Coma in adult cerebral venous thrombosis: The BEAST study.

BACKGROUND AND PURPOSE: Coma is an independent predictor of poor clinical outcomes in cerebral venous thrombosis (CVT). We aimed to describe the association of age, sex, and radiological characteristics of adult coma patients with CVT. METHODS: We used data from the international, multicentre prospective observational BEAST (Biorepository to Establish the Aetiology of Sinovenous Thrombosis) study. Only positively associated variables with coma with <10% missing data in univariate analysis were considered for the multivariate logistic regression model. RESULTS: Of the 596 adult patients with CVT (75.7% women), 53 (8.9%) patients suffered coma. Despite being a female-predominant disease, the prevalence of coma was higher among men than women (13.1% vs. 7.5%, p = 0.04). Transverse sinus thrombosis was least likely to be associated with coma (23.9% vs. 73.3%, p < 0.001). The prevalence of superior sagittal sinus thrombosis was higher among men than women in the coma sample (73.6% vs. 37.5%, p = 0.01). Men were significantly older than women, with a median (interquartile range) age of 51 (38.5-60) versus 40 (33-47) years in the coma (p = 0.04) and 44.5 (34-58) versus 37 (29-48) years in the non-coma sample (p < 0.001), respectively. Furthermore, an age- and superior sagittal sinus-adjusted multivariate logistic regression model found male sex (odds ratio = 1.8, 95% confidence interval [CI] = 1.0-3.4, p = 0.04) to be an independent predictor of coma in CVT, with an area under the receiver operating characteristic curve of 0.61 (95% CI = 0.52-0.68, p = 0.01). CONCLUSIONS: Although CVT is a female-predominant disease, men were older and nearly twice as likely to suffer from coma than women.

Development and validation of a lifetime prediction model for incident type 2 diabetes in patients with established cardiovascular disease: the CVD2DM model.

AIMS: Identifying patients with established cardiovascular disease (CVD) who are at high risk of type 2 diabetes (T2D) may allow for early interventions, reducing the development of T2D and associated morbidity. The aim of this study was to develop and externally validate the CVD2DM model to estimate the 10-year and lifetime risks of T2D in patients with established CVD. METHODS AND RESULTS: Sex-specific, competing risk-adjusted Cox proportional hazard models were derived in 19 281 participants with established CVD and without diabetes at baseline from the UK Biobank. The core model's pre-specified predictors were age, current smoking, family history of diabetes mellitus, body mass index, systolic blood pressure, fasting plasma glucose, and HDL cholesterol. The extended model also included HbA1c. The model was externally validated in 3481 patients from the UCC-SMART study. During a median follow-up of 12.2 years (interquartile interval 11.3-13.1), 1628 participants with established CVD were diagnosed with T2D in the UK Biobank. External validation c-statistics were 0.79 [95% confidence interval (CI) 0.76-0.82] for the core model and 0.81 (95% CI 0.78-0.84) for the extended model. Calibration plots showed agreement between predicted and observed 10-year risk of T2D. CONCLUSION: The 10-year and lifetime risks of T2D can be estimated with the CVD2DM model in patients with established CVD, using readily available clinical predictors. The model would benefit from further validation across diverse ethnic groups to enhance its applicability. Informing patients about their T2D risk could motivate them further to adhere to a healthy lifestyle.

In this study, we developed and externally validated the CVD2DM model, which predicts the 10-year and lifetime risk of type 2 diabetes (T2D) in individuals who already have cardiovascular disease (CVD). The key findings are as follows: The CVD2DM model is the first model to estimate the risk of developing T2D applicable in all patients with atherosclerotic CVD. The model is based on several factors available in clinical practice, such as age, fasting plasma glucose, family history of diabetes, and body mass index. It was developed in 19 281 patients from the UK Biobank. The model performed well in 3481 patients from the UCC-SMART study.Informing patients about their T2D risk could motivate them further to adhere to a healthy lifestyle.

Cost-effectiveness of Mediterranean diet and physical activity in secondary CVD prevention: results from the UCC-SMART cohort study.

