Background: Thoracic aortopathy is a serious complication which is more often seen in patients with Marfan syndrome (MFS) and patients with a bicuspid aortic valve (BAV) than in individuals with a... Show moreBackground: Thoracic aortopathy is a serious complication which is more often seen in patients with Marfan syndrome (MFS) and patients with a bicuspid aortic valve (BAV) than in individuals with a tricuspid aortic valve (TAV). The identification of common pathological mechanisms leading to aortic complications in non-syndromic and syndromic diseases would significantly improve the field of personalized medicine. Objective: This study sought to compare thoracic aortopathy between MFS, BAV, and TAV individuals. Materials and methods: Bicuspid aortic valve (BAV; n = 36), TAV (n = 23), and MFS (n = 8) patients were included. Ascending aortic wall specimen were studied for general histologic features, apoptosis, markers of cardiovascular ageing, expression of synthetic and contractile vascular smooth muscle cells (VSMC), and fibrillin-1 expression. Results: The MFS group showed many similarities with the dilated BAV. Both patient groups showed a thinner intima (p < 0.0005), a lower expression of contractile VSMCs (p < 0.05), more elastic fiber thinning (p < 0.001), lack of inflammation (p < 0.001), and a decreased progerin expression (p < 0.05) as compared to the TAV. Other features of cardiovascular ageing differed between the BAV and MFS. Dilated BAV patients demonstrated less medial degeneration (p < 0.0001), VSMC nuclei loss (p < 0.0001), apoptosis of the vessel wall (p < 0.03), and elastic fiber fragmentation and disorganization (p < 0.001), as compared to the MFS and dilated TAV. Conclusion: This study showed important similarities in the pathogenesis of thoracic aortic aneurysms in BAV and MFS. These common mechanisms can be further investigated to personalize treatment strategies in non-syndromic and syndromic conditions. Show less
Velickovic, V.M.; Spelman, T.; Clark, M.; Probst, S.; Armstrong, D.G.; Steyerberg, E. 2022
Significance: Chronic wounds are associated with significant morbidity, marked loss of quality of life, and considerable economic burden. Evidence-based risk prediction to guide improved wound... Show moreSignificance: Chronic wounds are associated with significant morbidity, marked loss of quality of life, and considerable economic burden. Evidence-based risk prediction to guide improved wound prevention and treatment is limited by the complexity in their etiology, clinical underreporting, and a lack of studies using large high-quality datasets. Recent Advancements: The objective of this review is to summarize key components and challenges in the development of personalized risk prediction tools for both prevention and management of chronic wounds, while highlighting several innovations in the development of better risk stratification. Critical Issues: Regression-based risk prediction approaches remain important for assessment of prognosis and risk stratification in chronic wound management. Advances in statistical computing have boosted the development of several promising machine learning (ML) and other semiautomated classification tools. These methods may be better placed to handle large number of wound healing risk factors from large datasets, potentially resulting in better risk prediction when combined with conventional methods and clinical experience and expertise. Future Directions: Where the number of predictors is large and heterogenous, the correlations between various risk factors complex, and very large data sets are available, ML may prove a powerful adjuvant for risk stratifying patients predisposed to chronic wounds. Conventional regression-based approaches remain important, particularly where the number of predictors is relatively small. Translating estimated risk derived from ML algorithms into practical prediction tools for use in clinical practice remains challenging. Show less
Background and importance Although aging societies in Western Europe use presenting complaints (PCs) in emergency departments (EDs) triage systems to determine the urgency and severity of the care... Show moreBackground and importance Although aging societies in Western Europe use presenting complaints (PCs) in emergency departments (EDs) triage systems to determine the urgency and severity of the care demand, it is unclear whether their prognostic value is age-dependent.Objective To assess the frequency and association of PCs with hospitalization and mortality across age categories.Methods An observational multicenter study using all consecutive visits of three EDs in the Netherlands Emergency department Evaluation Database. Patients were stratified