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Abstract Hepatocellular carcinoma (HCC) comprises 75 to 85% of all primary liver cancers. Current guidelines recommend a biannual HCC surveillance using ultrasound (US) for high-risk patients. However, due to its low sensitivity for detection of early-stage HCC lesions, there is an urgency for more sensitive surveillance tools. Here, we describe the potential of a short MRI surveillance (SMS) protocol for HCC, including axial T1-weighted in-out phase, fat-saturated T2-weighted, and diffusion-weighted sequences. In this prospective, multicenter, patient cohort study, patients will be recruited from existing HCC surveillance cohorts of six medical centers in The Netherlands. Surveillance patients who undergo biannual US, will be invited for SMS on the same day for 3 years. In case of a suspicious finding on either US or SMS, patients will be invited for a full MRI liver protocol including gadolinium-based contrast agent intravenous injection within 2 weeks. To our knowledge, this will be the first study to perform a head-to-head comparison with a paired US-MRI design. We hypothesize that the sensitivity of SMS for detection of early-stage HCC will be higher than that of US leading to improved survival of surveillance patients through timely HCC diagnosis. Furthermore, we hypothesize that the SMS-HCC protocol will prove cost-effective. Relevance statement The US sensitivity for detecting early-stage HCC has been reported to be less than 50%. We expect that the proposed SMS will detect at least twice as many early-stage HCC lesions and therefore prove to be cost-effective. Key points • The low sensitivity of US necessitates better imaging tools for HCC screening. • This is the first study with a paired US-MRI design. • This design will allow a head-to-head comparison in both diagnostics and patient-acceptance. • We expect that SMS can contribute to a higher survival rate. Graphical Abstract

Summary: Background: Increased cerebrovascular morbidity was reported in adults born small for gestational age (SGA) who were treated with growth hormone (GH) during childhood compared to the general population. Yet, previous studies lacked an appropriate control group which is a major limitation. We prospectively studied cerebral white matter hyperintensities (WMHs) in adults born SGA at 12 years after cessation of childhood GH-treatment (SGA-GH), compared to appropriate controls. Methods: In this prospective cohort study, performed between May 2016 and December 2020, total WMHs, periventricular WMHs (PVWMHs) and deep WMHs (DWMHs) were the primary outcomes of the study, they were qualitatively assessed using 3 Tesla (T) Magnetic Resonance Imaging (MRI) and scored using the Fazekas scale in SGA-GH adults and in 3 untreated control groups: adults born SGA with persistent short stature (SGA-S), adults born SGA with spontaneous catch-up growth to a normal height (SGA-CU) and adults born appropriate for gestational age with a normal height (AGA). Regression analyses were performed in the total cohort to evaluate the associations of GH-treatment and birth characteristics with WMHs. Findings: 297 adults were investigated (91 SGA-GH, 206 controls). Prevalence of total WMHs was 53.8% (95% CI 43.1–64.3) in SGA-GH, 40.5% (95% CI 25.6–56.7) in SGA-S, 73.9% (95% CI 61.9–83.7) in SGA-CU and 41.1% (95% CI 31.1–51.6) in AGA adults. No statistically significant differences in total WMHs, PVWMHs and DWMHs were found between SGA-GH compared to SGA-S and AGA adults. Highest prevalence of all type of WMHs was found in SGA-CU adults compared to all groups. Higher prevalence of total WMHs was associated with lower birth weight standard deviation score (SDS), but not with GH-treatment. Interpretation: Our findings suggest that GH-treatment in children born SGA has no negative impact on the prevalence of all type of WMHs at 12 years after GH cessation compared to appropriate controls. SGA-CU adults had the highest prevalence of all type of WMHs around age 30 years. Funding: Novo Nordisk.

Abstract Objective To provide a comprehensive framework for value assessment of artificial intelligence (AI) in radiology. Methods This paper presents the RADAR framework, which has been adapted from Fryback and Thornbury’s imaging efficacy framework to facilitate the valuation of radiology AI from conception to local implementation. Local efficacy has been newly introduced to underscore the importance of appraising an AI technology within its local environment. Furthermore, the RADAR framework is illustrated through a myriad of study designs that help assess value. Results RADAR presents a seven-level hierarchy, providing radiologists, researchers, and policymakers with a structured approach to the comprehensive assessment of value in radiology AI. RADAR is designed to be dynamic and meet the different valuation needs throughout the AI’s lifecycle. Initial phases like technical and diagnostic efficacy (RADAR-1 and RADAR-2) are assessed pre-clinical deployment via in silico clinical trials and cross-sectional studies. Subsequent stages, spanning from diagnostic thinking to patient outcome efficacy (RADAR-3 to RADAR-5), require clinical integration and are explored via randomized controlled trials and cohort studies. Cost-effectiveness efficacy (RADAR-6) takes a societal perspective on financial feasibility, addressed via health-economic evaluations. The final level, RADAR-7, determines how prior valuations translate locally, evaluated through budget impact analysis, multi-criteria decision analyses, and prospective monitoring. Conclusion The RADAR framework offers a comprehensive framework for valuing radiology AI. Its layered, hierarchical structure, combined with a focus on local relevance, aligns RADAR seamlessly with the principles of value-based radiology. Critical relevance statement The RADAR framework advances artificial intelligence in radiology by delineating a much-needed framework for comprehensive valuation. Keypoints • Radiology artificial intelligence lacks a comprehensive approach to value assessment. • The RADAR framework provides a dynamic, hierarchical method for thorough valuation of radiology AI. • RADAR advances clinical radiology by bridging the artificial intelligence implementation gap.

Abstract Background Although some evidence implicates the immune system in migraine attacks, its role during attack-free periods remains largely unexplored. Therefore, we assessed the association between the immune system and migraine status. Methods From the population-based Rotterdam Study, we included 6593 participants who underwent blood sampling and migraine assessments. In the blood samples, we measured white blood-cell-based immune markers. As a marker for the innate immune system, granulocyte and platelet counts were determined, whereas lymphocyte counts were used as a marker for the adaptive immune system. Migraine was assessed using a validated questionnaire based on ICHD-2 criteria. We investigated associations between blood-cell counts and migraine using logistic regression models adjusting for age, sex and other variables. Results Mean age of participants was 65.6 ± 11.2 years and 56.7% were female. The lifetime prevalence of migraine was 15.1% (995/6593). We found no statistically significant associations between granulocyte (odds ratio [OR] per standard deviation increase 1.01 95% Confidence Interval [CI]: 0.93–1.09), platelet (OR 1.01 CI: 0.94–1.09) or lymphocyte counts (OR 1.01 CI: 0.93–1.08) and migraine status. Conclusions Our results do not support an association between white blood-cell-based immunity markers and migraine status.

