Surrogate Biomarker Research Articles

Modeling the Interictal Epileptic State for Therapeutic Development with Tetanus Toxin.

Focal forms of epilepsy can result from a wide range of insults and can vary from focal symptoms to generalized convulsions. Most drugs that have been developed for epilepsy focus on the prevention of seizures. On Electroencephalography (EEG), seizures are characterized by a repetitive buildup of epileptic waveforms that can spread across the brain. Brain regions that produce seizures generate far more frequent 'interictal' spikes seen between seizures, and in animal models, these spikes occur prior to the development of seizures. Interictal spiking by itself has been shown to have significant adverse clinical effects on cognition and behavior in both patients and animal models. While the exact relationships between interictal spiking and seizures are not well defined, interictal spikes serve as an important biomarker that, for some forms of epilepsy, can serve as a surrogate biomarker and as a druggable target. While there are many animal models of seizures for drug development, here we review models of interictal spiking, focusing on tetanus toxin, to study the relationship between interictal spiking, seizures, cognition, and behavior. Studies on human cortical regions with frequent interictal spiking have identified potential therapeutic targets; therefore, having a highly consistent model of spiking will be invaluable not only for unraveling the initial stages of the pathological cascade leading to seizure development but also for testing novel therapeutics. This review offers a succinct overview of the use of tetanus toxin animal models for studying and therapeutic development for interictal spiking.

Arginine vasopressin in mood disorders: A potential biomarker of disease pathology and a target for pharmacologic intervention.

Vasopressin or arginine-vasopressin (AVP) is a neuropeptide molecule known for its antidiuretic effects and serves to regulate plasma osmolality and blood pressure. The existing literature suggests that AVP plays a multifaceted-though less well-known-role in the central nervous system (CNS), particularly in relation to the pathophysiology and treatment of mood disorders. Animal models have demonstrated that AVP is implicated in regulating social cognition, affiliative and prosocial behaviors, and aggression, often in conjunction with oxytocin. In humans, AVP is implicated in mood disorders through its effects on the hypothalamic-pituitary-adrenal (HPA) axis as well as on the serotoninergic and glutamatergic systems. Measuring plasma AVP has yielded interesting but mixed results in mood and stress-related disorders. Recent advances have led to the development of copeptin as a stable and reliable surrogate biomarker for AVP. Another interesting but relatively unexplored issue is the interaction between the osmoregulatory system and mood disorder pathophysiology, given that psychotropic medications often cause dysregulation of AVP receptor expression or signaling that can subsequently lead to clinical syndromes like syndrome of inappropriate diuresis and diabetes insipidus. Finally, pharmaceutical trials of agents that act on V1a and V1b receptor antagonists are still underway. This narrative review summarizes: (1) the neurobiology of the vasopressinergic system in the CNS; (2) the interaction between AVP and the monoaminergic and glutamatergic pathways in the pathophysiology and treatment of mood disorders; (3) the iatrogenic AVP dysregulation caused by psychotropic medications; and (4) the pharmaceutical development of AVP receptor antagonists for the treatment of mood disorders.

Serum IL-6 as a Surrogate Biomarker of Post-operative Complications in Invasive Orthopaedic Surgeries: A Prospective Observational Study.

Interleukin-6 (IL-6) is a cytokine released in response to tissue injury. Elevated serum IL-6 levels in trauma patients have been linked with increased risk of complications such as inapparent hypoxia (SpO2 < 94%), acute respiratory distress syndrome, fat embolism syndrome (FES), systemic inflammatory response syndrome, multiple organ dysfunction syndrome and sepsis. This study aims to determine the role of serum IL-6 as surrogate biomarker of post-operative complications after invasive orthopaedic surgeries. Thirty-seven adults between 18 and 65years of age undergoing invasive orthopaedic surgeries were included in this hospital-based study. Serum IL-6 levels were estimated serially in the pre-operative period, after 24h and 7days post-operatively. Cases were monitored for post-operative complications. Serum IL-6 levels showed maximum rise in the first 24h post-operatively especially among older patients (> 60years). Older patients undergoing bipolar hemiarthroplasty for neck of femur fracture showed highest median post-operative IL-6 level of 258pg/ml. Serum IL-6 level > 130pg/ml measured 24h after surgery was predictive of post-operative complications (sensitivity of 75%). Among the cases with post-operative complications, inapparent hypoxia was the most common complication/event observed. Cases with sub-clinical FES had highest level of serum IL-6 in first 24h following surgery with median IL-6 level of 300pg/ml (range 155-444 pg/ml). Monitoring serum IL-6 level may help in both anticipation and early detection of post-operative complications in patients undergoing invasive orthopaedic surgeries; potentially enhancing patient safety.

