Single-value brain activity scores reflect both severity and risk across the Alzheimer's continuum.

Single-value scores reflecting the deviation from (FADE score) or similarity with (SAME score) prototypical novelty-related and memory-related functional magnetic resonance imaging (fMRI) activation patterns in young adults have been proposed as imaging biomarkers of healthy neurocognitive aging. Here, we tested the utility of these scores as potential diagnostic and prognostic markers in Alzheimer's disease (AD) and risk states like mild cognitive impairment (MCI) or subjective cognitive decline (SCD). To this end, we analyzed subsequent memory fMRI data from individuals with SCD, MCI, and AD dementia as well as healthy controls (HC) and first-degree relatives of AD dementia patients (AD-rel) who participated in the multi-center DELCODE study (N = 468). Based on the individual participants' whole-brain fMRI novelty and subsequent memory responses, we calculated the FADE and SAME scores and assessed their association with AD risk stage, neuropsychological test scores, CSF amyloid positivity, and ApoE genotype. Memory-based FADE and SAME scores showed a considerably larger deviation from a reference sample of young adults in the MCI and AD dementia groups compared to HC, SCD and AD-rel. In addition, novelty-based scores significantly differed between the MCI and AD dementia groups. Across the entire sample, single-value scores correlated with neuropsychological test performance. The novelty-based SAME score further differed between Aß-positive and Aß-negative individuals in SCD and AD-rel, and between ApoE ε4 carriers and non-carriers in AD-rel. Hence, FADE and SAME scores are associated with both cognitive performance and individual risk factors for AD. Their potential utility as diagnostic and prognostic biomarkers warrants further exploration, particularly in individuals with SCD and healthy relatives of AD dementia patients.

Interactive exploration of adverse events and multimorbidity in CKD.

BACKGROUND AND HYPOTHESIS: Persons with chronic kidney disease (CKD) are at increased risk of adverse events, early mortality, and multimorbidity. A detailed overview of adverse event types and rates from a large CKD cohort under regular nephrological care is missing. We generated an interactive tool to enable exploration of adverse events and their combinations in the prospective, observational German CKD (GCKD) study. METHODS: The GCKD study enrolled 5217 participants under regular nephrological care with an estimated glomerular filtration rate of 30-60 or >60 mL/min/1.73m2 and an overt proteinuria. Cardio-, cerebro- and peripheral vascular, kidney, infection, and cancer events, as well as deaths were adjudicated following a standard operation procedure. We summarized these time-to-event data points for exploration in interactive graphs within an R shiny app. Multivariable adjusted Cox models for time to first event were fitted. Cumulative incidence functions, Kaplan-Meier curves and intersection plots were used to display main adverse events and their combinations by sex and CKD etiology. RESULTS: Over a median of 6.5 years, 10 271 events occurred in total and 680 participants (13.0%) died while 2947 participants (56.5%) experienced any event. The new publicly available interactive platform enables readers to scrutinize adverse events and their combinations as well as mortality trends as a gateway to better understand multimorbidity in CKD: incident rates per 1000 patient-years varied by event type, CKD etiology, and baseline characteristics. Incidence rates for the most frequent events and their recurrence were 113.6 (cardiovascular), 75.0 (kidney), and 66.0 (infection). Participants with diabetic kidney disease and men were more prone to experiencing events. CONCLUSION: This comprehensive explorative tool to visualize adverse events (https://gckd.diz.uk-erlangen.de/), their combination, mortality, and multimorbidity among persons with CKD may manifest as a valuable resource for patient care, identification of high-risk groups, health services, and public health policy planning.

A generalizable data-driven model of atrophy heterogeneity and progression in memory clinic settings.

