Standard Biomarkers Research Articles

Defining normal serum creatinine in pregnancy -results from the AKID UK prospective cohort study

Abstract Background Abnormal kidney function in pregnancy may represent chronic kidney disease or pregnancy-associated acute kidney injury - both associated with adverse outcomes during and after pregnancy. Serum creatinine remains the standard biomarker for kidney function in pregnancy but normal levels change dynamically through pregnancy and at term. Existing gestation-specific reference ranges for serum creatinine, and recommendations to investigate for abnormal kidney function in pregnancy are based on limited data. Data describing trajectories of serum creatinine through pregnancy and the normal, physiological increase in serum creatinine at term are also lacking. Methods We recruited 476 healthy pregnant individuals aged 16 years or over, 2019-21, measuring serum creatinine in the first, second and third trimesters of pregnancy, , at birth and postpartum. Clinical data were abstracted. Gestation-specific reference ranges for serum creatinine were defined as mean±1.96 x SD, after excluding those with adverse pregnancy outcomes. Trajectories of serum creatinine through pregnancy, and the change in serum creatinine at delivery were described. Results 1875 creatinine measurements were recorded. Reference ranges for serum creatinine in the first, second and third trimesters of healthy pregnancy were 37-67μmol/L (0.42-0.75mg/dl), 34-63μmol/L (0.38-0.71mg/dl), and 34-66μmol/L (0.39-0.75mg/dl). Increasing serum creatinine in early pregnancy was more common in those with hypertensive disorders of pregnancy, prior to disease onset. In healthy participants, median serum creatinine increase from 36 weeks to birth was 6.8% (95% CI 4.5%, 9.1%). Conclusions Investigation for abnormal kidney function in pregnancy should be considered at a lower creatinine threshold than currently recommended. Detecting abnormal creatinine trajectories may help early identification of high-risk pregnancies.

Mesoarchean Microbial Cd, Ba, and Ni Cycling: Evidence for Photosynthesis in Pongola Group Stromatolites through Novel Stable Isotopes and High-Resolution Trace Element Maps.

Nontraditional stable isotopes of bioactive metals emerged as novel proxies for reconstructing the biogeochemical cycling of metals, which serve as cofactors in major metabolic pathways. The fractionation of metal isotopes between ambient fluid and microorganisms is ultimately recorded in authigenic minerals, such as carbonates, which makes them potentially more reliable than standard biomarkers in organic matter. Stromatolitic carbonates are geochemical archives that allow for the study of the long-term interplay of the biosphere, atmosphere, and hydrosphere through deep time, with the unique potential to investigate early life environments and the evolution of the metallome. The present study uses stromatolites from the ∼2.95-billion-year-old Pongola Supergroup (S. Africa) as a field laboratory for combined in situ trace metal mapping and layer-specific, novel stable metal isotope compositions to infer early Earth microbial metal cycling via phototrophic and chemo-litho-autotrophic metabolisms. Quantitative in situ trace element maps reveal intrinsic biosedimentary enrichments of nickel (Ni), cadmium (Cd), phosphorus (P), iron (Fe), and manganese (Mn) in stromatolitic laminae. In contrast, barium (Ba) shows a more homogeneous distribution. Authigenic carbonates from pristine stromatolite laminae show distinct δ138Ba and δ112Cd fractionation above detrital background and bulk silicate Earth values, but opposing correlation with trace metal concentrations. Authigenic δ60Ni values overlap with Mesoarchean diamictite compositions. Nickel isotopic compositions in authigenic stromatolitic carbonates, potentially a new proxy for methanogenic metal uptake, do not show any proof of the presence of this metabolism in the samples of this study. Meanwhile, Cd isotopic compositions in authigenic carbonates follow typical Rayleigh-type isotope fractionation; that is, the isotopic composition of Cd evolves to heavy values close to modern surface compositions. Correlations of δ112Cd with the micronutrients copper (Cu), molybdenum (Mo), and P, at positively fractionated carbon (C) isotopes (δ13C ∼+2‰), argue for active photosynthesis in the Pongola microbial habitat. We show that Ba isotopes can be used to infer carbonate precipitation rates similar to modern microbial carbonates. Thus, the combination of Cd and Ni isotopes has the unique potential as novel isotope biomarkers for the biochemical sedimentary record of early Earth where traditional lipid biomarkers are not applicable due to the incomplete preservation of organic matter. Key Words: Early life-Stromatolites-Novel stable isotopes-Cadmium isotopes-Nickel isotopes-Barium isotopes-Trace element mapping.