Abstract Background Advanced glycation end products (AGEs) have been linked to cardiovascular disease (CVD), especially coronary heart disease (CHD), but their role in CVD pathogenesis remains unclear. Therefore, we investigated cross-sectional associations of skin AGEs with subclinical atherosclerosis, arterial stiffness, and hypertension after confirming their relation with CHD. Methods In the population-based Rotterdam Study, skin AGEs were measured as skin autofluorescence (SAF). Prevalent MI was obtained from digital medical records. Carotid plaques, carotid intima-media thickness (IMT), coronary artery calcification (CAC), pulse wave velocity (PWV), and hypertension were assessed. Associations of SAF with endophenotypes were investigated in logistic and linear regression models adjusting for common cardiovascular risk factors. Effect modification by sex, diabetes mellitus, and chronic kidney disease (CKD) was tested. Results 3001 participants were included (mean age 73 (SD 9) years, 57% women). One unit higher SAF was associated with the presence of carotid plaques (OR 1.2 (0.92, 1.57)), a higher max IMT (0.08 SD (0.01, 0.15)), higher CAC (OR 2.2 (1.39, 3.48)), and PWV (0.09 SD (0.01, 0.16)), but not with hypertension (OR 0.99 (0.81, 1.21)). The associations with endophenotypes were more pronounced in men and participants with diabetes or CKD with significant interactions. Conclusions Previously documented associations between SAF and CVD, also found in our study, may be explained by the endophenotypes atherosclerosis and arterial stiffness, especially in men and individuals with diabetes or CKD, but not by hypertension. Longitudinal studies are needed to replicate these findings and to test if SAF is an independent risk factor or biomarker of CVD. Trial registration: The Rotterdam Study has been entered into the Netherlands National Trial Register (NTR; www.trialregister.nl ) and the WHO International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/network/primary/en/ ) under shared catalogue number NTR6831.

Besides age, estrogen exposure plays a crucial role in changes in bone density (BD) in women. Premature ovarian insufficiency (POI) and polycystic ovary syndrome (PCOS) are conditions in reproductive-aged women in which the exposure to estrogen is substantially different. Women with a history of preeclampsia (P E) are expected to have normal estrogen exposure. Within the CREw IMAGO study, we investigated if trabecular BD is different in these women because of differences in the duration of estrogen exposure. Trabecular BD was measured in thoracic vertebrae on coronary CT scans. Women with a reduced estrogen exposure (POI) have a lower BD compared to women with an intermediate exposure (PE) (mean difference (MD) −26.8, 95% CI −37.2 to −16.3). Women with a prolonged estrogen exposure (PCOS) have the highest BD (MD 15.0, 95% CI 4.3–25.7). These results support the hypothesis that the duration of estrogen exposure in these women is associated with trabecular BD. Significance statement: Our results suggest that middle-aged women with PCOS have a higher BD and women with POI have a lower BD. We hypothesized that this is due to either a prolonged estrogen exposure, as seen in women with PCOS, or a reduced estrogen exposure, as in women with POI. In the counseling of women with reproductive disorders on long-term health issues, coronary CT provides a unique opportunity to assess both coronary artery calcium score for cardiovascular screening as w ell as trabecular BD.

Abstract Objective Intracranial arterial calcification (IAC) is a risk factor of ischemic stroke. However, the relationship between IAC patterns and clinical outcome of ischemic stroke remains controversial. We aimed to investigate the correlation between IAC patterns and the effects of reperfusion therapy among acute stroke patients. Methods Consecutive acute ischemic stroke patients who underwent reperfusion therapy were included. IAC was categorized as intimal or medial. Based on its involvement, IAC was further classified as diffuse or focal. Neurologic dysfunction was assessed by the National Institute of Health stroke scale (NIHSS). Clinical outcome including favorable neurologic outcome (FNO) and early neurologic deterioration (END) were assessed. Results Of 130 patients, 117 had IAC. Intimal IAC was identified in 74.6% of patients and medial IAC was present in 64.6% of patients. Diffuse IAC was present in 31.5% of patients. All diffuse IACs were medial pattern. Diffuse IAC was associated with higher baseline NIHSS (p = 0.011) and less FNO (p = 0.047). Compared with patients with focal or single diffuse IAC, patients with multiple diffuse IAC had higher baseline NIHSS (p = 0.002) and less FNO (p = 0.024). Multivariable linear regression (p

Background. Bacterial colonization (BC) of the lower airways is common in lung transplant recipients (LTRs) and increases the risk of chronic lung allograft dysfunction. Diagnosis often requires bronchoscopy. Exhaled breath analysis using electronic nose (eNose) technology may noninvasively detect BC in LTRs. Therefore, we aimed to assess the diagnostic accuracy of an eNose to detect BC in LTRs. Methods. We performed a cross-sectional analysis within a prospective, single-center cohort study assessing the diagnostic accuracy of detecting BC using eNose technology in LTRs. In the outpatient clinic, consecutive LTR eNose measurements were collected. We assessed and classified the eNose measurements for the presence of BC. Using supervised machine learning, the diagnostic accuracy of eNose for BC was assessed in a random training and validation set. Model performance was evaluated using receiver operating characteristic analysis. Results. In total, 161 LTRs were included with 80 exclusions because of various reasons. Of the remaining 81 patients, 16 (20%) were classified as BC and 65 (80%) as non-BC. eNose-based classification of patients with and without BC provided an area under the curve of 0.82 in the training set and 0.97 in the validation set. Conclusions. Exhaled breath analysis using eNose technology has the potential to noninvasively detect BC.

We present a fully automated method for carotid artery (CA) outer wall segmentation in black blood MRI using partially annotated data and compare it to the state-of-the-art reference model. Our model was trained and tested on multicentric data of patients (106 and 23 patients, respectively) with a carotid plaque and was validated on different MR sequences (24 patients) as well as data that were acquired with MRI systems of a different vendor (34 patients). A 3D nnU-Net was trained on pre-contrast T1w turbo spin echo (TSE) MR images. A CA centerline sliding window approach was chosen to refine the nnU-Net segmentation using an additionally trained 2D U-Net to increase agreement with manual annotations. To improve segmentation performance in areas with semantically and visually challenging voxels, Monte-Carlo dropout was used. To increase generalizability, data were augmented with intensity transformations. Our method achieves state-of-the-art results yielding a Dice similarity coefficient (DSC) of 91.7% (interquartile range (IQR) 3.3%) and volumetric intraclass correlation (ICC) with ground truth of 0.90 on the development domain data and a DSC of 91.1% (IQR 7.2%) and volumetric ICC with ground truth of 0.83 on the external domain data outperforming top-ranked methods for open-source CA segmentation. The uncertainty-based approach increases the interpretability of the proposed method by providing an uncertainty map together with the segmentation.

