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Background: Right ventricular (RV) function is predictive of outcome in patients with acute pulmonary embolism (PE). We assessed the possible incremental value of ventricular function with ECG-synchronized cardiac CT scanning over pulmonary CT scan angiography (CTA) for predicting short-term outcome in patients with suspected acute PE.Methods: The local ethics committee approved the study, and informed consent was obtained. In addition to standard CTA, 430 consecutive patients (193 men, 237 women; age, 55 ± 17 years) with suspected acute PE underwent ECG-synchronized CT scanning to assess ventricular function. RV/left ventricular (LV) function ratio and pulmonary obstruction index were obtained from non-ECG-synchronized CTA. Ventricular function was used to predict adverse events (< 6 weeks). Receiver operating characteristic analysis was performed to determine differences between ECG-synchronized CT scan and CTA in predicting outcome.Results: In 113 patients with PE, RV and LV ejection fraction (EF) and RV/LV diameter and volume ratios were associated with adverse outcome (P < .05), whereas vascular obstruction index was not. RVEF had the largest area under the receiver operating characteristic curve (0.75; 95% CI, 0.62-0.88) for predicting adverse outcome but had no significant incremental value over the RV/LV function ratio (0.72; 95% CI, 0.57-0.86; P = .25). All parameters revealed high negative predictive values (94%-98%) but low positive predictive values (13%-18%). For disease-specific outcome, areas under the curve were 0.80 (95% CI, 0.69-0.91) for RVEF vs 0.68 (95% CI, 0.48-0.88) for axial RV/LV ratio; the difference was not significant (P = .07). RVEF and RV/LV ratio proved better predictors for outcome than pulmonary obstruction index (both P < .001).Conclusions: RVEF was the best predictor for clinical outcome in patients with acute PE. However, incremental value of RVEF over axial RV/LV ratio was not found. [ABSTRACT FROM AUTHOR]

BACKGROUND: To evaluate the effect of lifestyle intervention in conjunction with rosiglitazone or placebo therapy on left ventricular (LV) mass, using cardiovascular magnetic resonance (CMR) in the metabolic syndrome. METHODS: The present study was a pre-specified substudy of a double-blind randomized controlled trial evaluating the effect of lifestyle intervention in conjunction with rosiglitazone or placebo therapy on carotid artery atherosclerosis in the metabolic syndrome. From this original study population, 10 subjects from the placebo group and 10 from the rosiglitazone group were randomly selected. At baseline and follow-up (52 weeks), clinical and laboratory measurements were assessed and a CMR-examination was performed to evaluate LV mass indexed for body surface area (LV mass-I). Subsequently, the effect of therapy (rosiglitazone vs. placebo) and clinical and laboratory variables on LV mass-I was evaluated. RESULTS: In both groups, body mass index, waist circumference, systolic and diastolic blood pressure significantly decreased during follow-up. Interestingly, LV mass-I significantly decreased in the placebo group (48.9 ± 5.3 g/m2 vs. 44.3 ± 5.6 g/m2, p < 0.001) indicating reverse remodeling, whereas LV mass-I remained unchanged in the rosiglitazone group (54.7 ± 9.9 g/m2 vs. 53.7 ± 9.2 g/m2, p = 0.3). After correction for systolic and diastolic blood pressure and triglyceride, the kind of therapy (rosiglitazone vs. placebo) remained the only significant predictor of LV mass-I reduction. CONCLUSIONS: Lifestyle intervention resulted in a reduction of LV mass-I in the metabolic syndrome, indicating reverse remodeling. However, rosiglitazone therapy may have inhibited this positive reverse remodeling. TRIAL REGISTRATION: Current Controlled Trials ISRCTN54951661. [ABSTRACT FROM AUTHOR]

Background: We previously developed an early reconnection/dormant conduction (ERC) prediction model for cryoballoon ablation to avoid a 30-min waiting period with adenosine infusion. We now aimed to validate this model based on time to isolation, number of unsuccessful cryo-applications, and nadir balloon temperature., Methods: Consecutive atrial fibrillation patients who underwent their first cryoballoon ablation in 2018-2019 at the Leiden University Medical Center were included. Model performance at the previous and at a new optimal cutoff value was determined., Results: A total of 201 patients were included (85.57% paroxysmal AF, 139 male, median age 61 years (IQR 53-69)). ERC was found in 35 of 201 included patients (17.41%) and in 41 of 774 veins (5.30%). In the present study population, the previous cutoff value of - 6.7 provided a sensitivity of 37.84% (previously 70%) and a specificity of 89.07% (previously 86%). Shifting the cutoff value to - 7.2 in both study populations resulted in a sensitivity of 72.50% and 72.97% and a specificity of 78.22% and 78.63% in data from the previous and present study respectively. Negative predictive values were 96.55% and 98.11%. Applying the model on the 101 patients of the present study with all necessary data for all veins resulted in 43 out of 101 patients (43%) not requiring a 30-min waiting period with adenosine testing. Two patients (2%) with ERC would have been missed when applying the model., Conclusions: The previously established ERC prediction model performs well, recommending its use for centers routinely using adenosine testing following PVI., (© 2024. The Author(s).)