Comprehensive RNA-seq Analysis Identifies Network Hub Genes and Biomarkers Differentiating Desmoid-type Fibromatosis from Reactive Fibrosis

Desmoid-type fibromatosis (DTF) is a benign but locally aggressive neoplasm characterized by the persistent fibroblast activation, unlike reactive fibrosis (RF), where fibroblast activation is transient. Although the Wnt/β-catenin signaling pathway is known to play a role in DTF pathogenesis, the specific genetic drivers contributing to this abnormal fibroblast activation are not fully understood.To identify additional driver genes that underlie the persistent activation of fibroblasts in DTF, we conducted a comparative transcriptome analysis between 29 DTF and 14 RF tissue samples, identifying 4,267 differentially expressed genes (DEGs) specific to DTF. These DTF-specific DEGs were significantly associated with pathways involved in embryonic limb morphogenesis and muscle contraction, whereas RF-specific DEGs were linked to immune response and apoptosis.Using weighted gene co-expression network analysis (WGCNA) to further elucidate the key regulatory circuits associated with the persistent activation of DTF fibroblasts, we identified a highly DTF-specific gene module comprising 120 genes. This module was also significantly enriched in other fibro-proliferative conditions showing the persistent fibroblasts activation, such as keloid disease and idiopathic pulmonary fibrosis. Subsequent analyses identified seven driver transcription factors (ZNF536, IRX5, TWIST2, NKD2, PAX9, SHOX2, and SALL4) within this DTF-specific module that may contribute to the sustained activation of DTF fibroblasts.We further assessed the utility of five key genes from this module (TWIST2, LRRC15, CTHRC1, SHOX2, and SALL4) as potential biomarkers to distinguish DTF from RF using immunohistochemistry. All markers demonstrated excellent diagnostic performance, with TWIST2 showing exceptionally high sensitivity and specificity, surpassing β-catenin, the current standard biomarker for DTF.In conclusion, our study identifies gene modules and driver transcription factors that are highly specific to DTF, offering new insights into the genetic underpinnings of abnormal fibroblast activation in DTF. We also propose novel biomarkers that could improve the diagnostic accuracy and clinical management of DTF.

Examining Brain Structures and Cognitive Functions in Patients with Recovered COVID-19 Infection: A Multicenter Study Using 7T MRI.

Emerging evidence suggests that severe acute respiratory syndrome, COVID-19, negatively impacts brain health, with clinical magnetic resonance imaging (MRI) showing a wide range of neurologic manifestations but no consistent pattern. Compared with 3 Tesla (3T) MRI, 7 Tesla (7T) MRI can detect more subtle injuries, including hippocampal subfield volume differences and additional standard biomarkers such as white matter lesions. 7T MRI could help with the interpretation of the various persistent post-acute and distal onset sequelae of COVID-19 infection. To investigate the differences in white matter hyperintensity (WMH), hippocampal subfields volumes, and cognition between patients hospitalized with COVID-19 and non-hospitalized participants in a multi-site/multi-national cohort. Original investigation of patients hospitalized with COVID-19 between 5/2020 and 10/2022 in 3 USA and 1 UK medical centers with follow-up at hospital discharge. A total of 179 participants without a history of dementia completed cognitive, mood and other assessments and MRI scans. COVID-19 severity, as measured by hospitalization vs no hospitalization. 7T MRI scans were acquired. All WMH and hippocampal subfield volumes were corrected for intracranial volumes to account for subject variability. Cognition was assessed using a comprehensive battery of tests. Pearson correlations and unpaired t-tests were performed to assess correlations and differences between hospitalized and non-hospitalized groups. We found similar WMH volume (4112 vs 3144mm³, p=0.2131), smaller hippocampal volume (11856 vs 12227mm³, p=0.0497) and lower cognitive and memory performance, especially the MoCA score (24.9 vs 26.4 pts, p=0.0084), duration completing trail making test B (97.6 vs 79.4 seconds, p=0.0285), Craft immediate recall (12.6 vs 16.4 pts, p<0.0001), Craft delay recall (12.0 vs 15.6 pts, p=0.0001), and Benson figure copy (15.2 vs 16.1 pts, p=0.0078) in 52 patients hospitalized for COVID-19 (19[37%] female; mean[SD] age, 61.1[7.4] years) compared with 111 age-matched non-hospitalized participants (66[59%] female; mean[SD] age, 61.5[8.4] years). Our results indicate that hospitalized COVID-19 cases show lower hippocampal volume when compared to non-hospitalized participants. We also show that WMH and hippocampal volumes correlate with worse cognitive scores in hospitalized patients compared with non-hospitalized participants, potentially indicating recent lesions and atrophy. Question: Do white matter hyperintensity burden, hippocampal whole and subfield volumes, and cognition differ between patients hospitalized with COVID-19 versus participants without hospitalization?Findings: We found no significant difference in white matter hyperintensity volume, but hippocampal volume was reduced, and cognitive and memory performance were worse in those hospitalized for COVID-19 compared with age-matched non-hospitalized group (either mild COVID-19 or no COVID-19 reported). In the hospitalized group, increased white matter hyperintensity and reduced hippocampal volumes are significantly higher correlated with worse cognitive and memory scores.Meaning: Adults hospitalized for COVID-19 had lower hippocampal volumes and worse cognitive performance than adults with COVID-19 that did not lead to hospitalization or without reported COVID-19 infection.

