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Patients with ischemic stroke (IS) are at increased risk of mortality and recurrent cerebro- or cardiovascular events. Determining prognosis after IS remains challenging but blood-based biomarkers might provide additional prognostic information. As platelets are crucially involved in the pathophysiology of vascular diseases, platelet surface proteins (PSP) are promising candidates as prognostic markers in the hyperacute stage. In this pilot study, feasibility of PSP analysis by flow cytometry (HMGB1, CD84, CXCR4, CXCR7, CD62p with and without ADP-stimulation, CD41, CD61, CD40, GPVI) was investigated in 99 (median 66 years, 67.5% male) acute IS patients admitted to Stroke Unit within a substudy of the Stroke-Induced Cardiac FAILure in mice and men (SICFAIL) cohort study. Association between PSP expression and unfavorable one-year outcome (cerebro- or cardiovascular event, all-cause mortality and care dependency defined as Barthel Index Trial registration: German Clinical Trials Register (DRKS00011615).

The German government initiated the Network University Medicine (NUM) in early 2020 to improve national research activities on the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic. To this end, 36 German Academic Medical Centers started to collaborate on 13 projects, with the largest being the National Pandemic Cohort Network (NAPKON). The NAPKON’s goal is creating the most comprehensive Coronavirus Disease 2019 (COVID-19) cohort in Germany. Within NAPKON, adult and pediatric patients are observed in three complementary cohort platforms (Cross-Sectoral, High-Resolution and Population-Based) from the initial infection until up to three years of follow-up. Study procedures comprise comprehensive clinical and imaging diagnostics, quality-of-life assessment, patient-reported outcomes and biosampling. The three cohort platforms build on four infrastructure core units (Interaction, Biosampling, Epidemiology, and Integration) and collaborations with NUM projects. Key components of the data capture, regulatory, and data privacy are based on the German Centre for Cardiovascular Research. By December 01, 2021, 34 university and 34 non-university hospitals have enrolled 4,241 patients with local data quality reviews performed on 2,812 (66%). 47% were female, the median age was 53 (IQR: 38-63)) and 3 pediatric cases were included. 30% of patients were hospitalized, 11% admitted to an intensive care unit, and 4% of patients deceased while enrolled. 7,143 visits with biosampling in 3,595 patients were conducted by November 29, 2021. In this overview article, we summarize NAPKON’s design, relevant milestones including first study population characteristics, and outline the potential of NAPKON for German and international research activities.Trial registration:· https://clinicaltrials.gov/ct2/show/NCT04768998· https://clinicaltrials.gov/ct2/show/NCT04747366· https://clinicaltrials.gov/ct2/show/NCT04679584

The German government initiated the Network University Medicine (NUM) in early 2020 to improve national research activities on the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic. To this end, 36 German Academic Medical Centers started to collaborate on 13 projects, with the largest being the National Pandemic Cohort Network (NAPKON). The NAPKON’s goal is creating the most comprehensive Coronavirus Disease 2019 (COVID-19) cohort in Germany. Within NAPKON, adult and pediatric patients are observed in three complementary cohort platforms (Cross-Sectoral, High-Resolution and Population-Based) from the initial infection until up to three years of follow-up. Study procedures comprise comprehensive clinical and imaging diagnostics, quality-of-life assessment, patient-reported outcomes and biosampling. The three cohort platforms build on four infrastructure core units (Interaction, Biosampling, Epidemiology, and Integration) and collaborations with NUM projects. Key components of the data capture, regulatory, and data privacy are based on the German Centre for Cardiovascular Research. By April 01, 2022, 34 university and 40 non-university hospitals have enrolled 5298 patients with local data quality reviews performed on 4727 (89%). 47% were female, the median age was 52 (IQR 36–62-) and 50 pediatric cases were included. 44% of patients were hospitalized, 15% admitted to an intensive care unit, and 12% of patients deceased while enrolled. 8845 visits with biosampling in 4349 patients were conducted by April 03, 2022. In this overview article, we summarize NAPKON’s design, relevant milestones including first study population characteristics, and outline the potential of NAPKON for German and international research activities.Trial registrationhttps://clinicaltrials.gov/ct2/show/NCT04768998.https://clinicaltrials.gov/ct2/show/NCT04747366.https://clinicaltrials.gov/ct2/show/NCT04679584