AIMS: The efficacy of a healthy lifestyle in secondary prevention of cardiovascular disease (CVD) is well established and a first-line recommendation in CVD prevention guidelines. The aim of this study was to assess if they are also cost-effective in patients with established CVD. METHODS: A cost-utility analysis (CUA) was performed comparing a combined Mediterranean diet and physical activity intervention to usual care in CVD patients. The CUA had a healthcare perspective and lifetime horizon. Costs and utilities were estimated using a microsimulation on a cohort of 100,000 CVD patients sampled from the UCC-SMART study (N = 8,947, mean age 62 ±8.7 years and 74% male). Cost-effectiveness was expressed as incrementalcost-effectiveness ratio (ICER), incremental net health benefit (INHB) and incremental net monetary benefit (INMB). RESULTS: Mediterranean diet and physical activity yielded 2.0 incremental quality-adjusted life years (QALYs) and cost reductions of €1,236 per person compared to usual care, resulting in an ICER of €-626/QALY (95%CI -1,929 to 2,673). At a willingness-to-pay of €20,000/QALY, INHB was 2.04 (95%CI 0.99-3.58) QALY and INMB was €40,757 (95%CI 19,819-71,605). The interventions remained cost-effective in a wide range of sensitivity analyses, including worst-case scenarios and scenarios with reimbursement for food and physical activity costs. CONCLUSION: In patients with established CVD, a combined Mediterranean diet and physical activity intervention was cost-saving and highly cost-effective compared to usual care. These findings strongly advocate for the incorporation of lifestyle interventions as integral components of care for all CVD patients.

Lifestyle optimization, including physical activity and healthy diet, is a central recommendation for preventing recurrent cardiovascular events. In this study, we assessed if improving physical activity habits and adherence to a heart-healthy Mediterranean diet would also be a cost-effective option. The results were remarkable - following the Mediterranean diet and engaging in physical activity was expected to result in an increase of 2.0 quality-adjusted life years (QALYs, equal to a life year in perfect health) and cost savings. This means that lifestyle optimization in secondary CVD prevention improves population health, while reducing overall health care costs. These findings underscore the importance of implementing lifestyle changes in the care for all individuals with CVD. A health lifestyle is not only effective in improving health but also a prudent financial decision. Key messages  A combined Mediterranean diet and physical activity intervention is expected to result in two additional QALYs and three additional life years free of recurrent cardiovascular events per patient with with established CVDTargeting a healthy lifestyle is expected to lead to costs savings compared to usual care, due to the low costs of the intervention and the high efficacy in preventing recurrent cardiovascular events.Lifestyle optimization in secondary CVD prevention was shown to result in a dominant incremental cost-effectiveness ratio (ICER) of €-626/QALY, which strongly advocates for healthy policy targeted at implementing lifestyle interventions in regular care for CVD patients.

Drug classes affecting intracranial aneurysm risk: Genetic correlation and Mendelian randomization.

INTRODUCTION: There is no non-invasive treatment to prevent aneurysmal subarachnoid hemorrhage (ASAH) caused by intracranial aneurysm (IA) rupture. We aimed to identify drug classes that may affect liability to IA using a genetic approach. PATIENTS AND METHODS: Using genome-wide association summary statistics we calculated genetic correlation between unruptured IA (N = 2140 cases), ASAH (N = 5140) or the combined group, and liability to drug usage from 23 drug classes (N up to 320,000) independent of the risk factor high blood pressure. Next, we evaluated the causality and therapeutic potential of correlated drug classes using three different Mendelian randomization frameworks. RESULTS: Correlations with IA were found for antidepressants, paracetamol, acetylsalicylic acid, opioids, beta-blockers, and peptic ulcer and gastro-esophageal reflux disease drugs. MR showed no evidence that genetically predicted usage of these drug classes caused IA. Genetically predicted high responders to antidepressant drugs were at higher risk of IA (odds ratio [OR] = 1.61, 95% confidence interval (CI) = 1.09-2.39, p = 0.018) and ASAH (OR = 1.68, 95% CI = 1.07-2.65, p = 0.024) if they used antidepressant drugs. This effect was absent in non-users. For beta-blockers, additional analyses showed that this effect was not independent of blood pressure after all. A complex and likely pleiotropic relationship was found between genetic liability to chronic multisite pain, pain medication usage (paracetamol, acetylsalicylic acid, and opioids), and IA. CONCLUSIONS: We did not find drugs decreasing liability to IA and ASAH but found that antidepressant drugs may increase liability. We observed pleiotropic relationships between IA and other drug classes and indications. Our results improve understanding of pathogenic mechanisms underlying IA.

The effects of etidronate on brain calcifications in Fahr's disease or syndrome: rationale and design of the randomised, placebo-controlled, double-blind CALCIFADE trial.