Memory clinic patients are a heterogeneous population representing various aetiologies of pathological aging. It is unknown if divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease (AD) patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± SD age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (CU; n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (SCD; n = 342), mild cognitive impairment (MCI; n = 118), or dementia of the Alzheimer's type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid AD biomarker levels, the Preclinical Alzheimer Cognitive Composite (PACC-5), as well as episodic memory and executive functioning. PACC-5 trajectories over up to 240 weeks were examined. To test if baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and MCI conversion rates of CU and SCD participants. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy first affected the medial temporal lobes, followed by further temporal and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological AD biomarker levels, APOE ε4 carriership, and an amnestic cognitive impairment. Hippocampal-sparing atrophy initially occurred outside the temporal lobe with the medial temporal lobe spared up to advanced atrophy stages. This atrophy pattern also affected individuals with positive AD biomarkers and was associated with more generalised cognitive impairment. Limbic-predominant atrophy, in all and in only unimpaired participants, was linked to more negative longitudinal PACC-5 slopes than observed in participants without or with hippocampal-sparing atrophy and increased the risk of MCI conversion. SuStaIn modelling was repeated in a sample from the Swedish BioFINDER-2 cohort. Highly similar atrophy progression patterns and associated cognitive profiles were identified. Cross-cohort model generalizability, both on the subject and group level, were excellent, indicating reliable performance in previously unseen data. The proposed model is a promising tool for capturing heterogeneity among older adults at early at-risk states for AD in applied settings. The implementation of atrophy subtype- and stage-specific end-points may increase the statistical power of pharmacological trials targeting early AD.

Aß oligomers peak in early stages of Alzheimer's disease preceding tau pathology.

INTRODUCTION: Soluble amyloid beta (Aß) oligomers have been suggested as initiating Aß related neuropathologic change in Alzheimer's disease (AD) but their quantitative distribution and chronological sequence within the AD continuum remain unclear. METHODS: A total of 526 participants in early clinical stages of AD and controls from a longitudinal cohort were neurobiologically classified for amyloid and tau pathology applying the AT(N) system. Aß and tau oligomers in the quantified cerebrospinal fluid (CSF) were measured using surface-based fluorescence intensity distribution analysis (sFIDA) technology. RESULTS: Across groups, highest Aß oligomer levels were found in A+ with subjective cognitive decline and mild cognitive impairment. Aß oligomers were significantly higher in A+T- compared to A-T- and A+T+. APOE Îµ4 allele carriers showed significantly higher Aß oligomer levels. No differences in tau oligomers were detected. DISCUSSION: The accumulation of Aß oligomers in the CSF peaks early within the AD continuum, preceding tau pathology. Disease-modifying treatments targeting Aß oligomers might have the highest therapeutic effect in these disease stages. Highlights: Using surface-based fluorescence intensity distribution analysis (sFIDA) technology, we quantified Aß oligomers in cerebrospinal fluid (CSF) samples of the DZNE-Longitudinal Cognitive Impairment and Dementia (DELCODE) cohortAß oligomers were significantly elevated in mild cognitive impairment (MCI)Amyloid-positive subjects in the subjective cognitive decline (SCD) group increased compared to the amyloid-negative control groupInterestingly, levels of Aß oligomers decrease at advanced stages of the disease (A+T+), which might be explained by altered clearing mechanisms.

Machine Learning-Based Perivascular Space Volumetry in Alzheimer Disease.

OBJECTIVES: Impaired perivascular clearance has been suggested as a contributing factor to the pathogenesis of Alzheimer disease (AD). However, it remains unresolved when the anatomy of the perivascular space (PVS) is altered during AD progression. Therefore, this study investigates the association between PVS volume and AD progression in cognitively unimpaired (CU) individuals, both with and without subjective cognitive decline (SCD), and in those clinically diagnosed with mild cognitive impairment (MCI) or mild AD. MATERIALS AND METHODS: A convolutional neural network was trained using manually corrected, filter-based segmentations (n = 1000) to automatically segment the PVS in the centrum semiovale from interpolated, coronal T2-weighted magnetic resonance imaging scans (n = 894). These scans were sourced from the national German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study. Convolutional neural network-based segmentations and those performed by a human rater were compared in terms of segmentation volume, identified PVS clusters, as well as Dice score. The comparison revealed good segmentation quality (Pearson correlation coefficient r = 0.70 with P < 0.0001 for PVS volume, detection rate in cluster analysis = 84.3%, and Dice score = 59.0%). Subsequent multivariate linear regression analysis, adjusted for participants' age, was performed to correlate PVS volume with clinical diagnoses, disease progression, cerebrospinal fluid biomarkers, lifestyle factors, and cognitive function. Cognitive function was assessed using the Mini-Mental State Examination, the Comprehensive Neuropsychological Test Battery, and the Cognitive Subscale of the 13-Item Alzheimer's Disease Assessment Scale. RESULTS: Multivariate analysis, adjusted for age, revealed that participants with AD and MCI, but not those with SCD, had significantly higher PVS volumes compared with CU participants without SCD (P = 0.001 for each group). Furthermore, CU participants who developed incident MCI within 4.5 years after the baseline assessment showed significantly higher PVS volumes at baseline compared with those who did not progress to MCI (P = 0.03). Cognitive function was negatively correlated with PVS volume across all participant groups (P ≤ 0.005 for each). No significant correlation was found between PVS volume and any of the following parameters: cerebrospinal fluid biomarkers, sleep quality, body mass index, nicotine consumption, or alcohol abuse. CONCLUSIONS: The very early changes of PVS volume may suggest that alterations in PVS function are involved in the pathophysiology of AD. Overall, the volumetric assessment of centrum semiovale PVS represents a very early imaging biomarker for AD.