Aims: To date, no studies have investigated the association between lipid species and coronary plaque changes over time, quantitatively assessed by serial imaging. We aimed to prospectively determine the association between lipid species quantified by a plasma lipidomic analysis and coronary plaque changes according to composition assessed by a quantitative serial analysis of coronary computed tomography angiography (CTA)., Methods and Results: Patients with suspected coronary artery disease (CAD) undergoing baseline coronary CTA were prospectively enrolled by seven EU centres in the SMARTool study and submitted to clinical, molecular, and coronary CTA re-evaluation at follow-up (an inter-scan period of 6.39 ± 1.17 years). Out of 202 patients who were analysed in the SMARTool main clinical study, a lipidomic analysis was performed in 154 patients before the baseline coronary CTA, and this group was included in the present study. A quantitative CTA analysis was performed by using a separate core laboratory blinded from clinical data. In the univariable analysis, it was found that no lipid species were significantly associated with annual total and calcified plaque changes. After adjusting for clinical variables at baseline and statin use, it was found that three lipid species were significantly associated with non-calcified plaque progression. In detail, cholesteryl ester(20:3), sphingomyelin (SM)(40:3), and SM(41:1) were found to be positively related to non-calcified plaque progression (Bonferroni-adjusted P-values = 0.005, 0.016, and 0.004, respectively)., Conclusion: The current study showed an independent relationship between specific lipid species determined by a plasma lipidomic analysis and non-calcified coronary plaque progression assessed by a serial, quantitative coronary CTA analysis., Competing Interests: Conflict of interest: A.S. received fees for consultancy or lectures from Abbot, Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective: Patients with a systemic right ventricle (sRV) in the context of transposition of the great arteries (TGA) after atrial switch or congenitally corrected TGA (ccTGA) are prone to sRV dysfunction. Pharmacological options for sRV failure remain poorly defined. This study aims to investigate the tolerability and effects of sacubitril/valsartan on sRV failure in adult patients with sRV., Methods: In this two-centre, prospective cohort study, all consecutive adult patients with symptomatic heart failure and at least moderately reduced sRV systolic function were initiated on sacubitril/valsartan and underwent structured follow-up., Results: Data of 40 patients were included (40% female, 30% ccTGA, median age 48 (44-53) years). Five patients discontinued therapy during titration. Median follow-up was 24 (12-36) months. The maximal dose was tolerated by 49% of patients. No episodes of hyperkalaemia or renal function decline occurred. Six-minute walking distance increased significantly after 6 months of treatment (569±16 to 597±16 m, p=0.016). Serum N-terminal-prohormone brain natriuretic peptide (NT-proBNP) levels decreased significantly after 3 months (567 (374-1134) to 404 (226-633) ng/L, p<0.001). Small, yet consistent echocardiographic improvements in sRV function were observed after 6 months (sRV global longitudinal strain: -11.1±0.5% to -12.6±0.7%, p<0.001, and fractional area change: 20% (16%-24%) to 26% (19%-30%), p<0.001). The linear mixed-effects model illustrated that after first follow-up moment, no time effect was present for the parameters., Conclusions: Treatment with sacubitril/valsartan was associated with a low rate of adverse effects in this adult sRV cohort. Persisting improvement in 6-minute walking test distance, NT-proBNP levels and echocardiographic parameters of sRV function was observed in an on-treatment analysis and showed no differential response based on sex or anatomy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate the prognostic impact of left ventricular (LV) diastolic dysfunction in patients with moderate aortic stenosis (AS) and preserved LV systolic function., Methods: Patients with a first diagnosis of moderate AS (aortic valve area >1.0 and ≤1.5 cm 2 ) and preserved LV systolic function (LV ejection fraction ≥50%) were identified. LV diastolic function was evaluated using echocardiographic criteria according to the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines. Clinical outcomes were defined as all-cause mortality and a composite of all-cause mortality and aortic valve replacement (AVR)., Results: Of 1247 patients (age 74±10 years, 47% men), 535 (43%) had LV diastolic dysfunction at baseline. Patients with LV diastolic dysfunction showed significantly higher mortality rates at 1-year, 3-year and 5-year follow-up (13%, 30% and 41%, respectively) when compared with patients with normal LV diastolic function (6%, 17% and 29%, respectively) (p<0.001). On multivariable analysis, LV diastolic dysfunction was independently associated with all-cause mortality (HR 1.368; 95% CI 1.085 to 1.725; p=0.008) and the composite endpoint of all-cause mortality and AVR (HR 1.241; 95% CI 1.035 to 1.488; p=0.020)., Conclusions: LV diastolic dysfunction is independently associated with all-cause mortality and the composite endpoint of all-cause mortality and AVR in patients with moderate AS and preserved LV systolic function. Assessment of LV diastolic function therefore contributes significantly to the risk stratification of patients with moderate AS. Future clinical trials are needed to investigate whether patients with moderate AS and LV diastolic dysfunction may benefit from earlier valve intervention., Competing Interests: Competing interests: The Department of Cardiology of the Leiden University Medical Centre received unrestricted research grants from Abbott Vascular, Bayer, Biotronik, Bioventrix, Boston Scientific, Edwards Lifesciences, GE Healthcare and Medtronic. JJB received speaker fees from Abbott Vascular. NAM received speaker fees from Abbott Vascular and GE Healthcare. VD received speaker fees from Abbott Vascular, Edwards Lifesciences, MSD and GE Healthcare. The remaining authors have nothing to disclose., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Catheter ablation of long-standing persistent atrial fibrillation (LSPAF) remains challenging, with suboptimal success rates obtained following multiple procedures. Thoracoscopic ablation has shown effective at creating transmural lesions around the pulmonary veins and box; however, long-term rhythm follow-up data are lacking. This study aims, for the first time, to assess the long-term outcomes of thoracoscopic pulmonary vein and box ablation in LSPAF., Methods: Rhythm follow-up consisted of continuous rhythm monitoring using implanted loop recorders or 24-h Holter recordings. Rhythm status and touch-up interventions were assessed up to 5 years., Results: Seventy-seven patients with symptomatic LSPAF underwent thoracoscopic ablation in 2 centres. Freedom from atrial arrhythmias at 5 years was 50% following a single thoracoscopic procedure and 68% allowing endocardial touch-up procedures (performed in 21% of patients). The mean atrial fibrillation burden in patients with continuous monitoring was reduced from 100% preoperatively to 0.1% at the end of the blanking period and 8.0% during the second year. Antiarrhythmic drug use decreased from 49.4% preoperative to 12.1% and 14.3% at 2 and 5 years, respectively (P < 0.001). Continuous rhythm monitoring resulted in higher recurrence detection rates compared to 24-h Holter monitoring at 2-year follow-up (hazard ratio: 6.5, P = 0.003), with comparable recurrence rates at 5-year follow-up., Conclusions: Thoracoscopic pulmonary vein and box isolation are effective in long-term restoration of sinus rhythm in LSPAF, especially when complemented by endocardial touch-up procedures, as demonstrated by the 68% freedom rate at 5 years. Continuous rhythm monitoring revealed earlier, but not more numerous documentation of recurrences at 5-year follow-up., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Long-term data on sex-differences in coronary plaque changes over time is lacking in a low-to-intermediate risk population of stable coronary artery disease (CAD). The aim of this study was to evaluate the role of sex on long-term plaque progression and evolution of plaque composition. Furthermore, the influence of menopause on plaque progression and composition was also evaluated. Patients that underwent a coronary computed tomography angiography (CTA) were prospectively included to undergo a follow-up coronary CTA. Total and compositional plaque volumes were normalized using the vessel volume to calculate a percentage atheroma volume (PAV). To investigate the influence of menopause on plaque progression, patients were divided into two groups, under and over 55 years of age. In total, 211 patients were included in this analysis, 146 (69%) men. The mean interscan period between baseline and follow-up coronary CTA was 6.2 ± 1.4 years. Women were older, had higher HDL levels and presented more often with atypical chest pain. Men had 434 plaque sites and women 156. On a per-lesion analysis, women had less fibro-fatty PAV compared to men (β -1.3 ± 0.4%; p < 0.001), with no other significant differences. When stratifying patients by 55 years age threshold, fibro-fatty PAV remained higher in men in both age groups (p < 0.05) whilst women younger than 55 years demonstrated more regression of fibrous (β -0.8 ± 0.3% per year; p = 0.002) and non-calcified PAV (β -0.7 ± 0.3% per year; p = 0.027). In a low-to-intermediate risk population of stable CAD patients, no significant sex differences in total PAV increase over time were observed. Fibro-fatty PAV was lower in women at any age and women under 55 years demonstrated significantly greater reduction in fibrous and non-calcified PAV over time compared to age-matched men. (ClinicalTrials.gov number, NCT04448691.)., (© 2021. The Author(s).)

Background: Predicting early reconnection/dormant conduction (ERC) immediately after pulmonary vein isolation (PVI) can avoid a waiting period with adenosine testing., Objective: To identify procedural and biophysical parameters predicting ERC., Methods: Consecutive atrial fibrillation (AF) patients undergoing a first cryoballoon ablation (Arctic Front Advance) between 2014 and 2017 were included. ERC was defined as manifest or dormant pulmonary vein (PV) reconnection with adenosine 30 minutes after PVI. Time to isolation (TTI), balloon temperatures (BT), and thawing times were evaluated as potential predictors for ERC. Based on a multivariable model, cut-off-values were defined and a formula was constructed to be used in clinical practice., Results: A total of 136 patients (60 ± 10 years, 96 male, 95% paroxysmal AF) were included. ERC was found in 40 (29%) patients (ERC group) and in 53 of 575 (9%) veins. Procedural and total ablation time and the number of unsuccessful freezes were significantly longer/higher in the ERC group compared to the non-ERC group (150 ± 40 vs 125 ± 34 minutes; 24 ± 5 vs 17 ± 4 minutes, and 38% vs 24%, respectively ( P = .028). Multivariable analysis showed that a higher nadir balloon temperature (hazard ratio [HR] 1.17 [1.09-1.23, P < .001), a higher number of unsuccessful freezes (HR 1.69 [1.15-2.49], P = .008) and a longer TTI (HR 1.02 [1.01-1.03], P < .001) were independently associated with ERC, leading to the following formula: 0.02 × TTI + 0.5 × number of unsuccessful freezes + 0.2 × nadir BT with a cut-off value of ≤-6.7 to refrain from a waiting period with adenosine testing., Conclusion: Three easily available parameters were associated with ERC. Using these parameters during ablation can help to avoid a 30-minute waiting period and adenosine testing., (© 2021 Heart Rhythm Society. Published by Elsevier Inc.)

