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Abstract Background Oxidative stress is heavily implicated in the pathogenic process of Parkinson's disease. Varying capacity to detoxify radical oxygen species through induction of phase II antioxidant enzymes in substantia nigra may influence disease risk. Here, we hypothesize that variation in NFE2L2 and KEAP1, the genes encoding the two major regulators of the phase II response, may affect the risk of Parkinson's disease. Methods The study included a Swedish discovery case-control material (165 cases and 190 controls) and a Polish replication case-control material (192 cases and 192 controls). Eight tag single nucleotide polymorphisms representing the variation in NFE2L2 and three representing the variation in KEAP1 were chosen using HapMap data and were genotyped using TaqMan Allelic Discrimination. Results We identified a protective NFE2L2 haplotype in both of our European case-control materials. Each haplotype allele was associated with five years later age at onset of the disease (p = 0.001) in the Swedish material, and decreased risk of PD (p = 2 × 10-6), with an odds ratio of 0.4 (95% CI 0.3-0.6) for heterozygous and 0.2 (95% CI 0.1-0.4) for homozygous carriers, in the Polish material. The identified haplotype includes a functional promoter haplotype previously associated with high transcriptional activity. Genetic variation in KEAP1 did not show any associations. Conclusion These data suggest that variation in NFE2L2 modifies the Parkinson's disease process and provide another link between oxidative stress and neurodegeneration.

Introduction: Chest pain is one of the most common reasons for contacting the emergency medical services (EMS). It is difficult for EMS personnel to distinguish between patients suffering from a high-risk condition in need of prompt hospital care and patients suitable for non-conveyance. A vast majority of patients with chest pain are therefore transported to the emergency department (ED) for further investigation even if hospital care is not necessary. Improved prehospital assessment and risk stratification, thus accurately and safely identifying patients suitable for non-conveyance, could prevent unnecessary transport to the ED. This would reduce ED crowding and overburdening sparse EMS resources. It would thus also probably reduce healthcare costs. Little is known about the prehospital use of the 5th generation, i.e. high-sensitivity troponin analyses. The aim of this project is to develop an EMS decision support tool using high-sensitivity troponin I for risk assessment of chest pain patients., Methods and Analysis: This is a prospective, multicentre, cohort study including adult unselected EMS patients with chest pain. Data is being collected from 20 May 2023 to 31 December 2025, aiming to include at least 2,000 patients. High-sensitivity troponin I is being analysed bedside using Siemens Healthineers Atellica VTLi. In addition to prehospital troponin I, data is being collected on patient medical history, onset, vital signs, symptoms, ECG and diagnosis at hospital discharge. Several statistical analyses (random forest, logistic regression, gradient boosting) will be conducted to identify the best model for identifying patients with low-risk conditions suitable for non-conveyance., Ethics and Dissemination: The study has been approved by the Swedish Ethical Review Authority (Dnr 2022-01066-01 and 2022-06846-02). Patients are being informed about the study both orally and in writing. The results of the study will be published in a peer-reviewed journal and will be presented at national and/or international conferences., Registration Details: The study is registered at ClinicalTrials.gov (NCT05767619)., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objective: Plasma copeptin is a relatively new biomarker for evaluation of arginine vasopressin (AVP) secretion. The aim of this study was to test the diagnostic performance of copeptin in patients with polyuria-polydipsia syndrome., Design, Patients and Measurements: This was a prospective study where 88 patients with polyuria-polydipsia syndrome were evaluated with a water deprivation test (WDT). Weight, urine osmolality, urine specific gravity, and plasma copeptin were collected at baseline, after 8 h, and at termination of the WDT when one of the following had been reached: (i) >3% weight reduction, (ii) urine specific gravity >1.017 or urine osmolality >600 mOsm/kg, or (iii) intolerable adverse symptoms., Results: Of 88 patients (57 women), 21 (24%) were diagnosed with central diabetes insipidus (cDI), 5 (6%) with nephrogenic DI (nDI), and 62 (71%) with primary polydipsia (PP). Median (interquartile range) copeptin at baseline was 1.7 (1.4-2.5) pmol/L in cDI, 22 (18-65) pmol/L in nDI, and 2.7 (2-4) pmol/L in PP. After 8 h of WDT, the highest copeptin in patients with cDI was 4.0 pmol/L. In patients with PP: (i) 41 had urine osmolality <600 mOsm/kg, 7 (17%) of these had copeptin >4.0 pmol/L, (ii) 21 had urine osmolality ≥600 mOsm/kg, 14 (67%) of these had copeptin >4.0 pmol/L., Conclusions: Copeptin >4.0 pmol/L after an overnight WDT can be used to rule out cDI and copeptin ≥21 pmol/L at baseline to diagnose nDI. The diagnostic performance of copeptin in the context of the WDT is otherwise limited in the diagnostic work-up of patients with polyuria-polydipsia syndrome., (© 2024 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Plasma copeptin is a biomarker that reflects arginine vasopressin (AVP) secretion. In this study we measured copeptin during insulin tolerance test (ITT) in 65 patients referred to our department for evaluation of anterior pituitary function. Plasma for measurements of copeptin were collected at the start of the test and regurarly up to 120 minutes thereafter. Of 60 patients who developed significant hypoglycemia and were included in the analyses, 13 (22%) had corticotropic deficiency, 11 (18%) had thyreotropic deficiency, 33 (55%) had growth hormone deficiency and 4 (6%) had AVP deficieny (AVPD). Thirty-seven (62%) patients had at least one anterior pituitary deficiency. In patients without AVPD, median (range) copeptin increased from 4.5 pmol/L (1.3-33.0) to a maximum of 6.2 pmol/L (2.0-34.4; p<0.001). Baseline copeptin was similar in men and women, but maximal copeptin during ITT was higher in men. Copeptin concentrations were not affected by age, BMI, somatotropic, or corticotropic function. Copeptin concentrations were lower in patients with AVPD than patiets without AVPD, and in patients with thyrotropic deficiency, compared to patients with intact thyrotropic function, both at baseline and during ITT. In conclusion, copeptin increases significantly during insulin induced hypoglycemia but is of limited value in predicting anterior pituitary hormonal function., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The term "single-sample rule-out" refers to the ability of very low concentrations of high-sensitivity cardiac troponin (hs-cTn) on presentation to exclude acute myocardial infarction with high clinical sensitivity and negative predictive value. Observational and randomized studies have confirmed this ability. Some guidelines endorse use of a concentration of hs-cTn at the assay's limit of detection, while other studies have validated the use of higher concentrations, allowing this approach to identify a greater proportion of patients at low risk. In most studies, at least 30% of patients can be triaged with this approach. The concentration of hs-cTn varies according to the assay used and sometimes how regulations permit reporting. It is clear that patients need to be at least 2 hours from the onset of symptoms being evaluated. Caution is warranted, particularly with older patients, women, and patients with underlying cardiac comorbidities., Competing Interests: Funding Support and Author Disclosures Dr Mills is supported by the British Heart Foundation through a Chair Award (CH/F/21/90010), a Programme Grant (RG/20/10/34966), and a Research Excellent Award (RE/18/5/34216). Dr Jaffe has consulted for Abbott, Beckman Coulter, Siemens, Roche, Ortho Diagnostics, ET Healthcare, SphingoTec, Radiometer, SpinChip, LumiraDX, Astellas, Amgen, Novartis, and RCE Technologies; and holds patent 20210401347 along with others. Dr Body has received consulting fees from Roche, Aptamer Group, Abbott, Psyros Diagnostics, Siemens Healthineers, Beckman Coulter, and Radiometer; and has participated on advisory boards for the FORCE Trial (funded by the National Institute for Health and Care Research), the REWIRE trial (Queen Mary University), the PRONTO trial (funded by the National Institute for Health and Care Research), and LumiraDx. Dr Mills has received research grants