Cardiac troponin concentrations following exercise and the association with cardiovascular disease and outcomes: rationale and design of the prospective TREAT cohort study.

Exercise can produce transient elevations of cardiac troponin (cTn) concentrations, which may resemble the cTn release profile of myocardial infarction. Consequently, clinical interpretation of postexercise cTn elevations (ie, values above the 99th percentile upper reference limit) remains challenging and may cause clinical confusion. Therefore, insight into the physiological versus pathological nature of postexercise cTn concentrations is warranted. We aim to (1) establish resting and postexercise reference values for recreational athletes engaged in walking, cycling or running exercise; (2) compare the prevalence of (sub)clinical coronary artery disease in athletes with high versus low postexercise cTn concentrations and (3) determine the association between postexercise cTn concentrations and the incidence of major adverse cardiovascular events (MACE) and mortality during long-term follow-up. For this purpose, the prospective TRoponin concentrations following Exercise and the Association with cardiovascular ouTcomes (TREAT) observational cohort study was designed to recruit 1500 recreational athletes aged ≥40 to <70 years who will participate in Dutch walking, cycling and running events. Baseline and postexercise high-sensitivity cTnT and cTnI concentrations will be determined. The prevalence and magnitude of coronary atherosclerosis on computed tomography (eg, coronary artery calcium score, plaque type, stenosis degree and CT-derived fractional flow reserve) will be compared between n=100 athletes with high postexercise cTn concentrations vs n=50 age-matched, sex-matched and sport type-matched athletes with low postexercise cTn concentrations. The incidence of MACE and mortality will be assessed in the entire cohort up to 20 years follow-up. The TREAT study will advance our understanding of the clinical significance of exercise-induced cTn elevations in middle-aged and older recreational athletes. Trial registration number NCT06295081.

Clinical Patterns of Sarcoidosis Patients with and without Uveitis: Insights from a Dutch Sarcoidosis Centre.

PURPOSE: Uveitis is a common ocular manifestation in individuals with sarcoidosis, a multisystem inflammatory disorder. This study aimed to explore clinical and genetic factors associated with the presence or absence of uveitis in sarcoidosis patients. METHODS: Total 625 Dutch sarcoidosis patients were included. Among these, 170 underwent ophthalmic examination, and 61 were diagnosed with uveitis. Demographic and clinical data, including age, gender, race, biopsy status, chest radiography findings, TNF-α inhibitor treatment, and uveitis classification were collected retrospectively from medical records. Genetic data was available for HLA haplotypes, TNF-α G-308A, and BTNL2 G16071A polymorphisms. RESULTS: The majority of the patients presented with bilateral uveitis (80.3%). The proportion of women was higher in the uveitis group compared to the non-uveitis group (67.2% and 47.7%; p = 0.014). Pulmonary involvement (chest radiographic stage II-III) was significantly lower in patients with uveitis (36.1% versus 64.2%; p < 0.001). Patients with uveitis were more often treated with TNF-α inhibitors (67.2% versus 29.4%; p < 0.001) and the outcome was better compared with the non-uveitis group, 92% vs 68%, responders (p < 0.012). Uveitis patients treated with TNF-α inhibitors (either adalimumab or infliximab) were more likely to suffer from intermediate or posterior uveitis than anterior uveitis. Genetic analysis identified a significant association between the BTNL2 G16071A GG genotype and uveitis (p = 0.012). CONCLUSION: This study highlights distinctive demographic, clinical and genetic features associated with uveitis in sarcoidosis patients. Ocular sarcoidosis was more prevalent in women. Further research is warranted to explore the implications of these findings for treatment strategies and prognostic assessments.

Differences in Cardiac Troponin T Composition in Myocardial Infarction and End-Stage Renal Disease Patients: A Blood Tube Effect?