by age category (0-18; 19-50; 51-65; 66-80; >80 years), in which the association between PCs and case-mix adjusted hospitalization and mortality was studied using multivariable logistic regression analysis (adjusting for demographics, hospital, disease severity, comorbidity and other PCs)Results We included 172 104 ED-visits. The most frequent PCs were 'extremity problems' [range across age categories (13.5-40.8%)], 'feeling unwell' (9.5-23.4%), 'abdominal pain' (6.0-13.9%), 'dyspnea' (4.5-13.3%) and 'chest pain' (0.6-10.7%). For most PCs, the observed and the case-mix-adjusted odds for hospitalization and mortality increased the higher the age category. The most common PCs with the highest adjusted odds ratios (AORs, 95% CI) for hospitalization were 'diarrhea and vomiting' [2.30 (2.02-2.62)] and 'feeling unwell' [1.60 (1.48-1.73)]. Low hospitalization risk was found for 'chest pain' [0.58 (0.53-0.63)] and `palpitations' [0.64 (0.58-0.71)].Conclusions Frequency of PCs in ED patients varies with age, but the same PCs occur in all age categories. For most PCs, (case-mix adjusted) hospitalization and mortality vary across age categories. 'Chest pain' and 'palpitations,' usually triaged 'very urgent', carry a low risk for hospitalization and mortality. European Journal of Emergency Medicine 29: 33-41 Copyright (c) 2021 Wolters Kluwer Health, Inc. All rights reserved. Show less
Biewenga, M.; Verhelst, X.P.D.M.J.; Baven-Pronk, M.A.M.C.; Putter, H.; Berg, A.P. van den; Nieuwkerk, K.C.M.J. van; ... ; Dutch Autoimmune Hepatitis Study G 2021
Background No prognostic score is currently available for long-term survival in autoimmune hepatitis (AIH) patients. Objective The aim of this study was to develop and validate such a prognostic... Show moreBackground No prognostic score is currently available for long-term survival in autoimmune hepatitis (AIH) patients. Objective The aim of this study was to develop and validate such a prognostic score for AIH patients at diagnosis. Methods The prognostic score was developed using uni- & multivariate Cox regression in a 4-center Dutch cohort and validated in an independent 6-center Belgian cohort. Results In the derivation cohort of 396 patients 19 liver transplantations (LTs) and 51 deaths occurred (median follow-up 118 months; interquartile range 60-202 months). In multivariate analysis age (hazard ratio [HR] 1.045; p < 0.001), non-caucasian ethnicity (HR 1.897; p = 0.045), cirrhosis (HR 3.266; p < 0.001) and alanine aminotransferase level (HR 0.725; p = 0.003) were significant independent predictors for mortality or LT (C-statistic 0.827; 95% CI 0.790-0.864). In the validation cohort of 408 patients death or LT occurred in 78 patients during a median follow-up of 74 months (interquartile range: 25-142 months). Predicted 5-year event rate did not differ from observed event rate (high risk group 21.5% vs. 15.7% (95% CI: 6.3%-24.2%); moderate risk group 5.8% versus 4.3% (95% CI: 0.0%-9.1%); low risk group 1.9% versus 5.4% (95% CI: 0.0%-11.4%); C-statistic 0.744 [95% CI 0.644-0.844]). Conclusions A Dutch-Belgian prognostic score for long-term transplant-free survival in AIH patients at diagnosis was developed and validated. Show less
Early detection of breast cancer through screening reduces breast cancer mortality. The benefits of screening must also be considered within the context of potential harms (e.g., false positives,... Show moreEarly detection of breast cancer through screening reduces breast cancer mortality. The benefits of screening must also be considered within the context of potential harms (e.g., false positives, overdiagnosis). Furthermore, while breast cancer risk is highly variable within the population, most screening programs use age to determine eligibility. A risk-based approach is expected to improve the benefit-harm ratio of breast cancer screening programs. The PERSPECTIVE I&I (Personalized Risk Assessment for Prevention and Early Detection of Breast Cancer: Integration and Implementation) project seeks to improve personalized risk assessment to allow for a cost-effective, population-based approach to risk-based screening and determine best practices for implementation in Canada. This commentary describes the four inter-related activities that comprise the PERSPECTIVE I&I project. 1: Identification and validation of novel moderate to high-risk susceptibility genes. 2: Improvement, validation, and adaptation of a risk prediction web-tool for the Canadian context. 3: Development and piloting of a socio-ethical framework to support implementation of risk-based breast cancer screening. 4: Economic analysis to optimize the implementation of risk-based screening. Risk-based screening and prevention is expected to benefit all women, empowering them to work with their healthcare provider to make informed decisions about screening and prevention. Show less