from Abbott Diagnostics and Siemens Healthineers; and has received personal fees for participation on advisory boards or speaking from Abbott Diagnostics, Roche Diagnostics, Siemens Healthineers, LumiraDx, and Psyros Diagnostics. Dr Aakre is an associate editor of Clinical Biochemistry; is chair of the International Federation of Clinical Chemistry and Laboratory Medicine Committee on Clinical Applications of Cardiac Bio-Markers; has served on advisory boards for Roche Diagnostics and SpinChip; has received consulting honoraria from CardiNor; has received lecture honorarium from Siemens Healthineers and Snibe Diagnostics; and has received research grants from Siemens Healthineers and Roche Diagnostics. Dr Collinson is an associate editor of the Journal of Applied Laboratory Medicine; is an advisory board member for Psyros Diagnostics; and has previously advised LumiraDX, Radiometer, and Siemens. Dr Saenger has received consulting fees from Radiometer. Dr Hammarsten has stock options with Aligned Bio. Dr Omland has received consulting fees from Roche, Bayer, and CardiNor; has received honoraria from Roche; has a patent pending with Roche; has participated on advisory boards for Bayer and Roche; has a fiduciary role with CardiNor; holds stock in CardiNor; and has received equipment and material from Novartis and Abbott. Dr Sandoval has been on advisory boards and has served as a speaker for Abbott Diagnostics and Roche Diagnostics; and holds patent 20210401347 along with others. Dr Ordonez-Llanos has received consulting fees from AWE Medical and Hemcheck. Dr Apple has received consulting fees from HyTest and AWE Medical; has received advisory fees from Werfen, Siemens Healthineers, and Qorvo Biotechnology; has received nonsalaried grant support through the Hennepin Healthcare Research Institute from Abbott Diagnostics, Abbott POC, Roche Diagnostics, Siemens Healthineers, Quidel/Ortho, Becton Dickinson, and Beckman Coulter; and has received fees for serving as associate editor for Clinical Chemistry. Dr Wereski has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Cardiac troponin T (cTnT) and troponin I (cTnI) are expressed as an obligate 1:1 complex in the myocardium. However, blood levels of cTnI often rise much higher than that of cTnT in myocardial infarction (MI), whereas cTnT is often higher in patients with stable conditions such as atrial fibrillation. Here we examine high-sensitive (hs) cTnI and hs-cTnT after different durations of experimental cardiac ischaemia., Methods and Results: hs-cTnI, hs-cTnT, and the hs-cTnT/hs-cTnI ratio were measured in plasma samples from rats before and at 30 and 120 min after 5, 10, 15, and 30 min of myocardial ischaemia. The animals were killed after 120 min of reperfusion, and the infarct volume and volume at risk were measured. hs-cTnI, hs-cTnT, and the hs-cTnT/hs-cTnI ratio were also measured in plasma samples collected from patients with ST-elevation myocardial infarction (STEMI). hs-cTnT and hs-cTnI increased over 10-fold in all rats subjected to ischaemia. The increase of hs-cTnI and hs-cTnT after 30 min was similar, resulting in a hs-cTnI/hs-cTnT ratio around 1. The hs-cTnI/hs-cTnT ratio was also around 1 in blood samples collected at 120 min in rats subjected to 5 or 10 min of ischaemia where no localized necrosis was observed. In contrast, the hs-cTnI/hs-cTnT ratio at 2 h was 3.6-5.5 after longer ischaemia that induced cardiac necrosis. The large hs-cTnI/hs-cTnT ratio was confirmed in patients with anterior STEMI., Conclusion: Both hs-cTnI and hs-cTnT increased similarly after brief periods of ischaemia that did not cause overt necrosis, whereas the hs-cTnI/hs-cTnT ratio tended to increase following longer ischaemia that induced substantial necrosis. A low hs-cTnI/hs-cTnT ratio around 1 may signify non-necrotic cTn release., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The cardiac damage biomarkers cardiac troponin T (cTnT) and troponin I (cTnI) are used to identify patients with myocardial infarction (MI). To make the correct clinical decisions it is important to identify false positive results due to troponin assay interference. Often interferences are caused by high-molecular weight immunocomplexes called macrotroponin that may result in false troponin elevations because of delayed troponin clearance, or heterophilic antibodies that crosslink troponin assay