BACKGROUND: Cardiac troponin T (cTnT) is key in diagnosing myocardial infarction (MI) but is also elevated in end-stage renal disease (ESRD) patients. Specific larger cTnT proteoforms were identified for the acute phase of MI, while in serum of ESRD patients solely small cTnT fragments were found. However, others allocated this to a pre-analytic effect due to abundant thrombin generation in serum. Therefore, we investigated the effect of various anticoagulation methods on cTnT composition and concentration and compared the cTnT composition of MI and ESRD patients. METHODS: The agreement of cTnT concentrations between simultaneously collected serum, lithium-heparin (LH) plasma, and ethylenediaminetetraacetic acid (EDTA) plasma was studied using the high-sensitivity (hs-)cTnT immunoassay. cTnT proteoform composition was investigated in a standardized time-dependent manner through spike experiments and in simultaneously collected blood matrixes of MI and ESRD patients. RESULTS: Excellent hs-cTnT concentration agreements were observed across all blood matrixes (slopes > 0.98; 95% CI, 0.96-1.04). Time-dependent degradation (40 kDa intact:29 kDa fragment:15 to 18 kDa fragments) was found in LH plasma and EDTA plasma, and serum in ratios (%) of 90:10:0, 0:5:95, and 0:0:100, respectively (48 h after blood collection). Moreover, gel filtration chromatography (GFC) profiles illustrated mainly larger cTnT proteoforms in MI patients, while in ESRD patients mainly 15 to 18 kDa fragments were found for all matrices. CONCLUSIONS: The extent of cTnT degradation in vitro is dependent on the (anti)coagulation method, without impacting hs-cTnT concentrations. Furthermore, mainly larger cTnT proteoforms were present in MI patients, while in ESRD patients mainly small 15 to 18 kDa cTnT fragments were found. These insights are essential when developing a novel hs-cTnT assay targeting larger cTnT proteoforms.

Is a Vitamin K Epoxide Reductase Complex Subunit 1 (VKORC1) Polymorphism a Risk Factor for Nephrolithiasis in Sarcoidosis?

Sarcoidosis is a systemic inflammatory disorder characterized by granuloma formation in various organs. It has been associated with nephrolithiasis. The vitamin K epoxide reductase complex subunit 1 (VKORC1) gene, which plays a crucial role in vitamin K metabolism, has been implicated in the activation of proteins associated with calcification, including in the forming of nephrolithiasis. This study aimed to investigate the VKORC1 C1173T polymorphism (rs9934438) in a Dutch sarcoidosis cohort, comparing individuals with and without a history of nephrolithiasis. Retrospectively, 424 patients with sarcoidosis were divided into three groups: those with a history of nephrolithiasis (Group I: n = 23), those with hypercalcemia without nephrolithiasis (Group II: n = 38), and those without nephrolithiasis or hypercalcemia (Group III: n = 363). Of the 424 sarcoidosis patients studied, 5.4% had a history of nephrolithiasis (Group I), only two of whom possessed no VKORC1 polymorphisms (OR = 7.73; 95% CI 1.79-33.4; p = 0.001). The presence of a VKORC1 C1173T variant allele was found to be a substantial risk factor for the development of nephrolithiasis in sarcoidosis patients. This study provides novel insights into the genetic basis of nephrolithiasis in sarcoidosis patients, identifying VKORC1 C1173T as a potential contributor. Further research is warranted to elucidate the precise mechanisms and explore potential therapeutic interventions based on these genetic findings.

Drug-Gene Risk Stratification in Patients with Suspected Drug-Induced Interstitial Lung Disease.