BackgroundGenomic tests may improve upon clinical risk estimation with traditional prognostic factors. We aimed to explore how evidence on the prognostic strength of a genomic signature (clinical... Show moreBackgroundGenomic tests may improve upon clinical risk estimation with traditional prognostic factors. We aimed to explore how evidence on the prognostic strength of a genomic signature (clinical validity) can contribute to individualized decision making on starting chemotherapy for women with breast cancer (clinical utility).MethodsThe MINDACT trial was a randomized trial that enrolled 6693 women with early-stage breast cancer. A 70-gene signature (Mammaprint) was used to estimate genomic risk, and clinical risk was estimated by a dichotomized version of the Adjuvant!Online risk calculator. Women with discordant risk results were randomized to the use of chemotherapy. We simulated the full risk distribution of these women and estimated individual benefit, assuming a constant relative effect of chemotherapy.ResultsThe trial showed a prognostic effect of the genomic signature (adjusted hazard ratio 2.4). A decision-analytic modeling approach identified far fewer women as candidates for genetic testing (4% rather than 50%) and fewer benefiting from chemotherapy (3% rather than 27%) as compared with the MINDACT trial report. The selection of women benefitting from genetic testing and chemotherapy depended strongly on the required benefit from treatment and the assumed therapeutic effect of chemotherapy.ConclusionsA high-quality pragmatic trial was insufficient to directly inform clinical practice on the utility of a genomic test for individual women. The indication for genomic testing may be far more limited than suggested by the MINDACT trial. Show less
Aims We aimed to update the logistic clinical SYNTAX score to predict 2 year all-cause mortality after contemporary percutaneous coronary intervention (PCI).Methods and results We analyzed 15,883... Show moreAims We aimed to update the logistic clinical SYNTAX score to predict 2 year all-cause mortality after contemporary percutaneous coronary intervention (PCI).Methods and results We analyzed 15,883 patients in the GLOBAL LEADERS study who underwent PCI. The logistic clinical SYNTAX model was updated after imputing missing values by refitting the original model (refitted original model) and fitting an extended new model (new model, with, selection based on the Akaike Information Criterion). External validation was performed in 10,100 patients having PCI at Fu Wai hospital.Chronic obstructive pulmonary disease, prior stroke, current smoker, hemoglobin level, and white blood cell count were identified as additional independent predictors of 2 year all-cause mortality and included into the new model.The c-indexes of the original, refitted original and the new model in the derivation cohort were 0.74 (95% CI 0.72-0.76), 0.75 (95% CI 0.73-0.77), and 0.78 (95% CI 0.76-0.80), respectively. The c-index of the new model was lower in the validation cohort than in the derivation cohort, but still showed improved discriminative ability of the newly developed model (0.72; 95% CI 0.67-0.77) compared to the refitted original model (0.69; 95% CI 0.64-0.74). The models overestimated the observed 2 year all-cause mortality of 1.11% in the Chinese external validation cohort by 0.54 percentage points, indicating the need for calibration of the model to the Chinese patient population.Conclusions The new model of the logistic clinical SYNTAX score better predicts 2 year all-cause mortality after PCI than the original model. The new model could guide clinical decision making by risk stratifying patients undergoing PCI. Show less
Aims In patients without obstructive coronary artery disease (CAD), we examined the prognostic value of risk factors and atherosclerotic extent.Methods and results Patients from the long-term... Show moreAims In patients without obstructive coronary artery disease (CAD), we examined the prognostic value of risk factors and atherosclerotic extent.Methods and results Patients from the long-term CONFIRM registry without prior CAD and without obstructive (>50%) stenosis were included. Within the groups of normal coronary computed tomography angiography (CCTA) (N = 1849) and non-obstructive CAD (N= 1698), the prognostic value of traditional clinical risk factors and atherosclerotic extent (segment involvement score, SIS) was assessed with Cox models. Major adverse cardiac events (MACE) were defined as all-cause mortality, non-fatal myocardial infarction, or late revascularization. In