antibodies and generate troponin-independent signals., Design & Methods: We describe and compare four methods for cTnI assay interference analysis using a protein G spin column method, gel filtration chromatography and two versions of a sucrose gradient ultracentrifugation for cTnI assay interference analysis on five patients with confirmed cTnI interference and one MI patient without cTnI interference from our troponin interference referral center., Results: The protein G spin column method had a high between run variability but was still able to identify all five patients with cTnI interference. The sucrose gradient ultracentrifugation methods and the gel filtration method had simlar performancec and correctly identified the immunocomplexes that caused the cTnI interference., Conclusions: Our experience is that these methods are sufficient to safely confirm or exclude positive cTnI assay interference., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

The International Federation of Clinical Chemistry Committee on Clinical Applications of Cardiac Biomarkers (IFCC C-CB) provides educational documents to facilitate the interpretation and use of cardiac biomarkers in clinical laboratories and practice. Our aim is to improve the understanding of certain key analytical and clinical aspects of cardiac biomarkers and how these may interplay. Measurements of cardiac troponin (cTn) have a prominent place in the clinical work-up of patients with suspected acute coronary syndrome. It is therefore important that clinical laboratories know how to recognize and assess analytical issues. Two emerging analytical issues resulting in falsely high cTn concentrations, often several fold higher than the upper reference limit (URL), are antibody-mediated assay interference due to long-lived cTn-antibody complexes, called macrotroponin, and crosslinking antibodies that are frequently referred to as heterophilic antibodies. We provide an overview of antibody-mediated cTn assay interference and provide recommendations on how to confirm the interference and interpret the results., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

The International Federation of Clinical Chemistry and Laboarator Medicine (IFCC) Committee on Clinical Applications of Cardiac Bio-Markers (C-CB) has provided evidence-based educational resources to aid and improve the understanding of important analytical and clinical aspects of cardiac biomarkers. The present IFCC C-CB educational report focuses on recommendations for appropriate use, analytical performance, and gaps in clinical studies related to the use of cardiac troponin (cTn) by point of care (POC) measurement, often referred to as a point of care testing (POCT). The use of high-sensitivity (hs)-cTn POC devices in accelerated diagnostic protocols used in emergency departments or outpatient clinics investigating acute coronary syndrome has the potential for improved efficacy, reduction of length of stay and reduced costs in the health care system. POCT workflow integration includes location of the instrument, assignment of collection and testing responsibility to (non-lab) staff, instrument maintenance, in-service and recurrent training, quality control, proficiency assessments, discrepant result trapping, and troubleshooting and inventory management., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

The use of biomarkers is undisputed in the diagnosis of primary myocardial infarction (MI), but their value for identifying MI is less well studied in the postoperative phase following coronary artery bypass grafting (CABG). To identify patients with periprocedural MI (PMI), several conflicting definitions of PMI have been proposed, relying either on cardiac troponin (cTn) or the MB isoenzyme of creatine kinase, with or without supporting evidence of ischaemia. However, CABG inherently induces the release of cardiac biomarkers, as reflected by significant cTn concentrations in patients with uncomplicated postoperative courses. Still, the underlying (patho)physiological release mechanisms of cTn are incompletely understood, complicating adequate interpretation of postoperative increases in cTn concentrations. Therefore, the aim of the current review is to present these potential underlying mechanisms of cTn release in general, and following CABG in particular (Graphical Abstract). Based on these