BACKGROUND: Pulmonary toxicity has been associated with drug use. This is often not recognized in clinical practice, and underestimated. OBJECTIVE: We aimed to establish whether polymorphisms in certain genes corresponding with a metabolic pathway of drug(s) used are associated with pulmonary toxicity in patients with suspected drug-induced interstitial lung disease (DI-ILD). METHODS: This retrospective observational study explored genetic variations in three clinically relevant cytochrome P450 (CYP) iso-enzymes (i.e., CYP2D6, CYP2C9, and CYP2C19) in a group of patients with a fibroticinterstitial lung disease, either non-specific interstitial pneumonia (n = 211) or idiopathic pulmonary fibrosis (n = 256), with a suspected drug-induced origin. RESULTS: Of the 467 patients, 79.0% showed one or more polymorphisms in the tested genes accompanied by the use of drug(s) metabolized by a corresponding affected metabolic pathway (60.0% poor metabolizers and/or using two or more drugs [likely DI-ILD], 37.5% using three or more [highly likely DI-ILD]). Most commonly used drugs were statins (63.1%) with a predominance among men (69.4 vs 47.1%, p < 0.0001). Nitrofurantoin, not metabolized by the tested pathways, was prescribed more frequently among women (51.9 vs 4.5%, p < 0.00001). CONCLUSIONS: In our cohort with suspected DI-ILD, 79% carried one or more genetic variants accompanied by the use of drugs metabolized by a corresponding affected pathway. In 60%, the diagnosis of DI-ILD was likely, whereas in 37.5%, it was highly likely, based on CYP analyses. This study underlines the importance of considering both drug use and genetic make-up as a possible cause, or at least a contributing factor, in the development and/or progression of fibrotic lung diseases. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00267800, registered in 2005.

Explainable Machine Learning Models for Rapid Risk Stratification in the Emergency Department: A Multicenter Study.

BACKGROUND: Risk stratification of patients presenting to the emergency department (ED) is important for appropriate triage. Diagnostic laboratory tests are an essential part of the workup and risk stratification of these patients. Using machine learning, the prognostic power and clinical value of these tests can be amplified greatly. In this study, we applied machine learning to develop an accurate and explainable clinical decision support tool model that predicts the likelihood of 31-day mortality in ED patients (the RISKINDEX). This tool was developed and evaluated in four Dutch hospitals. METHODS: Machine learning models included patient characteristics and available laboratory data collected within the first 2 h after ED presentation, and were trained using 5 years of data from consecutive ED patients from the Maastricht University Medical Center (Maastricht), Meander Medical Center (Amersfoort), and Zuyderland Medical Center (Sittard and Heerlen). A sixth year of data was used to evaluate the models using area under the receiver-operating-characteristic curve (AUROC) and calibration curves. The Shapley additive explanations (SHAP) algorithm was used to obtain explainable machine learning models. RESULTS: The present study included 266 327 patients with 7.1 million laboratory results available. Models show high diagnostic performance with AUROCs of 0.94, 0.98, 0.88, and 0.90 for Maastricht, Amersfoort, Sittard and Heerlen, respectively. The SHAP algorithm was utilized to visualize patient characteristics and laboratory data patterns that underlie individual RISKINDEX predictions. CONCLUSIONS: Our clinical decision support tool has excellent diagnostic performance in predicting 31-day mortality in ED patients. Follow-up studies will assess whether implementation of these algorithms can improve clinically relevant end points.

Cardiac troponin release following coronary artery bypass grafting: mechanisms and clinical implications.

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.

Protein Alterations in Cardiac Ischemia/Reperfusion Revealed by Spatial-Omics.

Myocardial infarction is the most common cause of death worldwide. An understanding of the alterations in protein pathways is needed in order to develop strategies that minimize myocardial damage. To identify the protein signature of cardiac ischemia/reperfusion (I/R) injury in rats, we combined, for the first time, protein matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) and label-free proteomics on the same tissue section placed on a conductive slide. Wistar rats were subjected to I/R surgery and sacrificed after 24 h. Protein MALDI-MSI data revealed ischemia specific regions, and distinct profiles for the infarct core and border. Firstly, the infarct core, compared to histologically unaffected tissue, showed a significant downregulation of cardiac biomarkers, while an upregulation was seen for coagulation and immune response proteins. Interestingly, within the infarct tissue, alterations in the cytoskeleton reorganization and inflammation were found. This work demonstrates that a single tissue section can be used for protein-based spatial-omics, combining MALDI-MSI and label-free proteomics. Our workflow offers a new methodology to investigate the mechanisms of cardiac I/R injury at the protein level for new strategies to minimize damage after MI.

