BackgroundThis was a cross-sectional study on the correlation between abdominal aortic calcification (AAC) and Modic changes (MC). Little is known regarding the etiology of MC in the lumbar spine.... Show moreBackgroundThis was a cross-sectional study on the correlation between abdominal aortic calcification (AAC) and Modic changes (MC). Little is known regarding the etiology of MC in the lumbar spine. Currently, insufficient vascularization of the endplate has been proposed to contribute to the appearance of MC. Our objective was to investigate whether AAC, a marker for a poor vascular status, is associated with MC in patients suffering from degenerative disc disease.MethodsRadiologic images of patients (n = 130) suffering from degenerative lumbar disc disease were reviewed. Type and severity of MC were assessed using magnetic resonance images, and severity of AAC was evaluated using computed tomography images or fluoroscopy. Both items were dichotomized into minimal and relevant grades. The correlation between them was studied using Spearman's correlation test, with age as a covariate.ResultsOf the patients, 113 (87%) demonstrated MC (31% type I, 63% type II, and 6% type III) (55% relevant grade), and 68% had AAC (44% relevant grade). Spearman statistical analysis revealed that AAC was correlated with age (P < 0.001), whereas MC were not (P = 0.142). AAC severity was significantly correlated with MC, remaining so after age adjustment (P < 0.05). While MC type I lacked correlation with AAC, MC type II were significantly correlated with AAC (0.288, P = 0.015); however, this association lost significance after adjusting for age (P = 0.057).ConclusionsAAC and MC (mainly MC type II) are associated, indicating that reduced blood supply or even a poor systemic vascularization status due to atherosclerotic disease may play a role in the formation of MC. Future studies focusing on the etiology of MC should pay more attention to patients' vascular status and determinants of abdominal aorta calcification. Show less
BACKGROUND: Lipoprotein(a) is a risk factor for cardiovascular events and modifies the benefit of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors. Lipoprotein(a) concentration can... Show moreBACKGROUND: Lipoprotein(a) is a risk factor for cardiovascular events and modifies the benefit of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors. Lipoprotein(a) concentration can be measured with immunoassays reporting mass or molar concentration or a reference measurement system using mass spectrometry. Whether the relationships between lipoprotein(a) concentrations and cardiovascular events in a high-risk cohort differ across lipoprotein(a) methods is unknown. We compared the prognostic and predictive value of these types of lipoprotein(a) tests for major adverse cardiovascular events (MACE).METHODS: The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the PCSK9 inhibitor alirocumab with placebo in patients with recent acute coronary syndrome. We compared risk of a MACE in the placebo group and MACE risk reduction with alirocumab according to baseline lipoprotein(a) concentration measured by Siemens N-latex nephelometric immunoassay (IA-mass; mg/dL), Roche Tina-Quant turbidimetric immunoassay (IA-molar; nmol/L), and a noncommercial mass spectrometry-based test (MS; nmol/L). Lipoprotein(a) values were transformed into percentiles for comparative modeling. Natural cubic splines estimated continuous relationships between baseline lipoprotein(a) and outcomes in each treatment group. Event rates were also determined across baseline lipoprotein(a) quartiles defined by each assay.RESULTS: Among 11 970 trial participants with results from all 3 tests, baseline median (Q1, Q3) lipoprotein(a) concentrations were 21.8 (6.9, 60.0) mg/dL, 45.0 (13.2, 153.8) nmol/L, and 42.2 (14.3, 143.1) nmol/ L for IA-mass, IA-molar, and MS, respectively. The strongest correlation was between IA-molar and MS (r=0.990), with nominally weaker correlations between IA-mass and MS (r=0.967) and IA-mass and IA-molar (r=0.972). Relationships of lipoprotein(a) with MACE risk in the placebo group were nearly identical with each test, with estimated cumulative incidences differing by <= 0.4% across lipoprotein(a) percentiles, and all were incrementally prognostic after accounting for low-density lipoprotein cholesterol levels (all spline P <= 0.0003). Predicted alirocumab treatment effects were also nearly identical for each of the 3 tests, with estimated treatment hazard ratios differing by <= 0.07 between tests across percentiles and nominally less relative risk reduction by alirocumab at lower percentiles for all 3 tests. Absolute risk reduction with alirocumab increased with increasing lipoprotein(a) measured by each test, with significant linear trends across quartiles.CONCLUSIONS: In patients with recent acute coronary syndrome, 3 lipoprotein(a) tests were similarly prognostic for MACE in the placebo group and predictive of MACE reductions with alirocumab at the cohort level. Show less