Investigating the spatiotemporal associations between meteorological conditions and air pollution in the federal state Baden-Württemberg (Germany).

When analyzing health data in relation to environmental stressors, it is crucial to identify which variables to include in the statistical model to exclude dependencies among the variables. Four meteorological parameters: temperature, ultraviolet radiation, precipitation, and vapor pressure and four outdoor air pollution parameters: ozone ( O 3 ), nitrogen dioxide ( NO 2 ), particulate matter ( P M 2.5 , P M 10 ) were studied on a daily basis for Baden-Württemberg (Germany). This federal state covers urban and rural compartments including mountainous and river areas. A temporal and spatial analysis of the internal relationships was performed among the variables using (a) cross-correlations, both on the grand ensemble of data as well as within subsets, and (b) the Local Indications of Spatial Association (LISA) method. Meteorological and air pollution variables were strongly correlated within and among themselves in time and space. We found a strong interaction between nitrogen dioxide and ozone, with correlation coefficients varying over time. The coefficients ranged from negative correlations in January (-0.84), April (-0.47), and October (-0.54) to a positive correlation in July (0.45). The cross-correlation plot showed a noticeable change in the correlation direction for O 3 and NO 2 . Spatially, NO 2 , P M 2.5 , and P M 10 concentrations were significantly higher in urban than rural regions. For O 3 , this effect was reversed. A LISA analysis confirmed distinct hot and cold spots of environmental stressors. This work examined and quantified the spatio-temporal relationship between air pollution and meteorological conditions and recommended which variables to prioritize for future health impact analyses. The results found are in line with the underlying physico-chemical atmospheric processes. It also identified postal code areas with dominant environmental stressors for further studies.

Pseudo-value regression trees.

This paper presents a semi-parametric modeling technique for estimating the survival function from a set of right-censored time-to-event data. Our method, named pseudo-value regression trees (PRT), is based on the pseudo-value regression framework, modeling individual-specific survival probabilities by computing pseudo-values and relating them to a set of covariates. The standard approach to pseudo-value regression is to fit a main-effects model using generalized estimating equations (GEE). PRT extend this approach by building a multivariate regression tree with pseudo-value outcome and by successively fitting a set of regularized additive models to the data in the nodes of the tree. Due to the combination of tree learning and additive modeling, PRT are able to perform variable selection and to identify relevant interactions between the covariates, thereby addressing several limitations of the standard GEE approach. In addition, PRT include time-dependent effects in the node-wise models. Interpretability of the PRT fits is ensured by controlling the tree depth. Based on the results of two simulation studies, we investigate the properties of the PRT method and compare it to several alternative modeling techniques. Furthermore, we illustrate PRT by analyzing survival in 3,652 patients enrolled for a randomized study on primary invasive breast cancer.

A Novel Scoring System Predicting Red Blood Cell Transfusion Requirements in Patients Undergoing Invasive Spine Surgery.

Background: Access to blood products is crucial for patient safety during the perioperative course. However, reduced donations and seasonally occurring blood shortages pose a significant challenge to the healthcare system, with surgeries being postponed. The German Blood Transfusion act requires that RBC packages become assigned to an individual patient, resulting in a significant reduction in the available blood products, further aggravating shortages. We aimed to develop a scoring system predicting transfusion probability in patients undergoing spine surgery to reduce assignment and, thus, increase the availability of blood products. Methods: The medical records of 252 patients who underwent spine surgery were evaluated and 18 potential predictors for RBC transfusion were tested to construct a logistic-regression-based predictive scoring system for blood transfusion in patients undergoing spine surgery. Results: The variables found to be the most important included the type of surgery, vertebral body replacement, number of stages, and pre-operative Hb concentration, indicating that surgical specification and the extent of the surgical procedure were more influential than the pre-existing patient condition and medication. Conclusions: Our model showed a good discrimination ability with an average AUC [min, max] of 0.87 [0.6, 0.97] and internal validation with a similar AUC of 0.84 [0.66, 0.97]. In summary, we developed a scoring system to forecast patients' perioperative transfusion needs when undergoing spine surgery using pre-operative predictors, potentially reducing the need for RBC allocation and, thus, resulting in an increased availability of this valuable resource.