High-Sensitivity Cardiac Troponin I and T Kinetics Differ following Coronary Bypass Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Cardiac troponin I and T are both used for diagnosing myocardial infarction (MI) after coronary artery bypass grafting (CABG), also known as type 5 MI (MI-5). Different MI-5 definitions have been formulated, using multiples of the 99th percentile upper reference limit (10×, 35×, or 70× URL), with or without supporting evidence. These definitions are arbitrarily chosen based on conventional assays and do not differentiate between troponin I and T. We therefore investigated the kinetics of high-sensitivity cardiac troponin I (hs-cTnI) and T (hs-cTnT) following CABG. METHODS: A systematic search was applied to MEDLINE and EMBASE databases including the search terms "coronary artery bypass grafting" AND "high-sensitivity cardiac troponin." Studies reporting hs-cTnI or hs-cTnT on at least 2 different time points were included. Troponin concentrations were extracted and normalized to the assay-specific URL. RESULTS: For hs-cTnI and hs-cTnT, 17 (n = 1661 patients) and 15 studies (n = 2646 patients) were included, respectively. Preoperative hs-cTnI was 6.1× URL (95% confidence intervals: 4.9-7.2) and hs-cTnT 1.2× URL (0.9-1.4). Mean peak was reached 6-8 h postoperatively (126× URL, 99-153 and 45× URL, 29-61, respectively). Subanalysis of hs-cTnI illustrated assay-specific peak heights and kinetics, while subanalysis of surgical strategies revealed 3-fold higher hs-cTnI than hs-cTnT for on-pump CABG and 5-fold for off-pump CABG. CONCLUSION: Postoperative hs-cTnI and hs-cTnT following CABG surpass most current diagnostic cutoff values. hs-cTnI was almost 3-fold higher than hs-cTnT, and appeared to be highly dependent on the assay used and surgical strategy. There is a need for assay-specific hs-cTnI and hs-cTnT cutoff values for accurate, timely identification of MI-5.

Drug-induced comorbidities in patients with sarcoidosis.

PURPOSE OF REVIEW: Sarcoidosis is a chronic multisystemic inflammatory disease of unknown aetiology with a wide range of highly variable clinical manifestations and unpredictable disease course. Sarcoidosis patients may present with specific organ-related symptoms involving functional impairments, and less specific symptoms. The decision whether and when to treat a sarcoidosis patient with pharmacotherapy depends on two major factors: risk of organ failure and/or death and impairment of quality of life. This decision is complex and not standardized. RECENT FINDINGS: Glucocorticoids (GCs) are recommended as initial treatment, when needed. Subsequent GC-sparing alternatives frequently follow. Comorbidities or adverse drug reactions (ADRs) from drugs used in sarcoidosis treatment are sometimes very hard to differentiate from symptoms associated with the disease itself, which may cause diagnostic dilemmas. An ideal approach to minimalize ADRs would involve genetic screening prior to prescribing certain 'high-risk drugs' and therapeutic drug monitoring during treatment. Pharmacogenomic testing aims to guide appropriate selection of medicines, with the potential of reducing unnecessary polypharmacy while improving clinical outcomes. SUMMARY: A multidisciplinary approach to the management of sarcoidosis may avoid unnecessary ADRs. It is important to consider the possibility of drug-induced damage in sarcoidosis, especially if the clinical situation deteriorates after the introduction of a particular drug.

Metformin and high-sensitivity cardiac troponin I and T trajectories in type 2 diabetes patients: a post-hoc analysis of a randomized controlled trial.