Background Progression of coronary artery disease using serial coronary computed tomography angiography (CTA) is of clinical interest. Our primary aim was to prospectively assess the impact of clinical characteristics and statin use on quantitatively assessed coronary plaque progression in a low-risk study population during long-term follow-up. Methods Patients who previously underwent coronary CTA for suspected coronary artery disease were prospectively included to undergo follow-up coronary CTA. The primary end point was coronary artery disease progression, defined as the absolute annual increase in total, calcified, and noncalcified plaque volume by quantitative CTA analysis. Results In total, 202 patients underwent serial coronary CTA with a mean interscan period of 6.2±1.4 years. On a per-plaque basis, increasing age (β=0.070; P =0.058) and hypertension (β=1.380; P =0.075) were nonsignificantly associated with annual total plaque progression. Male sex (β=1.676; P =0.009), diabetes mellitus (β=1.725; P =0.012), and statin use (β=1.498; P =0.046) showed an independent association with annual progression of calcified plaque. While hypertension (β=2.259; P =0.015) was an independent determinant of noncalcified plaque progression, statin use (β=-2.178; P =0.050) was borderline significantly associated with a reduced progression of noncalcified plaque. Conclusions Statin use was associated with an increased progression of calcified coronary plaque and a reduced progression of noncalcified coronary plaque, potentially reflecting calcification of the noncalcified plaque component. Whereas hypertension was the only modifiable risk factor predictive of noncalcified plaque progression, diabetes mellitus mainly led to an increase in calcified plaque. These findings could yield the need for intensified preventive treatment of patients with diabetes mellitus and hypertension to slow and stabilize coronary artery disease progression and improve clinical outcome.

Background: A high number of vitamin K antagonist (VKA) users have a low proportion of time in therapeutic range (TTR) resulting in a high number of bleeding and thromboembolism events., Objective: Can the quality of anticoagulation be improved by dispensing VKAs via multidose drug dispensing (MDD)., Method: A randomized controlled trial in the Netherlands. Patients who used VKAs, ≥65 years of age with a TTR <65% were eligible for inclusion. All oral drugs were dispensed via MDD. In MDD systems, all oral chronic medication intended for one dosing moment is packed in plastic disposable pouches. Controls received VKAs by manual dispensing. The difference in TTR between the 6 months after- and 6 months before the index date. A mixed-effects model with the intervention, TTR before the index date, MDD system at baseline as covariates, and pharmacy as random effect. A per-protocol analysis was performed with all patients who completed the study as intended., Results: One hundred and seventy-nine patients were included. Mean age was 80.0 (SD 6.9) years. Mean TTR during the study was 79.2 ± 18.0% in the intervention group and 72.5 ± 20.1% in the control group. The intervention resulted in a 5.6% (95% CI: 0.1-11.1) increase in TTR compared to the control group. Per-protocol analysis resulted in an 8.3% (95% CI: 0.99-15.61) increase in TTR compared to the control group. No differences in reduction were observed between the intervention and control group., Conclusion: The quality of anticoagulation can be improved with the use of MDD systems., (© 2019 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Aims: Quantitative flow ratio (QFR) is a recently developed technique to calculate fractional flow reserve (FFR) based on 3D quantitative coronary angiography and computational fluid dynamics, obviating the need for a pressure-wire and hyperaemia induction. QFR might be used to guide patient selection for FFR and subsequent percutaneous coronary intervention (PCI) referral in hospitals not capable to perform FFR and PCI. We aimed to investigate the feasibility to use QFR to appropriately select patients for FFR referral., Methods and Results: Patients who underwent invasive coronary angiography in a hospital where FFR and PCI could not be performed and were referred to our hospital for invasive FFR measurement, were included. Angiogram images from the referring hospitals were retrospectively collected for QFR analysis. Based on QFR cut-off values of 0.77 and 0.86, our patient cohort was reclassified to 'no referral' (QFR ≥0.86), referral for 'FFR' (QFR 0.78-0.85), or 'direct PCI' (QFR ≤0.77). In total, 290 patients were included. Overall accuracy of QFR to detect an invasive FFR of ≤0.80 was 86%. Based on a QFR cut-off value of 0.86, a 50% reduction in patient referral for FFR could be obtained, while only 5% of these patients had an invasive FFR of ≤0.80 (thus, these patients were incorrectly reclassified to the 'no referral' group). Furthermore, 22% of the patients that still need to be referred could undergo direct PCI, based on a QFR cut-off value of 0.77., Conclusion: QFR is feasible to use for the selection of patients for FFR referral., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Objectives: Clostridioides difficile infection (CDI) has become the main cause of nosocomial infective diarrhoea. To survey and control the spread of different C. difficile strains, there is a need for suitable rapid tests. The aim of this study was to identify peptide/protein markers for the rapid recognition of C. difficile strains by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS)., Methods: We analysed 44 well-characterized strains, belonging to eight different multi-locus sequence types (MLST), using ultrahigh-resolution Fourier transform ion cyclotron resonance (FTICR) MS. The amino acid sequence of two peptide markers specific for MLST-1 and MLST-11 strains was elucidated by MALDI-TOF-MS/MS. The investigation of 2689 C. difficile genomes allowed the determination of the sensitivity and specificity of these markers. C18-solid-phased extraction was used to enrich the MLST-1 marker., Results: Two peptide markers (m/z 4927.81 and m/z 5001.84) were identified and characterized for MLST-1 and MLST-11 strains, respectively. The MLST-1 marker was found in 786 genomes of which three did not belong to MLST-1. The MLST-11 marker was found in 319 genomes, of which 14 did not belong to MLST-11. Importantly, all MLST-1 and MLST-11 genomes were positive for their respective marker. Furthermore, a peptide marker (m/z 5015.86) specific for MLST-15 was found in 59 genomes. We translated our findings into a fast and simple method that allowed the unambiguous identification of the MLST-1 marker on a MALDI-TOF-MS platform., Conclusions: MALDI-FTICR MS-based peptide profiling resulted in the identification of peptide markers for C. difficile MLST-1 and MLST-11., (Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Multidose drug dispensing (MDD) is used to help patients take their medicines appropriately. Little is known about drug regimen changes within these MDD systems and how they are effectuated by the community pharmacist. Manual immediate adjustments of the MDD system could introduce dispensing errors. MDD guidelines therefore recommend to effectuate drug regimen changes at the start of a new MDD system., Objective: The aim of this study was to investigate the frequency, type, procedure followed, immediate necessity, and time taken to make MDD adjustments., Methods: This was a cross-sectional study in eight community pharmacies in the Netherlands. All adjustments to MDD systems were systematically documented for 3 weeks by the community pharmacist., Results: Overall, 261 MDD adjustments involving 364 drug changes were documented for 250 patients: 127 (35%) drug changes involved the addition of a new drug, 124 (34%) a change in dosage, and 95 (26%) drug discontinuation. Of the MDD adjustments, 135 (52%) were effectuated immediately: 81 (31%) by adjusting the MDD system manually, 49 (19%) by temporarily dispensing the drug separately from the MDD system, and 5 (2%) by ordering a new MDD system. Pharmacists considered that 36 (27%) of the immediate MDD adjustments could have been deferred until the next MDD system was produced. Immediate adjustment took significantly longer than deferred adjustment (p < 0.001)., Conclusions: This study shows that in patients using MDD systems, over half of the drug regimen changes are adjusted immediately. The necessity of these immediate changes should be critically evaluated., (Copyright © 2018. Published by Elsevier Inc.)

Background Automated multidose drug dispensing is used to support patients with their medication management. Though multidose drug dispensing systems are frequently used, little is known about patients' experiences with multidose drug dispensing systems. Objective To explore patients' experiences with the initiation and use of multidose drug dispensing systems. Setting A survey was carried out with patients using multidose drug dispensing systems through three community pharmacies. Method A semi-structured interview protocol was designed based on existing literature and a pilot study. Main outcome measures The main outcome measures were (1) patients' experiences with initiating multidose drug dispensing systems and (2) patients' experienced advantages and disadvantages of multidose drug dispensing systems. Results The start of multidose drug dispensing was discussed with 76% of the patients (n = 62). Ninety percent of patients expressed the opinion that the multidose drug dispensing system supported them with their medication management. Sixty patients reported 110 advantages, which can be organized into the following categories: improved medication adherence and medication safety (59%); patient's convenience (40%); and other (1%). Sixty-nine percent of patients reported no disadvantages, 24% had problems opening the bags or outer packaging and 13% had problems with the legibility of the printed text on the bag. Conclusion In concordance with the Dutch guideline, patients are generally involved in the decision to initiate an multidose drug dispensing system. Patients are very satisfied using the system and report multiple advantages. Multidose drug dispensing systems may be further improved by simplifying the manual opening of the bags and improving the legibility of the text on the bags.