Zusammenfassung Hintergrund Eine validierte telefonische Fassung der deutschen Version des Fragebogens „Informant Questionnaire on Cognitive Decline in the Elderly“ (IQCODE) zur Erfassung kognitiver Veränderungen von Schlaganfall-Patienten über einen Zeitraum von 10 Jahren vor Schlaganfall durch Befragung Angehöriger liegt bislang nicht vor. Eine deutsche telefonische Kurzversion existiert ebenfalls nicht. Methoden 60 Angehörige von 60 Patientinnen und Patienten mit ischämischem Schlaganfall wurden mit der persönlichen und der telefonischen 26-Item-Version des IQCODE in randomisierter Reihenfolge befragt. Als Maß zur Quantifizierung der Reliabilität beider IQCODE-Versionen wurde ein gewichtetes Kappa berechnet (Fleiss-Cohen Gewichte). Mithilfe von Varianzinflationsfaktoren wurde eine telefonische Kurzversion des IQCODE entwickelt und diese Version mit der 26-Item-Telefonversion mittels Spearman‘s Korrelationskoeffizienten verglichen. Ergebnisse Das gewichtete Kappa der telefonischen Befragung gegenüber der persönlichen betrug 0,84 (95 % Konfidenzintervall 0,72–0,97). Die neu entwickelte Kurzversion des telefonbasierten IQCODE umfasste 10 Items. Der Korrelationskoeffizient zwischen der Kurz- und der Langversion betrug 0,97 (95 % Konfidenzintervall 0,96–0,99). Schlussfolgerung Die telefonische Version des deutschsprachigen 26-Item IQCODE zeigte im Vergleich zur persönlichen Befragung exzellente Übereinstimmungswerte. Die telefonische 10-Item-Kurzversion zeigte eine exzellente Übereinstimmung mit der telefonischen Langversion. Somit stehen nun auch für den deutschen Sprachraum vereinfachte Werkzeuge für die effiziente Befragung großer Kollektive zur Verfügung.

Aims The Berlin Atrial Fibrillation Registry was designed to analyse oral anticoagulation (OAC) prescription in patients with atrial fibrillation (AF) and acute ischaemic stroke. Methods and results This investigator-initiated prospective multicentre registry enrolled patients at all 16 stroke units located in Berlin, Germany. The ongoing telephone follow-up is conducted centrally and will cover 5 years per patient. Within 2014 and 2016, 1080 patients gave written informed consent and 1048 patients were available for analysis. Median age was 77 years [interquartile range (IQR) 72–83], 503 (48%) patients were female, and 254 (24%) had a transient ischaemic attack (TIA). Overall, 470 (62%) out of 757 patients with known AF and a (pre-stroke) CHA2DS2-VASc ≥ 1 were anticoagulated at the time of stroke. At hospital discharge, 847 (81.3%) of 1042 patients were anticoagulated. Thereof 710 (68.1%) received a non-vitamin K-dependent oral anticoagulant (NOAC) and 137 (13.1%) a vitamin K antagonist (VKA). Pre-stroke intake of a NOAC [odds ratio (OR) 15.6 (95% confidence interval, 95% CI 1.97–122)] or VKA [OR 0.04 (95% CI 0.02–0.09)], an index TIA [OR 0.56 (95% CI 0.34–0.94)] rather than stroke, heart failure [OR 0.49 (95% CI 0.26–0.93)], and endovascular thrombectomy at hospital admission [OR 12.9 (95% CI 1.59–104)] were associated with NOAC prescription at discharge. Patients’ age or AF type had no impact on OAC or NOAC use, respectively. Conclusion About 60% of all registry patients with known AF received OAC at the time of stroke or TIA. At hospital discharge, more than 80% of AF patients were anticoagulated and about 80% of those were prescribed a NOAC.

Aims: Ischaemic stroke (IS) might induce alterations of cardiac function. Prospective data on frequency of cardiac dysfunction and heart failure (HF) after IS are lacking. We assessed prevalence and determinants of diastolic dysfunction (DD), systolic dysfunction (SD), and HF in patients with acute IS. Methods and results: The Stroke-Induced Cardiac FAILure in mice and men (SICFAIL) study is a prospective, hospital-based cohort study. Patients with IS underwent a comprehensive assessment of cardiac function in the acute phase (median 4 days after IS) including clinical examination, standardized transthoracic echocardiography by expert sonographers, and determination of blood-based biomarkers. Information on demographics, lifestyle, risk factors, symptoms suggestive of HF, and medical history was collected by a standardized personal interview. Applying current guidelines, cardiac dysfunction was classified based on echocardiographic criteria into SD (left ventricular ejection fraction

