Biomarker-based Assessment Research Articles

Story recall performance and AT classification via positron emission tomography: A comparison of logical memory and Craft Story 21

BackgroundEarly detection of Alzheimer's disease (AD) is one of the critical components of the global response to the growing dementia crisis. Analysis of serial position performance in story recall tests has yielded sensitive metrics for the prediction of AD at low cost. In this study, we examined whether serial position markers in two story recall tests (the logical memory test, LMT, and the Craft Story 21 test, CST) were sensitive to cross-sectional biomarker-based assessment of in vivo neuropathology. MethodsParticipants were selected from the Wisconsin Registry of Alzheimer's Prevention (n = 288; WRAP) and the Alzheimer's Disease Research Center (n = 156; ADRC), both from the University of Wisconsin–Madison. Average age at PET was 68.9 (6.7) and 67.0 (8.0), respectively. Data included tau and PiB PET, and LMT for WRAP participants and CST for ADRC participants. Two sets of Bayesian analyses (logistic regressions and ANCOVAs) were conducted within each cohort, separately. ResultsResults indicated that the A+T+ classification was best predicted, cross-sectionally, by the recency ratio (Rr), indexing how much of the end of the story was forgotten between initial learning and delayed assessment. Rr outperformed traditional scores and discriminated between A+T+ and A+T−/A-T-, in both cohorts. ConclusionsOverall, this study confirms that serial position analysis of LMT and CST data, and particularly Rr as an index of recency loss, is a valuable tool for the identification of in vivo tau pathology in individuals free of dementia. Diagnostic considerations are discussed.

Genome scale metabolic network modelling for metabolic profile predictions.

Metabolic profiling (metabolomics) aims at measuring small molecules (metabolites) in complex samples like blood or urine for human health studies. While biomarker-based assessment often relies on a single molecule, metabolic profiling combines several metabolites to create a more complex and more specific fingerprint of the disease. However, in contrast to genomics, there is no unique metabolomics setup able to measure the entire metabolome. This challenge leads to tedious and resource consuming preliminary studies to be able to design the right metabolomics experiment. In that context, computer assisted metabolic profiling can be of strong added value to design metabolomics studies more quickly and efficiently. We propose a constraint-based modelling approach which predicts in silico profiles of metabolites that are more likely to be differentially abundant under a given metabolic perturbation (e.g. due to a genetic disease), using flux simulation. In genome-scale metabolic networks, the fluxes of exchange reactions, also known as the flow of metabolites through their external transport reactions, can be simulated and compared between control and disease conditions in order to calculate changes in metabolite import and export. These import/export flux differences would be expected to induce changes in circulating biofluid levels of those metabolites, which can then be interpreted as potential biomarkers or metabolites of interest. In this study, we present SAMBA (SAMpling Biomarker Analysis), an approach which simulates fluxes in exchange reactions following a metabolic perturbation using random sampling, compares the simulated flux distributions between the baseline and modulated conditions, and ranks predicted differentially exchanged metabolites as potential biomarkers for the perturbation. We show that there is a good fit between simulated metabolic exchange profiles and experimental differential metabolites detected in plasma, such as patient data from the disease database OMIM, and metabolic trait-SNP associations found in mGWAS studies. These biomarker recommendations can provide insight into the underlying mechanism or metabolic pathway perturbation lying behind observed metabolite differential abundances, and suggest new metabolites as potential avenues for further experimental analyses.

Higher Renal Net Acid Excretion, but Not Higher Phosphate Excretion, during Childhood and Adolescence Associates with the Circulating Renal Tubular Injury Marker Interleukin-18 in Adulthood.

High dietary phosphorus intake (P-In) and high acid loads may adversely affect kidney function. In animal models, excessive phosphorus intake causes renal injury, which, in humans, is also inducible by chronic metabolic acidosis. We thus examined whether habitually high P-In and endogenous acid production during childhood and adolescence may be early indicators of incipient renal inflammatory processes later in adulthood. P-In and acid-base status were longitudinally and exclusively determined by biomarker-based assessment in 277 healthy children, utilizing phosphate and net acid excretion (NAE) measurements in 24 h urine samples repeatedly collected between the ages of 3 and 17 years. Standard deviation scores (by sex and age) were calculated for anthropometric data and for the urinary biomarkers available within age range 3-17 years. Multivariable linear regression was used to analyze the relations of phosphate excretion and NAE with the adulthood outcome circulating interleukin-18 (IL-18), a marker of inflammation and kidney dysfunction. After adjusting for growth- and adulthood-related covariates and pro-inflammatory biomarkers to rule out confounding by non-renal inflammatory processes, regression models revealed a significant positive relationship of long-term NAE (p = 0.01), but not of long-term phosphate excretion with adult serum IL-18. Similar significant positive regression results were obtained after replacing NAE with 24 h urinary ammonium excretion as the exposition variable. Our results suggest that even moderate elevations in renal ammonia production, as caused by habitually higher acid loading during growth, may affect the intrarenal pro-inflammatory system in the long-term, known to be boosted by acidosis-induced raised ammoniagenesis.