Aims: The aim of this study was to determine the long-term prognostic value of infarct size and myocardial ischaemia on single-photon emission computed tomography myocardial perfusion imaging (SPECT MPI) after primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI)., Methods and Results: In total, 1092 STEMI patients who underwent primary PCI and SPECT MPI within 1-6 months were included (median follow-up time of 6.9 years). In the entire cohort, SPECT infarct size was independently associated with the composite of cardiac death or reinfarction [hazard ratio (HR) per 10% increase in summed rest score 1.33; 95% confidence interval (95% CI) 1.12-1.58; P = 0.001], whereas myocardial ischaemia was not (HR per 5% increase in summed difference score 1.18; 95% CI 0.94-1.48; P = 0.16). Addition of SPECT infarct size to a model including the clinical variables provided significant incremental prognostic value for the prediction of cardiac death or reinfarction (global χ2 13.8 vs. 24.2; P = 0.002), whereas addition of SPECT ischaemia did not add significantly (global χ2 24.2 vs. 25.6; P = 0.24). In the subgroup of patients with left ventricular ejection fraction (LVEF) ≤ 45%, SPECT infarct size was independently associated with cardiac death or reinfarction (HR 1.59; 95% CI 1.15-2.22; P = 0.006), whereas in patients with LVEF > 45%, only SPECT ischaemia was independently associated with cardiac death or reinfarction (HR 1.28; 95% CI 1.00-1.63; P = 0.050)., Conclusion: In patients with first STEMI and primary PCI, SPECT infarct size was independently associated with cardiac death and/or reinfarction, whereas myocardial ischaemia was not. In patients with LVEF ≤ 45%, SPECT infarct size was independently associated with cardiac death or reinfarction, whereas myocardial ischaemia was not. Conversely, in patients with LVEF > 45%, only SPECT ischaemia was independently associated with cardiac death or reinfarction.

Purpose: It is unknown if multidose drug dispensing (MDD) systems are initiated for the appropriate patients. Therefore, the objective of this study was to compare the medication management problems of patients who were about to start with a MDD system (MDD patients) and patients who continued manually dispensed medication (non-MDD users) in order to identify if the appropriate patients receive a MDD system., Methods: Patient interviews (semi-structured) were conducted by 44 community pharmacists at the patient's home. Patients over 65 years of age, home dwelling and using at least five chronic drugs, were eligible for the study. An assessment tool was developed including 22 potential medication management problems, covering four domains: functional (7), organizational (7), medication adherence (6), and medication knowledge (2). Median scores were calculated with the interquartile range. Additionally, cognitive function was assessed with the Mini-Cog and frailty using the Groningen Frailty Indicator., Results: One hundred eighty-eight MDD users and 230 non-MDD users were interviewed. MDD users were older, more often female, and using more drugs. Forty-two percent of the MDD users were possibly cognitively impaired and 63% were assessed as frail compared to 20 and 27% respectively of the non-MDD users. MDD users had more potential organizational problems (3 vs. 1; p < 0.01), functional problems (2 vs. 1; p < 0.01), medication adherence problems (1 vs. 0; p < 0.01), and medication knowledge problems (1 vs. 0; p < 0.01) compared to non-MDD users. Seventy percent of the MDD users scored six or more potential medication management problems while this was 22% among non-MDD users., Conclusions: The majority of MDD systems were initiated for patients who experienced multiple potential medication management problems suggesting a decreased medication management capacity.

Purpose: A new method has been developed to calculate fractional flow reserve (FFR) from invasive coronary angiography, the so-called "contrast-flow quantitative flow ratio (cQFR)". Recently, cQFR was compared to invasive FFR in intermediate coronary lesions showing an overall diagnostic accuracy of 85%. The purpose of this study was to investigate the relationship between cQFR and myocardial ischemia assessed by single-photon emission computed tomography myocardial perfusion imaging (SPECT MPI)., Methods: Patients who underwent SPECT MPI and coronary angiography within 3 months were included. The cQFR computation was performed offline, using dedicated software. The cQFR computation was based on 3-dimensional quantitative coronary angiography (QCA) and computational fluid dynamics. The standard 17-segment model was used to determine the vascular territories. Myocardial ischemia was defined as a summed difference score ≥2 in a vascular territory. A cQFR of ≤0.80 was considered abnormal., Results: Two hundred and twenty-four coronary arteries were analysed in 85 patients. Overall accuracy of cQFR to detect ischemia on SPECT MPI was 90%. In multivariable analysis, cQFR was independently associated with ischemia on SPECT MPI (OR per 0.01 decrease of cQFR: 1.10; 95% CI 1.04-1.18, p = 0.002), whereas clinical and QCA parameters were not. Furthermore, cQFR showed incremental value for the detection of ischemia compared to clinical and QCA parameters (global chi square 48.7 to 62.6; p <0.001)., Conclusions: A good relationship between cQFR and SPECT MPI was found. cQFR was independently associated with ischemia on SPECT MPI and showed incremental value to detect ischemia compared to clinical and QCA parameters.

Background: The value of left atrial (LA) diameter, volume, and strain to risk stratify hypertrophic cardiomyopathy patients for new-onset atrial fibrillation (AF) was explored., Methods and Results: A total of 242 hypertrophic cardiomyopathy patients without AF history were evaluated by (speckle-tracking) echocardiography. During mean follow-up of 4.8±3.7 years, 41 patients (17%) developed new-onset AF. Multivariable analysis showed LA volume (≥37 mL/m 2 ; hazard ratio, 2.68; 95% confidence interval, 1.30-5.54; P =0.008) and LA strain (≤23.4%; hazard ratio, 3.22; 95% confidence interval, 1.50-6.88; P =0.003), but not LA diameter (≥45 mm; hazard ratio, 1.67; 95% confidence interval, 0.84-3.32; P =0.145), as independent AF correlates. Importantly, 59% (n=24) of AF events occurred despite a baseline LA diameter <45 mm, observed in 185 patients. In this patient subset, LA strain (area under the curve 0.73) and LA volume (area under the curve 0.83) showed good predictive value for new-onset AF. Furthermore, patients with LA volume <37 versus ≥37 mL/m 2 and LA strain >23.4% versus ≤23.4% had superior 5-year AF-free survival of 93% versus 80% ( P =0.003) and 98% versus 74% ( P =0.002), respectively. Importantly, LA volume <37 mL/m 2 and strain >23.4% yielded high negative predictive value (93% and 98%, respectively) for new-onset AF. Likelihood ratio test indicated incremental value of LA volume assessment ( P =0.011) on top of LA diameter to predict new-onset AF in hypertrophic cardiomyopathy patients with LA diameter <45 mm, which tended to increase further by addition of LA strain ( P =0.126)., Conclusions: LA diameter, volume, and strain all relate to new-onset AF in hypertrophic cardiomyopathy patients. In patients with normal LA size, however, both LA volume and strain further refine risk stratification for new-onset AF., (© 2017 American Heart Association, Inc.)

The Dutch Sciatica Trial represents a longitudinal study with complex time-varying confounders as patients with poorer health conditions (e.g. more severe pain) are more likely to opt for surgery, which, in turn, may affect future outcomes (pain severity). A straightforward classical as-treated comparison at the end point would lead to biased estimation of the surgery effect. We present several strategies of causal treatment effect estimation that might be applicable for analyzing such data. These include an inverse probability of treatment weighted regression analysis, a marginal weighted analysis, an unweighted regression analysis, and several propensity score-based approaches. In addition, we demonstrate how to evaluate these approaches in a thorough simulation study where we generate various realistic complex confounding patterns akin to the sciatica study.

