then phenotype and examine non-invasive biomarkers of these subgroups to identify under-diagnosis and/or treatment efficacy. The findings may further contribute to the development of future biologically plausible therapies, ultimately enhance patient care and quality of life. Although many studies have suggested interdependence between airway and digestive diseases, the causative factors and specific mechanisms remain unclear. The detection of the disease is further complicated by the invasiveness of conventional GERD diagnosis procedures and the limited availability of disease-specific biomarkers. The management of Refux is important, as it directly increases risk of cancer and negatively impacts quality of life. Therefore, it is vital to develop novel noninvasive disease markers that can effectively phenotype, facilitate early diagnosis of premalignant disease and identify potential therapeutic targets to improve patient care. ClinicalTrials.gov Identifier: NCT05216133; January 18, 2022.