BACKGROUND: Fahr's disease and syndrome are rare disorders leading to calcification of the small arteries in the basal ganglia of the brain, resulting in a wide range of symptoms comprising cognitive decline, movement disorders and neuropsychiatric symptoms. No disease-modifying therapies are available. Studies have shown the potential of treatment of ectopic vascular calcifications with bisphosphonates. This paper describes the rationale and design of the CALCIFADE trial which evaluates the effects of etidronate in patients with Fahr's disease or syndrome. METHODS: The CALCIFADE trial is a randomised, placebo-controlled, double-blind trial which evaluates the effects of etidronate 20 mg/kg during 12 months follow-up in patients aged ≥ 18 years with Fahr's disease or syndrome. Etidronate and placebo will be administered in capsules daily for two weeks on followed by ten weeks off. The study will be conducted at the outpatient clinic of the University Medical Center Utrecht, the Netherlands. The primary endpoint is the change in cognitive functioning after 12 months of treatment. Secondary endpoints are the change in mobility, neuropsychiatric symptoms, volume of brain calcifications, dependence in activities of daily living, and quality of life. RESULTS: Patient recruitment started in April 2023. Results are expected in 2026 and will be disseminated through peer-reviewed journals as well as presentations at national and international conferences. CONCLUSIONS: Fahr's disease and syndrome are slowly progressive disorders with a negative impact on a variety of health outcomes. Etidronate might be a new promising treatment for patients with Fahr's disease or syndrome. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05662111. Registered 22 December 2022, https://clinicaltrials.gov/ct2/show/NCT01585402 .

The Association between Intracranial Calcifications and Symptoms in Patients with Primary Familial Brain Calcification.

(1) Background: Primary Familial Brain Calcification (PFBC) is a neurodegenerative disease characterized by bilateral calcifications of the basal ganglia and other intracranial areas. Many patients experience symptoms of motor dysfunction and cognitive disorders. The aim of this study was to investigate the association between the amount and location of intracranial calcifications with these symptoms. (2) Methods: Patients with suspected PFBC referred to our outpatient clinic underwent a clinical work-up. Intracranial calcifications were visualized on Computed Tomography (CT), and a Total Calcification Score (TCS) was constructed. Logistic and linear regression models were performed. (3) Results: Fifty patients with PFBC were included in this study (median age 64.0 years, 50% women). Of the forty-one symptomatic patients (82.0%), 78.8% showed motor dysfunction, and 70.7% showed cognitive disorders. In multivariate analysis, the TCS was associated with bradykinesia/hypokinesia (OR 1.07, 95%-CI 1.02-1.12, p < 0.01), gait ataxia (OR 1.06, 95%-CI 1.00-1.12, p = 0.04), increased fall risk (OR 1.04, 95%-CI 1.00-1.08, p = 0.03), and attention/processing speed disorders (OR 1.06, 95%-CI 1.01-1.12, p = 0.02). Calcifications of the lentiform nucleus and subcortical white matter were associated with motor and cognitive disorders. (4) Conclusions: cognitive and motor symptoms are common among patients with PFBC, and there is an association between intracranial calcifications and these symptoms.

Graph convolutional networks for automated intracranial artery labeling.

Purpose: Unruptured intracranial aneurysms (UIAs) can cause aneurysmal subarachnoid hemorrhage, a severe and often lethal type of stroke. Automated labeling of intracranial arteries can facilitate the identification of risk factors associated with UIAs. This study aims to improve intracranial artery labeling using atlas-based features in graph convolutional networks. Approach: We included three-dimensional time-of-flight magnetic resonance angiography scans from 150 individuals. Two widely used graph convolutional operators, GCNConv and GraphConv, were employed in models trained to classify 12 bifurcations of interest. Cross-validation was applied to explore the effectiveness of atlas-based features in node classification. The results were tested for statistically significant differences using a Wilcoxon signed-rank test. Model repeatability and calibration were assessed on the test set for both operators. In addition, we evaluated model interpretability and node feature contribution using explainable artificial intelligence. Results: Atlas-based features led to statistically significant improvements in node classification (p<0.05). The results showed that the best discrimination and calibration performances were obtained using the GraphConv operator, which yielded a mean recall of 0.87, precision of 0.90, and expected calibration error of 0.02. Conclusions: The addition of atlas-based features improved node classification results. The GraphConv operator, which incorporates higher-order structural information during training, is recommended over the GCNConv operator based on the accuracy and calibration of predicted outcomes.

TopCoW: Benchmarking Topology-Aware Anatomical Segmentation of the Circle of Willis (CoW) for CTA and MRA.