total, 3547 patients were included (age 57.9 +/- 12.1 years, 57.8% male), experiencing 460 MACE during 5.4 years of follow-up. Age, body mass index, hypertension, and diabetes were the clinical variables associated with increased MACE risk, but the magnitude of risk was higher for CCTA defined atherosclerotic extent; adjusted hazard ratio (HR) for SIS >5 was 3.4 (95% confidence interval [CI] 2.3-4.9) white HR for diabetes and hypertension were 1.7 (95% CI 1.3-2.2) and 1.4 (95% CI 1.1-1.7), respectively. Exclusion of revascularization as endpoint did not modify the results. In normal CCTA, presence of >= 1 traditional risk factors did not worsen prognosis (tog-rank P= 0.248), white it did in non-obstructive CAD (log-rank P=0.025). Adjusted for SIS, hypertension and diabetes predicted MACE risk in non-obstructive CAD, while diabetes did not increase risk in absence of CAD (P-interaction = 0.004).Conclusion Among patients without obstructive CAD, the extent of CAD provides more prognostic information for MACE than traditional cardiovascular risk factors. An interaction was observed between risk factors and CAD burden, suggesting synergistic effects of both. Show less
BACKGROUND Urgency triage in the emergency department (ED) is important for early identification of potentially lethal conditions and extensive resource utilization. However, in older patients,... Show moreBACKGROUND Urgency triage in the emergency department (ED) is important for early identification of potentially lethal conditions and extensive resource utilization. However, in older patients, urgency triage systems could be improved by taking geriatric vulnerability into account. We investigated the association of geriatric vulnerability screening in addition to triage urgency levels with 30-day mortality in older ED patients.DESIGN Secondary analysis of the observational multicenter Acutely Presenting Older Patient (APOP) study.SETTING EDs within four Dutch hospitals.PARTICIPANTS Consecutive patients, aged 70 years or older, who were prospectively included.MEASUREMENTS Patients were triaged using the Manchester Triage System (MTS). In addition, the APOP screener was used as a geriatric screening tool. The primary outcome was 30-day mortality. Comparison was made between mortality within the geriatric high- and low-risk screened patients in every urgency triage category. We calculated the difference in explained variance of mortality by adding the geriatric screener (APOP) to triage urgency (MTS) by calculating Nagelkerke R-2.RESULTS We included 2,608 patients with a median age of 79 (interquartile range = 74-84) years, of whom 521 (20.0%) patients were categorized as high risk according to geriatric screening. Patients were triaged on urgency as standard (27.2%), urgent (58.5%), and very urgent (14.3%). In total, 132 (5.1%) patients were deceased within a period of 30 days. Within every urgency triage category, 30-day mortality was threefold higher in geriatric high-risk compared to low-risk patients (overall = 11.7% vs 3.4%; P < .001). The explained variance of 30-day mortality with triage urgency was 1.0% and increased to 6.3% by adding the geriatric screener.CONCLUSION Combining triage urgency with geriatric screening has the potential to improve triage, which may help clinicians to deliver early appropriate care to older ED patients. Show less
Background: Acutely hospitalised older patients with indications related to internal medicine have high risks of adverse outcomes. We investigated whether risk stratification using the Acutely... Show moreBackground: Acutely hospitalised older patients with indications related to internal medicine have high risks of adverse outcomes. We investigated whether risk stratification using the Acutely Presenting Older Patient (APOP) screening tool associates with clinical outcomes in this patient group.Methods: Patients aged >= 70 years who visited the Emergency Department (ED) and were acutely hospitalised for internal medicine were followed prospectively. The APOP screener assesses demographics, physical and cognitive function at ED presentation, and predicts 3-month mortality and functional decline in the older ED population. Patients with a predicted risk >= 45% were considered 'high risk'. Clinical outcome was hospital length of stay (LOS), and adverse outcomes were mortality and functional decline, 3 and 12 months after hospitalisation.Results: We included 319 patients, with a median age of 80 (IQR 74-85) years, of whom 94 (29.5%) were categorised as 'high risk' by the APOP screener. These patients had a longer hospital LOS compared to 'low risk' patients (5 (IQR 3-10) vs. 3 (IQR 1-7) days, respectively; p = 0.006). At 3 months, adverse outcomes were more frequent in 'high risk' patients compared to 'low risk' patients (59.6% vs. 34.7%, respectively; p < 0.001). At 12 months, adverse outcomes (67.0% vs. 46.2%, respectively; p = 0.001) and mortality (48.9% vs. 28.0%, respectively; p < 0.001) were greater in 'high risk' compared to 'low risk' patients.Conclusion: The APOP screener identifies acutely hospitalised internal medicine patients at high risk for poor short and long-term outcomes. Early risk stratification at admission could aid in individualised treatment decisions to optimise outcomes for older patients. Show less