BACKGROUND: Metformin has favorable effects on cardiovascular outcomes in both newly onset and advanced type 2 diabetes, as previously reported findings from the UK Prospective Diabetes Study and the HOME trial have demonstrated. Patients with type 2 diabetes present with chronically elevated circulating cardiac troponin levels, an established predictor of cardiovascular endpoints and prognostic marker of subclinical myocardial injury. It is unknown whether metformin affects cardiac troponin levels. The study aimed to evaluate cardiac troponin I and T trajectories in patients with diabetes treated either with metformin or placebo. METHODS: This study is a post-hoc analysis of a randomized controlled trial (HOME trial) that included 390 patients with advanced type 2 diabetes randomized to 850 mg metformin or placebo up to three times daily concomitant to continued insulin treatment. Cardiac troponin I and T concentrations were measured at baseline and after 4, 17, 30, 43 and 52 months. We evaluated cardiac troponin trajectories by linear mixed-effects modeling, correcting for age, sex, smoking status and history of cardiovascular disease. RESULTS: This study enrolled 390 subjects, of which 196 received metformin and 194 received placebo. In the treatment and placebo groups, mean age was 64 and 59 years; with 50% and 58% of subjects of the female sex, respectively. Despite the previously reported reduction of macrovascular disease risk in this cohort by metformin, linear mixed-effects regression modelling did not reveal evidence for an effect on cardiac troponin I and cardiac troponin T levels [- 8.4% (- 18.6, 3.2), p = 0.150, and - 4.6% (- 12, 3.2), p = 0.242, respectively]. A statistically significant time-treatment interaction was found for troponin T [- 1.6% (- 2.9, - 0.2), p = 0.021] but not troponin I concentrations [- 1.5% (- 4.2, 1.2), p = 0.263]. CONCLUSIONS: In this post-hoc analysis of a 4.3-year randomized controlled trial, metformin did not exert a clinically relevant effect on cardiac troponin I and cardiac troponin T levels when compared to placebo. Cardioprotective effects of the drug observed in clinical studies are not reflected by a reduction in these biomarkers of subclinical myocardial injury. Trial registration ClinicalTrials.gov identifier NCT00375388.

Fructose Intake From Fruit Juice and Sugar-Sweetened Beverages Is Associated With Higher Intrahepatic Lipid Content: The Maastricht Study.

OBJECTIVE: Epidemiological evidence regarding the relationship between fructose intake and intrahepatic lipid (IHL) content is inconclusive. We, therefore, assessed the relationship between different sources of fructose and IHL at the population level. RESEARCH DESIGN AND METHODS: We used cross-sectional data from The Maastricht Study, a population-based cohort study (n = 3,981; mean ± SD age: 60 ± 9 years; 50% women). We assessed the relationship between fructose intake (assessed with a food-frequency questionnaire)-total and derived from fruit, fruit juice, and sugar-sweetened beverages (SSB)-and IHL (quantified with 3T Dixon MRI) with adjustment for age, sex, type 2 diabetes, education, smoking status, physical activity, and intakes of total energy, alcohol, saturated fat, protein, vitamin E, and dietary fiber. RESULTS: Energy-adjusted total fructose intake and energy-adjusted fructose from fruit were not associated with IHL in the fully adjusted models (P = 0.647 and P = 0.767). In contrast, energy-adjusted intake of fructose from fruit juice and SSB was associated with higher IHL in the fully adjusted models (P = 0.019 and P = 0.009). Individuals in the highest tertile of energy-adjusted intake of fructose from fruit juice and SSB had a 1.04-fold (95% CI 0.99; 1.11) and 1.09-fold (95% CI 1.03; 1.16) higher IHL, respectively, in comparison with the lowest tertile in the fully adjusted models. Finally, the association for fructose from fruit juice was stronger in individuals with type 2 diabetes (P for interaction = 0.071). CONCLUSIONS: Fructose from fruit juice and SSB is independently associated with higher IHL. These cross-sectional findings contribute to current knowledge in support of measures to reduce the intake of fructose-containing beverages as a means to prevent nonalcoholic fatty liver disease at the population level.