Vessel density on optical coherence tomography angiography is prognostic for future disease course in intermediate uveitis.

As most rare diseases, intermediate uveitis lacks reliable endpoints necessary for randomized clinical trials. Therefore, we investigated longitudinal changes of retinal and choriocapillaris perfusion on optical coherence tomography angiography (OCT-A) in intermediate uveitis and their prognostic value for future best corrected visual acuity (BCVA) and central retinal thickness (CRT). In this retrospective, longitudinal cohort study eyes of patients with intermediate uveitis were imaged by swept-source OCT-A (macula-centered 3 × 3 mm; PLEX Elite 9000, Zeiss) and stratified into clinically stable, worsened and improved based on changes in clinical parameters. Superficial (SRL) and deep retinal layers (DRL) were automatically analyzed for vessel density (VD) and choriocapillaris layer for non-perfused area (CCNPA) using ImageJ. Mixed-effects regression analysis controlling for age, sex, and OCT-A signal strength index (SSI) was used to evaluate the prognostic value of OCT-A parameters. 91 eyes (62 stable, 12 worsened, and 17 improved) were included in the analysis and mean follow-up time was 296 days. Longitudinal changes of VD were different between all three groups (p = 0.002 for SRL and p = 0.017 for DRL). Clinically worsened eyes showed a decrease in VD (- 0.032 ± 0.055 for SRL and - 0.027 ± 0.025 for DRL), whereas clinically improved eyes showed an increase in VD (0.037 ± 0.039 for SRL and 0.001 ± 0.023 for DRL). No difference was found for CCNPA. When controlling for age, sex, and SSI, observed differences held true in clinically worsened eyes for DRL (p = 0.011) and in clinically improved eyes for SRL (p = 0.002). An increase of CCNPA in clinically worsened eyes (p = 0.03) compared to clinically stable and improved eyes was evident. Predictive analysis revealed an association of VD in SRL and DRL at baseline with BCVA at follow-up (p = 0.039 and p = 0.047, respectively) and of VD in SRL at baseline with CRT at follow-up (p = 0.046). Alterations in retinal perfusion on OCT-A in intermediate uveitis are partly reversible and OCT-A VD may serve to predict future BCVA and CRT. Thus, perfusion parameters on OCT-A might aid monitoring and serve as prognostic imaging-biomarker.

CT-derived Epicardial Adipose Tissue Inflammation Predicts Outcome in Patients Undergoing Transcatheter Aortic Valve Replacement.

PURPOSE: Inflammatory changes in epicardial (EAT) and pericardial adipose tissue (PAT) are associated with increased overall cardiovascular risk. Using routine, preinterventional cardiac CT data, we examined the predictive value of quantity and quality of EAT and PAT for outcome after transcatheter aortic valve replacement (TAVR). MATERIALS AND METHODS: Cardiac CT data of 1197 patients who underwent TAVR at the in-house heart center between 2011 and 2020 were retrospectively analyzed. The amount and density of EAT and PAT were quantified from single-slice CT images at the level of the aortic valve. Using established risk scores and known independent risk factors, a clinical benchmark model (BMI, Chronic kidney disease stage, EuroSCORE 2, STS Prom, year of intervention) for outcome prediction (2-year mortality) after TAVR was established. Subsequently, we tested whether the additional inclusion of area and density values of EAT and PAT in the clinical benchmark model improved prediction. For this purpose, the cohort was divided into a training (n=798) and a test cohort (n=399). RESULTS: Within the 2-year follow-up, 264 patients died. In the training cohort, particularly the addition of EAT density to the clinical benchmark model showed a significant association with outcome (hazard ratio 1.04, 95% CI: 1.01-1.07; P =0.013). In the test cohort, the outcome prediction of the clinical benchmark model was also significantly improved with the inclusion of EAT density (c-statistic: 0.589 vs. 0.628; P =0.026). CONCLUSIONS: EAT density as a surrogate marker of EAT inflammation was associated with 2-year mortality after TAVR and may improve outcome prediction independent of established risk parameters.