Health effect of multiple air pollutant mixture on sarcopenia among middle-aged and older adults in China

BackgroundAs the global aging process accelerates, the health challenges posed by sarcopenia among middle-aged and older adults are becoming increasingly prominent. However, the available evidence on the adverse effects of air pollution on sarcopenia is limited, particularly in the Western Pacific region. This study aimed to explore relationships of multiple air pollutants with sarcopenia and related biomarkers using the nationally representative database. MethodsTotally, 6585 participants aged over 45 years were enrolled from the China Health and Retirement Longitudinal Study (CHARLS) in 2011 and 3443 of them were followed up until 2015. Air pollutants were estimated from high-resolution satellite-based spatial-temporal models. In the cross-sectional analysis, we used generalized linear regression, unconditional logistic regression analytical and restricted cubic spline (RCS) methods to assess the single-exposure and non-linear effects of multiple air pollutants on sarcopenia and related surrogate biomarkers (serum creatinine and cystatin C). Several popular mixture analysis techniques such as Bayesian kernel machine regression (BKMR), weighted quantile sum (WQS) regression, and quantile-based g-computation (Qgcomp) were further used to examinate the combined effects of multiple air pollutants. Logistic regression was used to further analyze the longitudinal association between air pollution and sarcopenia. ResultsEach interquartile range increase in PM2.5, PM10 and NO2 was significantly associated with an increased risk of sarcopenia, with adjusted odds ratios (aORs) of 1.09 [95 % confidence interval (CI): 1.01, 1.20], 1.24 (95 % CI: 1.14, 1.35) and 1.18 (95 % CI: 1.08, 1.28), respectively. Our findings also showed that five air pollutants were significantly associated with the sarcopenia index. In addition, employing a mixture analysis approach, we confirmed significant combined effects of air pollution mixtures on sarcopenia risk and associated biomarkers, with PM10 and PM2.5 identified as major contributors to the combined effect. The results of the exposure-response (E-R) relationships, subgroup analysis, longitudinal analysis and sensitivity analysis all showed the unfavorable impact of air pollution on sarcopenia risk and related vulnerable populations. ConclusionsSingle-exposure and co-exposure to multiple air pollutants were positively associated with sarcopenia among middle-aged and older adults in China. Our study provided new evidence that air pollution mixture was significantly associated with sarcopenia related biomarkers.

Evaluation of the vitamin D response index in a Saudi cohort

The concept of the vitamin D response index was developed based on vitamin D intervention studies conducted with Finnish cohorts. In this study, we challenged the concept by performing a single vitamin D3 bolus (80,000 IU) intervention with a cohort of 100 native Saudis. The change of serum levels of the proinflammatory cytokines interleukin 6, interleukin 8 and tumor necrosis factor measured directly before intervention in comparison to samples taken one and thirty days after vitamin D3 supplementation were used as biomarkers for distinguishing low, mid and high responders. Interestingly, we identified 39 % of the study participants as low responders. In contrast, when we used in a subset of 37 study participants whole blood expression changes of seven well-known vitamin D target genes one and thirty days after supplementation as alternative biomarkers, only 9 persons (24 %) were identified as low responders. In conclusion, in Saudi Arabia the rate of low vitamin D responders is equal or even higher than that in Finland. Therefore, similar to Nordic countries also in Saudi Arabia appropriate vitamin D3 supplementation is essential, in order to fulfill the needs of low responders.

Clozapine treatment and astrocyte activity in treatment resistant schizophrenia: A proton magnetic resonance spectroscopy study