To date, no validated long or short telephone version of the German "Informant Questionnaire on Cognitive Decline in the Elderly" (IQCODE) exists for determining cognitive changes over a period of 10 years by interviewing relatives.Sixty relatives of 60 ischemic stroke patients were interviewed both face-to-face and by phone with the 26-item German IQCODE version in randomized order. Inter-method reliability was calculated as between-method agreement and quantified by a weighted kappa with Fleiss-Cohen weights. A short telephone version of the IQCODE was developed with the Variance Inflation Factor (VIF). Its reliability in regard to the 26-item telephone ICQODE version was calculated by Spearman's correlation coefficient.The weighted kappa between the telephone and face-to-face interview was 0.84 (95 % confidence interval: 0.72-0.97). The short version of the IQCODE consists of 10 items. Spearman's Correlation Coefficient in regard to the long and short telephone version of the IQCODE was 0.97 (95 % confidence interval 0.96-0.99).A long and short telephone version of the IQ-CODE for detecting cognitive changes in the elderly within a period of 10 years was developed by interviewing relatives.Eine validierte telefonische Fassung der deutschen Version des Fragebogens „Informant Questionnaire on Cognitive Decline in the Elderly“ (IQCODE) zur Erfassung kognitiver Veränderungen von Schlaganfall-Patienten über einen Zeitraum von 10 Jahren vor Schlaganfall durch Befragung Angehöriger liegt bislang nicht vor. Eine deutsche telefonische Kurzversion existiert ebenfalls nicht.60 Angehörige von 60 Patientinnen und Patienten mit ischämischem Schlaganfall wurden mit der persönlichen und der telefonischen 26-Item-Version des IQCODE in randomisierter Reihenfolge befragt. Als Maß zur Quantifizierung der Reliabilität beider IQCODE-Versionen wurde ein gewichtetes Kappa berechnet (Fleiss-Cohen Gewichte). Mithilfe von Varianzinflationsfaktoren wurde eine telefonische Kurzversion des IQCODE entwickelt und diese Version mit der 26-Item-Telefonversion mittels Spearman‘s Korrelationskoeffizienten verglichen.Das gewichtete Kappa der telefonischen Befragung gegenüber der persönlichen betrug 0,84 (95 % Konfidenzintervall 0,72–0,97). Die neu entwickelte Kurzversion des telefonbasierten IQCODE umfasste 10 Items. Der Korrelationskoeffizient zwischen der Kurz- und der Langversion betrug 0,97 (95 % Konfidenzintervall 0,96–0,99).Die telefonische Version des deutschsprachigen 26-Item IQCODE zeigte im Vergleich zur persönlichen Befragung exzellente Übereinstimmungswerte. Die telefonische 10-Item-Kurzversion zeigte eine exzellente Übereinstimmung mit der telefonischen Langversion. Somit stehen nun auch für den deutschen Sprachraum vereinfachte Werkzeuge für die effiziente Befragung großer Kollektive zur Verfügung.

Background: The Functioning Assessment Short Test (FAST) is an interviewer-administered scale assessing functional impairment originally developed for psychiatric patients. Objectives: To adapt the FAST for the general population, we developed a self-administered version of the scale and assessed its properties in a pilot study. Methods: The original FAST scale was translated into German via forward and backward translation. Afterwards, we adjusted the scale for self-administered application and inquired participants from two ongoing studies in Germany, ‘STAAB’ (Würzburg) and ‘BiDirect’ (Münster), both recruiting subjects from the general population across a wide age range (STAAB: 30-79 years, BiDirect: 35-65 years). To assess reliability, agreement of self-assessment with proxy-assessment by partners was measured via intraclass correlation coefficient (ICC) over the FAST score. Construct validity was estimated by conducting correlations with validated scales of depression (PHQ-9), anxiety (GAD-7), and health-related quality of life (SF-12) and regression analyses using these scales besides potentially disabling comorbidities (e.g. Chronic Back Pain (CBP)). Results: Participants (n=54) had a median age of 57.0 years (quartiles: 49.8, 65.3), 46.3% were female. Reliability was moderate: ICC 0.50 (95% CI 0.46-0.54). The FAST score significantly correlated with PHQ-9, GAD-7, and the mental sub-scale of SF-12. In univariable linear regression, all three scales and chronic back pain explained variance of the FAST score. In multivariable analysis, only CBP and the SF-12 remained significant predictors. Conclusion: The German self-administered version of the FAST yielded moderate psychometric properties in this pilot study, indicating its applicability to assess functional impairment in the general population.