Different inflammatory signatures based on CSF biomarkers relate to preserved or diminished brain structure and cognition.

Neuroinflammation is a hallmark of Alzheimer's disease (AD) and both positive and negative associations of individual inflammation-related markers with brain structure and cognitive function have been described. We aimed to identify inflammatory signatures of CSF immune-related markers that relate to changes of brain structure and cognition across the clinical spectrum ranging from normal aging to AD. A panel of 16 inflammatory markers, Aß42/40 and p-tau181 were measured in CSF at baseline in the DZNE DELCODE cohort (n = 295); a longitudinal observational study focusing on at-risk stages of AD. Volumetric maps of gray and white matter (GM/WM; n = 261) and white matter hyperintensities (WMHs, n = 249) were derived from baseline MRIs. Cognitive decline (n = 204) and the rate of change in GM volume was measured in subjects with at least 3 visits (n = 175). A principal component analysis on the CSF markers revealed four inflammatory components (PCs). Of these, the first component PC1 (highly loading on sTyro3, sAXL, sTREM2, YKL-40, and C1q) was associated with older age and higher p-tau levels, but with less pathological Aß when controlling for p-tau. PC2 (highly loading on CRP, IL-18, complement factor F/H and C4) was related to male gender, higher body mass index and greater vascular risk. PC1 levels, adjusted for AD markers, were related to higher GM and WM volumes, less WMHs, better baseline memory, and to slower atrophy rates in AD-related areas and less cognitive decline. In contrast, PC2 related to less GM and WM volumes and worse memory at baseline. Similar inflammatory signatures and associations were identified in the independent F.ACE cohort. Our data suggest that there are beneficial and detrimental signatures of inflammatory CSF biomarkers. While higher levels of TAM receptors (sTyro/sAXL) or sTREM2 might reflect a protective glia response to degeneration related to phagocytic clearance, other markers might rather reflect proinflammatory states that have detrimental impact on brain integrity.

Identification and comparison of sex-specific serious adverse drug reactions in spontaneous reports and systematically collected reports (ADRED).

AIMS: Adverse drug reactions (ADRs) are known to show sex-specific differences in occurrence and phenotype. The aim of this study was to analyse sex-specific differences in ADR-drug combinations that required hospitalization based on two different datasets. METHODS: We performed a complementary analysis of (i) spontaneously reported (n = 12 564, female = 51.7%) and (ii) systematically collected ADR reports from a prospective multicentre observational study (ADRED, n = 2355, female = 48.2%) from Germany in the ADR database EudraVigilance (EV). Both datasets were analysed separately concerning the suspected drugs, ADRs and ADR-drug combinations more frequently reported for females or males by calculating reporting odds ratios (ROR) with 95% confidence intervals. ADR-drug combinations more frequently reported for either females or males in EV reports were related to prescription data. Finally, the results from both datasets were discussed with regard to their (dis-)concordance. RESULTS: In both datasets, some antineoplastic agents and nervous system drugs were found to be reported more often for females than males (RORs ranging from 1.5 [1.1-2.1] for quetiapine in spontaneous reports to 41.3 [13.1-130.0] for trastuzumab in spontaneous reports). ADRs of the respiratory system, and haemorrhages were described predominantly for males in both datasets. In spontaneous reports the ADR-drug combination self-injurious behaviour-quetiapine was more often reported for females without and with consideration of drug prescriptions (ROR: 3.8 [1.3-11.0]). Quetiapine and psychiatric disorders (superordinate level) was exclusively reported for females in ADRED reports. CONCLUSIONS: Our results can contribute to raise awareness and further knowledge regarding sex-specific ADRs. The findings require further in-depth investigation.

Stage-Dependent Biomarker Changes in Spinocerebellar Ataxia Type 3.