Intrahepatic lipid content is independently associated with soluble E-selectin levels: The Maastricht study.

BACKGROUND: Evidence is accumulating that liver sinusoidal endothelial cells are involved in the pathogenesis of non-alcoholic fatty liver disease. Previous studies have suggested that the endothelial biomarker soluble E-selectin (sE-selectin) is to an important extent liver-derived. AIMS: To study the relationship of intrahepatic lipid (IHL) content with sE-selectin at the population level. METHODS: This study was conducted in participants of The Maastricht Study (n = 1,634), a population-based cohort study enriched with patients with type 2 diabetes. We assessed the cross-sectional association between IHL content, quantified by MRI, and sE-selectin via multivariable regression with adjustment for age, sex, type 2 diabetes, educational level, BMI, Dutch Healthy Diet index, physical activity, and the Matsuda index. RESULTS: Standardized IHL content was associated with (log) sE-selectin (age-, sex- and type 2 diabetes-adjusted regression coefficient [B]: 0.048 [95%CI:0.038;0.058], p<0.001), even after full adjustment (B: 0.030 [0.019;0.042], p<0.001). Such an association was not observed for soluble vascular cell adhesion molecule 1 (sVCAM-1) levels. CONCLUSION: IHL content is an independent determinant of sE-selectin at the population level. These findings support further studies to unravel the involvement of liver sinusoidal endothelial cells in the different stages of non-alcoholic fatty liver disease and the specific role of E-selectin herein.

Meta-Analysis Evaluating High-Sensitivity Cardiac Troponin T Kinetics after Coronary Artery Bypass Grafting in Relation to the Current Definitions of Myocardial Infarction.

Various definitions of myocardial infarction type 5 after coronary artery bypass grafting (CABG) have been proposed (myocardial infarction [MI-5], also known as peri-procedural MI), using different biomarkers and different and arbitrary cut-off values. This meta-analysis aims to determine the expected release of high-sensitivity cardiac troponin T (hs-cTnT) after CABG in general and after uncomplicated surgery and off-pump CABG in particular. A systematic search was applied to 3 databases. Studies on CABG as a single intervention and reporting on postoperative hs-cTnT concentrations on at least 2 different time points were included. All data on hs-cTnT concentrations were extracted, and mean concentrations at various points in time were stratified. Eventually, 15 studies were included, encompassing 2,646 patients. Preoperative hs-cTnT was 17 ng/L (95% confidence interval [CI] 13 to 20 ng/L). Hs-cTnT peaked at 6 to 8 hours postoperatively (628 ng/L, 95% CI 400 to 856 ng/L; 45x upper reference limit [URL]) and was still increased after 48 hours. In addition, peak hs-cTnT concentration was 614 ng/L (95% CI 282 to 947 ng/L) in patients with a definite uncomplicated postoperative course (i.e., without MI). For patients after off-pump CABG compared to on-pump CABG, the mean peak hs-cTnT concentration was 186 ng/L (95% CI 172 to 200 ng/L, 13 × URL) versus 629 ng/L (95% CI 529 to 726 ng/L, 45 × URL), respectively. In conclusion, postoperative hs-cTnT concentrations surpass most of the currently defined cut-off values for MI-5, even in perceived uncomplicated surgery, suggesting thorough reassessment. Hs-cTnT release differences following on-pump CABG versus off-pump CABG were observed, implying the need for different cut-off values for different surgical strategies.

Role of Drug-Gene Interactions and Pharmacogenetics in Simvastatin-Associated Pulmonary Toxicity.