- Multidose drug dispensing (MDD) systems are individualised forms of distribution that give structure to medication use. - Starting to use a multidose drug dispensing system must be initiated in joint discussion with the patient, once alternatives such as dosing schemes or automatic repeat-prescription services have been considered. The patient's autonomy and self-management are central.- Studies have shown positive effects of individualised forms of distribution on intermediary outcome measures such as HbA1c, LDL cholesterol, blood pressure and adherence. - Changes in medication should preferably be implemented when the pharmacist orders a new multidose drug dispensing system. It is difficult for the pharmacist to determine whether an immediate change is necessary if the indication and other possible reasons for change are not known. - The prescriber should preferably enquire whether the patient has a multidose dispensing system and should state the moment or the reason for the change on the prescription.- Pharmacotherapy in patients using a multidose drug dispensing system should be reviewed annually.

Background: To date, no validated risk scores exist for prediction of recurrence risk or potential treatment effect for older people with a history of a cardiovascular event. Therefore, we assessed predictive values for recurrent cardiovascular disease of models with age and sex, traditional cardiovascular risk markers, and 'SMART risk score', all with and without addition of N-terminal pro-B-type natriuretic peptide (NT-proBNP). Treatment effect of pravastatin was assessed across low and high risk groups identified by the best performing models., Design and Methods: Post-hoc analysis in 2348 participants (age 70-82 years) with a history of cardiovascular disease within the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study. Composite endpoint was a recurrent cardiovascular event/cardiovascular mortality., Results: The models with age and sex, traditional risk markers and SMART risk score had comparable predictive values (area under the curve (AUC) 0.58, 0.61 and 0.59, respectively). Addition of NT-proBNP to these models improved AUCs with 0.07 (p for difference ((pdiff)) = 0.003), 0.05 (pdiff = 0.009) and 0.06 (pdiff < 0.001), respectively. For the model with age, sex and NT-proBNP, the hazard ratio for the composite endpoint in pravastatin users compared with placebo was 0.67 (95% confidence interval 0.49-0.90) for those in the highest third of predicted risk and 0.91 (0.57-1.46) in the lowest third, number needed to treat 12 and 115 (pdiff = 0.038) respectively., Conclusion: In secondary cardiovascular prevention in old age addition of NT-proBNP improves prediction of recurrent cardiovascular disease, cardiovascular mortality and treatment effect of pravastatin. A minimal model including age, sex and NT-proBNP predicts as accurately as complex risk models including NT-proBNP., (© The European Society of Cardiology 2015.)

The introduction of standardized matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) platforms in the medical microbiological practice has revolutionized the way microbial species identification is performed on a daily basis. To a large extent, this is due to the ease of operation. Acquired spectra are compared to profiles obtained from cultured colonies present in a reference spectra database. It is fast and reliable, and costs are low compared to previous diagnostic approaches. However, the low resolution and dynamic range of the MALDI-TOF profiles have shown limited applicability for the discrimination of different bacterial strains, as achieved with typing based on genetic markers. This is pivotal in cases where certain strains are associated with, e.g., virulence or antibiotic resistance. Ultrahigh resolution MALDI-FTICR MS allows the measurement of small proteins at isotopic resolution and can be used to analyze complex mixtures with increased dynamic range and higher precision than MALDI-TOF MS, while still generating results in a similar time frame. Here, we propose to use ultrahigh resolution 15T MALDI-Fourier transform ion cyclotron resonance (FTICR) MS to discriminate clinically relevant bacterial strains after species identification performed by MALDI-TOF MS. We used a collection of well characterized Pseudomonas aeruginosa strains, featuring distinct antibiotic resistance profiles, and isolates obtained during hospital outbreaks. Following cluster analysis based on amplification fragment length polymorphism (AFLP), these strains were grouped into three different clusters. The same clusters were obtained using protein profiles generated by MALDI-FTICR MS. Subsequent intact protein analysis by electrospray ionization (ESI)-collision-induced dissociation (CID)-FTICR MS was applied to identify protein isoforms that contribute to the separation of the different clusters, illustrating the additional advantage of this analytical platform.

Background: Pancreatic cancer (PC) surveillance is currently offered to individuals with a genetic predisposition to PC, but routinely used radiological screening modalities are not entirely reliable in detecting early-stage PC or its precursor lesions. We recently identified a discriminating PC biomarker signature in a sporadic patient cohort. In this study, we investigated if protein profiling can accurately distinguish PC from non-PC in a pancreatic surveillance cohort of genetically predisposed individuals., Methods: Serum samples of 66 individuals with a CDKN2A germline mutation who participated in the pancreatic surveillance program (5 cases, 61 controls) were obtained following a standardized protocol. After sample clean-up, peptide and protein profiles were obtained on an ultrahigh-resolution matrix-assisted laser desorption/ionization-Fourier transform ion cyclotron resonance mass spectrometry platform. A discriminant score for each sample was calculated with a previously designed prediction rule, and the median discriminant scores of cases and controls were compared. Individuals with precursor lesions of PC (n = 4) and individuals with a recent diagnosis of melanoma (n = 4) were also separately considered., Results: Cases had a higher median discriminant score than controls (0.26 vs 0.016; P = .001). The only individual with pathologically confirmed precursor lesions of PC could also be clearly distinguished from controls, and having a (recent) medical history of melanoma did not influence the protein signatures., Conclusions: Peptide and protein signatures are able to accurately distinguish PC cases from controls in a pancreatic surveillance setting. Mass spectrometry-based protein profiling therefore seems to be a promising candidate for implementation in the pancreatic surveillance program as an additional screening modality., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The detection of pancreatic tumors lacks a sensitive and specific diagnostic tool. Mass spectrometry (MS)-based profiling of serum proteins is a promising approach for discovery of new clinical biomarkers or biomarker signatures., Methods: Serum samples from pancreatic cancer (PC) patients and control individuals were collected and processed using a standardized protocol. Samples were divided in a calibration set (n = 49 PC and 110 controls) and a validation set (n = 39 PC and 75 controls). Peptide profiles were obtained using a combination of automated solid-phase extraction with reversed-phase C18 paramagnetic beads and matrix-assisted laser desorption ionization time-of-flight MS., Results: Linear discriminant analysis with double cross-validation resulted in a discriminating peptide signature for PC in the calibration set with a sensitivity of 78 % and a specificity of 91 % [area under the curve (AUC) of 92 %]. Classification was validated with a sensitivity of 93 % and a specificity of 100 % (AUC of 98 %), and the results were compared with carbohydrate antigen 19-9 levels and currently available clinical imaging techniques. The ten most discriminating peptide peaks were identified as fragments of proteins involved in the clotting cascade, acute phase response and immunologic response., Conclusions: In this study, it is shown that MS-based serum peptide profiles can discriminate between PC and control samples. The approach has great potential for high-throughput analysis in surveillance programs and appears to be most promising for patients with an inherited risk for PC, who benefit from more frequent screening.

Aim: Colorectal cancer (CRC) screening programmes detect early cancers but unfortunately have limited sensitivity and specificity. Mass spectrometry-based determination of serum peptide and protein profiles provides a new approach for improved screening., Method: Serum samples were obtained from 126 CRC patients before treatment and 277 control individuals. An additional group of samples from 50 CRC patients and 82 controls was used for validation. Peptide and protein enrichments were carried out using reverse-phase C18 and weak-cation exchange magnetic beads in an automated solid-phase extraction and spotting procedure. Profiles were acquired on a matrix-assisted laser desorption/ionization time-of-flight system. Discriminant rules using logistic regression were calibrated for the peptide and protein signatures separately, followed by combining the classifications to obtain double cross-validated predicted class probabilities. Results were validated on an identical patient set., Results: A discriminative power was found for patients with CRC representative for all histopathological stages compared with controls with an area under the curve of 0.95 in the test set (0.93 for the validation set) and with a high specificity (94-95%)., Conclusion: The study has shown that a serum peptide and protein biomarker signature can be used to distinguish CRC patients from healthy controls with high discriminative power. This relatively simple and cheap test is promising for CRC screening., (Colorectal Disease © 2014 The Association of Coloproctology of Great Britain and Ireland.)