Clozapine is the only antipsychotic approved for treating treatment-resistant schizophrenia (TRS), characterized by persistent positive symptoms despite adequate antipsychotic treatment. Unfortunately, clozapine demonstrates clinical efficacy in only ~30–60 % of patients with TRS (clozapine-responders; ClzR+), while the remaining ~40–70 % are left with no pharmacological recourse for improvement (clozapine-resistant; ClzR−). Mechanism(s) underlying clozapine's superior efficacy remain unclear. However, in vitro evidence suggests clozapine may mitigate glutamatergic dysregulations observed in TRS, by modulating astrocyte activity in ClzR+, but not ClzR−. A factor that if proven correct, may help the assessment of treatment response and development of more effective antipsychotics. To explore the presence of clozapine-astrocyte interaction and clinical improvement, we used 3 T proton-magnetic resonance spectroscopy to quantify levels of myo-Inositol, surrogate biomarker of astrocyte activity, in regions related to schizophrenia neurobiology: Dorsal-anterior-cingulate-cortex (dACC), left-dorsolateral-prefrontal-cortex (left-DLPFC), and left-striatum (left-striatum) of 157 participants (ClzR− = 30; ClzR+ = 37; responders = 38; controls = 52). Clozapine treatment was assessed using clozapine to norclozapine plasma levels, 11–12 h after last clozapine dose. Measures for symptom severity (i.e., Positive and Negative Symptoms Scale) and cognition (i.e., Mini-Mental State Examination) were also recorded. Higher levels of myo-Inositol were observed in TRS groups versus responders and controls (dACC (p < 0.001); left-striatum (p = 0.036); left-DLPFC (p = 0.023)). In ClzR+, but not ClzR−, clozapine to norclozapine ratios were positively associated with myo-Inositol levels (dACC (p = 0.004); left-DLPFC (p < 0.001)), and lower positive symptom severity (p < 0.001). Our results support growing in vitro evidence of clozapine-astrocyte interaction in clozapine-responders. Further research may determine the viability of clozapine-astrocyte interactions as an early marker of clozapine response.

The diagnostic value of salivary C-reactive protein in neonatal infections: a meta-analysis.

C-reactive protein (CRP), as an acute phase protein, is a sensitive indicator of neonatal bacterial infection. Some recent studies have shown that there is a correlation between CRP levels in serum and saliva, and using saliva to detect CRP levels is expected to be an ideal and non-invasive method to predict neonatal infection. The purpose of this Meta-analysis was to evaluate the diagnostic value of salivary CRP for neonatal infection. We searched PubMed, Embase, Web of Science, and Scopus databases in October 2023 and included observational studies that examined salivary CRP in newborns with bacterial infections. Data was extracted regarding the methodology, participant characteristics, and outcome measures. Nine articles were included, with a total of 696 newborns. Salivary CRP levels are significantly higher in neonates with infections compared to non-infected group (SMD = 0.58, 95%CI [0.40-0.76], P < 0.001). The accuracy for salivary CRP to predict serum CRP abnormality is high (sensitivity 86%, specificity 88%, area under the curve = 0.94). Our meta-analysis suggested that salivary CRP can be used as an alternative biomarker to serum CRP for detecting neonatal infection.

The Potential Role of CA-125 as a Biomarker for Short-Term Mortality Risk in Patients with Acute Symptomatic Pulmonary Embolism.

Background: Antigen carbohydrate 125 (CA-125) is a complex glycoprotein extensively studied as a prognostic biomarker in heart failure, yet its potential role in the short-term prognosis of an acute pulmonary embolism (PE) remains unexplored. Methods: In this observational, prospective, single-center study, consecutive patients aged 18 and older with a confirmed acute symptomatic PE and no history of prior anticoagulant therapy were enrolled. Primary and secondary objectives aimed to assess the prognostic capacity of CA-125 at PE diagnosis for 30-day mortality and major bleeding, respectively. Results: A total of 164 patients were included (mean age 69.8 years, SD 17), with 56.1% being male. Within 30 days, 17 patients (10.4%) died and 9 patients (5.5%) suffered major bleeding. ROC curve analysis for 30-day mortality yielded an area under the curve of 0.69 (95% CI 0.53-0.85) with an optimal CA-125 cut-off point of 20 U/mL and a negative predictive value of 96%. Multivariate analysis revealed a significant association between CA-125 levels exceeding 20 U/mL and 30-day mortality (adjusted odds ratio 4.95; 95% CI 1.61-15.2) after adjusting for age, cancer, NT-proBNP > 600 ng/mL, and the simplified pulmonary embolism severity index score. Survival analysis for 30-day mortality exhibited a hazard ratio of 5.47 (95% CI 1.78-16.8). No association between CA-125 levels and 30-day major bleeding was found. Conclusions: CA-125 emerges as a promising surrogate biomarker for short-term mortality prediction in an acute symptomatic PE. Future investigations should explore the integration of CA-125 into PE mortality prediction scores to enhance the prognostic accuracy in this patient population.

Long-term pharmacodynamic and clinical effects of twice- versus once-daily low-dose aspirin in essential thrombocythemia: The ARES trial.