Correlation Between Serum Copeptin and NTproBNP Levels in Heart Failure

Introduction: Heart Failure is a leading cause of morbidity and mortality worldwide. It is associated with upregulation and dysfunction of the renin-angiotensin aldosterone system, the sympathetic nervous system and the vasopressin system. In heart failure, the levels of vasopressin are elevated and out of sync with the osmotic status. Arginine Vasopressin has a half-life of only 20 minutes and is bound to circulating platelets. Hence, it is not useful as a biomarker. Copeptin, a by-product of vasopressin metabolism has been used as a surrogate marker for Arginine Vasopressin in clinical practice. Thus, our study aims to find the use of copeptin in studying heart failure and its use in predicting severity. We also sought to correlate copeptin with NTproBNP the standard biomarker used in heart failure. Methods: Our study was a single-centre cross-sectional observational study involving 90 admitted heart failure patients over 18 months. NYHA Class was used to assess the severity of heart failure. Copeptin levels were measured using Human Copeptin ELISA Kit. Results: In these patients, elevated levels of copeptin and NTproBNP were found. In patients with higher NYHA Class, a greater rise in serum copeptin and NTproBNP levels was noted. Moreover, a strong positive correlation between NTproBNP and copeptin (rho = 0.7) was found in our study. Conclusion: Our study puts forward copeptin as a simple additional cost-effective biomarker for predicting the severity of heart failure.

Fluorescence Lifetime Imaging Enables In vivo Quantification of PD-L1 Expression and Inter-tumoral Heterogeneity.

Patient selection for cancer immunotherapy requires precise, quantitative readouts of biomarker expression in intact tumors that can be reliably compared across multiple subjects over time. The current clinical standard biomarker for assessing immunotherapy response is programmed death-ligand-1 (PD-L1) expression, typically quantified using immunohistochemistry. This method, however, only provides snapshots of PD-L1 expression status in microscopic regions of ex vivo specimens. While various targeted probes have been investigated for in vivo imaging of PD-L1, non-specific probe accumulation within the tumor microenvironment (TME) has hindered accurate quantification, limiting the utility for preclinical and clinical studies. Here, we demonstrated that in vivo time-domain (TD) fluorescence imaging of an anti-PD-L1 antibody tagged with the near-infrared fluorophore IRDye 800CW (αPDL1-800) can yield quantitative estimates of baseline tumor PD-L1 heterogeneity across untreated mice, as well as variations in PD-L1 expression in mice undergoing clinically relevant anti-PD1 treatment. The fluorescence lifetime (FLT) of PD-L1 bound αPDL1-800 was significantly longer than the FLT of nonspecifically accumulated αPDL1-800 in the TME. This FLT contrast allowed quantification of PD-L1 expression across mice both in superficial breast tumors using planar FLT imaging and in deep-seated liver tumors (>5 mm depth) using the asymptotic TD algorithm for fluorescence tomography. These findings suggest that fluorescence lifetime imaging can accelerate the preclinical investigation and clinical translation of new immunotherapy treatments by enabling robust quantification of receptor expression across subjects.

Added value of inflammatory plasma biomarkers to pathologic biomarkers in predicting preclinical Alzheimer's disease.

Plasma biomarkers have recently emerged for the diagnosis, assessment, and disease monitoring of Alzheimer's disease (AD), but have yet to be fully validated in preclinical AD. In addition to AD pathologic plasma biomarkers (amyloid-β (Aβ) and phosphorylated tau (p-tau) species), a proteomic panel can discriminate between symptomatic AD and cognitively unimpaired older adults in a dementia clinic population. Examine the added value of a plasma proteomic panel, validated in symptomatic AD, over standard AD pathologic plasma biomarkers and demographic and genetic (apolipoprotein (APOE) ɛ4 status) risk factors in detecting preclinical AD. 125 cognitively unimpaired older adults (mean age = 66 years) who completed Aβ PET and plasma draw were analyzed using multiple regression with Aβ PET status (positive versus negative) as the outcome to determine the best fit for predicting preclinical AD. Model 1 included age, education, and gender. Model 2 and 3 added predictors APOE ɛ4 status (carrier versus non-carrier) and AD pathologic blood biomarkers (Aβ42/40 ratio, p-tau181), respectively. Random forest modeling established the 5 proteomic markers from the proteomic panel that best predicted Aβ PET status, and these markers were added in Model 4. The best model for predicting Aβ PET status included age, years of education, APOE ɛ4 status, Aβ42/40 ratio, and p-tau181. Adding the top 5 proteomic markers did not significantly improve the model. Proteomic markers in plasma did not add predictive value to standard AD pathologic plasma biomarkers in predicting preclinical AD in this sample.

Immunosensing of Cardiac Troponin I (cTnI) Using a Two-Electrode Electrochemiluminescence Platform with Near Persisting Luminescence Generated on a Ru(bpy)32+-Tripropylamine System.