We consider a re-analysis of the wait-and-see (control) arm of a recent clinical trial on sciatica. While the original randomised trial was designed to evaluate the public policy effect of a conservative wait-and-see approach versus early surgery, we investigate the impact of surgery at the individual patient level in a re-analysis of the wait-and-see group data. Both marginal structural model re-weighted estimates as well as propensity score adjusted analyses are presented. Results indicate that patients with high propensity to receive surgery may have beneficial effects at 2 years from delayed disc surgery.

Background: Currently, no suitable biomarkers for the early detection of pancreatic cancer (PC) are available. Proteins present in the serum could reflect a state of the disease. In this study, these profiles as a diagnostic marker for PC were evaluated., Methods: Serum samples were obtained from PC patients (n = 50 calibration set, n = 39 validation set) and healthy volunteers (n = 110 and n = 75 respectively) according to a uniform standardized collection and processing protocol. For peptide and protein isolation, automated solid-phase extraction (SPE) with Weak Cation Exchange (WCX) magnetic beads (MB) was performed using a 96-channel liquid handling platform. Protein profiles were obtained by mass spectrometry (MS) and evaluated by linear discriminant analysis with double cross-validation., Results: A discriminating profile for PC has been identified, with a sensitivity of 78% and a specificity of 89% in the calibration set with an area under the curve (AUC) of 90%. These results were validated with a sensitivity of 74% and a specificity of 91% (AUC 90%)., Conclusion: Serum profiles of healthy controls and PC can be discrimated between. Further research is warranted to evaluate specificity and whether this biosignature can be used for early detection in a high risk population., (© 2012 International Hepato-Pancreato-Biliary Association.)

To evaluate the effect of radiation dose reduction on image quality and diagnostic accuracy of coronary computed tomography (CT) angiography. Coronary CT angiography studies of 40 patients with (n = 20) and without (n = 20) significant (≥50 %) stenosis were included (26 male, 14 female, 57 ± 11 years). In addition to the original clinical reconstruction (100 % dose), simulated images were created that correspond to 50, 25 and 12.5 % of the original dose. Image quality and diagnostic performance in identifying significant stenosis were determined. Receiver-operator-characteristics analysis was used to assess diagnostic accuracy at different dose levels. The identification of patients with significant stenosis decreased consistently at doses of 50, 25 and 12.5 of the regular clinical acquisition (100 %). The effect was relatively weak at 50 % dose, and was strong at dose levels of 25 and 12.5 %. At lower doses a steady increase was observed for false negative findings. The number of coronary artery segments that were rated as diagnostic decreased gradually with dose, this was most prominent for smaller segments. The area-under-the-curve (AUC) was 0.90 (p = 0.4) at 50 % dose; accuracy decreased significantly with 25 % (AUC 0.70) and 12.5 % dose (AUC 0.60) (p < 0.0001), with underestimation of patients having significant stenosis. The clinical acquisition protocol for evaluation of coronary artery stenosis with CT angiography represents a good balance between image quality and patient dose. A potential for a modest (<50 %) reduction of tube current might exist. However, more substantial reduction of tube current will reduce diagnostic performance of coronary CT angiography substantially.

Purpose: Detection of breast cancer at early stage increases patient's survival. Mass spectrometry-based protein analysis of serum samples is a promising approach to obtain biomarker profiles for early detection. A combination of commonly applied solid-phase extraction procedures for clean-up may increase the number of detectable peptides and proteins. In this study, we have evaluated whether the classification performance of breast cancer profiles improves by using two serum workup procedures., Methods: Serum samples from 105 breast cancer patients and 202 healthy volunteers were processed according to a standardized protocol implemented on a high-end liquid-handling robot. Peptide and protein enrichments were carried out using weak-cation exchange (WCX) and reversed-phase (RP) C18 magnetic beads. Profiles were acquired on a matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometer. In this way, two different biomarker profiles were obtained for each serum sample, yielding a WCX- and RPC18-dataset., Results: The profiles were statistically evaluated with double cross-validation. Classification results of WCX- and RPC18-datasets were determined for each set separately and for the combination of both sets. Sensitivity and specificity were 82 and 87 % (WCX) and 73 and 93 % (RPC18) for the individual workup procedures. These values increased up to 84 and 95 %, respectively, upon combining the data., Conclusion: It was found that MALDI-TOF peptide and protein profiles can be used for classification of breast cancer with high sensitivity and specificity. The classification performance even improved when two workup procedures were applied, since these provide a greater number of features (proteins).

Purpose: Limited or absent axial rotation of the mobile insert of total knee prostheses could lead to high contact stresses and stresses at the bone-implant interface, which in turn might lead to implant loosening. The aim of this study was to assess knee kinematics and muscle activation and their possible change over time in patients with a highly congruent, mobile-bearing total knee prosthesis., Methods: A prospective series of 11 rheumatoid arthritis patients was included to participate in this fluoroscopic and EMG study; only 7 patients completed the study. Kinematic evaluations took place 7 months, 1 and 2 years post-operatively. Repeated measurements ANOVA and linear mixed-effects model for longitudinal data were used to compare the differences between the follow-ups., Results: There are no significant changes in axial rotations between follow-up moments for the femoral component as well as the mobile insert. The insert remained mobile and followed the femoral component from 0° until approximately 60° of knee flexion. Diverging and reversed axial rotations and translations were seen during the dynamic motions., Conclusions: Knee kinematics and muscle activation do not appear to change in the first 2 post-operative years. Reversed and divergent axial rotations with increasing knee flexion indicate that as soon as the congruency decreases, the femoral component is no longer forced in a certain position by the insert and moves to a self-imposed position. At lower knee flexion angles, the femoral component might be obstructed by the highly congruent insert and therefore might not be able to move freely., Level of Evidence: Therapeutic study, Level IV.

Background: The mobile-bearing variant of a single-radius design is assumed to provide more freedom of motion compared to the fixed-bearing variant because the insert does not restrict the natural movements of the femoral component. This would reduce the contact stresses and wear which in turn may have a positive effect on the fixation of the prosthesis to the bone and thereby decreases the risk for loosening. The aim of this study was to evaluate early migration of the tibial component and kinematics of a mobile-bearing and fixed-bearing total knee prosthesis of the same single-radius design., Methods: Twenty Triathlon single-radius posterior-stabilized knee prostheses were implanted (9 mobile-bearing and 11 fixed-bearing). Fluoroscopy and roentgen stereophotogrammetric analysis (RSA) were performed 6 and 12 months post-operatively., Findings: The 1 year post-operative RSA results showed considerable early migrations in 3 out of 9 mobile-bearing patients and 1 out of 11 fixed-bearing patients. The range of knee flexion was the same for the mobile-bearing and fixed-bearing group. The mobile insert was following the femoral component during motion., Interpretation: Despite the mobile insert following the femoral component during motion, and therefore performing as intended, no kinematic advantages of the mobile-bearing total knee prosthesis were seen. The fixed-bearing knee performed as good as the mobile-bearing knee and maybe even slightly better based on less irregular kinematics and less early migrations., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Radiologic evaluation of adults with febrile urinary tract infection (UTI) is frequently performed to exclude urological disorders. This study aims to develop a clinical rule predicting need for radiologic imaging., Methods: We conducted a prospective, observational study including consecutive adults with febrile UTI at 8 emergency departments (EDs) in the Netherlands. Outcomes of ultrasounds and computed tomographs of the urinary tract were classified as "urgent urological disorder" (pyonephrosis or abscess), "nonurgent urologic disorder," "normal," and "incidental nonurological findings." Urgent and nonurgent urologic disorders were classified as "clinically relevant radiologic findings." The data of 5 EDs were used as the derivation cohort, and 3 EDs served as the validation cohort., Results: Three hundred forty-six patients were included in the derivation cohort. Radiologic imaging was performed for 245 patients (71%). A prediction rule was derived, being the presence of a history of urolithiasis, a urine pH ≥7.0, and/or renal insufficiency (estimated glomerular filtration rate, ≤40 mL/min/1.73 m(3)). This rule predicts clinically relevant radiologic findings with a negative predictive value (NPV) of 93% and positive predictive value (PPV) of 24% and urgent urological disorders with an NPV of 99% and a PPV of 10%. In the validation cohort (n = 131), the NPV and PPV for clinically relevant radiologic findings were 89% and 20%, respectively; for urgent urological disorders, the values were 100% and 11%, respectively. Potential reduction of radiologic imaging by implementing the prediction rule was 40%., Conclusions: Radiologic imaging can selectively be applied in adults with febrile UTI without loss of clinically relevant information by using a simple clinical prediction rule.