Patients with essential thrombocythemia (ET) are treated with once-daily low-dose aspirin to prevent thrombosis, but their accelerated platelet turnover shortens the antiplatelet effect. The short-term Aspirin Regimens in EsSential Thrombocythemia trial showed that twice-daily aspirin dosing restores persistent platelet thromboxane (TX) inhibition. However, the long-term pharmacodynamic efficacy, safety and tolerability of twice-daily aspirin remain untested. We performed a multicenter, randomized, open-label, blinded-endpoint, phase-2 trial in which 242 patients with ET were randomized to 100 mg aspirin twice- or once-daily and followed for 20 months. The primary endpoint was the persistence of low serum TXB2, a surrogate biomarker of antithrombotic efficacy. Secondary endpoints were major and clinically relevant non-major bleedings, serious vascular events, symptom burden assessed by validated questionnaires, and in vivo platelet activation. Serum TXB2 was consistently lower in the twice-daily versus once-daily regimen on 10 study visits over 20 months: median 3.9 ng/mL versus 19.2 ng/mL, respectively; p < .001; 80% median reduction; 95% CI, 74%-85%. No major bleeding occurred. Clinically relevant non-major bleedings were non-significantly higher (6.6% vs. 1.7%), and major thromboses lower (0.8% vs. 2.5%) in the twice-daily versus once-daily group. Patients on the twice-daily regimen had significantly lower frequencies of disease-specific symptoms and severe hand and foot microvascular pain. Upper gastrointestinal pain was comparable in the two arms. In vivo platelet activation was significantly reduced by the twice-daily regimen. In patients with ET, twice-daily was persistently superior to once-daily low-dose aspirin in suppressing thromboxane biosynthesis and reducing symptom burden, with no detectable excess of bleeding and gastrointestinal discomfort.

Utilizing synchronous care to improve cardiovascular and renal health among patients with type 2 diabetes: Proof-of-concept results from the DECIDE-CV clinical programme.

The management of patients with type 2 diabetes is asynchronous, i.e. not coordinated in time, resulting in delayed access to care and low use of guideline-directed medical therapy (GDMT). We retrospectively analysed consecutive patients assessed in the 'synchronized' DECIDE-CV clinic. In this outpatient clinic, patients with type 2 diabetes and cardiovascular or chronic kidney disease are simultaneously assessed by an endocrinologist, cardiologist and nephrologist in the same visit. The primary outcome was use of GDMT before and after the assessment in the clinic, including sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, renin-angiotensin system blockers and mineralocorticoid receptor antagonists. Secondary outcomes included the baseline-to-last-visit change in surrogate laboratory biomarkers. The first 232 patients evaluated in the clinic were included. The mean age was 67 ± 12 years, 69% were men and 92% had diabetes. In total, 73% of patients had atherosclerotic cardiovascular disease, 65% heart failure, 56% chronic kidney disease and 59% had a urinary albumin-to-creatinine ratio ≥30 mg/g. There was a significant increase in the use of GDMT:sodium-glucose cotransporter 2 inhibitors (from 44% to 87% of patients), glucagon-like peptide 1 receptor agonists (from 8% to 45%), renin-angiotensin system blockers (from 77% to 91%) and mineralocorticoid receptor antagonists (from 25% to 45%) (p < .01 for all). Among patients with paired laboratory data, glycated haemoglobin, urinary albumin-to-creatinine ratio and N-terminal proB-type natriuretic peptide levels significantly dropped from baseline (p < .05 for all). Joint assessment of patients with diabetes in a synchronized cardiometabolic clinic holds promise for enhancing GDMT use and has led to significant reductions in surrogate cardiovascular and renal laboratory biomarkers.

Oxidative Status, Iron Plasma Levels in Venous Thrombosis Patients.

Exaggerated clot induces venous thrombosis (VTE); oxidative stress (OxS) can to be postulated as additional risk factor. This study evaluates firstly OxS by measuring surrogate biomarkers (malondialdehyde-MDA, 4-hydroxinonenal-4-HNE, superoxide desmutase enzyme (SOD)), secondly the iron (Fe) plasma level and thirdly the hepcidin protein (Hep) level in patients with VTE. A case control study was performed enrolling twenty hospitalized patients and an equal number of healthy individuals. In VTE patients, the following results were found. The MDA was 8.38 ± 0.5 µM/L, the 4-HNE measured 2.75 ± 0.03 µM/L and the SOD was 0.025 ± 0.01 U/mL. The I was 73.10 ± 10 µg/dL and the He was 4.77 ± 0.52 ng/mL. In the control group, the MDA measured 5.5 ± 0.6 µM/L, the 4-HNE 2.24 ± 0.021 µM/L and the SOD 0.08 ± 0.12 U/mL. The Hep was 2.1 ± 0.55 ng/mL and the Fe was 88.2 ± 9.19 µg/dL. Differences were statistically significant. Results suggest that in VTE there is activated OxS, Fe deregulation and over-production of Hep. Fe deregulation induces OxS, leading both to inflammation in the clot activator and stimulation of the pro-thrombotic status. The study highlights OxS and Fe and their regulation as intriguing indicators for risk of VTE.