The Circle of Willis (CoW) is an important network of arteries connecting major circulations of the brain. Its vascular architecture is believed to affect the risk, severity, and clinical outcome of serious neuro-vascular diseases. However, characterizing the highly variable CoW anatomy is still a manual and time-consuming expert task. The CoW is usually imaged by two angiographic imaging modalities, magnetic resonance angiography (MRA) and computed tomography angiography (CTA), but there exist limited public datasets with annotations on CoW anatomy, especially for CTA. Therefore we organized the TopCoW Challenge in 2023 with the release of an annotated CoW dataset. The TopCoW dataset was the first public dataset with voxel-level annotations for thirteen possible CoW vessel components, enabled by virtual-reality (VR) technology. It was also the first large dataset with paired MRA and CTA from the same patients. TopCoW challenge formalized the CoW characterization problem as a multiclass anatomical segmentation task with an emphasis on topological metrics. We invited submissions worldwide for the CoW segmentation task, which attracted over 140 registered participants from four continents. The top performing teams managed to segment many CoW components to Dice scores around 90%, but with lower scores for communicating arteries and rare variants. There were also topological mistakes for predictions with high Dice scores. Additional topological analysis revealed further areas for improvement in detecting certain CoW components and matching CoW variant topology accurately. TopCoW represented a first attempt at benchmarking the CoW anatomical segmentation task for MRA and CTA, both morphologically and topologically.

Analysis of aneurysmal subarachnoid hemorrhage as a multistep process.

BACKGROUND AND PURPOSE: Aneurysmal subarachnoid hemorrhage (ASAH) is a complex disease with higher incidence in women compared to men and in Japan compared to other countries. It was hypothesized that ASAH is consistent with a multistep model of disease. The following assessments were made: (1) the number of steps needed for the disease to occur and (2) whether this number may be different in female versus male and in Japanese versus non-Japanese patients. METHODS: Incidence data were generated from a meta-analysis on ASAH incidence until 2017, which was supplemented with a literature search from 2017 to April 2023. Age- and sex-adjusted incidences per 10-year age groups were calculated and the logarithm of age-specific incidence against the logarithm of age was regressed with least-squares regression. RESULTS: In 2317 ASAH patients a linear relationship between logarithm of incidence and logarithm of age was found with a slope estimate of 3.13 (95% confidence interval 2.60-3.65), consistent with a four-step process. Similar estimates were found for female, male, Japanese and non-Japanese patients. CONCLUSIONS: Our results suggest that ASAH is a four-step process, also in subgroups with higher ASAH incidence. Elucidation of the exact nature of these steps can provide important clues for identification of disease mechanisms underlying ASAH.

Long-term lifestyle change and risk of mortality and Type 2 diabetes in patients with cardiovascular disease.

AIMS: To quantify the relationship between self-reported, long-term lifestyle changes (smoking, waist circumference, physical activity, and alcohol consumption) and clinical outcomes in patients with established cardiovascular disease (CVD). METHODS AND RESULTS: Data were used from 2011 participants (78% male, age 57 ± 9 years) from the Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease cohort who returned for a re-assessment visit (SMART2) after ∼10 years. Self-reported lifestyle change was classified as persistently healthy, improved, worsened, or persistently unhealthy. Cox proportional hazard models were used to quantify the relationship between lifestyle changes and the risk of (cardiovascular) mortality and incident Type 2 diabetes (T2D). Fifty-seven per cent of participants was persistently healthy, 17% improved their lifestyle, 8% worsened, and 17% was persistently unhealthy. During a median follow-up time of 6.1 (inter-quartile range 3.6-9.6) years after the SMART2 visit, 285 deaths occurred, and 99 new T2D diagnoses were made. Compared with a persistently unhealthy lifestyle, individuals who maintained a healthy lifestyle had a lower risk of all-cause mortality [hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.36-0.63], cardiovascular mortality (HR 0.57, 95% CI 0.38-0.87), and incident T2D (HR 0.46, 95% CI 0.28-0.73). Similarly, those who improved their lifestyle had a lower risk of all-cause mortality (HR 0.52, 95% CI 0.37-0.74), cardiovascular mortality (HR 0.46, 95% CI 0.26-0.81), and incident T2D (HR 0.50, 95% CI 0.27-0.92). CONCLUSION: These findings suggest that maintaining or adopting a healthy lifestyle can significantly lower mortality and incident T2D risk in CVD patients. This study emphasizes the importance of ongoing lifestyle optimization in CVD patients, highlighting the potential for positive change regardless of previous lifestyle habits.

In this study, we investigated whether lifestyle changes were related to improved health outcomes in individuals with cardiovascular disease (CVD). We assessed self-reported lifestyle behaviours (smoking, waist circumference, alcohol consumption, and physical activity), at inclusion in the cohort and again ∼10 years later. The results emphasize the importance of making healthy lifestyle choices, even for individuals already diagnosed with CVD, and suggest that it is never too late to improve one's lifestyle.

Hemodynamic Parameters in the Parent Arteries of Unruptured Intracranial Aneurysms Depend on Aneurysm Size and Are Different Compared to Contralateral Arteries: A 7 Tesla 4D Flow MRI Study.