Duijl, T.T. van; Ruhaak, R.; Hoogeveen, E.; Mutsert, R. de; Rosendaal, F.; Cessie, S. le; ... ; Cobbaert, C. 2022
Background and aims: There is an ongoing need to recognize early kidney injury and its progression in structural chronic pathologies. The proteins NGAL, IGFBP7, TIMP2, KIM-1, CXCL9, TGF-beta 1,... Show moreBackground and aims: There is an ongoing need to recognize early kidney injury and its progression in structural chronic pathologies. The proteins NGAL, IGFBP7, TIMP2, KIM-1, CXCL9, TGF-beta 1, SLC22A2, nephrin, cubilin and uromodulin have been proposed as early kidney injury biomarkers. To guide clinical interpretation, their urinary concentrations should be accompanied by reference intervals, which we here establish in a representative Dutch middle-aged population. Materials and Methods: The 24-h urine samples from 1443 Caucasian middle-aged men and women, were analyzed for the biomarkers by quantitative LC-MS/MS. Biomarker excretion per 24-h were calculated, and urine creatinine and osmolality were measured for dilution normalization. This population was characterized by demographic and anthropometric parameters, comorbid conditions, and conventional kidney function measures. Results: NGAL, IGFBP7, TIMP2, KIM-1 and uromodulin could be quantified in this population, whereas nephrin, SLC22A2 and CXCL9 were below their detection limits. Urine creatinine and osmolality ( r= -were correlated to urine volume (r = -0.71; -0.74) and to IGFBP7 (r = 0.73; 0.71) and TIMP2 (r = 0.71; 0.69). Crude and normalized biomarker concentrations were affected by sex, but not by age, BMI, smoking, kidney function or common comorbid conditions. The reference intervals (men; women) were 18-108; 21-131 pmol IGFBP7/mmol creatinine, 1- 63; 4-224 pmol NGAL/mmol creatinine, 7-48; 7- 59 pmol TIMP2/mmol creatinine, <1-9; <1-12 pmol KIM-1/mmol creatinine and 0.1-1.2; 0.1-1.7 mg uromodulin/mmol creatinine. Conclusion: We present dilution-normalized and sex-stratified urinary reference intervals of kidney injury biomarkers in a middle-aged Caucasian population. Show less
Laboratory medicine in the European Union is at the dawn of a regulatory revolution as it reaches the end of the transition from IVDD 98/79/EC (https://eur-lex.europa.eu/legal-content/EN/TXT/?uri... Show moreLaboratory medicine in the European Union is at the dawn of a regulatory revolution as it reaches the end of the transition from IVDD 98/79/EC (https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A31998L00 79&qid=1628781352814) to IVDR 2017/746 https://eur-lex. europa.eu/eli/reg/2017/746. Without amendments and contingency plans, implementation of the IVDR in May 2022 will lead the healthcare sector into uncharted waters due to unpreparedness of the EU regulatory infrastructure. Prospective risk analyses were not made by the European Commission, and if nothing happens it can be anticipated that the consequences will impact all stakeholders of the medical test pipeline, may seriously harm patients and may prevent caregivers from making appropriate clinical decisions due to non-availability of medical tests. Finally, it also may discourage manufacturers and academia from developing specialty tests, thereby hampering innovation in medical diagnostic care. We hereby inform laboratory professionals about the imminent diagnostic collapse using testimonies from representative stakeholders of the diagnostic supply chain and from academia developing innovative in-house tests in domains of unmet clinical needs. Steps taken by the EFLM Task Force on European Regulatory Affairs, under the umbrella of the Biomedical Alliance in Europe, will be highlighted, as well as the search for solutions through dialogue with the European Commission. Although we recognize that the IVDR promotes positive goals such as increased clinical evidence, surveillance, and transparency, we need to ensure that the capabilities of the diagnostic sector are not damaged by infra structural unpreparedness, while at the same time being forced to submit to a growing bureaucratic and unsupportive structure that will not support its "droit d'exister". Show less