Biochemical and Anthropometric Indices of Insulin Resistance in Obese and Overweight Children with Metabolic Dysfunction-Associated Fatty Liver Disease.

BACKGROUND The prevalence of metabolic (dysfunction)-associated fatty liver disease (MAFLD) increases together with the epidemic of childhood obesity. An important mechanism in the phenomenon appears to be insulin resistance (IR), the assessment of which in children is problematic. The homeostatic model assessment of IR (HOMA-IR), commonly used for this, is not standardized and appears not to correlate with IR in the pediatric population. Therefore, our study aimed to evaluate potential substitute indices of IR, including the triglyceride-glucose index (TyG), triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C), modified TyG indices: TyG-waist circumference (TyG-WC) and TyG-body mass index (TyG-BMI) as surrogate markers of MAFLD in obese children suspected to have liver disease. MATERIAL AND METHODS The retrospective study included 264 obese children admitted to the Department to diagnose suspected liver disease. MAFLD was diagnosed according to the International Expert Consensus Statement. Anthropometric measurements and laboratory tests were made and the indices were calculated. Receiver operating characteristics analysis was performed to calculate the power of the indices. RESULTS MAFLD was diagnosed in 184 patients (70%). Obese children with MAFLD showed significantly higher activity of liver enzymes and concentration of total cholesterol, TG, WC, and waist-to-hip ratio compared to non-hepatopathic obese controls (n=80). The most important indices in identifying MAFLD were: TyG (AUC=0.641, p<0.001, cut-off =8.41, sensitivity=57.4%, specificity=68.8%), and TG/HDL-C (AUC=0.638, p<0.001, cut-off=2.5, sensitivity=48.6%, specificity=76.3%). TyG-BMI and HOMA-IR were not useful predictors. CONCLUSIONS TyG and TG/HDL-C can be considered as potential surrogate biomarkers in predicting MAFLD in obese children.

Effect of low-dose tamoxifen on IGF-I/IGFBP-3 and estradiol/SHBG ratio and their prognostic/predictive effect in DCIS/LCIS/ADH.

10510 Background: Babytam (BT), 5 mg/day for 3 years (y) is a popular choice for preventive therapy after breast DCIS/LCIS/ADH given its 10-y efficacy to prevent recurrence without adverse events (1). Here we investigated the effect of BT on serum biomarkers and their role as prognostic and predictive factors. Methods: In a phase-III trial of BT or placebo (P), 406 out of 500 women consented to blood sampling at baseline, 1 and 3 y. Serum estradiol (E2), SHBG, IGF-I, IGFBP-3 and their molar ratios were measured by CLIA. Biomarker changes were estimated with mixed-effects models for repeated measures and Incidence Rate Ratios (IRR) of the primary endpoint (invasive breast cancer or DCIS) were calculated after 5 and 10 y of follow-up with Poisson regression. Subgroup analyses were performed by interaction test. Results: There were no differences in event rates between women with blood samples and those w/out. Compared with P at 1 y, IGF-I/IGFBP-3 decreased by 0.039 (95%CI, 0.027-0.052), relative difference (rd), 22% (15-29) (p&lt;0.001), whereas E2/SHBG increased by 2.967 (1.767-4.166), rd, 79% (47-111) in pre- and decreased by 0.121 (-1.117-0.874), rd, -9% (-84-66), in postmenopausal women on BT (p-interaction=0.001). The mean annual rate of events (x1000 PY) after 5 and 10 y follow-up according to baseline level of IGF-I/IGFBP-3 (all women) and E2/SHBG (postmenopausal). Conclusions: BT significantly lowers IGF-I/IGFBP-3 ratio, increases E2/SHBG in premenopause to a lesser extent than 20 mg/d and is effective in most subgroups regardless of baseline biomarker levels. While lower baseline IGF-I/IGFBP-3 levels were predictive of BT efficacy at 5 and 10 y, higher levels at 10 y were associated with a lower benefit of BT. E2/SHBG had a tendency to be prognostic and predictive of BT efficacy at 5 y, but softened down at 10 y. These biomarkers may help differentiate which women benefit most from BT. The role of IGF-I change as surrogate biomarker of BT effect requires further studies. 1. Lazzeroni et al: JCO 41:3116, 2023. Clinical trial information: NCT01357772 . [Table: see text]

Prognostic effect of triglyceride glucose-related parameters on all-cause and cardiovascular mortality in the United States adults with metabolic dysfunction-associated steatotic liver disease