An economical, rapid, and ultrasensitive detection of biomolecules in clinical settings is very crucial, particularly for the early detection of Cardiac Troponin I (cTnI), which is the gold standard biomarker for Acute Myocardial Infarction (AMI). Electrochemiluminescence (ECL) has risen in prominence as an important technique for in vitro diagnosis and detection by virtue of its high sensitivity reaching a femtomolar level. This study introduces an economically feasible nanoplatform for ECL immunosensing, consisting of a gold nanoparticle (AuNP) with Ru(bpy)32+ and tripropylamine (TPA) system, which is a potential ECL luminophore and coreactant system. AuNPs serve the role of an ECL signal enhancer as well as the carrier of antibody, which enables the creation of a label-free immunosensor for antigen-antibody interactions. The prepared immunosensor detected cTnI with a detection limit (LOD) of 0.03 ng/mL. This potential immunosensor provides appreciable results in the detection of cTnI from spiked real serum analysis, which shows its potential application in low-resource clinical settings.

Increased circulating levels of standardized inflammatory and endothelial dysfunction biomarkers in patients with myocardial infarction with nonobstructive coronary arteries

Abstract Introduction Around 10% of patients with acute myocardial infarction (AMI) present with nonobstructive coronary arteries (MINOCA), for which the underlying pathophysiology is often uncertain. Our aim was to evaluate inflammatory burden and endothelial dysfunction in MINOCA patients by assessing biomarkers in both acute and stable phases. Methods An analytical and observational study at a University Hospital involving 166 MI patients admitted over the past 3years. Following ESC guidelines, patients were categorized into MINOCA or myocardial infarction with significant coronary artery disease (MI-CAD) groups. Circulating levels of inflammatory biomarkers (interleukin-6(IL-6), tumor necrosis factor-α(TNF-α) and high-sensitivity C-reactive protein(hs-CRP)) and of endothelial dysfunction (asymmetric dimethylarginine (ADMA)) were measured in 44 MINOCA patients and 122 MI-CAD patients at acute phase (admission and discharge) and stable phase (2months after MI). As biomarker levels may vary with MI size, each value was standardized by dividing it by the peak troponin, resulting in a biomarker/troponinT ratio. We evaluated the effects of standardized (SB) and non-standardized (NSB) biomarker values using a multivariate regression model adjusted for age and sex. Results We analyzed 166 patients (median age:68 years, 70% males). MI-CAD patients had higher peak high-sensitive troponinT (hs-TnT) levels upon admission compared to those with MINOCA (1491ng/L vs 247ng/L,p&amp;lt;0.001),likely due to larger infarctions generating higher levels of inflammation. When examining the association between infarct size, as measured by peak hs-TnT values, and biomarker levels, we observed a significant dose-response relationship for hs-CRP at admission (βcoefficient 0.16 [95%CI,0.02-0.29],p0.02) and IL-6 at admission (βcoefficient 0.15 [95%CI,0.04-0.27],p0.01). Significant positive associations were found between MINOCA and all SBs, both during the acute phase and in follow-up. During the acute phase ORs ranged from 1.35to2.7 (p&amp;lt;0.05) for inflammatory biomarkers and from 2.34 to 2.76 (p&amp;lt;0.01) for ADMA. In the stable phase ORs ranged from 1.49to3.06 (p&amp;lt;0.05) for inflammatory biomarkers, and OR was 2.79(p&amp;lt;0.01) for ADMA (Figure 1). In contrast, none of the NSBs were associated with MINOCA. Regarding temporal biomarker changes, during the acute phase of MI and 2 months post-event, both MINOCA and MI-CAD patients showed similar trends. However, MINOCA patients consistently maintained elevated inflammatory activity and ADMA concentrations only when biomarkers were standardized by infarct size (Figure 2). Conclusions Higher levels of SBs were consistently associated with MINOCA, both during the acute phase of the event and in follow-up, compared to MI-CAD. Consequently, this study suggests that the inflammatory burden, measured by heightened levels of standardized inflammatory biomarkers, and endothelial dysfunction, as measured by ADMA, may play a role in the pathophysiology of MINOCA.Boxplots for SBs at three time points.Temporal changes in biomarker levels.

Refining risk stratification in hypertrophic cardiomyopathy: the role of late gadolinium enhancement and syncope in predicting adverse outcomes