Low-flow in aortic valve stenosis patients with reduced ejection fraction does not depend on left ventricular function.

Patients with severe aortic stenosis (AS) and reduced left ventricular ejection fraction (LVEF) can be distinguished into high- (HG) and low-gradient (LG) subgroups. However, less is known about their characteristics and underlying (pathophysiological) hemodynamic mechanisms. 98 AS patients with reduced LVEF were included. Subgroup characteristics were analyzed by a multimodal approach using clinical and histological data, next-generation sequencing (NGS) and applying echocardiography as well as cardiovascular magnetic resonance (CMR) imaging. Biopsy samples were analyzed with respect to fibrosis and mRNA expression profiles. 40 patients were classified as HG-AS and 58 patients as LG-AS. Severity of AS was comparable between the subgroups. Comparison of both subgroups revealed no differences in LVEF (p = 0.1), LV mass (p = 0.6) or end-diastolic LV diameter (p = 0.12). Neither histological (HG: 23.2% vs. LG: 25.6%, p = 0.73) and circulating biomarker-based assessment (HG: 2.6 ± 2.2% vs. LG: 3.2 ± 3.1%; p = 0.46) of myocardial fibrosis nor global gene expression patterns differed between subgroups. Mitral regurgitation (MR), atrial fibrillation (AF) and impaired right ventricular function (MR: HG: 8% vs. LG: 24%; p < 0.001; AF: HG: 30% vs. LG: 51.7%; p = 0.03; RVSVi: HG 36.7 vs. LG 31.1ml/m2, p = 0.045; TAPSE: HG 20.2 vs. LG 17.3mm, p = 0.002) were more frequent in LG-AS patients compared to HG-AS. These pathologies could explain the higher mortality of LG vs. HG-AS patients. In patients with low-flow severe aortic stenosis, low transaortic gradient and cardiac output are not primarily due to LV dysfunction or global changes in gene expression, but may be attributed to other additional cardiac pathologies like mitral regurgitation, atrial fibrillation or right ventricular dysfunction. These factors should also be considered during planning of aortic valve replacement.

Adverse outcome pathways as a tool for optimization of the biomarker-based assessment of pollutant toxicity: A case study of cadmium in the blue mussels Mytilus edulis

Technogenic metals like cadmium (Cd) are discharged into the environment posing significant ecological risks to wildlife and contributing to a decline in biodiversity. Recent developments in toxicity testing and environmental risk assessment have shifted the focus towards prioritizing biological effects. To ensure effective environmental risk assessment, it is essential to develop sensitive sub-organismal biomarkers correlated with ecologically relevant organismal-level responses. Our study proposes a novel approach to enhance the evaluation of biomarker-based toxicity based on adverse outcome pathways (AOP) concept. We exposed the blue mussels M. edulis to Cd concentrations ranging from 200 to 600 µg l−1 (10–30 % of LC50) for 14 days, and assessed a comprehensive panel of 26 biomarkers related to molecular initiation events (Cd uptake and binding), key cellular events (oxidative stress, metabolic disturbances, and cytotoxicity), and adverse organismal outcomes (survival, energy metabolism, and reef-building capacity) in the putative AOP of Cd. Tissue Cd burdens increased linearly with exposure concentrations in the mussels. Although the condition index of the mussels remained unaffected, their biofiltration activity was suppressed at the highest Cd concentration. The negative effects of Cd exposure on the mussels' feeding were linked to reduced energetic scope for growth, impaired byssus production, increased hemocyte mortality, and altered functional traits of hemocytes. Additionally, Cd exposure induced oxidative stress, as evidenced by lower total antioxidant capacity and thiol pool, along with increased lipid peroxidation, leading to enhanced autophagy. Through Random Forest Analysis, we identified a minimal set of sensitive Cd effect biomarkers, including hemocyte mortality (contributing ∼0.32 to classification accuracy), hemocyte acid phosphatase activity, nitric oxide and metallothionein levels in the digestive gland, and whole-organism clearance rate and scope for growth (each contributing ∼0.02–0.08 to classification accuracy). These biomarkers collectively achieved a high accuracy of 90–100 % in distinguishing between control and Cd-exposed groups. Increasing the number of biomarkers did not improve classification accuracy. These findings suggest that using a smaller number of optimized biomarkers based on Adverse Outcome Pathways (AOP) can enhance the assessment of contaminant-induced negative effects while reducing testing costs in environmental risk assessments.