Purpose of review The 2019 European Society of Cardiology/European Atherosclerosis Society Guidelines concluded that apolipoprotein B (apoB) was a more accurate measure of cardiovascular risk and a... Show morePurpose of review The 2019 European Society of Cardiology/European Atherosclerosis Society Guidelines concluded that apolipoprotein B (apoB) was a more accurate measure of cardiovascular risk and a better guide to the adequacy of lipid lowering than low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (HDL-C). Also, they stated that apoB can be measured more accurately than LDL-C or non-HDL-C. This strong endorsement of the central role of apoB contrasts with the limited endorsement of apoB by the 2018 American College of Cardiology/American Heart Association Multisociety Guidelines. Nevertheless, both retained LDL-C as the primary metric to guide statin/ezetimibe/Proprotein convertase subtilisin/kexin type 9 (PCSK9) therapy. Recent findings This essay will review the most important recent advances in knowledge about apoB with particular emphasis on the results of Mendelian randomization studies and a new discordance analysis in subjects on statin therapy. We will also lay out why using LDL-C to guide the adequacy of lipid lowering therapy represents an interpretive error of the results of the statin/ezetimibe/PCSK9 inhibitor randomized clinical trials and therefore why apoB should be the primary metric to guide statin/ezetimibe/PCSK9 therapy. There is now a robust body of evidence demonstrating the superiority of apoB over LDL-C and non-HDL-C as a clinical marker of cardiovascular risk. LDL-C is not the appropriate marker to assess the benefits of statin/ezetimibe/PCSK9 therapy. Show less
Hulzebos, C.V.; Vitek, L.; Zabetta, C.C.D.; Dvorak, A.; Schenk, P.; Hagen, E.A.E. van der; ... ; Tiribelli, C. 2021
Invasive bilirubin measurements remain the gold standard for the diagnosis and treatment of infants with severe neonatal hyperbilirubinemia. The present paper describes different methods currently... Show moreInvasive bilirubin measurements remain the gold standard for the diagnosis and treatment of infants with severe neonatal hyperbilirubinemia. The present paper describes different methods currently available to assess hyperbilirubinemia in newborn infants. Novel point-of-care bilirubin measurement methods, such as the BiliSpec and the Bilistick, would benefit many newborn infants, especially in low-income and middle-income countries where the access to costly multi-analyzer in vitro diagnostic instruments is limited. Total serum bilirubin test results should be accurate within permissible limits of measurement uncertainty to be fit for clinical purposes. This implies correct implementation of internationally endorsed reference measurement systems as well as participation in external quality assessment programs. Novel analytic methods may, apart from bilirubin, include the determination of bilirubin photoisomers and bilirubin oxidation products in blood and even in other biological matrices. ImpactKey message: Bilirubin measurements in blood remain the gold standard for diagnosis and treatment of severe neonatal hyperbilirubinemia (SNH). External quality assessment (EQA) plays an important role in revealing inaccuracies in diagnostic bilirubin measurements. What does this article add to the existing literature? We provide analytic performance data on total serum bilirubin (TSB) as measured during recent EQA surveys. We review novel diagnostic point-of-care (POC) bilirubin measurement methods and analytic methods for determining bilirubin levels in biological matrices other than blood. Impact: Manufacturers should make TSB test results traceable to the internationally endorsed total bilirubin reference measurement system and should ensure permissible limits of measurement uncertainty. Show less
Hulzebos, C.V.; Vitek, L.; Zabetta, C.C.D.; Dvorak, A.; Schenk, P.; Hagen, E.A.E. van der; ... ; Tiribelli, C. 2021