BACKGROUND: Different Circle of Willis (CoW) variants have variable prevalences of aneurysm development, but the hemodynamic variation along the CoW and its relation to presence and size of unruptured intracranial aneurysms (UIAs) are not well known. PURPOSE: Gain insight into hemodynamic imaging markers of the CoW for UIA development by comparing these outcomes to the corresponding contralateral artery without an UIA using 4D flow magnetic resonance imaging (MRI). STUDY TYPE: Retrospective, cross-sectional study. SUBJECTS: Thirty-eight patients with an UIA, whereby 27 were women and a mean age of 62 years old. FIELD STRENGTH/SEQUENCE: Four-dimensional phase-contrast (PC) MRI with a 3D time-resolved velocity encoded gradient echo sequence at 7 T. ASSESSMENT: Hemodynamic parameters (blood flow, velocity pulsatility index [vPI], mean velocity, distensibility, and wall shear stress [peak systolic (WSSMAX ), and time-averaged (WSSMEAN )]) in the parent artery of the UIA were compared to the corresponding contralateral artery without an UIA and were related to UIA size. STATISTICAL TESTS: Paired t-tests and Pearson Correlation tests. The threshold for statistical significance was P < 0.05 (two-tailed). RESULTS: Blood flow, mean velocity, WSSMAX , and WSSMEAN were significantly higher, while vPI was lower, in the parent artery relative to contralateral artery. The WSSMAX of the parent artery significantly increased linearly while the WSSMEAN decreased linearly with increasing UIA size. CONCLUSIONS: Hemodynamic parameters and WSS differ between parent vessels of UIAs and corresponding contralateral vessels. WSS correlates with UIA size, supporting a potential hemodynamic role in aneurysm pathology. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Gadolinium-enhanced intracranial aneurysm wall imaging and risk of aneurysm growth and rupture: a multicentre longitudinal cohort study.

OBJECTIVES: In patients with an unruptured intracranial aneurysm, gadolinium enhancement of the aneurysm wall is associated with growth and rupture. However, most previous studies did not have a longitudinal design and did not adjust for aneurysm size, which is the main predictor of aneurysm instability and the most important determinant of wall enhancement. We investigated whether aneurysm wall enhancement predicts aneurysm growth and rupture during follow-up and whether the predictive value was independent of aneurysm size. MATERIALS AND METHODS: In this multicentre longitudinal cohort study, individual patient data were obtained from twelve international cohorts. Inclusion criteria were as follows: 18 years or older with ≥ 1 untreated unruptured intracranial aneurysm < 15 mm; gadolinium-enhanced aneurysm wall imaging and MRA at baseline; and MRA or rupture during follow-up. Patients were included between November 2012 and November 2019. We calculated crude hazard ratios with 95%CI of aneurysm wall enhancement for growth (≥ 1 mm increase) or rupture and adjusted for aneurysm size. RESULTS: In 455 patients (mean age (SD), 60 (13) years; 323 (71%) women) with 559 aneurysms, growth or rupture occurred in 13/194 (6.7%) aneurysms with wall enhancement and in 9/365 (2.5%) aneurysms without enhancement (crude hazard ratio 3.1 [95%CI: 1.3-7.4], adjusted hazard ratio 1.4 [95%CI: 0.5-3.7]) with a median follow-up duration of 1.2 years. CONCLUSIONS: Gadolinium enhancement of the aneurysm wall predicts aneurysm growth or rupture during short-term follow-up, but not independent of aneurysm size. CLINICAL RELEVANCE STATEMENT: Gadolinium-enhanced aneurysm wall imaging is not recommended for short-term prediction of growth and rupture, since it appears to have no additional value to conventional predictors. KEY POINTS: • Although aneurysm wall enhancement is associated with aneurysm instability in cross-sectional studies, it remains unknown whether it predicts risk of aneurysm growth or rupture in longitudinal studies. • Gadolinium enhancement of the aneurysm wall predicts aneurysm growth or rupture during short-term follow-up, but not when adjusting for aneurysm size. • While gadolinium-enhanced aneurysm wall imaging is not recommended for short-term prediction of growth and rupture, it may hold potential for aneurysms smaller than 7 mm.

Performance of a diagnostic model for the presence of unruptured intracranial aneurysms in the general population.