Medical care and biomarker-based assessment of mortality in two cohorts of patients with chronic coronary syndrome 10 years apart

BackgroundThis study aimed to describe the characteristics and mortality of two cohorts of patients with chronic coronary syndrome (CCS) recruited with identical study designs in the same rehabilitation clinics but approximately 10 years apart.MethodsThe KAROLA cohorts included patients with CCS participating in an inpatient cardiac rehabilitation programme in Germany (KAROLA-I: years 1999/2000, KAROLA-II: 2009–2011). Blood samples and information on sociodemographic factors, lifestyle, and medical treatment were collected at baseline, at the end of rehabilitation, and after one year of follow-up. A biomarker-based risk model (ABC-CHD model) and Cox regression analysis were used to evaluate cardiovascular (CV) and non-CV mortality risk.ResultsWe included 1130 patients from KAROLA-I (mean age 58.7 years, 84.4% men) and 860 from KAROLA-II (mean age 60.4 years, 83.4% men). Patients in the KAROLA-I cohort had significantly higher concentrations of CV biomarkers and fewer patients were taking CV medications, except for statins. The biomarker-based ABC-CHD model provided a higher estimate of CV death risk for patients in the KAROLA-I cohort (median 3-year risk, 3.8%) than for patients in the KAROLA-II cohort (median 3-year risk, 2.7%, p-value for difference < 0.001). After 10 years of follow-up, 91 (8.1%) patients in KAROLA-I and 45 (5.2%) in KAROLA-II had died from a CV event.ConclusionsAdvances in disease management over the past 20 years may have led to modest improvements in pharmacological treatment during cardiac rehabilitation and long-term outpatient care for patients with CCS. However, modifiable risk factors such as obesity have increased in the more recent cohort and should be targeted to further improve the prognosis of these patients.

Biomarker-Based Assessment Model for Detecting Sepsis: A Retrospective Cohort Study.

The concept of the quick sequential organ failure assessment (qSOFA) simplifies sepsis detection, and the next SOFA should be analyzed subsequently to diagnose sepsis. However, it does not include the concept of suspected infection. Thus, we simply developed a biomarker-based assessment model for detecting sepsis (BADS). We retrospectively reviewed the electronic health records of patients admitted to the intensive care unit (ICU) of a 2000-bed university tertiary referral hospital in South Korea. A total of 989 patients were enrolled, with 77.4% (n = 765) of them having sepsis. The patients were divided into a ratio of 8:2 and assigned to a training and a validation set. We used logistic regression analysis and the Hosmer-Lemeshow test to derive the BADS and assess the model. BADS was developed by analyzing the variables and then assigning weights to the selected variables: mean arterial pressure, shock index, lactate, and procalcitonin. The area under the curve was 0.754, 0.615, 0.763, and 0.668 for BADS, qSOFA, SOFA, and acute physiology and chronic health evaluation (APACHE) II, respectively, showing that BADS is not inferior in sepsis prediction compared with SOFA. BADS could be a simple scoring method to detect sepsis in critically ill patients quickly at the bedside.

On gaps of clinical diagnosis of dementia subtypes: A study of Alzheimer's disease and Lewy body disease.

Alzheimer's disease (AD) and Lewy body disease (LBD) are the two most common neurodegenerative dementias and can occur in combination (AD+LBD). Due to overlapping biomarkers and symptoms, clinical differentiation of these subtypes could be difficult. However, it is unclear how the magnitude of diagnostic uncertainty varies across dementia spectra and demographic variables. We aimed to compare clinical diagnosis and post-mortem autopsy-confirmed pathological results to assess the clinical subtype diagnosis quality across these factors. We studied data of 1,920 participants recorded by the National Alzheimer's Coordinating Center from 2005 to 2019. Selection criteria included autopsy-based neuropathological assessments for AD and LBD, and the initial visit with Clinical Dementia Rating (CDR) stage of normal, mild cognitive impairment, or mild dementia. Longitudinally, we analyzed the first visit at each subsequent CDR stage. This analysis included positive predictive values, specificity, sensitivity and false negative rates of clinical diagnosis, as well as disparities by sex, race, age, and education. If autopsy-confirmed AD and/or LBD was missed in the clinic, the alternative clinical diagnosis was analyzed. In our findings, clinical diagnosis of AD+LBD had poor sensitivities. Over 61% of participants with autopsy-confirmed AD+LBD were diagnosed clinically as AD. Clinical diagnosis of AD had a low sensitivity at the early dementia stage and low specificities at all stages. Among participants diagnosed as AD in the clinic, over 32% had concurrent LBD neuropathology at autopsy. Among participants diagnosed as LBD, 32% to 54% revealed concurrent autopsy-confirmed AD pathology. When three subtypes were missed by clinicians, "No cognitive impairment" and "primary progressive aphasia or behavioral variant frontotemporal dementia" were the leading primary etiologic clinical diagnoses. With increasing dementia stages, the clinical diagnosis accuracy of black participants became significantly worse than other races, and diagnosis quality significantly improved for males but not females. These findings demonstrate that clinical diagnosis of AD, LBD, and AD+LBD are inaccurate and suffer from significant disparities on race and sex. They provide important implications for clinical management, anticipatory guidance, trial enrollment and applicability of potential therapies for AD, and promote research into better biomarker-based assessment of LBD pathology.