INTRODUCTION: Simvastatin has previously been associated with drug-induced interstitial lung disease. In this retrospective observational study, cases with non-specific interstitial pneumonia (NSIP) or idiopathic pulmonary fibrosis (IPF) with simvastatin-associated pulmonary toxicity (n = 34) were evaluated. OBJECTIVE: To identify whether variations in genes encoding cytochrome P450 (CYP) enzymes or in the SLCO1B1 gene (Solute Carrier Organic anion transporting polypeptide 1B1 gene, encoding the organic anion transporting polypeptide 1B1 [OATP1B1] drug transporter enzyme), and/or characteristics of concomitantly used drugs, predispose patients to simvastatin-associated pulmonary toxicity. METHODS: Characteristics of concomitantly used drugs and/or variations in the CYP or SLCO1B1 genes and drug-gene interactions were assessed. The outcome after withdrawal of simvastatin and/or switch to another statin was assessed after 6 months. RESULTS: Multiple drug use involving either substrates and/or inhibitors of CYP3A4 and/or three or more drugs with the potential to cause acidosis explained the simvastatin-associated toxicity in 70.5% (n = 24) of cases. Cases did not differ significantly from controls regarding CYP3A4, CYP2C9, or OATP1B1 phenotypes, and genetic variation explained only 20.6% (n = 7) of cases. Withdrawal of simvastatin without switching to another statin or with a switch to a hydrophilic statin led to improvement or stabilization in all NSIP cases, whereas all cases who were switched to the lipophilic atorvastatin progressed. CONCLUSION: Simvastatin-associated pulmonary toxicity is multifactorial. For patients with this drug-induced pulmonary toxicity who need to continue taking a statin, switching to a hydrophilic statin should be considered. CLINICALTRIALS. GOV IDENTIFIER: NCT00267800, registered in 2005.

Differential Impact of Cytochrome 2C19 Allelic Variants on Three Different Platelet Function Tests in Clopidogrel-Treated Patients.

On-treatment platelet reactivity in clopidogrel-treated patients can be measured with several platelet function tests (PFTs). However, the agreement between different PFTs is only slight to moderate. Polymorphisms of the CYP2C19 gene have an impact on the metabolization of clopidogrel and, thereby, have an impact on on-treatment platelet reactivity. The aim of the current study is to evaluate the differential effects of the CYP2C19 genotype on three different PFTs. METHODS: From a prospective cohort study, we included patients treated with clopidogrel following percutaneous coronary intervention (PCI). One month after PCI, we simultaneously performed three different PFTs; light transmission aggregometry (LTA), VerifyNow P2Y12, and Multiplate. In whole EDTA blood, genotyping of the CYP2C19 polymorphisms was performed. RESULTS: We included 308 patients treated with clopidogrel in combination with aspirin (69.5%) and/or anticoagulants (33.8%) and, based on CYP2C19 genotyping, classified them as either extensive (36.4%), rapid (34.7%), intermediate (26.0%), or poor metabolizers (2.9%). On-treatment platelet reactivity as measured by LTA and VerifyNow is significantly affected by CYP2C19 metabolizer status (p < 0.01); as metabolizer status changes from rapid, via extensive and intermediate, to poor, the mean platelet reactivity increases accordingly (p < 0.01). On the contrary, for Multiplate, no such ordering of metabolizer groups was found (p = 0.10). CONCLUSIONS: For VerifyNow and LTA, the on-treatment platelet reactivity in clopidogrel-treated patients correlates well with the underlying CYP2C19 polymorphism. For Multiplate, no major effect of genetic background could be shown, and effects of other (patient-related) variables prevail. Thus, besides differences in test principles and the influence of patient-related factors, the disagreement between PFTs is partly explained by differential effects of the CYP2C19 genotype.

Machine learning-based glucose prediction with use of continuous glucose and physical activity monitoring data: The Maastricht Study.