Abstract Background Obesity is a well-established risk factor for atrial fibrillation (AF). Whether body fat depots differentially associate with AF development remains unknown. Methods In the prospective population-based Rotterdam Study, body composition was assessed using dual-energy X-ray absorptiometry (DXA) and liver and epicardial fat using computed tomography (CT). A body composition score was constructed by adding tertile scores of each fat depot. Principal component analysis was conducted to identify potential body fat distribution patterns. Cox proportional hazards regression was used to calculate hazard ratios and 95% confidence intervals (HR; 95% CI) per 1-standard deviation increase in corresponding fat depots to enable comparisons. Results Over a median follow-up of 9.6 and 8.6 years, 395 (11.4%) and 172 (8.0%) AF cases were ascertained in the DXA and the CT analyses, respectively. After adjustments for cardiovascular risk factors, absolute fat mass (HR; 95% CI 1.33; 1.05–1.68), gynoid fat mass (HR; 95% CI 1.36; 1.12–1.65), epicardial fat mass (HR; 95% CI 1.27; 1.09-1.48), and android-to-gynoid fat ratio (HR; 95% CI 0.81; 0.70-0.94) were independently associated with new-onset AF. After further adjustment for lean mass, associations between fat mass (HR; 95% CI 1.17; 1.04-1.32), gynoid fat mass (HR; 95% CI 1.21; 1.08–1.37), and android-to-gynoid fat ratio (HR; 95% CI 0.84; 0.72–0.97) remained statistically significant. Larger body fat score was associated with a higher AF risk (HR; 95% CI 1.10; 1.02–1.20). Borderline significant association was found between a subcutaneous fat predominant pattern with AF onset (HR; 95% CI 1.21; 0.98–1.49). Conclusions Various body fat depots were associated with new-onset AF. Total fat mass and gynoid fat mass were independently associated with AF after adjustment for body size. The inverse association between android-to-gynoid fat ratio with AF presents a novel finding. A significant dose-response relationship between body fat accumulation and AF was observed. Our results underscore the predominant role of subcutaneous fat on AF development among a middle-aged and elderly population. Graphical abstract Associations betw2een body fat depots, fat distribution and new-onset atrial fibrillation. Abbreviations: AF, atrial fibrillation.

Background The purpose of this study was to validate a technique for measuring mean calcium density and to determine associations of cardiovascular risk factors with carotid calcium density. Methods and Results We performed a cross‐sectional study in a random sample of 100 stroke‐free participants from the population‐based Rotterdam Study. The mean calcium density of the combined left and right carotid bifurcations was quantified with a threshold of 130 Hounsfield Units (HU) using a novel density technique. To validate the methodology, carotid calcium volumes acquired using the technique in the current study were compared with measurements computed using dedicated clinical software (semiautomatic technique based on a threshold of ≥130 HU). Next, we investigated the associations of participant demographics, total calcium volume, and known cardiovascular risk factors (hypertension, diabetes, hypercholesterolemia, obesity, and smoking status) with the newly derived mean carotid calcium density measurement using linear regression analyses. Calcium volumes obtained with the 2 methods showed a high agreement (intraclass correlation coefficient=0.99, P

Summary: Background: After an initial stroke, current clinical practice is aimed at preventing recurrent stroke. Thus far, population-based estimates on the risk of recurrent stroke remain scarce. Here we describe the risk of recurrent stroke in a population-based cohort study. Methods: We included Rotterdam Study participants who developed a first-ever incident stroke during follow-up between 1990 until 2020. During further follow-up, these participants were monitored for the occurrence of a recurrent stroke. We determined stroke subtypes based on clinical and imaging information. We calculated ten-year overall and sex-specific cumulative incidences of first recurrent stroke. To reflect changing secondary preventive strategies employed in recent decades, we then calculated the risk of recurrent stroke within ten-year epochs based on first-ever stroke date (1990–2000, 2000–2010 and 2010–2020). Findings: In total, 1701 participants (mean age 80.3 years, 59.8% women) from 14,163 community-living individuals suffered a first stroke between 1990 and 2020. Of these strokes, 1111 (65.3%) were ischaemic, 141 (8.3%) haemorrhagic, and 449 (26.4%) unspecified. During 6585.3 person-years of follow-up, 331 (19.5%) suffered a recurrent stroke, of which 178 (53.8%) were ischaemic, 34 (10.3%) haemorrhagic and 119 (36.0%) unspecified. Median time between first and recurrent stroke was 1.8 (interquartile range 0.5–4.6) years. Overall ten-year recurrence risk following first-ever stroke was 18.0% (95% CI 16.2%–19.8%), 19.3% (16.3%–22.3%) in men and 17.1% (14.8%–19.4%) in women. Recurrent stroke risk declined over time, with a ten-year risk of 21.4% (17.9%–24.9%) between 1990 and 2000 and 11.0% (8.3%–13.8%) between 2010 and 2020. Interpretation: In this population-based study, almost one in five people with first-ever stroke suffered a recurrence within ten years of the initial stroke. Furthermore, recurrence risk declined between 2010 and 2020. Funding: Netherlands Organization for Health Research and Development, EU’s Horizon 2020 research programme and the Erasmus Medical Centre MRACE grant.

Background: Right ventricular failure (RVF) is a significant cause of morbidity and mortality in patients with a left ventricular assist device (LVAD). This study is aimed to investigate the influence of a pectus excavatum on early and late outcomes, specifically RVF, following LVAD implantation. Methods: A retrospective study was performed, that included patients with a HeartMate 3 LVAD at our tertiary referral center. The Haller index (HI) was calculated using computed tomography (CT) scan to evaluate the chest-wall dimensions. Results: In total, 80 patients (median age 57 years) were included. Two cohorts were identified: 28 patients (35%) with a normal chest wall (HI 30 days) recurrent readmission for RVF occurred more often in patients with pectus excavatum (p = 0.008). The onset of late RVF started around 18 months after implantation and increased thereafter in the overall study cohort. Conclusions: Pectus excavatum is observed frequently in patients with a LVAD implantation. These patients have an increased rate of readmissions and late RVF. Further investigation is required to explore the extent and severity of chest-wall abnormalities on the risk of RVF.