Spinocerebellar ataxia type 3/Machado-Joseph disease is the most common autosomal dominant ataxia. In view of the development of targeted therapies, knowledge of early biomarker changes is needed. We analyzed cross-sectional data of 292 spinocerebellar ataxia type 3/Machado-Joseph disease mutation carriers. Blood concentrations of mutant ATXN3 were high before and after ataxia onset, whereas neurofilament light deviated from normal 13.3 years before onset. Pons and cerebellar white matter volumes decreased and deviated from normal 2.2 years and 0.6 years before ataxia onset. We propose a staging model of spinocerebellar ataxia type 3/Machado-Joseph disease that includes a biomarker stage characterized by objective indicators of neurodegeneration before ataxia onset. ANN NEUROL 2024;95:400-406.

Development of a clinical algorithm to predict phenotypic switches between atopic dermatitis and psoriasis (the "Flip-Flop" phenomenon).

BACKGROUND: Atopic dermatitis (AD) and psoriasis vulgaris (PV) are almost mutually exclusive diseases with different immune polarizations, mechanisms and therapeutic targets. Switches to the other disease ("Flip-Flop" [FF] phenomenon) can occur with or without systemic treatment and are often referred to as paradoxical reactions under biological therapy. METHODS: The objective was to develop a diagnostic algorithm by combining clinical criteria of AD and PV to identify FF patients. The algorithm was prospectively validated in patients enrolled in the CK-CARE registry in Bonn, Germany. Afterward, algorithm refinements were implemented based on machine learning. RESULTS: Three hundred adult Caucasian patients were included in the validation study (n = 238 with AD, n = 49 with PV, n = 13 with FF; mean age 41.2 years; n = 161 [53.7%] female). The total FF scores of the PV and AD groups differed significantly from the FF group in the validation data (p < .001). The predictive mean generalized Youden-Index of the initial model was 78.9% [95% confidence interval 72.0%-85.6%] and the accuracy was 89.7%. Disease group-specific sensitivity was 100% (FF), 95.0% (AD), and 61.2% (PV). The specificity was 89.2% (FF), 100% (AD), and 100% (PV), respectively. CONCLUSION: The FF algorithm represents the first validated tool to identify FF patients.

A Platform for the Liebeskind-Srogl Coupling of Heteroaromatic Thioethers for Medicinal-Chemistry-Relevant Transformations.

General and robust conditions for the Liebeskind-Srogl coupling were developed and used in functionalization of medicinal-chemistry-relevant heterocyclic substrates. Applicability in HTE and library synthesis, combined with its orthogonality to other cross-coupling reactions, make it highly attractive for discovery chemistry workflows. Additionally, the results suggest that the nature of the Cu(I)-carboxylate plays a more prominent role in the reaction performance than the nature of Pd-catalysts, which is rather uncommon for Pd-catalysis and can be used in further optimization of Liebeskind-Srogl coupling.

Pre-Interventional Risk Assessment in The Elderly (PIRATE): Development of a scoring system to predict 30-day mortality using data of the Peri-Interventional Outcome Study in the Elderly.

Risk assessment before interventions in elderly patients becomes more and more vital due to an increasing number of elderly patients requiring surgery. Existing risk scores are often not tailored to marginalized groups such as patients aged 80 years or older. We aimed to develop an easy-to-use and readily applicable risk assessment tool that implements pre-interventional predictors of 30-day mortality in elderly patients (≥80 years) undergoing interventions under anesthesia. Using Cox regression analysis, we compared different sets of predictors by taking into account their ease of availability and by evaluating predictive accuracy. Coefficient estimates were utilized to set up a scoring system that was internally validated. Model building and evaluation were based on data from the Peri-Interventional Outcome Study in the Elderly (POSE), which was conducted as a European multicenter, observational prospective cohort study. Our risk assessment tool, named PIRATE, contains three predictors assessable at admission (urgency, severity and living conditions). Discriminatory power, as measured by the concordance index, was 0.75. The estimated prediction error, as measured by the Brier score, was 0.036 (covariate-free reference model: 0.043). PIRATE is an easy-to-use risk assessment tool that helps stratifying elderly patients undergoing interventions with anesthesia at increased risk of mortality. PIRATE is readily available and applies to a wide variety of settings. In particular, it covers patients needing elective or emergency surgery and undergoing in-hospital or day-case surgery. Also, it applies to all types of interventions, from minor to major. It may serve as a basis for multidisciplinary and informed shared decision-making.

Prospective Cohort Study of Soluble Urokinase Plasminogen Activation Receptor and Cardiovascular Events in Patients With CKD.