Environmental heat exposure and implications on renal health of pediatric communities in the dry climatic zone of Sri Lanka: An approach with urinary biomarkers.

Prolonged heat exposure during outdoor physical exertion can result in adverse renal health outcomes, and it is also supposed to be a driver of chronic kidney disease of uncertain etiology (CKDu) in tropical regions. School students are more likely to experience high heat exposure during outdoor sports practices, and the current knowledge on potential renal health outcomes associated with heat exposure carries many knowledge gaps. Hence, the present study aimed to perform biomarker-based assessment of the likelihood of pediatric renal injury focusing the communities in the dry climatic zone in Sri Lanka, where it prevails relatively harsh climate and high prevalence of CKDu. School students who engaged in regular outdoor sports practices (high-heat exposure), and an age-matched control of students who did not engage in sports practices (low-heat exposure) from four educational zones: Padavi Sripura (N = 159) and Medirigiriya (N = 171), Uhana (N = 165) and Thanamalwila (N = 169) participated in this cross-sectional study representing CKDu endemic and non-endemic regions. Effective temperature (ET), wet-bulb globe temperature (WBGT), heat index (HI) and humidex were used for comparison of thermal comfort in the environment. The intensity of environmental heat measured by thermal comfort indices showed no significant difference (p > 0.05) among the study regions. Urinary kidney injury molecule (KIM-1) and albumin-creatinine ratio (ACR) in participants with high heat exposure did not differ significantly from those in the control groups in the four study zones, where urinary neutrophil gelatinase-associated lipocalin showed substantial differences in some groups. Irrespective of heat exposure, increased KIM-1 excretion was observed (p < 0.01) in participants of CKDu endemic regions compared to those in non-endemic areas. Within the context of our findings, there is no plausibly strong evidence to establish potential association of heat exposure with the likelihood of developing renal injury or abnormal renal outcomes in dry zone school students in Sri Lanka.

Salinity variation modulates cellular stress response to ZnO nanoparticles in a sentinel marine bivalve, the blue mussel Mytilussp.

Zinc oxide nanoparticles are released into marine environments from industrial, medical and consumer uses sparking concerns about their potential ecotoxicological effects. Ecological hazard assessment of nZnO in marine ecosystems is hindered by the lack of understanding of the potential interactive effects of nZnO toxicity with other common abiotic stressors, such as salinity fluctuations, in marine organisms. To close this gap in our knowledge, we carried out a comprehensive biomarker-based assessment of the combined effects of salinity and nZnO in a sentinel marine bivalve, the blue mussels Mytilus edulis. The mussels were exposed for 21 days to clean seawater (control), an environmentally relevant concentration (100 μg Zn l−1) of nZnO or dissolved Zn (to identify the toxic effects attributable to Zn2+ toxicity) under the normal (15), low (5) and fluctuating (5–15) salinity regimes. The selected molecular and biochemical markers focused on the oxidative stress, apoptosis, detoxification system and inflammation in the gills and the digestive gland of the mussels. Biomarker analysis showed different effects of nZnO and dissolved Zn on biomarkers of oxidative stress, xenobiotic detoxification and apoptosis but similar effects of both pollutants on the levels of metallothioneins and inflammatory markers. Exposure to nZnO led to elevated levels of lipid peroxidation, upregulation of p53 and p38 stress kinases and apoptosis-related genes, most notably in the gills. Exposure to dissolved Zn led to accumulation of protein carbonyls and activated redox-sensitive detoxification enzymes (NADPH-P450 reductase and glutathione-S-transferase) in the mussels. The ambient salinity had significant effects the cellular adverse effects of nZnO in the mussels. The nZnO-induced cellular stress was detectable under the normal (15) and fluctuating (5–15) salinity conditions in the studied brackish water population of the mussels. At low salinity (5), nZnO toxicity signal was almost completely dampened. These findings indicate that chronic osmotic stress close to the tolerance limits of M. edulis prevails over the effects of the environmentally relevant nZnO and dissolved Zn concentrations in combined exposures. These stressor interactions might ameliorate the cellular toxicity of nZnO in the mussels but limit applicability of cellular stress biomarkers for detecting the toxic effects of nanopollutants in low salinity habitats.