Restoring blood flow to brain tissue at risk of infarction is essential for tissue survival and clinical outcome. We used cerebral blood flow (CBF) quantified with multiple post-labeling delay (PLD) pseudocontinuous arterial spin labeling (ASL) MRI after ischemic stroke and assessed the association between CBF and early neurological outcome. We acquired ASL with 7 PLDs at 3.0 T in large vessel occlusion stroke patients at 24 h. We quantified CBF relative to the contralateral hemisphere (rCBF) and defined hyperperfusion as a ≥30% increase and hypoperfusion as a ≥40% decrease in rCBF. We included 44 patients (median age: 70 years, median NIHSS: 13, 40 treated with endovascular thrombectomy) of whom 37 were recanalized. Hyperperfusion in ischemic core occurred in recanalized but not in non-recanalized patients (65.8% vs 0%, p = 0.006). Hypoperfusion occurred only in the latter group (0% vs 85.7%, p

Background Larger epicardial fat volume (EFV) has been associated with increased risks of cardiovascular disease and atrial fibrillation. Yet, evidence on the association of EFV with cardiac function and incident heart failure (HF) remains scarce. Methods and Results We included 2103 participants (mean age, 68 years; 54.4% women) from the prospective population‐based RS (Rotterdam Study) with computed tomography–based EFV and repeated echocardiography‐based assessment of left ventricular (LV) systolic and diastolic function. Linear mixed effects and Cox‐proportional hazard regression models, adjusted for cardiovascular risk factors, were used to assess the associations of EFV with repeated measurements of echocardiographic parameters and with incident HF. During a median follow‐up of 9.7 years, 124 HF events occurred (incidence rate, 6.37 per 1000 person‐years). For LV systolic function, 1‐SD larger EFV was associated with 0.76 (95% CI, 0.54–0.98) mm larger LV end‐diastolic dimension, 0.66 (95% CI, 0.47–0.85) mm larger LV end‐systolic dimension, and 0.56% (95% CI, −0.86% to −0.27%) lower LV ejection fraction. Interactions between EFV and time were small. For LV diastolic function, 1‐SD larger EFV was associated with 1.02 (95% CI, 0.78–1.27) mm larger left atrial diameter. Larger EFV was also associated with incident HF (hazard ratio per 1‐SD increase in EFV, 1.34 [95% CI, 1.07–1.68] per 1‐SD larger EFV). Conclusions We report an independent association between EFV with new‐onset HF in the general population. EFV seems to exert its influence on HF through different pathways contributing to deteriorations in systolic function and larger left atrial size in part, likely through mechanical restraint and hypertrophy.

Resumo Fundamento O aumento no volume de gordura epicárdica (VGE) está relacionado com doença arterial coronariana (DAC), independentemente de gordura visceral ou subcutânea. O mecanismo dessa associação não é claro. O escore de cálcio coronariano (CC) e a disfunção endotelial estão relacionados com eventos coronarianos, mas não está bem esclarecido se o VGE está relacionado com esses marcadores. Objetivos Avaliar a associação entre VGE medido por método automatizado, fatores de risco cardiovasculares, escore de CC, e função endotelial. Métodos: Em 470 participantes do Estudo Longitudinal de Saúde do Adulto LSA-Brasil com medidas de VGE, escore de CC e função endotelial, realizamos modelos multivariados para avaliar a relação entre fatore de risco cardiovascular e VGE (variável resposta), e entre VGE (variável explicativa), e função endotelial ou escore de CC. Valor de p

Abstract Background Arterial calcification, the hallmark of arteriosclerosis, has a widespread distribution in the human body with only moderate correlation among sites. Hitherto, a single measure capturing the systemic burden of arterial calcification was lacking. In this paper, we propose the C-factor as an overall measure of calcification burden. Methods To quantify calcification in the coronary arteries, aortic arch, extra- and intracranial carotid arteries, and vertebrobasilar arteries, 2384 Rotterdam Study participants underwent cardiac and extra-cardiac non-enhanced CT. We performed principal component analyses on the calcification volumes of all twenty-six possible combinations of these vessel beds. Each analysis’ first principal component represents the C-factor. Subsequently, we determined the correlation between the C-factor derived from all vessel beds and the other C-factors with intraclass correlation coefficient (ICC) analyses. Finally, we examined the association of the C-factor and calcification in the separate vessel beds with cardiovascular, non-cardiovascular, and overall mortality using Cox–regression analyses. Results The ICCs ranged from 0.80 to 0.99. Larger calcification volumes and a higher C-factor were all individually associated with higher risk of cardiovascular, non-cardiovascular, and overall mortality. When included simultaneously in a model, the C-factor was still associated with all three mortality types (adjusted hazard ratio per standard deviation increase (HR) > 1.52), whereas associations of the separate vessel beds with mortality attenuated substantially (HR

Background Hyperphosphatemia has been associated with coronary artery calcification (CAC) mostly in chronic kidney disease, but the association between phosphate levels within the normal phosphate range and CAC is unclear. Our objectives were to evaluate associations between phosphate levels and CAC among men and women from the general population and assess causality through Mendelian randomization. Methods and Results CAC, measured by electron‐beam computed tomography, and serum phosphate levels were assessed in 1889 individuals from the RS (Rotterdam Study). Phenotypic associations were tested through linear models adjusted for age, body mass index, blood pressure, smoking, prevalent cardiovascular disease and diabetes, 25‐hydroxyvitamin D, total calcium, C‐reactive protein, glucose, and total cholesterol : high‐density lipoprotein cholesterol ratio. Mendelian randomization was implemented through an allele score including 8 phosphate‐related single‐nucleotide polymorphisms. In phenotypic analyses, serum phosphate (per 1 SD) was associated with CAC with evidence for sex interaction (Pinteraction=0.003) (men β, 0.44 [95% CI, 0.30–0.59]; P=3×10−9; n=878; women β, 0.24 [95% CI, 0.08–0.40]; P=0.003; n=1011). Exclusion of hyperphosphatemia, chronic kidney disease (estimated glomerular filtration rate

BackgroundTwenty-four-hour and nighttime blood pressure (BP) levels are more strongly associated with cardiovascular risk than office or daytime BP measurements. However, it remains undocumented which of the office and ambulatory BP measurements have the strongest association and predictive information in relation to the presence of type I, or arteriolosclerosis type, cerebral small vessel diseases (CSVD).MethodsA subset of 429 participants from the Maracaibo Aging Study [aged ≥40 years (women, 73.7%; mean age, 59.3 years)] underwent baseline brain magnetic resonance imaging (MRI) to visualize CSVD, which included log-transformed white matter hyperintensities (log-WMH) volume and the presence (yes/no) of lacunes, cerebral microbleeds (CMB), or enlarged perivascular spaces (EPVS). Linear and logistic regression models were applied to examine the association between CSVD and each +10-mmHg increment in the office and ambulatory systolic BP measurements. Improvement in the fit of nested logistic models was assessed by the log-likelihood ratio and the generalized R2 statistic.ResultsOffice and ambulatory systolic BP measurements were related to log-WMH (β-correlation coefficients ≥0.08; P < 0.001). Lacunes and CMB were only associated with ambulatory systolic BP measurements (odds ratios [OR] ranged from 1.31 [95% confidence interval, 1.10-1.55] to 1.46 [1.17–1.84], P ≤ 0.003). Accounted for daytime systolic BP, both the 24-h (β-correlation, 0.170) and nighttime (β-correlation, 0.038) systolic BP measurements remained related to log-WMH. When accounted for 24-h or daytime systolic BP levels, the nighttime systolic BP retained the significant association with lacunes (ORs, 1.05–1.06; 95% CIs, ≥1.01 to ≤ 1.13), whereas the 24-h and daytime systolic BP levels were not associated with lacunes after adjustments for nighttime systolic BP (ORs, ≤ 0.88; 95% CI, ≥0.77 to ≤ 1.14). On top of covariables and office systolic BP, ambulatory systolic BP measurements significantly improved model performance (1.05% ≥ R2 ≤ 3.82%). Compared to 24-h and daytime systolic BP, nighttime systolic BP had the strongest improvement in the model performance; for WMH (1.46 vs. 1.05%) and lacunes (3.06 vs. ≤ 2.05%).ConclusionsTwenty-four-hour and nighttime systolic BP were the more robust BP measurements associated with CSVD, but the nighttime systolic BP level had the strongest association. Controlling ambulatory BP levels might provide additional improvement in the prevention of CSVD.