Abstract Background The presence of late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (MRI) is recognized as a significant marker of myocardial fibrosis and a predictor of adverse outcomes in hypertrophic cardiomyopathy (HCM). Nevertheless, the specific quantity of LGE that correlates with poor outcomes is still under debate. Therefore, this study sought to assess the combined impact of LGE presence and a history of syncopal events and its association with clinical prognosis. Methods Between May 2018 and June 2023, a total of 230 HCM patients was prospectively enrolled at our Medical University, a tertiary referral center. The primary endpoint was a composite of new-onset ventricular tachycardia (VT), appropriate ICD therapy, and all-cause mortality. Results Median age of enrolled patients was 56 (IQR 44-64) years and 40% (n=94) were female. Median interventricular septal thickness (IVS) was 21 (IQR 18–25) mm and 43 % (n=84) had significant left ventricular outflow tract obstruction (LVOTO). Over a median follow-up of 3.2 years, 30 patients (13%) met the composite endpoint. These patients had a significantly higher LGE quantity compared to the non-event group (1.1 % vs. % 9.0, P=0.012). An LGE threshold of 5.2% was identified as an optimal predictor of the composite endpoint, with an area under the curve of 0.72, which increased to 0.77 when including at least one syncopal event in medical history. LGE &amp;gt; 5.2% and/or syncope were independently associated with adverse outcomes after multivariable adjustment (Adj HR 7.26 [95%CI 2.54-20.72]). Furthermore, NTproBNP and hsTnT were associated with the presence of LGE or syncope (OR for a 1-unit increase in standardized log-transformed biomarker NTproBNP 3.35 [95%CI 1.42-10.85]; hsTnT 3.48 [95%CI 1.48-10.24], respectively). Interestingly, typically used variables for risk stratification, such as age, IVS or LVOT were not significantly associated with these cardiac biomarkers. Conclusion An extent of LGE &amp;gt; 5.2% and the history of at least one syncope are associated with unfavorable clinical outcomes in HCM patients. These findings call for detailed MRI appraisal and suggest adopting a holistic approach to accurately identify high-risk patients.

Biomarkers of microbial translocation and generalized inflammation are associated with frailty among people with HIV.

Frailty occurs at higher rates and younger ages among people with HIV (PWH) compared to the general population and is often attributed to chronic inflammation and subsequent immune exhaustion. We assessed how inflammatory biomarkers are associated with frailty among PWH. The Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort is comprised of adult PWH in care at 10 sites, and harmonizes demographic, clinical, and patient-reported outcomes (PRO) data. A panel of 13 inflammatory biomarkers was collected from a subset of virally suppressed PWH once per person between 2010-2018. Frailty was measured with a validated PRO phenotype, scored 0-4, from biomarker collection date through July 2022. With adjusted linear mixed models, we estimated longitudinal associations between standard deviation-scaled log2-transformed biomarkers and frailty score. Among 273 PWH, most were male (91%), average age at baseline was 45, 42% were non-Hispanic White while 35% were non-Hispanic Black, and average follow-up time was 5.5 years. Several biomarkers were associated with higher frailty, including those linked to microbial translocation (sCD14, LBP, KT ratio) and systemic inflammation (CRP, IL-6, suPAR, sTNFR1, sTNFR2). Higher IL-6 was associated with a 0.25-point higher frailty score (95%CI:0.12-0.39). Higher sTNFR1 (0.35 [0.13-0.56]), sCD14 (0.21 [0.11-0.31]), and suPAR (0.24 [0.11-0.36]) levels were also associated with higher frailty scores over follow-up. Higher levels of biomarkers linked to microbial translocation and systemic inflammation are associated with higher average frailty scores over time in a cohort of virally suppressed PWH, highlighting these pathways as potential interventional targets for mitigating frailty in PWH.

Toxicological and Biomarker Assessment of Freshwater Zebra Mussels (Dreissena polymorpha) Exposed to Nano-Polystyrene.

The presence of sub-micron-sized plastics in the environment has been increasing, with the possible risks of these particles remaining relatively unknown. In order to assess the toxicity of these particles, 100 nm diameter green fluorescent nano-polystyrene spheres (NPS) (20-60 mg/L) were exposed to zebra mussels (Dreissena polymorpha) to investigate the mortality, clearance rate and stress-related biomarker responses. D. polymorpha were collected and analysed with standard OECD toxicological tests and biomarker analysis to detect both physical and biochemical responses after exposure to NPS. The toxicity of the NPS to D. polymorpha was low, with 60 mg/L NPS causing a mortality rate of 11.1% at 96 h which was statistically significant compared to the 4.2% control. No statistical change could be found for the condition factor (kc) of D. polymorpha after NPS exposure. Clearance rates in D. polymorpha using R. subcapitata algae showed NPS-exposed mussels had a reduction of filtering efficiency of up to 30.5%. Bioassay testing shows a mixed but undeniably negative response from the D. polymorpha to the NPS, notably a significant rise in DNA Strand Breaks (DSB) and Metallothionein (MT) responses for high NPS concentrations. Additionally, Lipid Peroxidation (LPO) and Ferric Reducing Antioxidant Power (FRAP) assay tests showed a significant increase in response from the higher (>40 mg/L) concentrations of NPS exposure. Although Glutathione S-Transferase (GST) assay showed no statistical change from the control for all NPS-exposed samples, an increase of 20% had occurred for 60 mg/L NPS. Overall, a minimal toxic response from D. polymorpha to the NPS exposure below 40 mg/L was seen. After 40 mg/L NPS, mussels presented more acute toxicity in terms of mortality, along with reduced algal clearance rates and anincrease in biomarker response. This study revealed a clear induction of oxidative stress and DSB in the digestive gland of zebra mussels following exposure to nano-polystyrene. While these findings provide valuable insights into the potential harmful effects of nanoplastics in freshwater bivalves, further studies are necessary to help understand the level of threat plastic pollution may pose to the health of freshwater ecosystems.