mechanisms, dissimilarities in the release of cTnI and cTnT are discussed, with potentially important implications for clinical practice. Consequently, currently proposed cTn biomarker cut-offs by the prevailing definitions of PMI might warrant re-assessment, with differentiation in cut-offs for the separate available assays and surgical strategies. To resolve these issues, future prospective studies are warranted to determine the prognostic influence of biomarker release in general and PMI in particular., Competing Interests: Conflict of interest: A.M.A.M. has received nonfinancial support from Abbott Diagnostics and Roche Diagnostics. These manufacturers had no role in the preparation of this review, or the decision to submit the article for publication. A.W.J.V.H. reports his institution received unrestricted grants from Abbott, Roche Medtronic, Boehringer Ingelheim and Astra Zeneca, unrelated to this work. All other authors have no conflicts of interest to declare., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Using a novel thrombolytic technique, we present long-term transplant function, measured by creatinine and iohexol clearance, after utilizing kidneys from porcine donors with uncontrolled donation after circulatory deaths, with 4.5-5 h of warm ischemia., Methods: Pigs in the study group were subjected to simulated circulatory death. After 2 h, ice slush was inserted into the abdomen and 4.5 h after death, the kidneys were retrieved. Lys-plasminogen, antithrombin-III, and alteplase were injected through the renal arteries on the back table. Subsequent ex vivo perfusion was continued for 3 h at 15°C, followed by 3 h with red blood cells at 32°C, and then transplanted into pigs as an autologous graft as only renal support. Living-donor recipient pigs that did not receive ex vivo perfusion, and unilateral nephrectomized pigs served as the controls., Results: Pigs in the study group (n = 13), surviving 10 d or more were included, of which 7 survived for 3 mo. Four animals in the living-donor group (n = 6) and all 5 nephrectomized animals survived for 3 mo. Creatinine levels in the plasma and urine, neutrophil gelatinase-associated lipocalin levels, Kidney Injury Marker-1 expression, and iohexol clearance at 3 mo did not differ significantly between the study and living-donor groups. Histology and transmission electron microscopy after 3 mo showed negligible fibrosis and no other damage., Conclusions: The present method salvages kidneys from extended unontrolled donation after circulatory death using thrombolytic treatment while preserving histology and enabling transplantation after ex vivo reconditioning, with clinically acceptable late function after 3 mo, as measured by creatinine and iohexol clearance., Competing Interests: M.O. is the inventor of several patents. The other authors declare no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Measurement of high-sensitivity (hs) cardiac troponin (cTn) T and I is widely studied for cardiac assessment of stable populations. Recent data suggest clinical and prognostic discrepancies between both hs-cTn. We aimed at reviewing published studies with respect to underlying causes and clinical implications., Content: We summarized current evidence on release and clearance mechanisms of cTnT and I, and on preanalytical and assay-related issues potentially portending to differences in measured concentrations. We also performed a systematic review of outcome studies comparing both hs-cTn in the general population, patients with congestive heart failure, stable coronary artery disease and atrial fibrillation., Summary and Outlook: For the interpretation of concentrations of hs-cTnT, stronger association with renal dysfunction compared to hs-cTnI should be considered. Hs-cTnT also appears to be a stronger indicator of general cardiovascular morbidity and all-cause mortality. Hs-cTnI concentrations tend to be more sensitive to coronary artery disease and ischemic outcomes. These findings apparently reflect variations in the mechanisms of cardiac affections resulting in cTn release. Whether these differences are of clinically relevance remains to be elucidated. However, having the option of choosing between either hs-cTn might represent an option for framing individualized cardiac assessment in the future., (© 2022 the author(s), published by De Gruyter, Berlin/Boston.)