BackgroundsInsulin resistance (IR) plays a vital role in the pathogenesis of the metabolic dysfunction-associated steatotic liver disease (MASLD). However, it remains unclear whether triglyceride–glucose (TyG) related parameters, which serve as useful biomarkers to assess IR, have prognostic effects on mortality outcomes of MASLD.MethodsParticipants in the National Health and Nutrition Examination Survey (NHANES) database from 1999 to 2018 years were included. TyG and its related parameters [TyG-waist circumference (TyG-WC) and TyG-waist to height ratio (TyG-WHtR)] were calculated. Kaplan–Meier curves, Cox regression analysis, and restricted cubic splines (RCS) were conducted to evaluate the association between TyG-related indices with the all-cause and cardiovascular mortality of adults with MASLD. The concordance index (C-index) was used to evaluate the prediction accuracy of TyG-related indices.ResultsA total of 8208 adults (4209 men and 3999 women, median age 49.00 years) with MASLD were included in this study. Multivariate-adjusted Cox regression analysis revealed that high quartile levels of TyG-related indices were significantly associated with the all-cause mortality of participants with MASLD [TyGadjusted hazard ratio (aHR) = 1.25, 95% confidence interval (CI) 1.05–1.50, P = 0.014; TyG-WCaHR for all-cause mortality = 1.28, 95% CI 1.07–1.52, P = 0.006; TyG-WHtRaHR for all-cause mortality = 1.50, 95% CI 1.25–1.80, P < 0.001; TyG-WCaHR for cardiovascular mortality = 1.81, 95% CI 1.28–2.55, P = 0.001; TyG-WHtRaHR for cardiovascular mortality = 2.22, 95% CI 1.55–3.17, P < 0.001]. The C-index of TyG-related indices for predicting all-cause mortality was 0.563 for the TyG index, 0.579 for the TyG-WC index, and 0.585 for the TyG-WHtR index, respectively. Regarding cardiovascular mortality, the C-index was 0.561 for the TyG index, 0.607 for the TyG-WC index, and 0.615 for the TyG-WHtR index, respectively. Nonlinear trends were observed between TyG and TyG-WC indices with all-cause mortality of MASLD (P < 0.001 and = 0.012, respectively). A non-linear relationship was observed between the TyG index and cardiovascular mortality of MASLD (P = 0.025). Subgroup analysis suggested that adults aged < 65 years old and those without comorbidities were more sensitive to the mortality prediction of TyG-related indices.Conclusion Findings of this study highlight the predictive value of TyG-related indices, especially the TyG-WHtR index, in the mortality outcomes of adults with MASLD. TyG-related indices would be surrogate biomarkers for the clinical management of MASLD.

Analytical validation of the Mindray CL1200i analyzer high sensitivity cardiac troponin I assay: MERITnI study.

This study performed an analytical validation study of the Mindray high-sensitivity cardiac troponin I (hs-cTnI) assay addressing limit of blank (LoB), limit of detection (LoD), precision, linearity, analytical specificity and sex-specific 99th percentile upper reference limits. LoB, LoD, precision, linearity and analytical specificity were studied according to Clinical and Laboratory Standards Institute. We used one reagent lot and one CL1200i analyzer. Skeletal troponin I and T, cardiac troponin T, troponin C, actin, tropomyosin, myosin light chain, myoglobin and creatine kinase (CK-MB) were studied for cross-reactivity. Interference with biotin was examined. Lithium heparin samples (one freeze thaw cycle) from healthy males and females were measured to determine the 99th percentiles by using the non-parametric method. Analyses were performed before and after excluding subjects with clinical conditions and/or increased surrogate biomarkers. The Mindray hs-cTnI assay met criteria to be considered as a hs-cTn assay. LoB and LoD was <0.1 ng/L and 0.1 ng/L, respectively. Repeatability had a coefficient of variation 1.2-3.8 %, and within-laboratory imprecision 1.7-5.0 %. The measuring interval ranged from 1.1 to 28,180 ng/L. The analytical specificity was clinically acceptable for the interferents studied. After exclusions, the 99th percentile URLs obtained were 10 ng/L overall, 5 ng/L for females and 12 ng/L for males. Analytical observations of the Mindray hs-cTnI assay demonstrated excellent LoB, LoD, precision, linearity and analytical specificity, that were in alignment with the manufacturer's claims and regulatory guidelines for hs-cTnI. The assay is suitable for clinical investigation for patient-oriented studies.