Biomarker-Based Assessment for Infectious Risk Before and After Heart Transplantation.

Purpose of ReviewSurvival outcomes for heart transplant recipients have improved in recent decades, but infection remains a significant cause of morbidity and mortality. In this review, we discuss several biological markers, or biomarkers, that may be used to monitor immunologic status in this patient population.Recent FindingsWhile modest, data on the utility of immune biomarkers in heart transplant recipients suggest correlation between low level of immune response and increased infection risk. More novel assays, such as the detection of circulating levels of pathogen cell-free DNA in plasma and the use of Torque teno virus load as a surrogate for net state of immunosuppression, have potential to be additional important biomarkers.SummaryBiomarker approaches to individualize immunosuppression therapy among heart transplant recipients is a promising area of medicine. However, additional studies are needed to inform the optimal protocol in which to incorporate these biomarkers into clinical practice.

Novel Bruton's tyrosine kinase inhibitor remibrutinib: Assessment of drug-drug interaction potential as a perpetrator of cytochrome P450 enzymes and drug transporters and the impact of covalent binding on possible drug interactions

Pharmacokinetic drug-drug interactions (DDIs) are investigated to ensure safety for patients receiving concomitant medications. Here, we present a strategy to characterise the DDI potential of remibrutinib, as an inhibitor of drug-metabolising enzymes and drug transporters, and as an inducer. Initial in vitro studies were performed, followed by a biomarker-based assessment of induction in a first in human study, concluded by a clinical study to verify initial results. Remibrutinib is a covalent inhibitor of Bruton's Tyrosine kinase (BTKi) carrying a reactive acrylamide moiety (warhead), thus the potential contribution of covalent binding (off-target) to observed interactions was investigated as this could lead to prolonged and more potent drug interactions. DDI assessment was focused on the putative inhibition of key metabolic enzymes (Cytochrome P450, CYP), drug transporters and a potential effect on oral contraceptives (OC) by induction of enzymes that are involved in their clearance (CYP3A4). The impact of covalent binding was assessed by synthesising an identical reference molecule but with an inactivated warhead. An interaction potential of limited clinical relevance was revealed for remibrutinib for CYP enzymes and drug transporters. The reactive warhead of remibrutinib had no impact on CYP enzyme and transporter inhibition, including time-dependent inhibition of CYP3A4, but may increase the induction potential of remibrutinib. Observed inhibition of metabolic enzymes indicated that remibrutinib is a weak inhibitor of CYP3A4 and CYP2C9 and is not a clinically relevant inhibitor of uptake and efflux transporters, except for intestinal P-glycoprotein and breast cancer resistance protein inhibition. OC may be safely administered and are effective when given with pharmacologically relevant doses of remibrutinib.

Adipogenesis of ear mesenchymal stem cells (EMSCs): adipose biomarker-based assessment of genetic variation, adipocyte function, and brown/brite differentiation.

Ear mesenchymal stem cells (EMSCs) have been investigated to differentiate into adipocytes, chondrocytes, and muscle cells in vitro. However, the factors controlling adipogenesis of this stem cell population in vitro, function, and type of adipocytes raised from them are still unclear. Here we found that genetics have a modest effect on adipogenic capacity of EMSCs. Adipocytes differentiated from EMSCs have a potential function in lipid metabolism as indicated by expression of lipogenic genes and this function of EMSC adipocytes is regulated by genetics. EMSCs failed to be differentiated into brite/brown adipocytes due to their lack of a thermogenic program, but adipocytes raised from EMSCs showed a fate of white adipocytes. Overall, our data suggest that EMSCs differentiate into functional white adipocytes in vitro and this is genetic-dependent.

Biomarker-based assessment of collagen cross-linking identifies patients at risk of heart failure more likely to benefit from spironolactone effects on left atrial remodelling. Insights from the HOMAGE clinical trial.