INTRODUCTION: The prevalence of unruptured intracranial aneurysms (UIAs) in the general population is 3%. Aneurysmal subarachnoid hemorrhage (aSAH) can be prevented by screening for UIAs followed by monitoring and, if needed, preventive neurosurgical or endovascular treatment of identified UIAs. Therefore, we developed a diagnostic model for presence of UIAs in the general population to help identify persons at high risk of having UIAs. METHODS: Between 2005-2015, participants from the population-based Rotterdam Study underwent brain magnetic resonance imaging at 1.5 Tesla, on which presence of incidental UIAs was evaluated. We developed a multivariable logistic regression model using candidate diagnostic markers that were selected based on the literature, including sex, age, hypertension, smoking, hypercholesterolemia, diabetes, alcohol, and their interactions. We corrected for overfitting using bootstrapping. Model performance was assessed with discrimination, calibration, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: 5835 persons were included (55.0% women, mean age 64.9 ± 10.9 years) with a 2.2% UIA prevalence. Sex, age, hypertension, smoking, diabetes, and interactions of sex with age, hypertension, and smoking were independent diagnostic markers. The resulting model had a c-statistic of 0.65 (95% confidence interval [CI] 0.60 - 0.68) and 56% sensitivity, 52% specificity, 98% PPV, and 3% NPV for UIA presence at a cut-off value of 4%. Because of interactions with sex, additional models for men and women separately were developed. The model for men had a c-statistic of 0.70 (95% CI 0.62 - 0.78) with age, hypertension, and smoking as diagnostic markers and comparable additional performance values as for the full model. The model for women had a c-statistic of 0.58 (95% CI 0.52 - 0.63) with smoking as the only diagnostic marker. CONCLUSION: Our diagnostic model had insufficient performance to help identify persons at high risk of having UIAs in the general population. Rather, it provides insight in risk factors contributing to UIA risk and shows that these may be in part sex-specific.

Serial quality of life assessment around screening for familial intracranial aneurysms: a prospective cohort study.

INTRODUCTION: Screening for intracranial aneurysms (IAs) is cost-effective in first-degree relatives of aneurysmal subarachnoid haemorrhage (aSAH) patients, but its psychosocial impact is largely unknown. PATIENTS AND METHODS: A consecutive series of persons aged 20-70 years visiting the University Medical Centre Utrecht for first screening for familial IA was approached between 2017-2020. E-questionnaires were administered at six time points, consisting of the EQ-5D for health-related quality of life (QoL), HADS for emotional functioning and USER-P for social participation. QoL outcomes were compared with the general population, and between participants with a positive and negative screening for IA. Predictors of QoL outcomes were assessed with linear mixed effects models. RESULTS: 105 participants from 75 families were included; in 10 (10%) an IA was found. During the first year after screening we found no negative effect on QoL, except for a temporary decrease in QoL six months after screening in participants with a positive screen (EQ-5D -11.3 [95%CI:-21.7 to -0.8]). Factors associated with worse QoL were psychiatric disease (EQ-5D -10.3 [95%CI:-15.1 to -5.6]), physical complaints affecting mood (EQ-5D -8.1 [95%CI:-11.7 to -4.4]), and a passive coping style (EQ-5D decrease per point increase on the Utrecht Coping List -1.1 [95%CI:-1.5 to -0.6]). DISCUSSION AND CONCLUSION: We did not find a lasting negative effect on QoL during the first year after screening for familial IA. Predictors for a worse QoL were psychiatric disease, physical complaints affecting mood, and a passive coping style. This information can be used in counselling about familial IA screening.

Effect of adipose tissue quantity and dysfunction on the risk of cancer in individuals with and without type 2 diabetes.

OBJECTIVE: To determine the role of waist circumference and metabolic dysfunction in the risk of cancer in individuals with type 2 diabetes (T2D) and to compare this to individuals without T2D. METHODS: Individuals with (n = 1925) and without T2D (n = 10,204) were included from the UCC-SMART cohort. Incident cancer diagnoses were obtained by linkage with the Netherlands Cancer Registry. Metabolic dysfunction was defined as ≥ 3 adapted NCEP ATP-III metabolic syndrome criteria. The effects of waist circumference and metabolic dysfunction on cancer were assessed using Cox proportional hazards models, adjusted for confounders. RESULTS: During a median follow-up of 8.3 years (IQR 4.2-13.1), 1740 individuals were diagnosed with cancer. Incidence rates of total cancer were 19.3 and 15.5/1000 person-years for individuals with and without T2D, respectively. In individuals without T2D, a higher waist circumference was associated with an increased risk of colorectal (per standard deviation: HR 1.23; 95%CI 1.03-1.46), urinary tract (HR 1.28; 95%CI 1.05-1.56) and total cancer (HR 1.06; 95%CI 1.02-1.13). Metabolic dysfunction was related to an increased risk of colorectal (HR 1.35; 95%CI 1.01-1.82), lung (HR 1.37; 95%CI 1.07-1.75) and total cancer (HR 1.13; 95%CI 1.01-1.25) in individuals without T2D. In individuals with T2D, no significant associations were found. CONCLUSION: Incidence rates of cancer are higher among individuals with T2D. However, higher waist circumference and metabolic dysfunction are only associated with an increased cancer risk in patients without T2D. These findings provide novel insights into the role of metabolic dysfunction in the occurrence of cancer.