Background: Intraplaque hemorrhage (IPH) is a hallmark of atherosclerotic plaque instability. Biliverdin reductase B (BLVRB) is enriched in plasma and plaques from patients with symptomatic carotid atherosclerosis and functionally associated with IPH. Objective: We explored the biomarker potential of plasma BLVRB through (1) its correlation with IPH in carotid plaques assessed by magnetic resonance imaging (MRI), and with recurrent ischemic stroke, and (2) its use for monitoring pharmacotherapy targeting IPH in a preclinical setting. Methods: Plasma BLVRB levels were measured in patients with symptomatic carotid atherosclerosis from the PARISK study (n = 177, 5 year follow-up) with and without IPH as indicated by MRI. Plasma BLVRB levels were also measured in a mouse vein graft model of IPH at baseline and following antiangiogenic therapy targeting vascular endothelial growth factor receptor 2 (VEGFR-2). Results: Plasma BLVRB levels were significantly higher in patients with IPH (737.32 ± 693.21 vs. 520.94 ± 499.43 mean fluorescent intensity (MFI), p = 0.033), but had no association with baseline clinical and biological parameters. Plasma BLVRB levels were also significantly higher in patients who developed recurrent ischemic stroke (1099.34 ± 928.49 vs. 582.07 ± 545.34 MFI, HR = 1.600, CI [1.092–2.344]; p = 0.016). Plasma BLVRB levels were significantly reduced following prevention of IPH by anti-VEGFR-2 therapy in mouse vein grafts (1189 ± 258.73 vs. 1752 ± 366.84 MFI; p = 0.004). Conclusions: Plasma BLVRB was associated with IPH and increased risk of recurrent ischemic stroke in patients with symptomatic low- to moderate-grade carotid stenosis, indicating the capacity to monitor the efficacy of IPH-preventive pharmacotherapy in an animal model. Together, these results suggest the utility of plasma BLVRB as a biomarker for atherosclerotic plaque instability.

Abstract Background Coronary artery calcification (CAC) is a noninvasive measure of coronary atherosclerosis, the proximal pathophysiology underlying most cases of myocardial infarction (MI). We sought to identify expression signatures of early MI and subclinical atherosclerosis in the Framingham Heart Study (FHS). In this study, we conducted paired-end RNA sequencing on whole blood collected from 198 FHS participants (55 with a history of early MI, 72 with high CAC without prior MI, and 71 controls free of elevated CAC levels or history of MI). We applied DESeq2 to identify coding-genes and long intergenic noncoding RNAs (lincRNAs) differentially expressed in MI and high CAC, respectively, compared with the control. Results On average, 150 million paired-end reads were obtained for each sample. At the false discovery rate (FDR)

Abstract Background Evidence has pointed towards differences in the burden of arteriosclerosis according to its location and sex. Yet there is a scarcity of population-based data on aggregated sex-specific cardiovascular risk profiles, instead of single risk factors, and mortality risk according to the location of arteriosclerosis. We assessed sex-specific cardiovascular risk profiles and mortality risk associated with arteriosclerosis. Methods From the population-based Rotterdam Study, 2357 participants (mean age 69 years, 53% women) underwent non-contrast computed tomography to quantify calcification, as a proxy for arteriosclerosis, in the coronary arteries (CAC), aortic arch (AAC), extracranial (ECAC) and intracranial carotid arteries (ICAC), vertebrobasilar arteries (VBAC), and aortic valve (AVC). Principal component analysis (PCA) of eight distinct cardiovascular risk factors was performed, separately for women and men, to derive risk profiles based on the shared variance between factors. We used sex-stratified multivariable logistic regression to examine the associations between PCA-derived risk profiles and severe calcification at different locations. We investigated the associations of severe calcification with mortality risk using sex-stratified multivariable Cox regression. Results PCA identified three cardiovascular risk profiles in both sexes: (1) anthropometry, glucose, and HDL cholesterol; (2) blood pressure; and (3) smoking and total cholesterol. In women, the strongest associations were found for profile 2 with severe ECAC and ICAC (adjusted OR [95% CI] 1.32 [1.14–1.53]) and for profile 3 with severe at all locations, except AVC. In men, the strongest associations were found for profile 2 with VBAC (1.31 [1.12–1.52]) and profile 3 with severe AAC (1.28 [1.09–1.51]). ECAC and AVC in women and CAC in men showed the strongest, independent associations with cardiovascular mortality (HR [95% CI] 2.11 [1.22–3.66], 2.05 [1.21–3.49], 2.24 [1.21–3.78], respectively). Conclusions Our findings further underline the existence of sex- and location-specific differences in the etiology and consequences of arteriosclerosis. Future research should unravel which distinct pathological processes underlie differences in risk profiles for arteriosclerosis.

Abstract Background Exercise may be a promising target for depression interventions. However, evidence for a beneficial effect of exercise interventions on the prevention of depression differs substantially across different studies. Methods A systematic search was performed up to July 2018 using PubMed, Embase, PsycINFO, and Cochrane. Articles were included if a meta-analysis of randomized controlled trials was performed that examined the effect of exercise interventions on the onset of depression or depressive symptoms in the general population. Meta-analyses focusing on treatment of diagnosed depression were excluded. Two authors independently screened the articles and graded the quality of included meta-analyses using AMSTAR 2. Results Eight meta-analyses were included that showed little overlap in 134 included studies. All meta-analyses reported on depressive symptoms rather than onset of depression. Five of these were rated as moderate quality and three of low quality. Six meta-analyses found significant effects, and two found non-significant effects of exercise interventions in reducing depressive symptoms in children, adolescents, adults and the elderly (effect sizes ranging from − 0.10 to − 0.81). Scarce evidence did not allow to draw conclusions about the role of sex and characteristics of exercise on depression. However, some findings suggest that low intensity exercise was as effective as high intensity exercise. Heterogeneity among primary studies was high, likely caused by differences in study quality and exercise characteristics. Conclusions The evidence from this study suggests that exercise interventions have a beneficial effect on depressive symptoms in the general population across a wide age-range.