The HOMAGE randomized trial found that spironolactone reduced left atrial volume index (LAVI), E:A ratio, and a marker of collagen type I synthesis (procollagen type I C-terminal propeptide) in patients at risk of heart failure (HF). Previous trials showed that patients with HF, preserved ejection fraction and low serum collagen type I C-terminal telopeptide to matrix metalloproteinase-1 ratio (CITP:MMP-1), associated with high collagen cross-linking, had less improvement in diastolic function with spironolactone. We evaluated the interaction between serum CITP:MMP-1 and spironolactone on cardiac function in the HOMAGE trial. Patients at risk of HF were randomized to spironolactone (n=260) or not (n=255). Blood sampling and echocardiography were done at baseline, one and nine months. CITP:MMP-1 was used as an indirect measure of collagen cross-linking. Higher baseline CITP:MMP-1 (i.e. lower collagen cross-linking) was associated with greater reductions in LAVI with spironolactone at both one (p=0.003) and nine (p=0.01) months, but no interaction was observed for E:A ratio. Spironolactone reduced LAVI after one and nine months only for those patients in the third tertile of CITP:MMP-1 (estimated lowest collagen cross-linking) [mean differencesspiro/control : -1.77 (95% confidence interval, CI -2.94 to -0.59) and -2.52 (95% CI -4.46 to -0.58) mL/m2 ; interaction pacross-tertiles =0.005; interaction pthird tertile =0.008] with a similar trend for N-terminal pro-B-type natriuretic peptide which was consistently reduced by spironolactone only in the lowest collagen cross-linking tertile [mean differencesspiro/control : -0.47 (95% CI -0.66 to -0.28) and -0.31 (95% CI -0.59 to -0.04) ng/L; interaction pacross-tertiles =0.09; interaction pthird tertile < 0.001]. These findings suggest that, for patients at risk of HF, the effects of spironolactone on left atrial remodelling may be more prominent in patients with less collagen cross-linking (indirectly assessed by serum CITP:MMP-1).

Biomarker-based assessment of sublethal toxicity of organic UV filters (ensulizole and octocrylene) in a sentinel marine bivalve Mytilus edulis

The global occurrence of organic UV filters in the marine environment is of increasing ecotoxicological concern. Here we assessed the toxicity of UV filters ensulizole and octocrylene in the blue mussels Mytilus edulis exposed to 10 or 100 μg l−1 of octocrylene and ensulizole for two weeks. An integrated battery of biochemical and molecular biomarkers related to xenobiotics metabolism and cellular toxicity (including oxidative stress, DNA damage, apoptosis, autophagy and inflammation) was used to assess the toxicity of these UV filters in the mussels. Octocrylene (but not ensulizole) accumulated in the mussel tissues during the waterborne exposures. Both studied UV filters induced sublethal toxic effects in M. edulis at the investigated concentrations. These effects involved induction of oxidative stress, genotoxicity (indicated by upregulation of DNA damage sensing and repair markers), upregulation of apoptosis and inflammation, and dysregulation of the xenobiotic biotransformation system. Octocrylene induced cellular stress in a concentration-dependent manner, whereas ensulizole appeared to be more toxic at the lower (10 μg l−1) studied concentration than at 100 μg l−1. The different concentration-dependence of sublethal effects and distinct toxicological profiles of ensulizole and octocrylene show that the environmental toxicity is not directly related to lipophilicity and bioaccumulation potential of these UV filters and demonstrate the importance of using bioassays for toxicity assessment of emerging pollutants in coastal marine ecosystems.

Salinity-dependent effects of ZnO nanoparticles on bioenergetics and intermediate metabolite homeostasis in a euryhaline marine bivalve, Mytilus edulis

Engineered nanoparticles including ZnO nanoparticles (nZnO) are important emerging pollutants in aquatic ecosystems creating potential risks to coastal ecosystems and associated biota. The toxicity of nanoparticles and its interaction with the important environmental stressors (such as salinity variation) are not well understood in coastal organisms and require further investigation. Here, we examined the interactive effects of 100 μg l−1 nZnO or dissolved Zn (as a positive control for Zn2+ release) and salinity (normal 15, low 5, and fluctuating 5–15) on bioenergetics and intermediate metabolite homeostasis of a keystone marine bivalve, the blue mussel Mytilus edulis from the Baltic Sea. nZnO exposures did not lead to strong disturbances in energy or intermediate metabolite homeostasis regardless of the salinity regime. Dissolved Zn exposures suppressed the mitochondrial ATP synthesis capacity and coupling as well as anaerobic metabolism and modified the free amino acid profiles in the mussels indicating that dissolved Zn is metabolically more damaging than nZnO. The environmental salinity regime strongly affected metabolic homeostasis and altered physiological and biochemical responses to nZnO or dissolved Zn in the mussels. Exposure to low (5) or fluctuating (5–15) salinity affected the physiological condition, energy metabolism and homeostasis, as well as amino acid metabolism in M. edulis. Generally, fluctuating salinity (5–15) appeared bioenergetically less stressful than constantly hypoosmotic stress (salinity 5) in M. edulis indicating that even short (24 h) periods of recovery might be sufficient to restore the metabolic homeostasis in this euryhaline species. Notably, the biological effects of nZnO and dissolved Zn became progressively less detectable as the salinity stress increased. These findings demonstrate that habitat salinity must be considered in the biomarker-based assessment of the toxic effects of nanopollutants on coastal organisms.