Early diagnosis of cancer is of pivotal importance to reduce disease-related mortality. There is great need for non-invasive screening methods, yet current screening protocols have limited sensitivity and specificity. The use of serum biomarkers to discriminate cancer patients from healthy persons might be a tool to improve screening programs. Mass spectrometry based proteomics is widely applied as a technology for mapping and identifying peptides and proteins in body fluids. One commonly used approach in proteomics is peptide and protein profiling. Here, we present an overview of profiling methods that have the potential for implementation in a clinical setting and in national screening programs.

Objective: Remission has become an attainable goal of rheumatoid arthritis (RA) treatment, especially since the advent of biologic antirheumatic therapy. Because little is known about patients who achieve disease remission with conventional treatment, we used 2 large independent inception cohorts to study the prevalence of and predictive factors for disease-modifying antirheumatic drug (DMARD)-free sustained remission after treatment with conventional therapy., Methods: Remission of disease was assessed in 454 patients from the Leiden Early Arthritis Clinic (EAC) and in 895 patients from the British Early Rheumatoid Arthritis Study (ERAS) who fulfilled the American College of Rheumatology 1987 revised criteria for the classification of RA and were treated with conventional therapy. Sustained DMARD-free remission was defined as fulfilling the following criteria for at least 1 year: 1) no current DMARD use, 2) no swollen joints, and 3) classification as DMARD-free remission by the patient's rheumatologist. Predictive factors were identified by Cox regression analysis., Results: Sustained DMARD-free remission was achieved by 68 of 454 patients (15.0%) in the Leiden EAC and by 84 of 895 patients (9.4%) in the ERAS. Six factors were associated with sustained DMARD-free remission in both cohorts: acute onset, short symptom duration before inclusion, not smoking, little radiographic damage at baseline, absence of IgM rheumatoid factor (IgM-RF), and absence of HLA shared epitope alleles. In the ERAS, low disease activity at baseline was also predictive of remission. Multivariate analyses revealed symptom duration and the absence of autoantibodies (anti-cyclic citrullinated peptide 2 and IgM-RF) as independent predictors., Conclusion: Sustained DMARD-free remission in RA patients treated with conventional therapy is not uncommon. Symptom duration at presentation and the absence of autoantibodies are associated with sustained DMARD-free remission.

This paper present a summary and overview of an international competition on the construction of classifiers for mass spectrometry proteomic diagnosis. Design, data and preliminary results from the study are discussed.

We describe the usage of various assistive devices and identify factors associated with usage in patients with rheumatoid arthritis (RA). A cross-sectional, multicentre study was performed in three outpatient rheumatology clinics in the Netherlands. Two hundred forty patients with RA participated in the study. The main measures were questionnaires and a semi-structured interview regarding the possession and usage of 21 common assistive devices in the ISO9999 categories orthopaedic footwear, personal care, mobility, household and adaptations for housing. Potential factors associated with usage included sociodemographic variables, health status, quality of life, coping strategies, self-efficacy, outcome expectations and satisfaction. Out of 240 patients, 213 (89%) had one or more assistive devices in possession (median number of devices 3.0, interquartile range 3.0). The proportions of patients never using a device in possession varied between 8% for orthopaedic insoles and 23% for grab bars. The main factors related to usage varied among categories, but common determinants were a specific impairment or disability, satisfaction with the device or related services, self-efficacy and the number of devices in possession. In conclusion, in patients with RA, possession rates are high, with 23% or less of the devices in possession being abandoned. Overall, satisfaction rates were high. Factors associated with usage varied among categories and comprised, apart from the number of devices in possession and variables related to health status, also aspects of satisfaction with the device or related services or self-efficacy. The latter findings underline the need for a systematic evaluation of the outcomes of assistive devices by prescribing health professionals or suppliers in every individual case.

Objective: To evaluate the influence of lipid and glucose metabolism in the metabolic syndrome on aortic pulse wave velocity (PWV) and left ventricular (LV) diastolic function using magnetic resonance imaging (MRI)., Research Design and Methods: Aortic PWV and LV diastolic function were assessed using MRI in 16 subjects with the metabolic syndrome and 16 subjects without the metabolic syndrome matched for age, waist circumference, and blood pressure. The groups were compared using the unpaired t test or Mann-Whitney U test, and linear regression analysis was applied., Results: Aortic PWV was increased and LV diastolic function was decreased in subjects with compared with those without the metabolic syndrome. HDL cholesterol was independently associated with aortic PWV (R = -0.470, P < 0.01) and LV diastolic function (R = -0.421, P = 0.02)., Conclusions: Increased aortic PWV and decreased LV diastolic function is observed in subjects with the metabolic syndrome, regardless of blood pressure. Moreover, HDL cholesterol is independently associated with aortic PWV and LV diastolic function.

The objective of the study was to assess the effect of heart rate, filling condition and slice thickness on the accuracy of volumetric analysis based on multidetector-row computed tomography (MDCT) of a cardiac phantom. Retrospective electrocardiogram-gated MDCT of a pulsating phantom was performed under different conditions. End-diastolic volume (EDV) and end-systolic volume (ESV) for different heart rates (60-75 beats per minute), filling volumes and reconstructed slice thicknesses (2 mm and 5 mm) were obtained by three observers. Results were analysed by a linear mixed-effects model. Significant effects on the accuracy were found for heart rate (F-value, 7.3-39.2; p<0.004) and filling condition (F-value, 7.4-55.6; p<0.004), but not for slice thickness. Small relative differences in the assessment of EDV were found (range, -3% to 3%), but there was a trend for overestimation of the ESV (range, -1% to 18%). Underestimation of stroke volume and ejection fraction (range, -1% to -11%) became smaller under conditions of improved temporal resolution and larger EDV. Good interobserver agreement was found (SD <1.8 ml and <0.5%). In conclusion, MDCT allows sufficient and reliable measurements of ventricular volumes and calculation of left ventricle function for clinical applications. Heart rate and filling conditions significantly affect the accuracy of volumetrics, as demonstrated in this cardiac phantom. Thicker slices provide similar accuracy to thin slices.

Protein profiling in blood serum by fractionation and MS analysis has been applied in mice to assess its applicability as a fast, economical alternative to current DNA and RNA analyses for diagnosis of neuromuscular disorders. Mass spectra of peptides and proteins were generated using serum from dystrophin-deficient mdx and control mice by WCX ClinProt bead fractionation, followed by MALDI-MS. Double cross-validatory linear discriminant and logistic regression data analysis methods were compared with a new Bayesian logistic regression method. These were evaluated on their ability to discriminate between healthy and dystrophic samples, and to identify the discriminatory peaks in the mass spectra. All three approaches classified the spectra with comparable misclassification rates (between 18.4 and 20.6%), with much overlap between the differential peaks identified between the methods. The differential peak pattern from the Bayesian method was sparser and easier to interpret than from the other two methods, without compromising classifying strength. One of the two main differentiating peaks at m/z 3908 was identified as an N-terminal peptide of coagulation Factor XIIIa, previously identified in human serum. This work underlines the translational aspect of serum protein profiling in mice and supports a further study with serum from patients with neuromuscular disorders.