Background and PurposeIntracranial arterial calcification (IAC) may be present in the intimal or medial arterial layer. This study aimed to elucidate the link between the calcification and atherosclerotic disease in the intracranial vasculature.MethodsConsecutive patients with acute ischemic stroke were included. Bilateral intracranial segment of the internal carotid artery, M1 segment of the middle cerebral artery, intracranial segment of the vertebral artery, and the basilar artery were visualized by the multi-detector computed tomography (CT) and vessel-wall magnetic resonance imaging (vwMRI) within 14 days after stroke onset. IAC was into the intimal or medial pattern. Subsequently, on the vwMRI, we assessed the luminal stenosis, eccentricity, plaque burden, and intraplaque hemorrhage (IPH) as markers of atherosclerosis at each IAC site.ResultsAmong 69 patients with stroke, IAC was identified in 35% of (161/483) artery segments, of which 61.5% were predominantly intimal calcification and 38.5% were predominantly medial calcification. About 79.8% of intimal calcifications and 64.5% of medial calcifications co-existed with atherosclerotic plaques. Intimal calcification was associated with luminal stenosis (p = 0.003) caused by atherosclerotic lesions. Compared with the medial IAC, intimal IAC was more often accompanied by eccentric plaques (p = 0.02), larger plaque burden (p = 0.001), and IPH (p = 0.001).ConclusionOur multimodal imaging-based comparison study on intracranial arteriosclerosis demonstrated that intimal IAC, compared with medial IAC, was more often accompanied by the luminal stenosis, larger plaque burden, eccentricity, and IPH, providing strong evidence for clinical evaluation on the mechanism, risk, and prognosis of ischemic stroke.

Carotid atherosclerotic plaque rupture and its sequelae are among the leading causes of acute ischemic stroke. The risk of rupture and subsequent thrombosis is, among others, determined by vulnerable plaque characteristics and linked to activation of the immune system, in which neutrophil extracellular traps (NETs) potentially play a role. The aim of this study was to investigate how plaque vulnerability is associated with NETs levels. We included 182 patients from the Plaque At RISK (PARISK) study in whom carotid imaging was performed to measure plaque ulceration, fibrous cap integrity, intraplaque hemorrhage, lipid-rich necrotic core, calcifications and plaque volume. Principal component analysis generated a 'vulnerability index' comprising all plaque characteristics. Levels of the NETs marker myeloperoxidase-DNA complex were measured in patient plasma. The association between the vulnerability index and low or high NETs levels (dependent variable) was assessed by logistic regression. No significant association between the vulnerability index and NETs levels was detected in the total population (odds ratio 1.28, 95% confidence interval 0.90-1.83, p = 0.18). However, in the subgroup of patients naive to statins or antithrombotic medication prior to the index event, this association was statistically significant (odds ratio 2.08, 95% confidence interval 1.04-4.17, p = 0.04). Further analyses revealed that this positive association was mainly driven by intraplaque hemorrhage, lipid-rich necrotic core and ulceration. In conclusion, plaque vulnerability is positively associated with plasma levels of NETs, but only in patients naive to statins or antithrombotic medication prior to the index event.

Background and Purpose: Shear stress (WSS) is involved in the pathophysiology of atherosclerotic disease and might affect plaque ulceration. In this case-control study, we compared carotid plaques that developed a new ulcer during follow-up and plaques that remained silent for their exposure to time-dependent oscillatory shear stress parameters at baseline.Materials and Methods: Eighteen patients who underwent CTA and MRI of their carotid arteries at baseline and 2 years follow-up were included. These 18 patients consisted of six patients who demonstrated a new ulcer and 12 control patients selected from a larger cohort with similar MRI-based plaque characteristics as the ulcer group. (Oscillatory) WSS parameters [time average WSS, oscillatory shear index (OSI), and relative residence time (RRT)] were calculated using computational fluid dynamics applying the MRI-based geometry of the carotid arteries and compared among plaques (wall thickness>2 mm) with and without ulceration (Mann–Whitney U test) and ulcer-site vs. non-ulcer-site within the plaque (Wilcoxon signed rank test). More detailed analysis on ulcer cases was performed and the predictive value of oscillatory WSS parameters was calculated using linear and logistic mixed-effect regression models.Results: The ulcer group demonstrated no difference in maximum WSS [9.9 (6.6–18.5) vs. 13.6 (9.7–17.7) Pa, p = 0.349], a lower maximum OSI [0.04 (0.01–0.10) vs. 0.12 (0.06–0.20) p = 0.019] and lower maximum RRT [1.25 (0.78–2.03) Pa−1 vs. 2.93 (2.03–5.28) Pa−1, p = 0.011] compared to controls. The location of the ulcer (ulcer-site) within the plaque was not always at the maximal WSS, but demonstrated higher average WSS, lower average RRT and OSI at the ulcer-site compared to the non-ulcer-sites. High WSS (WSS>4.3 Pa) and low RRT (RRT < 0.25 Pa) were associated with ulceration with an odds ratio of 3.6 [CI 2.1–6.3] and 2.6 [CI 1.54–4.44] respectively, which remained significant after adjustment for wall thickness.Conclusion: In this explorative study, ulcers were not exclusively located at plaque regions exposed to the highest WSS, OSI, or RRT, but high WSS and low RRT regions had a significantly higher odds to present ulceration within the plaque even after adjustment for wall thickness.

Background: Intracranial arterial calcification (IAC) is highly prevalent in ischemic stroke patients. However, data on the association of IAC with stroke recurrence and mortality remains limited. We examined the effect of IAC on the long-term recurrence of stroke and the risk of post-stroke mortality.Methods: Using a prospective stroke registry, we recruited 694 patients (mean age 71.6 ± 12.4; male sex 50.3%) since December 2004. IAC was visualized using the computed tomography exam that was made at hospital admission and was quantified with the Agatston method. All patients were regularly followed up till July 2016. The impacts of IAC on stroke recurrence and mortality were assessed using Cox-regression models with adjustments for age, sex, and relevant cardiovascular risk factors.Results: During a median follow-up period of 8.8 years, 156 patients (22.5%) suffered a recurrent stroke and 84 died (12.1%). We found that a higher IAC Agatston score related to a higher risk of stroke recurrence (HR per 1-SD increase in IAC: 1.30; 95% CI, 1.08–1.56, p = 0.005) and a higher risk of post-stroke mortality (HR per 1-SD increase, 1.44; 95% CI, 1.06–1.96, p = 0.019). After investigating etiology-specific risks of stroke-recurrence, we found that a higher IAC Agatston score specifically associated with small-vessel occlusive stroke.Conclusions: IAC is a strong risk factor for recurrent stroke and post-stroke mortality. Among stroke subtypes, IAC relates to higher risk of stroke recurrence among patients with small-vessel disease, which indicates chronic calcification detected in large cerebral arteries may have potential effects on the cerebrovascular beds extending to small vessels.