The Biomarker-Based Prediction Rule for Risk Stratification in Patients with Acute Coronary Syndromes: A Development and Validation Study: Results from BIPass Registry

Background: Patients with acute coronary syndromes (ACS), the acute and severe manifestation of coronary artery disease, are highly heterogeneous in their risk for recurrent cardiovascular events. Several biomarkers carry prognostic information for cardiovascular events. However, instruments integrating clinical characteristics and biomarkers to accurately predict the occurrence of cardiovascular events, thus facilitating individualization of ACS care are lacking. Methods: Using data from 4,407 ACS patients enrolled in a prospective and multicenter Chinese cohort, BIomarker-based Prognostic Assessment for Patients with Stable Angina and Acute Coronary Syndromes (BIPass) registry, we developed a risk model to predict the major adverse cardiovascular events (MACE, defined as the composite of cardiac death, myocardial infarction [MI] and ischemic stroke) within 12 months after hospital admission. Validation was performed in 1,409 patients from an independent cohort. Findings: Over 12 months, MACE occurred in 196 patients (incidence rate 5·07 per 100 person- years, 95% CI [4·42-5·81]/100 person-years). Predictors of MACE included N-terminal pro-B-type natriuretic peptide (NT-proBNP) and growth differentiation factor 15 (GDF-15) biomarkers, and clinical variables of age, hypertension, previous MI, previous stroke, Killip class, and heart rate. The developed BIPass risk model displayed excellent discriminative capability (C statistic 0·82, 95% CI 0·78-0·86) and calibration, outperformed GRACE and TIMI risk scores. Similar discrimination, calibration and clinical decision curves were confirmed in the validation cohort. Cumulative rates for MACE demonstrated good separation in BIPass predicted low, intermediate and high-risk groups in both the development and validation cohorts. The BIPass risk model consistently provided enhanced predictions of MACE over a broad-spectrum of ACS and across clinically important subgroups (i.e. age, diagnosis, coronary revascularization, medications). Interpretation: BIPass risk model integrating clinical variables and biomarkers measured at admission is useful to predict risk of 12-month cardiovascular events in ACS, which offers the potential to identify higher-risk patients as candidates for early aggressive treatments. Trial Registration: NCT04044066 Funding Statement: National Key R＆D Program of China (2017YFC0908700, 2017YFC0908703), National S&T Fundamental Resources Investigation Project (2018FY100600, 2018FY100602), Taishan Pandeng Scholar Program of Shandong Province (tspd20181220), Taishan Young Scholar Program of Shandong Province (tsqn20161065, tsqn201812129). Declaration of Interests: None. Ethics Approval Statement: The BIPass study was approved by the research ethics committee of Qilu Hospital, Shandong University which was accepted by all the collaborating hospitals.

Abstract 15018: Incremental Prognostic Utility of Adverse Right Ventricular Remodeling in Patients With Covid-19 Infection: A Multicenter Cohort Study