Background: Elevations of high-sensitivity cardiac troponin (hs-cTn) concentrations not related to type 1 myocardial infarction are common in chest pain patients presenting to emergency departments. The discrimination of these patients from those with type 1 myocardial infarction (MI) is challenging and resource-consuming. We aimed to investigate whether the hs-cTn I/T ratio might provide diagnostic and prognostic increment in this context., Methods: We calculated the hs-cTn I/T ratio in 888 chest pain patients having hs-cTnI (Abbott Laboratories) or hs-cTnT (Roche Diagnostics) concentrations above the respective 99th percentile at 2 hours from presentation. All patients were followed for one year regarding mortality., Results: The median hs-cTn I/T ratio was 3.45 (25th, 75th percentiles 1.80-6.59) in type 1 MI patients (n = 408 ☯46.0%]), 1.18 (0.81-1.90) in type 2 MI patients (n = 56 ☯6.3%]) and 0.67 (0.39-1.12) in patients without MI. The hs-cTn I/T ratio provided good discrimination of type 1 MI from no type 1 MI (area under the receiver-operator characteristic curve 0.89 ☯95% confidence interval 0.86-0.91]), of type 1 MI from type 2 MI (area under the curve 0.81 ☯95% confidence interval 0.74-0.87]), and was associated with type 1 MI in adjusted analyses. The hs-cTn I/T ratio provided no consistent prognostic value., Conclusions: The hs-cTn I/T ratio appears to be useful for early diagnosis of type 1 MI and its discrimination from type 2 MI in chest pain patients presenting with elevated hs-cTn. Differences in hs-cTn I/T ratio values may reflect variations in hs-cTn release mechanisms in response to different types of myocardial injury., Competing Interests: Dr Eggers has consulted for Roche Diagnostics. Professor Cullen has consulted for Abbott Diagnostics, Siemens Healthineers and Beckman Coulter. Dr Parsonage has consulted for Abbott Diagnostics and Siemens Healthineers. Professor Cullens and Dr Parsonages institution has received research funding from Abbott Diagnostics, Siemens Healthineers and Beckman Coulter. Professor Pickering has consulted for Abbott Diagnostics. Professor Richards has consulted for and/or received grants/in-kind support from Roche Diagnostics, Abbott Laboratories and Thermo Fisher. Dr Than has consulted for Abbott Diagnostics, Radiometer, Roche Diagnostics, Siemens Healthineers and received funding from Abbott Diagnostics, Beckman Coulter and Roche Diagnostics. The authors have declared that no competing interests exist.

Competing Interests: Conflict of interest: N.L.M. reports research grants awarded to the University of Edinburgh from Abbott Diagnostics and Siemens Healthineers outside the submitted work and honoraria from Abbott Diagnostics, Siemens Healthineers, Roche Diagnostics and LumiraDx. C.M. has received research support from the Swiss National Science Foundation, the Swiss Heart Foundation, the KTI, the University Hospital Basel, the University of Basel; Abbott, Beckman Coulter, Brahms, Idorsia, Novartis, Ortho Diagnostics, Quidel, Roche, Siemens, Singulex, Sphingotec outside the submitted work, as well as speaker honoraria/consulting honoraria from Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, BMS, Novartis, Osler, Roche, and Sanofi, all paid to the institution. O.H. and M.W. have no conflicts to report.

Background: Few studies are available on how to optimize time points for sampling and how to estimate effects of analytical uncertainty when glomerular filtration rate (GFR) is calculated., Methods: We explored the underlying regression mathematics of how analytical variation of a kidney filtration marker affects 1-compartment, slope-and-intercept GFR calculations, using 2 or 3 time points following a bolus injection, and used this to examine the results from 731 routine 3-point iohexol plasma clearance measurements., Results: GFR calculations inflated analytical uncertainty if the time points were taken too late after the bolus injection and too close after each other. The uncertainty in GFR calculation was, however, the same as the analytical uncertainty if optimal time points were used. The middle of the 3 samples was of little value. The first sample should be taken as early as possible after the distribution phase. Sampling before the patient specific half-life of the kidney filtration marker resulted in an exponential error inflation whereas no error inflation was seen when sampling occurred later than 2 half-lives. Theoretical GFR uncertainty could be lowered 2.6-fold if individually optimized time points for sampling had been used in our 731 clearance measurements. Using Taylor expansions to approximate the moments of transformed random variables, the uncertainty of an individual GFR measurement could be calculated in a simple enough way to be applicable by laboratory software., Conclusions: We provide a theoretical foundation to select patient-optimal time points that may both limit errors and allow calculation of GFR uncertainty., Competing Interests: Authors’ Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:, (© American Association for Clinical Chemistry 2022.)