Screening for intracranial aneurysms in persons ⩾35 years with hypertension and atherosclerotic disease who smoke(d).

INTRODUCTION: Lifetime risk of aneurysmal subarachnoid haemorrhage (aSAH) is high (7%) in persons ⩾35 years with hypertension who smoke(d). Whether screening for intracranial aneurysms (IAs) to prevent aSAH is effective in these patients is unknown. PATIENTS AND METHODS: Participants were retrieved from a cohort of patients with clinically manifest atherosclerotic vascular disease included between 2012 and 2019 at the University Medical Centre Utrecht (SMART-ORACLE, NCT01932671) in whom CT-angiography (CTA) of intracranial arteries was performed. We selected patients ⩾35 years with hypertension who smoke(d). CTAs were reviewed for the presence of IAs by experienced neuroradiologists. Patients with IAs were offered follow-up imaging to detect aneurysmal growth. We determined aneurysm prevalence and developed a diagnostic model for IA risk at screening using multivariable logistic regression. RESULTS: IA were found in 25 of 500 patients (5.0% prevalence, 95%CI: 3.3%-7.3%). Median 5 year risk of rupture assessed with the PHASES score was 0.9% (IQR: 0.7%-1.3%). During a median follow-up of 57 months (IQR: 39-83 months) no patients suffered from aSAH. Aneurysmal growth was detected in one patient for whom preventive treatment was advised. IA risk at screening ranged between 1.6% and 13.4% with predictors being age, female sex and current smoking. DISCUSSION AND CONCLUSION: IA prevalence in persons ⩾35 years with hypertension and atherosclerotic vascular disease who smoke(d) was 5%. Given the very small proportion of IA that needed preventive treatment, we currently do not advise screening for Caucasian persons older than 35 years of age who smoke and have hypertension in general. Whether screening may be effective for certain subgroups (e.g. women older than 50 years of age) or other ethnic populations should be the subject of future studies.

Aneurysm Prevalence and Quality of Life During Screening in Relatives of Patients With Unruptured Intracranial Aneurysms: A Prospective Study.

BACKGROUND AND OBJECTIVES: Screening for unruptured intracranial aneurysms (UIAs) is effective for first-degree relatives (FDRs) of patients with aneurysmal subarachnoid hemorrhage (aSAH). Whether screening is also effective for FDRs of patients with UIA is unknown. We determined the yield of screening in such FDRs, assessed rupture risk and treatment decisions of aneurysms that were found, identified potential high-risk subgroups, and studied the effects of screening on quality of life (QoL). METHODS: In this prospective cohort study, we included FDRs, aged 20-70 years, of patients with UIA without a family history of aSAH who visited the Neurology outpatient clinic in 1 of 3 participating tertiary referral centers in the Netherlands. FDRs were screened for UIA with magnetic resonance angiography between 2017 and 2021. We determined UIA prevalence and developed a prediction model for UIA risk at screening using multivariable logistic regression. QoL was evaluated with questionnaires 6 times during the first year after screening and assessed with a linear mixed-effects model. RESULTS: We detected 24 UIAs in 23 of 461 screened FDRs, resulting in a 5.0% prevalence (95% CI 3.2-7.4). The median aneurysm size was 3 mm (interquartile range [IQR] 2-4 mm), and the median 5-year rupture risk assessed with the PHASES score was 0.7% (IQR 0.4%-0.9%). All UIAs received follow-up imaging, and none were treated preventively. After a median follow-up of 24 months (IQR 13-38 months), no UIA had changed. Predicted UIA risk at screening ranged between 2.3% and 14.7% with the highest risk in FDRs who smoke and have excessive alcohol consumption (c-statistic: 0.76; 95% CI 0.65-0.88). At all survey moments, health-related QoL and emotional functioning were comparable with those in a reference group from the general population. One FDR with a positive screening result expressed regret about screening. DISCUSSION: Based on the current data, we do not advise screening FDRs of patients with UIA because all identified UIAs had a low rupture risk. We observed no negative effect of screening on QoL. A longer follow-up should determine the risk of aneurysm growth requiring preventive treatment.