Severe neonatal hyperbilirubinemia (SNH) is a serious condition that occurs worldwide. Timely recognition with bilirubin determination is key in the management of SNH. Visual assessment of jaundice... Show moreSevere neonatal hyperbilirubinemia (SNH) is a serious condition that occurs worldwide. Timely recognition with bilirubin determination is key in the management of SNH. Visual assessment of jaundice is unreliable. Fortunately, transcutaneous bilirubin measurement for screening newborn infants is routinely available in many hospitals and outpatient settings. Despite a few limitations, the use of transcutaneous devices facilitates early recognition and appropriate management of neonatal jaundice. Unfortunately, however, advanced and often costly screening modalities are not accessible to everyone, while there is an urgent need for inexpensive yet accurate instruments to assess total serum bilirubin (TSB). In the near future, novel icterometers, and in particular optical bilirubin estimates obtained with a smartphone camera and processed with a smartphone application (app), seem promising methods for screening for SNH. If proven reliable, these methods may empower outpatient health workers as well as parents at home to detect jaundice using a simple portable device. Successful implementation of ubiquitous bilirubin screening may contribute substantially to the reduction of the worldwide burden of SNH. The benefits of non-invasive bilirubin screening notwithstanding, any bilirubin determination obtained through non-invasive screening must be confirmed by a diagnostic method before treatment. ImpactKey message: Screening methods for neonatal hyperbilirubinemia facilitate early recognition and timely treatment of severe neonatal hyperbilirubinemia (SNH). Any bilirubin screening result obtained must be confirmed by a diagnostic method. What does this article add to the existing literature? Data on optical bilirubin estimation are summarized. Niche research strategies for prevention of SNH are presented. Impact: Transcutaneous screening for neonatal hyperbilirubinemia contributes to the prevention of SNH. A smartphone application with optical bilirubin estimation seems a promising low-cost screening method, especially in low-resource settings or at home. Show less
To more comprehensively support clinical management of patients in our hospital, we redesigned the diagnostic Total Testing Process (TTP) from request to report. To that end, clinical needs were... Show moreTo more comprehensively support clinical management of patients in our hospital, we redesigned the diagnostic Total Testing Process (TTP) from request to report. To that end, clinical needs were identified and a vision on Total Laboratory Automation (TLA) of the TTP was developed. The Delft Systems Engineering Approach was used for mapping a desirable laboratory testing process. The desirable "To Be" diagnostic process was tendered and the translation of a functional design into a specific TLA-configuration - compliant with the vision and the predefined functional design - was accomplished using a competitive dialogue tender variant (based on art. 29 of the EU guideline 2014/24). Realization of this high-end TLA-solution enabled a high-quality testing process with numerous improvements such as clear and supportive digital request forms, specimen consolidation, track and trace and non-conformity registration at the specimen level, better blood management (similar to 40% less blood sampled), lean and in line processing with increased productivity (42% rise in test productivity per capita), and guaranteed total turn-around-times of medical tests (95% of TLA-rooted in line tests are reported <120 min). The approach taken for improving the brain-to-brain loop of medical testing, as fundament for better diagnostic stewardship, is explained. Show less
The joint consensus panel of the European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) recently addressed present and future... Show moreThe joint consensus panel of the European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) recently addressed present and future challenges in the laboratory diagnostics of atherogenic lipoproteins. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDLC), LDL cholesterol (LDLC), and calculated non-HDLC (=total - HDLC) constitute the primary lipid panel for estimating risk of atherosclerotic cardiovascular disease (ASCVD) and can be measured in the nonfasting state. LDLC is the primary target of lipid-lowering therapies. For on-treatment follow-up, I.DLC shall be measured or calculated by the same method to attenuate errors in treatment decisions due to marked between-method variations. Lipoprotein(a) [Lp(a)]-cholesterol is part of measured or calculated LDLC and should be estimated at least once in all patients at risk of ASCVD, especially in those whose LDLC declines poorly upon statin