Circulating Extracellular Matrix Products as Indicators of Disease Burden and Predictors of Disease Course in Ulcerative Colitis.

Ulcerative colitis (UC) is characterized by recurrent inflammation and challenging disease monitoring, with invasive endoscopy as the primary diagnostic tool despite the inadequacy of standard noninvasive biomarkers. This study evaluates serum extracellular matrix (ECM) fragments, which reflect the remodeling of mucosa and submucosa, as potential indicators of disease burden and treatment efficacy. We aim to determine whether serum ECM levels correlate with the extent and severity and predict treatment response. We conducted a prospective study comparing serum ECM formation (PRO-C3, PRO-C7, PRO-C11, PRO-C22), turnover (PRO-C4), and degradation markers (C1M, C3M, C4M, C7M) at Weeks 0, 12, and 24 in 49 UC patients and 50 healthy controls measured by enzyme-linked immunosorbent assay. ECM biomarkers, notably PRO-C11, differentiated UC patients from controls (area under the curve [AUC] 0.77), and PRO-C3 predicted endoscopic treatment response vs nonresponse (AUC 0.74). C7M separated moderate from severe disease in endoscopy (AUC 0.74) as well as mild from severe disease (AUC 0.84), as did the ratio C7M/PRO-C7 (AUC 0.82). Combining new and conventional markers, including hemoglobin, C-reactive protein, PRO-C3, and PRO-C22, achieved a combined AUC of 0.84 for predicting 24-week endoscopic response, adding index endoscopic activity increased the AUC to 0.92 compared to an AUC of 0.84 for endoscopy alone. Soluble ECM fragments reflect endoscopic disease severity and extent and are also predictive of therapeutic efficacy. They may as well reflect degenerative aspects of UC and may as such be future therapeutic targets aimed at prevention of intestinal damage.

THE RELATIONSHIP BETWEEN SERUM ANGIOPOIETIN-LIKE PROTEIN 8 LEVELS AND HYPERTENSION STAGES

OBJECTIVE: Hypertension is a serious condition that can lead to serious complications. Currently, there is no standard biomarker used in clinical practice to diagnose hypertension and stage the disease. The aim of this study was to investigate whether serum levels of angiopoietin-like protein 8 (sANGPTL8) change in hypertensive patients and advanced stages of hypertension. MATERIAL AND METHODS: Our study is a prospective observational study. We used an ELISA kit to measure sANGPTL8 levels in 42 hypertensive patients and 41 healthy non-hypertensive patients at our cardiology clinic and evaluated statistical differences between the groups. A two-tailed p&amp;lt; 0.05 was considered statistically significant. RESULTS: The mean sANGPTL8 levels in the stage 2 hypertension group are statistically significantly higher than in the stage 1 and non-hypertensive group (813 pg/ml vs 524.89 pg/ml and 518.07 pg/ml respectively) (p= 0.001). CONCLUSIONS: According to our study, mean sANGPTL8 levels were higher in stage 2 hypertensive patients compared to stage 1 hypertensive and normotensive individuals (p=0.001). Additional biomarkers that can be used in combination with ANGPTL8 and further research on ANGPTL8 may enable this adipokine to be used as an effective biomarker in diagnosing advanced hypertension.

Aptamer-Based Electrochemical Biosensing Platform for Analysis of Cardiac Biomarkers.

Monitoring biomarkers secreted by cardiomyocytes is critical to evaluate anticancer drug-induced myocardial injury (MI). Cardiac troponin I (cTnI) is considered the gold standard biomarker for MI. Herein, an electrochemical aptasensor is engineered for cTnI detection based on lanthanide europium metal-organic frameworks (Eu-MOFs) and a hybridization chain reaction-directed DNAzyme strategy. Three types of Eu-MOF morphologies were easily synthesized by changing the solvent, and the Eu-MOF modulated by mixing the solvent of dimethylformamide and H2O (D-Eu-MOF) exhibited the best performance compared to other morphologies of the Eu-MOFs. Multifunctional nanoprobes were constructed from D-Eu-MOF@Pt loaded with natural horseradish peroxidase and combined with an aptamer-initiated nuclear acid hybridization chain reaction to form G-quadruplex/hemin DNAzymes for signal amplification. A novel capture probe is constructed on the basis of DNA nanotetrahedrons modified on screen-printed gold electrodes to enhance the capture of the target and multifunctional nanoprobes for signal amplification. It exhibits a detection limit of 0.17 pg mL-1 and a linear range from 0.5 pg mL-1 to 15 ng mL-1. The practicality of the platform is evaluated by measuring cTnI in real samples and secreted by cardiomyocytes after drug treatment, which provides great potential in drug-induced MI evaluation for clinical application.

High-Sensitivity Troponin: Finding a Meaningful Delta.