Introduction: Soluble urokinase plasminogen activation receptor (suPAR) is an immune-derived pathogenic factor for kidney and atherosclerotic disease. Whether the association between suPAR and cardiovascular (CV) outcomes is dependent on the severity of underlying kidney disease is unclear. Methods: We measured serum suPAR levels in 4994 participants (mean age 60 years; 60% men; 36% with diabetes mellitus; mean estimated glomerular filtration rate (eGFR) 49 ml/min per 1.73 m2, SD 18) of the German Chronic Kidney Disease (GCKD) cohort and examined its association with all-cause death, CV death, and major CV events (MACE) across the range of eGFR and urine albumin-to-creatinine ratio (UACR). Results: The median suPAR level was 1771 pg/ml (interquartile range [IQR] 1447-2254 pg/ml). SuPAR levels were positively and independently correlated with age, eGFR, UACR, and parathyroid hormone levels. There were 573 deaths, including 190 CV deaths and 683 MACE events at a follow-up time of 6.5 years. In multivariable analyses, suPAR levels (log2) were associated with all-cause death (hazard ratio [HR] 1.36, 95% confidence interval [CI] 1.21-1.53), CV death (HR 1.27, 95% CI 1.03-1.57), and MACE (HR 1.13, 95% CI 1.00-1.28), and were not found to differ according to diabetes mellitus status, baseline eGFR, UACR, or parathyroid hormone levels. In mediation analysis, suPAR's direct effect on all-cause death, CV death, and MACE accounted for 77%, 67%, and 60% of the total effect, respectively; whereas the effect mediated through eGFR accounted for 23%, 34%, and 40%, respectively. Conclusion: In a large cohort of individuals with chronic kidney disease (CKD), suPAR levels were associated with mortality and CV outcomes independently of indices of kidney function, consistent with its independent role in the pathogenesis of atherosclerosis.

Cardiovascular risk due to diabetes mellitus in patients with chronic kidney disease-prospective data from the German Chronic Kidney Disease cohort.

Background: Diabetes mellitus (DM) and chronic kidney disease (CKD) are well-known cardiovascular and mortality risk factors. To what extent they act in an additive manner and whether the etiology of CKD modifies the risk is uncertain. Methods: The multicenter, prospective, observational German Chronic Kidney Disease study comprises 5217 participants (1868 with DM) with a baseline mean estimated glomerular filtration rate of 30-60 mL/min/1.73 m2 and/or proteinuria >0.5 g/day. We categorized patients whose CKD was caused by cardiovascular or metabolic diseases (CKDcvm) with and without DM, as opposed to genuine CKD (CKDgen) with and without DM. Recorded outcomes were first events of non-cardiovascular and cardiovascular death, 4-point major adverse cardiovascular events (4-point MACE) and hospitalization for heart failure (HHF). Results: During the 6.5-year follow-up 603 (12%) non-cardiovascular and 209 (4%) cardiovascular deaths, 645 (12%) 4-point MACE, and 398 (8%) HHF were observed, most frequently in patients with DM having CKDcvm. DM increased the risk of non-cardiovascular [hazard ratio (HR) 1.92; 95% confidence interval (CI) 1.59-2.32] and cardiovascular (HR 2.25; 95% CI 1.62-3.12) deaths, 4-point MACE (HR 1.93; 95% CI 1.62-2.31) and HHF (HR 1.87; 95% CI 1.48-2.36). Mortality risks were elevated by DM to a similar extent in CKDcvm and CKDgen, but for HHF in CKDcvm only (HR 2.07; 95% CI 1.55-2.77). In patients with DM, CKDcvm (versus CKDgen) only increased the risk for HHF (HR 1.93; 95% CI 1.15-3.22). Conclusions: DM contributes to cardiovascular and mortality excess risk in patients with moderate to severe CKD in both, CKDcvm and CKDgen. Patients with DM and CKDcvm are particularly susceptible to HHF.

Copeptin, Natriuretic Peptides, and Cardiovascular Outcomes in Patients With CKD: The German Chronic Kidney Disease (GCKD) Study.