BACKGROUND: Closed-loop insulin delivery systems, which integrate continuous glucose monitoring (CGM) and algorithms that continuously guide insulin dosing, have been shown to improve glycaemic control. The ability to predict future glucose values can further optimize such devices. In this study, we used machine learning to train models in predicting future glucose levels based on prior CGM and accelerometry data. METHODS: We used data from The Maastricht Study, an observational population-based cohort that comprises individuals with normal glucose metabolism, prediabetes, or type 2 diabetes. We included individuals who underwent >48h of CGM (n = 851), most of whom (n = 540) simultaneously wore an accelerometer to assess physical activity. A random subset of individuals was used to train models in predicting glucose levels at 15- and 60-minute intervals based on either CGM data or both CGM and accelerometer data. In the remaining individuals, model performance was evaluated with root-mean-square error (RMSE), Spearman's correlation coefficient (rho) and surveillance error grid. For a proof-of-concept translation, CGM-based prediction models were optimized and validated with the use of data from individuals with type 1 diabetes (OhioT1DM Dataset, n = 6). RESULTS: Models trained with CGM data were able to accurately predict glucose values at 15 (RMSE: 0.19mmol/L; rho: 0.96) and 60 minutes (RMSE: 0.59mmol/L, rho: 0.72). Model performance was comparable in individuals with type 2 diabetes. Incorporation of accelerometer data only slightly improved prediction. The error grid results indicated that model predictions were clinically safe (15 min: >99%, 60 min >98%). Our prediction models translated well to individuals with type 1 diabetes, which is reflected by high accuracy (RMSEs for 15 and 60 minutes of 0.43 and 1.73 mmol/L, respectively) and clinical safety (15 min: >99%, 60 min: >91%). CONCLUSIONS: Machine learning-based models are able to accurately and safely predict glucose values at 15- and 60-minute intervals based on CGM data only. Future research should further optimize the models for implementation in closed-loop insulin delivery systems.

Cardiac Troponin T: The Impact of Posttranslational Modifications on Analytical Immunoreactivity in Blood up to the Excretion in Urine.

Cardiac troponin T (cTnT) is a sensitive and specific biomarker for detecting cardiac muscle injury. Its concentration in blood can be significantly elevated outside the normal reference range under several pathophysiological conditions. The classical analytical method in routine clinical analysis to detect cTnT in serum or plasma is a single commercial immunoassay, which is designed to quantify the intact cTnT molecule. The targeted epitopes are located in the central region of the cTnT molecule. However, in blood cTnT exists in different biomolecular complexes and proteoforms: bound (to cardiac troponin subunits or to immunoglobulins) or unbound (as intact protein or as proteolytic proteoforms). While proteolysis is a principal posttranslational modification (PTM), other confirmed PTMs of the proteoforms include N-terminal initiator methionine removal, N-acetylation, O-phosphorylation, O-(N-acetyl)-glucosaminylation, N(ɛ)-(carboxymethyl)lysine modification and citrullination. The immunoassay probably detects several of those cTnT biomolecular complexes and proteoforms, as long as they have the centrally targeted epitopes in common. While analytical cTnT immunoreactivity has been studied predominantly in blood, it can also be detected in urine, although it is unclear in which proteoform cTnT immunoreactivity is present in urine. This review presents an overview of the current knowledge on the pathophysiological lifecycle of cTnT. It provides insight into the impact of PTMs, not only on the analytical immunoreactivity, but also on the excretion of cTnT in urine as one of the waste routes in that lifecycle. Accordingly, and after isolating the proteoforms from urine of patients suffering from proteinuria and acute myocardial infarction, the structures of some possible cTnT proteoforms are reconstructed using mass spectrometry and presented.

Mass Spectrometry Spatial-Omics on a Single Conductive Slide.

Mass spectrometry imaging (MSI) can analyze the spatial distribution of hundreds of different molecules directly from tissue sections usually placed on conductive glass slides to provide conductivity on the sample surface. Additional experiments are often required for molecular identification using consecutive sections on membrane slides compatible with laser capture microdissection (LMD). In this work, we demonstrate for the first time the use of a single conductive slide for both matrix-assisted laser desorption ionization (MALDI)-MSI and direct proteomics. In this workflow, regions of interest can be directly ablated with LMD while preserving protein integrity. These results offer an alternative for MSI-based multimodal spatial-omics.