Geometric Deep Learning Using Vascular Surface Meshes for Modality-Independent Unruptured Intracranial Aneurysm Detection.

Early detection of unruptured intracranial aneurysms (UIAs) enables better rupture risk and preventative treatment assessment. UIAs are usually diagnosed on Time-of-Flight Magnetic Resonance Angiographs (TOF-MRA) or contrast-enhanced Computed Tomography Angiographs (CTA). Various automatic voxel-based deep learning UIA detection methods have been developed, but these are limited to a single modality. We propose a modality-independent UIA detection method using a geometric deep learning model with high resolution surface meshes of brain vessels. A mesh convolutional neural network with ResU-Net style architecture was used. UIA detection performance was investigated with different input and pooling mesh resolutions, and including additional edge input features (shape index and curvedness). Both a higher resolution mesh (15,000 edges) and additional curvature edge features improved performance (average sensitivity: 65.6%, false positive count/image (FPC/image): 1.61). UIAs were detected in an independent TOF-MRA test set and a CTA test set with average sensitivity of 52.0% and 48.3% and average FPC/image of 1.04 and 1.05 respectively. We provide modality-independent UIA detection using a deep-learning vascular surface mesh model with comparable performance to state-of-the-art UIA detection methods.

Physical exercise volume, type, and intensity and risk of all-cause mortality and cardiovascular events in patients with cardiovascular disease: a mediation analysis.

Aims: To estimate the relation between physical exercise volume, type, and intensity with all-cause mortality and recurrent vascular events in patients with cardiovascular disease (CVD) and to quantify to what extent traditional cardiovascular risk factors mediate these relations. Methods and results: In the prospective UCC-SMART cohort (N = 8660), the associations of clinical endpoints and physical exercise volume (metabolic equivalent of task hours per week, METh/wk), type (endurance vs. endurance + resistance), and intensity (moderate vs. vigorous) were estimated using multivariable-adjusted Cox models. The proportion mediated effect (PME) through body mass index, systolic blood pressure, low-density lipoprotein cholesterol, insulin sensitivity, and systemic inflammation was assessed using structural equation models. Sixty-one percent of patients (73% male, age 61 ± 10 years, >70% receiving lipid-lowering and blood pressure-lowering medications) reported that they did not exercise. Over a median follow-up of 9.5 years [interquartile range (IQR) 5.1-14.0], 2256 deaths and 1828 recurrent vascular events occurred. The association between exercise volume had a reverse J-shape with a nadir at 29 (95% CI 24-29) METh/wk, corresponding with a HR 0.56 (95% CI 0.48-0.64) for all-cause mortality and HR 0.63 (95% CI 0.55-0.73) for recurrent vascular events compared with no exercise. Up to 38% (95% CI 24-61) of the association was mediated through the assessed risk factors of which insulin sensitivity (PME up to 12%, 95% CI 5-25) and systemic inflammation (PME up to 18%, 95% CI 9-37) were the most important. Conclusion: Regular physical exercise is significantly related with reduced risks of all-cause mortality and recurrent vascular events in patients with CVD. In this population with high rates of lipid-lowering and blood pressure--lowering medication use, exercise benefits were mainly mediated through systemic inflammation and insulin resistance.

Age of onset of cerebral venous thrombosis: the BEAST study.

Background: Cerebral venous thrombosis (CVT) is an uncommon cause of stroke in young adults. We aimed to determine the impact of age, gender and risk factors (including sex-specific) on CVT onset. Methods: We used data from the BEAST (Biorepository to Establish the Aetiology of Sinovenous Thrombosis), a multicentre multinational prospective observational study on CVT. Composite factors analysis (CFA) was performed to determine the impact on the age of CVT onset in males and females. Results: A total of 1309 CVT patients (75.3% females) aged ⩾18 years were recruited. The overall median (IQR-interquartile range) age for males and females was 46 (35-58) years and 37 (28-47) years (p < 0.001), respectively. However, the presence of antibiotic-requiring sepsis (p = 0.03, 95% CI 27-47 years) among males and gender-specific risk factors like pregnancy (p < 0.001, 95% CI 29-34 years), puerperium (p < 0.001, 95% CI 26-34 years) and oral contraceptive use (p < 0.001, 95% CI 33-36 years) were significantly associated with earlier onset of CVT among females. CFA demonstrated a significantly earlier onset of CVT in females, ~12 years younger, in those with multiple (⩾1) compared to '0' risk factors (p < 0.001, 95% CI 32-35 years). Conclusions: Women suffer CVT 9 years earlier in comparison to men. Female patients with multiple (⩾1) risk factors suffer CVT ~12 years earlier compared to those with no identifiable risk factors.