Introduction: COVID-19 is a growing pandemic that confers augmented risk for RV dysfunction and dilation; prognostic utility of adverse RV remodeling in COVID-19 patients is uncertain. Hypothesis: To test whether adverse RV remodeling (dysfunction/dilation) predicts COVID-19 prognosis independent of clinical and biomarker risk stratification. Methods: Consecutive adult COVID-19 patients undergoing clinical transthoracic echo at three NYC hospitals were studied; images were analyzed by a central core lab blinded to clinical and biomarker data. Results: Of 510 patients (64±14 years, 66% male) studied, RV dilation and dysfunction were present in 35% and 15%, respectively. RV dysfunction increased stepwise in relation to RV chamber size (p=0.015). During inpatient follow-up (median 20 days), there were 165 deaths (32%) and 229 discharges (45%). RV dysfunction (HR 2.25 [CI 1.26-3.98]; p=0.006) and dilation (HR 1.82 [CI 1.11-2.97]; p=0.02) each independently conferred mortality risk. Patients without adverse RV remodeling were more likely to survive to hospital discharge (HR 1.39 [CI 1.01-1.90]; p=0.04). Figure 1A demonstrates prognostic utility for each echo-quantified RV parameter (p&lt;0.05) in relation to all-cause mortality. Figure 1B shows RV indices to provide risk stratification beyond biomarker strata, as evidenced by greatest risk for death among patients with both adverse RV remodeling and positive biomarkers, and lesser risk among patients with isolated biomarker elevations. RV remodeling conferred over a 2-fold increase in mortality risk (HR 2.68 [CI 1.70-4.23]; p&lt;0.001), which remained significant when controlling for biomarker elevations, irrespective of whether analyses were performed using troponin, D-dimer, or ferritin. (p&lt;0.01). Conclusions: Adverse RV remodeling predicts mortality in COVID-19 independent of standard clinical and biomarker-based assessment.

Prognostic Utility of Right Ventricular Remodeling Over Conventional Risk Stratification in Patients With COVID-19

BackgroundCoronavirus disease 2019 (COVID-19) is a growing pandemic that confers augmented risk for right ventricular (RV) dysfunction and dilation; the prognostic utility of adverse RV remodeling in COVID-19 patients is uncertain. ObjectivesThe purpose of this study was to test whether adverse RV remodeling (dysfunction/dilation) predicts COVID-19 prognosis independent of clinical and biomarker risk stratification. MethodsConsecutive COVID-19 inpatients undergoing clinical transthoracic echocardiography at 3 New York City hospitals were studied; images were analyzed by a central core laboratory blinded to clinical and biomarker data. ResultsIn total, 510 patients (age 64 ± 14 years, 66% men) were studied; RV dilation and dysfunction were present in 35% and 15%, respectively. RV dysfunction increased stepwise in relation to RV chamber size (p = 0.007). During inpatient follow-up (median 20 days), 77% of patients had a study-related endpoint (death 32%, discharge 45%). RV dysfunction (hazard ratio [HR]: 2.57; 95% confidence interval [CI]: 1.49 to 4.43; p = 0.001) and dilation (HR: 1.43; 95% CI: 1.05 to 1.96; p = 0.02) each independently conferred mortality risk. Patients without adverse RV remodeling were more likely to survive to hospital discharge (HR: 1.39; 95% CI: 1.01 to 1.90; p = 0.041). RV indices provided additional risk stratification beyond biomarker strata; risk for death was greatest among patients with adverse RV remodeling and positive biomarkers and was lesser among patients with isolated biomarker elevations (p ≤ 0.001). In multivariate analysis, adverse RV remodeling conferred a >2-fold increase in mortality risk, which remained significant (p < 0.01) when controlling for age and biomarker elevations; the predictive value of adverse RV remodeling was similar irrespective of whether analyses were performed using troponin, D-dimer, or ferritin. ConclusionsAdverse RV remodeling predicts mortality in COVID-19 independent of standard clinical and biomarker-based assessment.

The anserine to carnosine ratio: an excellent discriminator between white and red meats consumed by free-living overweight participants of the PREVIEW study.

Biomarkers of meat intake hold promise in clarifying the health effects of meat consumption, yet the differentiation between red and white meat remains a challenge. We measure meat intake objectively in a free-living population by applying a newly developed, three-step strategy for biomarker-based assessment of dietary intakes aimed to indicate if (1) any meat was consumed, (2) what type it was and (3) the quantity consumed. Twenty-four hour urine samples collected in a four-way crossover RCT and in a cross-sectional analysis of a longitudinal lifestyle intervention (the PREVIEW Study) were analyzed by untargeted LC-MS metabolomics. In the RCT, healthy volunteers consumed three test meals (beef, pork and chicken) and a control; in PREVIEW, overweight participants followed a diet with high or moderate protein levels. PLS-DA modeling of all possible combinations between six previously reported, partially validated, meat biomarkers was used to classify meat intake using samples from the RCT to predict consumption in PREVIEW. Anserine best separated omnivores from vegetarians (AUROC 0.94-0.97), while the anserine to carnosine ratio best distinguished the consumption of red from white meat (AUROC 0.94). Carnosine showed a trend for dose-response between non-consumers, low consumers and high consumers for all meat categories, while in combination with other biomarkers the difference was significant. It is possible to evaluate red meat intake by using combinations of existing biomarkers of white and general meat intake. Our results are novel and can be applied to assess qualitatively recent meat intake in nutritional studies. Further work to improve quantitation by biomarkers is needed.