Histopathological evaluation including subtyping and grading is the current cornerstone for endometrial cancer (EC) classification. This provides clinicians with prognostic information and input... Show moreHistopathological evaluation including subtyping and grading is the current cornerstone for endometrial cancer (EC) classification. This provides clinicians with prognostic information and input for further treatment recommendations. Nonetheless, patients with histologically similar ECs may have very different outcomes, notably in patients with high-grade endometrial carcinomas. For endometrial cancer, four molecular subgroups have undergone extensive studies in recent years:POLEultramutated (POLEmut), mismatch repair-deficient (MMRd), p53 mutant (p53abn) and those EC lacking any of these alterations, referred to as NSMP (non-specific molecular profile). Several large studies confirm the prognostic relevance of these molecular subgroups. However, this 'histomolecular' approach has so far not been implemented in clinical routine. The ongoing PORTEC4a trial is the first clinical setting in which the added value of integrating molecular parameters in adjuvant treatment decisions will be determined. For diagnostics, the incorporation of the molecular parameters in EC classification will add a level of objectivity which will yield biologically more homogeneous subclasses. Here we illustrate how the management of individual EC patients may be impacted when applying the molecular EC classification. We describe our current approach to the integrated diagnoses of EC with a focus on scenarios with conflicting morphological and molecular findings. We also address several pitfalls accompanying the diagnostic implementation of molecular EC classification and give practical suggestions for diagnostic scenarios. Show less
OBJECTIVES This study was designed to assess the prognostic value of a new comprehensive coronary computed tomography angiography (CTA) score compared with the stenosis severity component of the... Show moreOBJECTIVES This study was designed to assess the prognostic value of a new comprehensive coronary computed tomography angiography (CTA) score compared with the stenosis severity component of the Coronary Artery Disease-Reporting and Data System (CAD-RADS).BACKGROUND Current risk assessment with coronary CTA is mainly focused on maximal stenosis severity. Integration of plaque extent, location, and composition in a comprehensive model may improve risk stratification.METHODS A total of 2,134 patients with suspected but without known CAD were included. The predictive value of the comprehensive CTA score (ranging from 0 to 42 and divided into 3 groups: 0 to 5, 6 to 20, and >20) was compared with the CAD-RADS combined into 3 groups (0% to 30%, 30% to 70% and >= 70% stenosis). Its predictive performance was internally and externally validated (using the 5-year follow-up dataset of the CONFIRM [Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry], n = 1,971).RESULTS The mean age of patients was 55 +/- 13 years, mean follow-up 3.6 +/- 2.8 years, and 130 events (myocardial infarction or death) occurred. The new, comprehensive CTA score showed strong and independent predictive value using the Cox proportional hazard analysis. A model including clinical variables plus comprehensive CTA score showed better discrimination of events compared with a model consisting of clinical variables plus CAD-RADS (0.768 vs. 0.742, p = 0.001). Also, the comprehensive CTA score correctly reclassified a significant proportion of patients compared with the CAD-RADS (net reclassification improvement 12.4%, p < 0.001). Good predictive accuracy was reproduced in the external validation cohort.CONCLUSIONS The new comprehensive CTA score provides better discrimination and reclassification of events compared with the CAD-RADS score based on stenosis severity only. The score retained similar prognostic accuracy when externally validated. Anatomic risk scores can be improved with the addition of extent, location, and compositional measures of atherosclerotic plaque. (C) 2019 by the American College of Cardiology Foundation. Show less