treatment. Residual risk of ASCVD even under optimal LDL-lowering treatment should be also assessed by non-HDLC or apolipoprotein B (apoB), especially in patients with mild-to-moderate hypertriglyceridemia (2-10 mmol/L). Non-HDLC includes the assessment of remnant lipoprotein cholesterol and shall be reported in all standard lipid panels. Additional apoB measurement can detect elevated LDL particle (LDLP) numbers often unidentified on the basis of LDLC alone. Reference intervals of lipids, lipoproteins, and apolipoproteins are reported for European men and women aged 20-100 years. How-ever, laboratories shall flag abnormal lipid values with reference to therapeutic decision thresholds. Show less
The joint consensus panel of the European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) recently addressed present and future... Show moreThe joint consensus panel of the European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) recently addressed present and future challenges in the laboratory diagnostics of atherogenic lipoproteins. Total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, and calculated non-HDL cholesterol (= total - HDL cholesterol) constitute the primary lipid panel for estimating risk of atherosclerotic cardiovascular disease (ASCVD) and can be measured in the nonfasting state. LDL cholesterol is the primary target of lipid-lowering therapies. For on-treatment follow-up, LDL cholesterol shall be measured or calculated by the same method to attenuate errors in treatment decisions due to marked between-method variations. Lipoprotein(a)-cholesterol is part of measured or calculated LDL cholesterol and should be estimated at least once in all patients at risk of ASCVD, especially in those whose LDL cholesterol decline poorly upon statin treatment. Residual risk of ASCVD even under optimal LDL-lowering treatment should be also assessed by non-HDL cholesterol or apolipoprotein B, especially in patients with mild-to-moderate hypertriglyceridemia (2-10 mmol/L). Non-HDL cholesterol includes the assessment of remnant lipoprotein cholesterol and shall be reported in all standard lipid panels. Additional apolipoprotein B measurement can detect elevated LDL particle numbers often unidentified on the basis of LDL cholesterol alone. Reference intervals of lipids, lipoproteins, and apolipoproteins are reported for European men and women aged 20-100 years. However, laboratories shall flag abnormal lipid values with reference to therapeutic decision thresholds. Show less
Orsi, F.A.; Lijfering, W.M.; Laarse, A. van der; Ruhaak, L.R.; Rosendaal, F.R.; Cannegieter, S.C.; Cobbaert, C. 2019
Purpose: Apolipoproteins C-I, C-II, C-III and E have been associated with risk of arterialthrombotic diseases. We investigated whether these apolipoproteins have prothromboticproperties and are... Show morePurpose: Apolipoproteins C-I, C-II, C-III and E have been associated with risk of arterialthrombotic diseases. We investigated whether these apolipoproteins have prothromboticproperties and are associated with risk of venous thromboembolism (VTE).Patients and methods: A total of 127 VTE patients and 299 controls were randomlyselected from the Multiple Environmental and Genetic Assessment of Risk Factors forVenous Thrombosis study (1999–2004), in the Netherlands. The apolipoproteins were quan-tified using mass spectrometry (LC/MS/MS), and their levels were analyzed as continuousvariable (per SD increase).Results: In controls, increases in levels of apolipoproteins were associated with increases inlevels of vitamin K-dependent factors, factor XI, antithrombin and clot lysis time.Additionally, increasing apolipoproteins C-III and E levels were associated with higherfactor VIII and von Willebrand factor levels. Levels of C-reactive protein were not associatedwith any apolipoprotein. The age- and sex-adjusted odds ratios of apolipoproteins E, C-III,CII and CI to the risk of venous thrombosis were 1.21 (95% CI, 0.98–1.49), 1.19 (95% CI,0.99–1.44), 1.24 (95% CI, 0.95–1.61) and 1.06 (95% CI, 0.87–1.30) per SD increase,respectively. These odds ratios did not attenuate after adjustments for statin use, estrogenuse, BMI, alcohol use, and self-reported diabetes.Conclusions: Levels of apolipoproteins C-I, C-II, C-III and E are associated with those ofseveral coagulation factors. However, whether these apolipoproteins are also associated withan increased risk of VTE remains to be established.Keywords: thrombosis, proteomics, lipids, cholesterol, coagulation, risk factors Show less