Rationale & Objective: Copeptin and Midrange pro-atrial natriuretic peptide (MR-pro-ANP) are associated with outcomes independently of N-terminal pro-brain natriuretic peptide (NT-pro-BNP) in patients with heart failure (HF). The value of these markers in patients with chronic kidney disease (CKD) has not been studied. Study Design: Prospective cohort study. Setting & Participants: A total of 4,417 patients enrolled in the German Chronic Kidney Disease (GCKD) study with an estimated glomerular filtration rate of 30-60 mL/min/1.73m2 or overt proteinuria (urinary albumin-creatinine ratio >300mg/g or equivalent). Exposures: Copeptin, MR-pro-ANP, and NT-pro-BNP levels were measured in baseline samples. Outcomes: Noncardiovascular death, cardiovascular (CV) death, major adverse CV event (MACE), and hospitalization for HF. Analytical Approach: HRs for associations of Copeptin, MR-pro-ANP, and NT-pro-BNP with outcomes were estimated using Cox regression analyses adjusted for established risk factors. Results: During a maximum follow-up of 6.5 years, 413 non-CV deaths, 179 CV deaths, 519 MACE, and 388 hospitalizations for HF were observed. In Cox regression analyses adjusted for established risk factors, each one of the 3 markers were associated with all the 4 outcomes, albeit the highest HRs were found for NT-pro-BNP. When models were extended to include all the 3 markers, NT-pro-BNP remained associated with all 4 outcomes. Conversely, from the 2 novel markers, associations remained only for Copeptin with non-CV death (HR, 1.62; 95% CI, 1.04-2.54 for highest vs lowest quintile) and with hospitalizations for HF (HR, 1.73; 95% CI, 1.08-2.75). Limitations: Single-point measurements of Copeptin, MR-pro-ANP, and NT-pro-BNP. Conclusions: In patients with moderately severe CKD, we confirm NT-pro-BNP to be strongly associated with all outcomes examined. As the main finding, the novel marker Copeptin demonstrated independent associations with non-CV death and hospitalizations for HF, and should therefore be evaluated further for risk assessment in CKD. Plain-Language Summary: A blood sample-based biomarker that indicates high cardiovascular risk in a patient with kidney disease would help to guide interventions and has the potential to improve outcomes. In 4,417 patients of the German Chronic Kidney Disease study, we assessed the relationship of Copeptin, pro-atrial natriuretic peptide, and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) with important outcomes over a follow-up period of 6.5 years. NT-pro-BNP was strongly associated with all of the 4 outcomes, including death unrelated to cardiovascular disease, death because of cardiovascular disease, a major cardiovascular event, and hospitalization for heart failure. Copeptin was associated with death unrelated to cardiovascular disease and hospitalization for heart failure. NT-pro-BNP and Copeptin are, therefore, promising candidates for a blood sample-based strategy to identify patients with kidney disease at high cardiovascular risk.

Prevention of cerebral thromboembolism by oral anticoagulation with dabigatran after pulmonary vein isolation for atrial fibrillation: the ODIn-AF trial.

BACKGROUND AND OBJECTIVES: Long-term oral anticoagulation (OAC) following successful catheter ablation of atrial fibrillation (AF) remains controversial. Prospective data are missing. The ODIn-AF study aimed to evaluate the effect of OAC on the incidence of silent cerebral embolic events and clinically relevant cardioembolic events in patients at intermediate to high risk for embolic events, free from AF after pulmonary vein isolation (PVI). METHODS: This prospective, randomized, multicenter, open-label, blinded endpoint interventional trial enrolled patients who were scheduled for PVI to treat paroxysmal or persistent AF. Six months after PVI, AF-free patients were randomized to receive either continued OAC with dabigatran or no OAC. The primary endpoint was the incidence of new silent micro- and macro-embolic lesions detected on brain MRI at 12 months of follow-up compared to baseline. Safety analysis included bleedings, clinically evident cardioembolic, and serious adverse events (SAE). RESULTS: Between 2015 and 2021, 200 patients were randomized into 2 study arms (on OAC: n = 99, off OAC: n = 101). There was no significant difference in the occurrence of new cerebral microlesions between the on OAC and off OAC arm [2 (2%) versus 0 (0%); P = 0.1517] after 12 months. MRI showed no new macro-embolic lesion, no clinical apparent strokes were present in both groups. SAE were more frequent in the OAC arm [on OAC n = 34 (31.8%), off OAC n = 18 (19.4%); P = 0.0460]; bleedings did not differ. CONCLUSION: Discontinuation of OAC after successful PVI was not found to be associated with an elevated risk of cerebral embolic events compared with continued OAC after a follow-up of 12 months.