Background: Atherosclerosis and cancer share multiple disease pathways. Yet, it is unclear if atherosclerosis is associated with a subsequent higher cancer risk. We determined the association of atherosclerotic calcification in the aortic arch, as proxy for systemic atherosclerosis, with the risk of cancer.Methods: Between 2003 and 2006, 2,404 participants (mean age: 69.5 years, 52.5% women) from the prospective population-based Rotterdam Study underwent computed tomography to quantify calcification in the aortic arch. Participants were followed for the onset of cancer, death, loss to follow-up, or January 1st, 2015, whichever came first. We computed sex-specific tertiles of aortic arch calcification volumes. Next, we examined the association between the volume and severity (i.e., tertiles) of aortic arch calcification and the risk of cancer using Cox proportional hazard models.Results: During a median (interquartile range) follow-up of 9.6 years (8.9–10.5), 348 participants were diagnosed with cancer. Participants with the greatest severity of aortic arch calcification had a higher risk of cancer [hazard ratio for the third tertile compared to the first tertile of aortic arch calcification volume in the total population is 1.39 (95% CI = 1.04–1.86)].Conclusions: Individuals with the most severe aortic arch calcification had a higher risk of cancer. While this could reflect the impact of long-term exposure to shared risk factors, it might also point toward the co-occurrence of both conditions.

BackgroundAtherosclerotic cardiovascular disease (ASCVD) is driven by multifaceted contributions of the immune system. However, the dysregulation of immune cells that leads to ASCVD is poorly understood. We determined the association of components of innate and adaptive immunity longitudinally with ASCVD, and assessed whether arterial calcifications play a role in this association.Methods and findingsGranulocyte (innate immunity) and lymphocyte (adaptive immunity) counts were determined 3 times (2002-2008, mean age 65.2 years; 2009-2013, mean age 69.0 years; and 2014-2015, mean age 78.5 years) in participants of the population-based Rotterdam Study without ASCVD at baseline. Participants were followed-up for ASCVD or death until 1 January 2015. A random sample of 2,366 underwent computed tomography at baseline to quantify arterial calcification volume in 4 vessel beds. We studied the association between immunity components with risk of ASCVD and assessed whether immunity components were related to arterial calcifications at baseline. Of 7,730 participants (59.4% women), 801 developed ASCVD during a median follow-up of 8.1 years. Having an increased granulocyte count increased ASCVD risk (adjusted hazard ratio for doubled granulocyte count [95% CI] = 1.78 [1.34-2.37], P < 0.001). Higher granulocyte counts were related to larger calcification volumes in all vessels, most prominently in the coronary arteries (mean difference in calcium volume [mm3] per SD increase in granulocyte count [95% CI] = 32.3 [9.9-54.7], P < 0.001). Respectively, the association between granulocyte count and incident coronary heart disease and stroke was partly mediated by coronary artery calcification (overall proportion mediated [95% CI] = 19.0% [-10% to 32.3%], P = 0.08) and intracranial artery calcification (14.9% [-10.9% to 19.1%], P = 0.05). A limitation of our study is that studying the etiology of ASCVD remains difficult within an epidemiological setting due to the limited availability of surrogates for innate and especially adaptive immunity.ConclusionsIn this study, we found that an increased granulocyte count was associated with a higher risk of ASCVD in the general population. Moreover, higher levels of granulocytes were associated with larger volumes of arterial calcification. Arterial calcifications may explain a proportion of the link between granulocytes and ASCVD.

In order to assess coronary artery calcium (CAC) quantification reproducibility for photon-counting computed tomography (PCCT) at reduced tube potential, an anthropomorphic thorax phantom with low-, medium-, and high-density CAC inserts was scanned with PCCT (NAEOTOM Alpha, Siemens Healthineers) at two heart rates: 0 and 60–75 beats per minute (bpm). Five imaging protocols were used: 120 kVp standard dose (IQ level 16, reference), 90 kVp at standard (IQ level 16), 75% and 45% dose and tin-filtered 100 kVp at standard dose (IQ level 16). Each scan was repeated five times. Images were reconstructed using monoE reconstruction at 70 keV. For each heart rate, CAC values, quantified as Agatston scores, were compared with the reference, whereby deviations >10% were deemed clinically relevant. Reference protocol radiation dose (as volumetric CT dose index) was 4.06 mGy. Radiation dose was reduced by 27%, 44%, 67%, and 46% for the 90 kVp standard dose, 90 kVp 75% dose, 90 kVp 45% dose, and Sn100 standard dose protocol, respectively. For the low-density CAC, all reduced tube current protocols resulted in clinically relevant differences with the reference. For the medium- and high-density CAC, the implemented 90 kVp protocols and heart rates revealed no clinically relevant differences in Agatston score based on 95% confidence intervals. In conclusion, PCCT allows for reproducible Agatston scores at a reduced tube voltage of 90 kVp with radiation dose reductions up to 67% for medium- and high-density CAC.

Background: It is known that obesity [measured with body mass index (BMI)] relates to brain structure and markers of cerebral small vessel disease (CSVD). However, BMI may not adequately represent body composition. Furthermore, whether those cross-sectional associations hold longitudinally remains uncertain.Methods: Three thousand six hundred and fourty-eight participants underwent baseline (2006–2014) dual-energy X-ray absorptiometry (DXA)-scan to obtain detailed measures of body composition and a magnetic resonance imaging (MRI) scan to assess brain structure. One thousand eight hundred and fourty-four participants underwent a second MRI-scan at follow-up (2010–2017; median follow-up: 5.5 years). To assess cross-sectional and longitudinal associations (measures of change have been calculated) between body composition [BMI, fat mass index (FMI), fat-free mass index (FFMI)], and brain tissue volume (gray matter, white matter, hippocampus), white matter microstructure [fractional anisotropy (FA), mean diffusivity (MD)], and CSVD markers (white matter hyperintensity volume, lacunes, microbleeds) we used multivariable linear and logistic regression models.Results: A higher BMI and FMI were cross-sectionally associated with smaller white matter volumes (difference in Z-score per SD higher BMI: −0.064 [95% CI: −0.094, −0.035]) and FMI: −0.067 [95% CI: −0.099, −0.034], higher FA and MD. A higher FFMI was associated larger gray matter volume (difference: 0.060 [95% CI: 0.018, 0.101]). There was no statistically significant or clinically relevant association between body composition and brain changes.Conclusions: Body composition, distinguishing between fat mass and fat-free mass, does not directly influence changes in brain tissue volume, white matter integrity and markers of CSVD. Cross-sectional associations between body composition and brain tissue volume likely reflect cumulative risk or shared etiology.