High-sensitivity cardiac troponin (hs-cTn) assays have significantly refined the resolution of biomarker-level detection and have emerged as the gold standard cardiac biomarker in evaluating myocardial injury. Since its introduction, hs-cTn has been integrated into the Fourth Universal Definition of Myocardial Infarction and various European Society of Cardiology (ESC) and American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the evaluation and diagnosis of chest pain syndromes. However, despite its integral role in caring for patients with chest pain, there are still substantive gaps in our knowledge of the clinical interpretation of dynamic changes in hs-cTn values. Whether a relative or absolute hs-cTn delta should be used to detect acute myocardial injury remains debatable. There are also emerging considerations of possible sex and racial/ethnic differences in clinically significant troponin deltas. In the emergency department, there is debate about the optimal time frame to recheck hs-cTn after symptom onset for myocardial infarction rule-out and whether hs-cTn deltas should be integrated into clinical risk scores. In this review, we will provide an overview of the history of clinical utilization of cardiac biomarkers, the development of hs-cTn assays, and the ongoing search for a meaningful delta that can be clinically applicable.

Early Fever in Allogeneic Stem Cell Transplantation: Are Presepsin and YKL-40 Valuable Diagnostic Tools?

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a lifesaving treatment but carries a high infection risk. Diagnosing infections remains challenging due to the limited accuracy of standard biomarkers. Methods: This single-center study aimed to evaluate presepsin (PSP) and YKL-40 as infection biomarkers in febrile patients during the allo-HSCT pre-engraftment phase. Biomarker levels were prospectively measured in 61 febrile episodes from 54 allo-HSCT patients at admission, representing baseline levels, and then at Day 1, 3, 5, and 7 following fever onset. The diagnostic value was compared to that of procalcitonin (PCT). Results: PSP showed fair diagnostic value on Day 1 (AUC 0.656; 95% CI: 0.510-0.802) and Day 3 (AUC 0.698; 95% CI: 0.559-0.837). YKL-40 did not provide any significant diagnostic value across measured time points. PCT outperformed PSP and YKL-40, particularly on Day 3 (AUC 0.712; 95% CI: 0.572-0.852). When combining biomarkers, the best model for predicting infection used PSP > 3.144 ng/mL and PCT > 0.28 μg/L on Day 3, resulting in R2 of about 31% (p < 0.001). Conclusions: Neither test showed sufficient discriminative power for early infection to recommend their use as individual diagnostic tools in clinical practice.

A-016 Can You Believe Your Troponin? Using Laboratory Automation and Programmed Rules to Reduce Non-Repeatable False Positive Troponin Results

Abstract Background Cardiac troponin is currently the standard biomarker for evaluating patients with suspected acute coronary syndrome. Like all immunoassays, troponin testing is susceptible to non-repeatable positive results. Because this can cause a clinical challenge, we assessed our false positive rate by manipulating the timing and conditions of repeat troponin testing. Methods A prospective observational study established the repeatability failure (RF) rate in three scenarios, where a suspicious initial result prompts a repeat test. Protocol 1: We programed our middleware (Remisol, Beckman Coulter) to route the specimen to online storage after initial testing. After a 120-minute delay, the specimen was automatically retrieved from storage and tested again. Protocol 2: We programmed DxI 800 systems (Beckman Coulter) to aspirate a specimen reserve volume sufficient for two test replicates simultaneously. Protocol 3: We restricted repeat testing to 18-50 ng/L where the majority of RF occurred. To analyze RF in 4 and 18 ng/L interval (limit of reporting and URL, respectively), an absolute 3.5 ng/L bias was considered an RF. For specimens &amp;gt;18 ng/L, a difference of ±4.0 SD difference between replicates with a CV of 7% was a RF, equating to a relative difference of 28% (Method 1). Method 2 used a relative difference of 35% for RF. Method 3 defined RF as a critical difference of z×√2×SDanalytical where z=3.5 and SD=1.8 for results &amp;lt;19 ng/L and SD for results ≥19 ng/L were calculated from a fixed 7% CV for each result. A z-value of 3.5 represents a probability of 0.0005 (5 in 10,000). Results Using Protocol 1, RF rate was significantly higher in delayed repeat testing (1.6%, CI 1.5-1.8, n=23,525) compared to immediate repeat testing (0.4%, CI 0.4-0.5, n=14,880, p&amp;lt;0.0001) in two-tailed analysis. Because the first result was more commonly larger than the second (77.7% v. 52.2%, respectively), one-tailed analysis was used and found RF in delayed repeat testing was 0.9% (CI 0.8-1.0) v. immediate repeat testing (0.4%, CI 0.3-0.4, p&amp;lt;0.0001). A similar percentage of results were found in the 18-50 ng/L range in delayed testing (88.6%) v. immediate repeat (86.8%). Protocol 2 (with one-tailed analysis) yielded similar RF rates: 0.8%, CI 0.8-1.0 v. 0.3%, CI 0.3-0.4, delayed and immediate repeat testing, respectively. Protocol 3 yielded RF rate of 0.6%, CI 0.5-0.7 v. 0.2%, CI 0.2-0.3, delayed and immediate repeat testing, respectively, with all p-values &amp;lt;0.0001. Conclusions By programming auto-repeating hsTnI testing only in the 18-50 ng/L range, we found &amp;gt;80% of specimens with potential RF results could be retested using either the delayed- or immediate-repeat protocols. This suggests automated protocols could repeat testing with potential RFs without staff intervention or increasing container movement on the automation line. Reagent usage because of repeat testing could be conserved by limiting repeat testing to specimens most likely to create provider confusion. Rules to automate selected retesting of hsTnI in testing systems and/or middleware can enhance quality of results without human intervention and subsequent burden on staff, reduce reagent waste and enhance provider decision making in a critical population.