Objective: To describe the usage of functional wrist orthoses and to identify factors contributing to usage in patients with rheumatoid arthritis (RA)., Methods: A multicentre, cross-sectional study, including a random selection of patients with RA visiting outpatient clinics. A total of 240/362 eligible patients (66%) completed questionnaires, a semi-structured interview and a clinical assessment. Usage was registered according to eight categories ranging from 'always' to 'never'. Factors potentially associated with usage included demographic variables, the presence of wrist and hand complaints, general disease characteristics, mental and physical functioning, coping strategies and satisfaction with functional wrist orthoses. Logistic regression analyses were used to determine which factors were associated with the usage of wrist splints., Results: One hundred twenty-eight patients (53%) possessed functional wrist orthoses, whereas 74/128 (58%) were actually using them. Patients used them mainly during house keeping and cycling/driving. Main reasons for using the orthoses were relief of pain and joint protection, and main reasons for not using them were no need and problems with ease of use. Factors significantly associated with usage included the presence of wrist and hand complaints, worse physical functioning and greater satisfaction with comfort of the wrist orthoses., Conclusion: About half of patients with RA possessed functional wrist orthoses, with 58% of them actually being used. Apart from local complaints and general functional ability, satisfaction with comfort of the functional wrist orthoses appears to be an important factor for their usage. These results point at the need for additional research regarding modifiable factors associated with compliance, such as comfort and ease of use.

The aim of the study was to investigate whether radiologists can rank the image quality of digital radiographs with different doses; a preliminary study investigated whether reduced dose images provide sufficient diagnostic quality. Raw data of 40 chest radiographs (posteroanterior (PA) and lateral) obtained with a full-field slot-scan charge-coupled device system in 20 patients with chest pathology were used. Noise was added to simulate reduced dose levels to 50%, 25% and 12%. Four observers ranked the quality of the corresponding images and judged the diagnostic quality. Linear regression analysis was performed. Differences were found in image quality at the different dose levels for both PA (p

Background: Exhaled breath contains thousands of volatile organic compounds (VOCs) that could serve as biomarkers of lung disease. Electronic noses can distinguish VOC mixtures by pattern recognition., Objective: We hypothesized that an electronic nose can discriminate exhaled air of patients with asthma from healthy controls, and between patients with different disease severities., Methods: Ten young patients with mild asthma (25.1 +/- 5.9 years; FEV(1), 99.9 +/- 7.7% predicted), 10 young controls (26.8 +/- 6.4 years; FEV(1), 101.9 +/- 10.3), 10 older patients with severe asthma (49.5 +/- 12.0 years; FEV(1), 62.3 +/- 23.6), and 10 older controls (57.3 +/- 7.1 years; FEV(1), 108.3 +/- 14.7) joined a cross-sectional study with duplicate sampling of exhaled breath with an interval of 2 to 5 minutes. Subjects inspired VOC-filtered air by tidal breathing for 5 minutes, and a single expiratory vital capacity was collected into a Tedlar bag that was sampled by electronic nose (Cyranose 320) within 10 minutes. Smellprints were analyzed by linear discriminant analysis on principal component reduction. Cross-validation values (CVVs) were calculated., Results: Smellprints of patients with mild asthma were fully separated from young controls (CVV, 100%; Mahalanobis distance [M-distance], 5.32), and patients with severe asthma could be distinguished from old controls (CVV, 90%; M-distance, 2.77). Patients with mild and severe asthma could be less well discriminated (CVV, 65%; M-distance, 1.23), whereas the 2 control groups were indistinguishable (CVV, 50%; M-distance, 1.56). The duplicate samples replicated these results., Conclusion: An electronic nose can discriminate exhaled breath of patients with asthma from controls but is less accurate in distinguishing asthma severities., Clinical Implication: These findings warrant validation of electronic noses in diagnosing newly presented patients with asthma.

Aim of the Study: To investigate the seroprevalence of Helicobacter pylori infection in young children from the general population in The Netherlands., Methods: Determination of IgG antibodies against H. pylori, using an enzyme-linked immunosorbent assay technique [cutoff 0.32 Absorption Index (AI)], in serum from 1258 children who were 2-4 years of age. The serum was obtained from a serum bank of 6127 children who attended the community child healthcare centers in the Dutch province of Zuid-Holland., Results: In general, we found a seroprevalence of 1.2% of H. pylori infection, with a significant difference between the children with parents who were both Dutch (0.5%), and the children with at least one non-Dutch parent (2.6%) (P<0.001)., Conclusions: The prevalence of H. pylori infection in young infants in the general population in The Netherlands is low. Children with at least one non-Dutch parent form a risk group, however, for H. pylori infection in The Netherlands.

Background: The absolute risk of recurrences among patients using aspirin for prevention of cardiovascular events remains high. Persistent platelet reactivity despite aspirin therapy might explain this in part. Reported prevalences of this so-called aspirin resistance vary widely, between 0% and 57%., Objectives: The aim of the study was to systematically review all available evidence on prevalence of aspirin resistance and to study determinants of reported prevalence., Methods: Using a predefined search strategy, we searched electronic databases MEDLINE, EMBASE, CENTRAL, and Web of Science. To be included in our analysis, articles had to contain a laboratory definition of aspirin resistance, use aspirin as secondary prevention, and report associated prevalence., Results: We included 34 full-text articles and 8 meeting abstracts. The mean prevalence of aspirin resistance was 24% (95% CI 20%-28%). After adjustment for differences in definition, used dosage, and population, a statistically significant higher prevalence was found in studies with aspirin dosage < or =100 mg compared with > or =300 mg (36% [95% CI 28%-43%] vs 19% [95% CI 11%-26%], P < .0001). Studies measuring platelet aggregation using light aggregometry with arachidonic acid as an agonist had a pooled unadjusted prevalence of 6% (95% CI 0%-12%). In studies using point-of-care platelet function-analyzing devices, the unadjusted prevalence was significantly higher, at 26% (95% CI 21%-31%)., Conclusions: Prevalences widely differ between studies reporting on aspirin resistance. Both aspirin dosage and the method of defining aspirin resistance strongly influence estimated prevalence, which explains found heterogeneity among studies. On average, it appears that about 1 in 4 individuals may express biochemically defined aspirin resistance.

Our aim is to develop methods for identifying a (causal) variant or variants from a dense panel of single-nucleotide polymorphisms (SNPs) that are genotyped on the evidence of previous studies. Because a large number of SNPs are in close proximity to each other, the magnitude of linkage disequilibrium (LD) plays an important role. Namely, highly correlated SNPs may hamper standard methods such as multivariate logistic regression due to multicolinearity between the covariates. Sequences of models with high dimension naturally raise questions about model selection strategies. We investigate three variable selection methods based on logistic regression. The penalties on stepwise selection were imposed using the Akaike's Information Criterion (AIC), and using the lasso penalty. Finally, a Bayesian variable-selection logistic regression model was implemented. The methods are illustrated using the simulated dense SNPs including the causal DR/C locus on chromosome 6. We also evaluate model selection in terms of average prediction error across nine replicates. We conclude that for the Genetic Analysis Workshop 15 (GAW15) data, the newly developed Bayesian selection method performs well.

Purpose: To determine to what extent dose reduction results in decreased detection of simulated nodules on patient digital posteroanterior (PA) chest radiographs., Materials and Methods: Raw data from 20 clinical digital PA chest images that were reported as having normal findings and that were obtained with a slot-scan charge-coupled device system were used. For research protocol that concerns data with patient identities concealed, institutional review board approval is not required. One hundred twenty nodules varying in size and signal intensity were digitally simulated and added to the chest images. Hard copies were printed to represent a 100% dose and, by adding noise, to represent simulated patient doses of 50%, 25%, and 12%. Four radiologists reviewed images. Each lesion was registered as "detected" or "not detected." A semiparametric logistic regression model was used for statistical analysis., Results: The decrease in radiation dose from 100% to 50%, 25%, or 12% had no effect on lesion detection in the lungs. The decrease in radiation dose had an effect on lesion detection in the mediastinum, as probabilities deteriorated from the 100% dose to the 50%, 25%, and 12% dose with each step. Probabilities of smaller detection rates when compared with that of the reference category (100% dose) were 0.97 (95% confidence interval [CI]: -0.86, 0.012) for the 50% dose, 1 (CI: -0.59, -0.61) for the 25% dose, and 1 (CI: -2.41, -1.22) for the 12% dose. CIs for the effects were on the log(odds). Detection probability decreased with smaller and lower signal intensity lesions., Conclusion: At clinical digital radiography, dose reduction resulted in decreased observer detection of simulated nodules in the mediastinum but not in the lungs.