Background The purpose of this study was to investigate the association between kidney function and arterial calcification in major vascular beds and to establish whether arterial calcification mediates the relation between kidney function measures and cardiovascular disease (CVD) incidence. Methods and Results In 2241 participants from the Rotterdam Study (mean age 69 years, 52% female), kidney function was assessed using the estimated glomerular filtration rate and urine albumin‐to‐creatinine ratio. All participants underwent noncontrast computed tomography to quantify the amount of arterial calcification in the coronary arteries, aortic arch, extracranial, and intracranial internal carotid arteries. We used linear regression models, adjusted for age, sex, and cardiovascular risk factors, to evaluate the association between kidney function and arterial calcification volume in the 4 vessel beds. Incidence rate of CVD was calculated in 3 groups of participants based on their kidney function and presence of arterial calcification. We conducted mediation analysis to evaluate whether arterial calcification mediates this association. We found that in age‐ and sex‐adjusted models, lower estimated glomerular filtration rate and higher albumin‐to‐creatinine ratio were associated with larger calcification volumes in all 4 vascular beds. Adjusting for cardiovascular risk factors attenuated the effect estimates. CVD incidence was higher in participants with estimated glomerular filtration rate 60 and no calcification. After adjusting for cardiovascular risk factors, arterial calcification did not mediate the association between kidney function measures and CVD incidence. Conclusions The association of impaired kidney function and larger volumes of arterial calcification is partly explained by cardiovascular risk factors. Arterial calcification does not mediate the association between kidney function and CVD beyond cardiovascular risk factors.

Background The role of subtle disturbances of brain perfusion in the risk of transient ischemic attack (TIA) or ischemic stroke remains unknown. We examined the association between global brain perfusion and risk of TIA and ischemic stroke in the general population. Methods and Results Between 2005 and 2015, 5289 stroke‐free participants (mean age, 64.3 years; 55.6% women) from the Rotterdam Study underwent phase‐contrast brain magnetic resonance imaging at baseline to assess global brain perfusion. These participants were followed for incident TIA or ischemic stroke until January 1, 2016. We investigated associations between global brain perfusion (mL of blood flow/100 mL of brain/min) and risk of TIA and ischemic stroke using Cox regression models with adjustment for age, sex, and cardiovascular risk factors. Additionally, we investigated whether associations were modified by retinal vessel calibers, small and large vessel disease, blood pressure, and heart rate. During a median follow‐up of 7.2 years (36 103 person‐years), 137 participants suffered a TIA and another 108 an ischemic stroke. We found that lower global brain perfusion was associated with a higher risk of TIA, but not with the risk of ischemic stroke (adjusted hazard ratio, 95% CI, per standard deviation decrease of global brain perfusion: 1.29, 1.07–1.55 for TIA and adjusted hazard ratio of 1.06, 0.87–1.30 for ischemic stroke). Across strata of wider arteriolar retinal calibers, lower brain perfusion was more prominently associated with TIA, but not with ischemic stroke. Conclusions In a community‐dwelling population, impaired global brain perfusion increased the risk of TIA, but not of ischemic stroke.

BACKGROUND:Non-communicable diseases (NCDs) are leading causes of premature disability and death worldwide. However, the lifetime risk of developing any NCD is unknown, as are the effects of shared common risk factors on this risk. METHODS AND FINDINGS:Between July 6, 1989, and January 1, 2012, we followed participants from the prospective Rotterdam Study aged 45 years and older who were free from NCDs at baseline for incident stroke, heart disease, diabetes, chronic respiratory disease, cancer, and neurodegenerative disease. We quantified occurrence/co-occurrence and remaining lifetime risk of any NCD in a competing risk framework. We additionally studied the lifetime risk of any NCD, age at onset, and overall life expectancy for strata of 3 shared risk factors at baseline: smoking, hypertension, and overweight. During 75,354 person-years of follow-up from a total of 9,061 participants (mean age 63.9 years, 60.1% women), 814 participants were diagnosed with stroke, 1,571 with heart disease, 625 with diabetes, 1,004 with chronic respiratory disease, 1,538 with cancer, and 1,065 with neurodegenerative disease. NCDs tended to co-occur substantially, with 1,563 participants (33.7% of those who developed any NCD) diagnosed with multiple diseases during follow-up. The lifetime risk of any NCD from the age of 45 years onwards was 94.0% (95% CI 92.9%-95.1%) for men and 92.8% (95% CI 91.8%-93.8%) for women. These risks remained high (>90.0%) even for those without the 3 risk factors of smoking, hypertension, and overweight. Absence of smoking, hypertension, and overweight was associated with a 9.0-year delay (95% CI 6.3-11.6) in the age at onset of any NCD. Furthermore, the overall life expectancy for participants without these risk factors was 6.0 years (95% CI 5.2-6.8) longer than for those with all 3 risk factors. Participants aged 45 years and older without the 3 risk factors of smoking, hypertension, and overweight at baseline spent 21.6% of their remaining lifetime with 1 or more NCDs, compared to 31.8% of their remaining life for participants with all of these risk factors at baseline. This difference corresponds to a 2-year compression of morbidity of NCDs. Limitations of this study include potential residual confounding, unmeasured changes in risk factor profiles during follow-up, and potentially limited generalisability to different healthcare settings and populations not of European descent. CONCLUSIONS:Our study suggests that in this western European community, 9 out of 10 individuals aged 45 years and older develop an NCD during their remaining lifetime. Among those individuals who develop an NCD, at least a third are subsequently diagnosed with multiple NCDs. Absence of 3 common shared risk factors is associated with compression of morbidity of NCDs. These findings underscore the importance of avoidance of these common shared risk factors to reduce the premature morbidity and mortality attributable to NCDs.

Centerline extraction of the carotid artery in MRI is important to analyze the artery geometry and to provide input for further processing such as registration and segmentation. The centerline of the artery bifurcation is often extracted by means of two independent minimum cost paths ranging from the common to the internal and the external carotid artery. Often the cost is not well defined at the artery bifurcation, leading to centerline errors. To solve this problem, we developed a method to cooperatively extract both centerlines, where in the cost to extract each centerline, we integrate a constraint region derived from the estimated position of the neighbor centerline. This method avoids that both centerlines follow the same cheapest path after the bifurcation, which is a common error when the paths are extracted independently. We show that this method results in less error compared to extracting them independently: 10 failed centerlines Vs. 3 failures in a data set of 161 arteries with manual annotations. Additionally, we show that the new method improves the non-cooperative approach in 28 cases (p < 0.0001) in a data set of 3,904 arteries.