N-terminal pro-B-type natriuretic peptide, eGFR, and progression of kidney disease in chronic kidney disease patients without heart failure.

Cardiorenal syndrome highlights the bidirectional relationship between kidney and heart dysfunction. N-terminal pro-B-type natriuretic peptide (NT-proBNP), which is the gold standard biomarker in heart failure (HF), may be an important biomarker for chronic kidney disease (CKD) progression. However, NT-proBNP is negatively related with estimated glomerular filtration rate (eGFR). In this study, we investigated the association of NT-proBNP, eGFR, and progression of kidney disease in CKD patients without HF. This multicentric retrospective cohort study recruited 23 860 CKD patients without HF, who had at least one NT-proBNP record from China Renal Data System database. Linear regression model evaluated the relationship between eGFR and NT-proBNP. Cox regression analysis assessed the association between NT-proBNP and CKD progression. Sensitivity analysis examined the robustness of the main findings. This study involved 23 860 CKD patients without HF, distributed across different CKD stages: 10 526 in stages G1-2, 4665 in G3a, 3702 in G3b, 2704 in G4, and 2263 in G5. NT-proBNP was negatively correlated with eGFR, particularly in stages 4-5 CKD. A 15-unit decrease in eGFR was associated with increases in log (NT-proBNP) levels by 1.04-fold, 1.27-fold, 1.29-fold, 1.80-fold, and 3.50-fold for stages 1-2, 3a, 3b, 4, and 5, respectively. After excluding patients who developed CKD progression within 1 year, the Cox regression analysis revealed that the relationship between NT-proBNP and CKD progression was not significant in stages 4 and 5. However, for stages 1-3, each standard deviation increase in log (NT-proBNP) was associated with a 26%, 36%, and 28% higher risk of CKD progression, with P interaction ≤.001. The hazard ratios were 1.26 (95% confidence intervals (CI), 1.18 to 1.35), 1.36 (95% CI, 1.22 to 1.51), and 1.28 (95% CI, 1.14 to 1.43) for stages 1-2, stage 3a, and stage 3b, respectively. Despite its strong inverse association with eGFR, NT-proBNP was positively associated with the risk of progression of kidney disease in CKD patients with stages 1-3 without HF. Future studies should investigate the effectiveness of NT-proBNP as a predictive biomarker for the progression of kidney disease across diverse racial groups and healthcare settings.

Using Cerebrospinal Fluid Biomarkers To Enhance Diagnostic Testing For Alzheimer's Disease In A Tertiary Memory Service

Abstract Background Cerebrospinal Fluid (CSF) biomarkers are useful in the definitive diagnosis of Alzheimer’s disease (AD) when basic investigations and neuroimaging are inconclusive. In our tertiary memory clinic, the standard CSF biomarker panel consists of Amyloid Beta (AB) 42, Total tau, and Phosphorylated tau. AB42/40 is an additional CSF biomarker which has been shown to improve diagnostic accuracy for AD but is not part of our standard CSF biomarker panel (1). We examined the use of AB42/40 in patients attending our service. Methods In our service, diagnosis of dementia is based on a multidisciplinary consensus meeting (including Geriatricians, Neurologists, Psychiatrists) who review clinical presentation and neuroimaging. In a minority of cases, CSF analysis is performed. We retrospectively evaluated how the addition of AB40/42 to our standard CSF panel impacted diagnostic accuracy for AD, taking a ratio of &amp;lt;0.067 to indicate AD (2). Results Of 1853 patients attending the Memory service between September 2022 and December 2023, CSF was available for 107 patients. Of these 107, average age was 68. 56 were female (52%) and 51 were male (48%). At the multidisciplinary consensus meeting, 81 of these 107 patients were diagnosed with AD (75%), with the remaining 26 (24%) patients being diagnosed with a non-AD process (Vascular disease, Lewy Body etc) or an inconclusive diagnosis. After the addition of AB42/40 to CSF, 8 of the 26 patients (31%) with non-AD or an inconclusive diagnosis were identified as potential AD. Of the 81 with a diagnosis of AD, none were reclassified after addition of AB42/40. Receiver Operating Characteristic (ROC) curve analysis was performed to determine relevant cut off values. Conclusion This study suggests the addition of AB42/40 ratio to our standard CSF biomarker panel improves identification of potential AD cases in our sample. This biomarker is being added to the standard CSF panel for our Memory service.