Long-term QT interval analysis for real world patients with Insertable cardiac monitors taking antiarrhythmic drugs

Abstract Background The QT interval serves as a surrogate biomarker for ventricular repolarization. Variance in QT intervals can clinically lead to pro-arrhythmia and sudden cardiac death. An insertable cardiac monitor (ICM) device capable of continuously monitoring the QT interval over a long period can provide diagnostic value for evaluating physiologic or drug induced variations in QT interval. Objective To analyze feasibility of continuous QTc interval monitoring in patients with ICM and evaluate the QTc interval changes in patients taking antiarrhythmic drugs. Methods Patients QT intervals detected from daily ICM ECG data from real-world patients taking antiarrhythmic drugs such as sotalol, amiodarone and dofetilide during hospitalization while implanted with ICM were analyzed from the de-identified Electronic Health Record (EHR) database linked with ICM device data warehouse. The ICM ECG was processed through the previously defined QT detection algorithm which calculates the QTc interval for every beat to generate continuous long term QTc trends. A patient contributed to the prescription group if they were prescribed antiarrhythmics drugs prior to hospitalization in the EHR database otherwise they contributed to the non-prescription group. Patients from the prescription group who were administered antiarrhythmic drugs via injection or IV during hospitalization were removed from the analysis. A 30-day median QTc interval from 30-60 days prior to hospitalization was used as baseline. Wilcoxon signed-rank test was used to compare the paired difference from days 1-5, 1-10, 30-60, and 60-90 after hospitalization to their respective baseline. Results 441 patients (avg. age: 70±11, 50.5% female) were included with 220 prescription and 221 non-prescription. The baseline QTc intervals were 414 and 417.3 msec for non-prescription and prescription groups, respectively. There was a significant increase in QTc on days 1-5, 1-10, 30-60, and 60-90 after hospital admission compared to the baseline (all p &amp;lt; 0.001) for the non-prescription group. The prescription group showed increase in QTc only on days 30-60 after hospitalization when compared to baseline (p&amp;lt;0.05). A larger QTc increase was observed in non-prescription receiving anti-arrhythmic loading on days 1-5 after hospitalization compared to patients on prescription prior to hospitalization (P&amp;lt;0.05). Conclusion Utilizing a QT interval detection algorithm from an ICM can provide long term QT trends for patients with an ICM. Continuous monitoring of QT can help to detect sudden changes in QT due to antiarrhythmic drugs which may lead to increased risk of arrhythmias or cardiac arrest.

#2307 Serum NGAL, MMP-9 and suPAR in the assessment of kidney impairment and cardiovascular risk in children and adolescents with type 1 diabetes or obesity

Abstract Background and Aims Type 1 diabetes mellitus (DM1) and obesity represent two chronic paediatric diseases with worryingly rising incidence, characterized by chronic inflammation, endothelial dysfunction and increased risk for kidney impairment and cardiovascular disease. The aim of this cross-sectional study was to explore the potential usefulness of serum Neutrophil Gelatinase-Associated Lipocalin (NGAL), Matrix Metalloproteinase-9 (MMP-9) and Soluble Urokinase Plasminogen Activator Receptor (suPAR) for predicting early kidney injury or increased cardiovascular risk in children and adolescents with DM1 or obesity. Method Serum samples were obtained from children and adolescents aged &amp;lt;18 years old with DM1 (n=35) or obesity (n=38) and normal renal function with no history of albuminuria, as well as from healthy controls (n=23). Serum NGAL, MMP-9 and suPAR concentrations were measured using commercially available sandwich ELISA kits (NGAL: (DY1757-05), MMP-9: (DMP900); suPAR: (DUP00); R&amp;D systems). All patients were evaluated for anthropometric indices (weight, height, BMI) while for different degrees of weight status we used the body mass index (BMI) z-score adjusted for age and sex. Estimated glomerular filtration rate (eGFR) was calculated according to the revised bedside Schwartz formula. Results Serum NGAL values were found significantly higher in patients with obesity but not in those with DM1. A positive correlation was found in patients with T1DM with diabetes duration (Spearman rho 0.364, p=0.044), and in all study participants with BMI z-score (Spearman rho 0.401, p=0.004). Furthermore, serum MMP-9 levels were significantly increased in patients with T1DM and in patients with obesity compared to controls. Mean serum suPAR levels were significantly higher in patients with obesity compared to patients with T1DM and controls, while children with T1DM had similar suPAR levels to controls (Table 1). Finally, serum suPAR levels showed a negative correlation with age (Spearman rho −0.359, p&amp;lt;0.001) and creatinine levels (Spearman rho −0.334, p=0.005), and a positive correlation with BMI z-score (Spearman rho 0.354, p=0.009). Conclusion Circulating NGAL, MMP-9 levels may prove useful as surrogate biomarkers to creatinine, GFR and albumin excretion rate for early detection of kidney injury, inflammation or endothelial dysfunction and cardiovascular complications in children and adolescents with T1DM or obesity. Children with obesity may have impaired inflammation status, kidney and endothelial function to a higher degree compared to children with T1DM, which may suggest that obesity may impose a greater health burden than T1DM, at least during childhood or the first years after T1DM diagnosis.

Aqueous humor proteomics analyzed by bioinformatics and machine learning in PDR cases versus controls

BackgroundTo comprehend the complexities of pathophysiological mechanisms and molecular events that contribute to proliferative diabetic retinopathy (PDR) and evaluate the diagnostic value of aqueous humor (AH) in monitoring the onset of PDR.MethodsA cohort containing 16 PDR and 10 cataract patients and another validation cohort containing 8 PDR and 4 cataract patients were studied. AH was collected and subjected to proteomics analyses. Bioinformatics analysis and a machine learning-based pipeline called inference of biomolecular combinations with minimal bias were used to explore the functional relevance, hub proteins, and biomarkers.ResultsDeep profiling of AH proteomes revealed several insights. First, the combination of SIAE, SEMA7A, GNS, and IGKV3D-15 and the combination of ATP6AP1, SPARCL1, and SERPINA7 could serve as surrogate protein biomarkers for monitoring PDR progression. Second, ALB, FN1, ACTB, SERPINA1, C3, and VTN acted as hub proteins in the profiling of AH proteomes. SERPINA1 was the protein with the highest correlation coefficient not only for BCVA but also for the duration of diabetes. Third, “Complement and coagulation cascades” was an important pathway for PDR development.ConclusionsAH proteomics provides stable and accurate biomarkers for early warning and diagnosis of PDR. This study provides a deep understanding of the molecular mechanisms of PDR and a rich resource for optimizing PDR management.

Test characteristics of glycated albumin in the diagnosis of gestational diabetes mellitus

This study determined the test characteristics of glycated albumin in the diagnosis of gestational diabetes mellitus. The gold standard for diagnosing gestational diabetes mellitus is the oral glucose tolerance test which requires patient preparation, drinking of glucose solution, and multiple sample collections. A possible alternative biomarker for the diagnosis of gestational diabetes is glycated albumin does not require patient preparation and only one sample is collected. Glycated albumin levels are higher among Black Americans than in Caucasians.The study involved 200 pregnant women attending the antenatal clinic at the University of Port Harcourt Teaching Hospital. The diagnosis of gestational diabetes mellitus was made using the World Health Organization 2013 diagnostic criteria. The test characteristics of glycated albumin were determined using the area under the curve of the receiver operator characteristic curve, sensitivity, specificity, positive predictive value, and negative predictive value. The prevalence of gestational diabetes mellitus was 9.0%. The area under the receiver operator characteristic curve for glycated albumin was 0.8 (95% CI 0.7-0.9; p=0.0001). The sensitivity and specificity of glycated albumin were 83.3% and 86.8% respectively. The positive predictive value was 38.5% and the negative predictive value was 98.1%. Glycated albumin has high sensitivity, specificity, and negative predictive values and therefore, can be used as a preliminary test for gestational diabetes mellitus.

Exploring the Relationship Between Sod1, 2 And 3 Gene Polymorphisms With Post-Covid19 Symptoms

The coronavirus disease 19 (COVID-19) has become a challenge for the media world. Even though they have been declared cured, some Covid-19 survivors still have health complaints. Abnormal symptoms, signs, or clinical parameters that persist two weeks or more after the onset of COVID-19 and do not return to their initial healthy state are potentially considered long-term effects of the disease. Although such changes are primarily reported in people with severe and critical illness, lasting effects also occur in individuals with mild infections that do not require hospitalization. This study aims to explore the role of antioxidants on the pathogenesis of Covid19 and its relationship with SOD1, 2 and 3 genomic variations. Getting alternative biomarkers for long covid19 detection. Research Method: The research sample is blood and questionnaires that will be taken from respondents affected by Covid19 a maximum of 6 months before data collection is held. Furthermore, DNA isolation, DNA amplification, cutting with restriction enzymes, and DNA band documentation with gel electrophoresis will be carried out. Symptoms related to systemic are the most common symptoms found in respondents with Long Covid19. A total of 8 respondents had systemic related symptoms, namely weakness, lethargy and sweating, while skin-related complaints were found in three respondents and one respondent had lung-related complaints. The average SOD activity value of respondents was 2.19 U/ml. In this study, more symptoms of long COVID-19 were found associated with systemic and cardiovascular symptoms. The complaints were not differentiated by the sex of the respondents. The output draft will be processed immediately after getting other results.