Background and Purpose— Data on recent time trends in stroke mortality by subtypes and regions are lacking for Germany. We investigated sex- and age-standardized trends in stroke mortality in Germany for different stroke subtypes from 1998 to 2015 and assessed potential regional variations between the former Eastern and former Western part of Germany. Methods— Mortality and population data from the German Federal Statistical Office were used to calculate sex- and age-standardized mortality rates for hemorrhagic stroke, ischemic stroke, and total strokes from 1998 to 2015 for all age groups. Joinpoint regression was used to examine trends and its changes. Estimations were stratified for Eastern and Western part of Germany. Results— From 1998 to 2015, age-standardized total stroke mortality decreased by >50% in men (from 78.0 to 34.1 per 100 000) and women (from 62.1 to 28.4 women per 100 000). The decrease was more pronounced for ischemic stroke mortality (rate change: men, −66%; women, −63%) than for hemorrhagic stroke mortality (men, −40%; women, −31%). Total and ischemic stroke mortality declined more in Eastern than in Western part of Germany. From 1998 to 2015, there were no differences in the decline between the regions in hemorrhagic stroke mortality. Total stroke mortality was higher in Eastern compared with Western part of Germany throughout the study period. Differences in subtype- and sex-specific mortality between the regions decreased from 1998 to 2015. Conclusions— Between 1998 and 2015, stroke mortality declined substantially in Germany with differing time trends in stroke subtypes between sexes and regions. Differences in stroke mortality rates between East and West Germany are negligible 24 years after the German reunification.

Der maligne Mediainfarkt (MMI) ist eine Erkrankung, fur die neben der einzig nachgewiesenermasen effektiven Therapie, der fruhen Hemikraniektomie (HC), eine Vielzahl von intensivmedizinischen Therapien zur Verfugung steht. Wie mit der HC und den konservativen Therapien an deutschen Kliniken im Detail verfahren wird und welche Strukturen an den einzelnen Kliniken zur Behandlung des MMI vorhanden sind, ist nicht bekannt. Es wurden anonyme Fragebogen an 297 neurologische und 133 neurochirurgische Akutkliniken in Deutschland versandt. Der Rucklauf betrug 24,7 %. Die meisten teilnehmenden Kliniken gaben an, personliche Erfahrung in der Behandlung des MMI zu haben (83,8 %). Eine HC kann meist fruhzeitig vor Ort durchgefuhrt werden (65,1 %). Die Indikationsstellung erfolgt in der Regel auf hoher fachlicher und hierarchischer Ebene anhand klinischer und bildgebender Kriterien (78,2 %). Ein fester Behandlungsalgorithmus ist in 70,8 % der Kliniken etabliert. 74,5 % der mittels HC behandelten Patienten und 42,5 % der konservativ behandelten Patienten werden auf einer Intensivstation behandelt. Eine Uberwachung des intrakraniellen Drucks erfolgt nicht regelhaft. Die Ergebnisse hinsichtlich Diagnosestellung und Therapie des MMI sind allerdings sehr heterogen und ohne erkennbaren klaren Konsens. In den teilnehmenden Kliniken sind die Strukturen fur die Behandlung des MMI prinzipiell vorhanden. Andererseits ist die Heterogenitat in der Versorgung des MMI auffallend. Eine Optimierung der Versorgung des MMI durch die Implementierung fester Behandlungsalgorithmen und die Adharenz an bestehende Leitlinien ist notwendig.

Adipositas ist ein wesentlicher Risikofaktor fur eine diastolische Herzinsuffizienz, die sog. Adipositas-Kardiomyopathie. Typischerweise findet sich bei normotensiven Patienten mit Adipositas ein verminderter peripherer Widerstand, ein erhohtes Blutvolumen und eine verstarkte Herzarbeit, sodass Hypertrophie und diastolische Funktionsstorung die Folge sind, die echokardiographisch gut untersucht werden konnen. Liegt zusatzlich eine arterielle Hypertonie vor, unterscheidet sich die kardiale Geometrie nicht von einem Cor hypertonicum ohne Adipositas. Auch lassen sich die typischen Veranderungen, wie verandertes Blutvolumen und verminderter peripherer Widerstand, dann nicht mehr nachweisen. Ein obstruktives Schlafapnoesyndrom (OSAS) ist uberdurchschnittlich haufig bei Adipositas, sodass ein Screening geboten ist. Der Herzinsuffizienzmarker N-terminales Propeptid BNP (NT-ProBNP) ist bei Adipositas aufgrund verminderter Werte nicht evaluiert und hilft differenzialdiagnostisch nur bedingt weiter. Die konservative Gewichtsreduktion ist uberaus schwierig und der Nachweis einer Verbesserung der Prognose wurde nicht erbracht. Hingegen kann mit bariatrischen Operationen die kardiovaskulare Mortalitat bei Adipositas gesenkt werden. Nicht zuletzt durch die effektive Gewichtsreduktion infolge bariatrischer Operationen und die damit verbundene Verbesserung der Prognose ruckt die Therapie der Adipositas immer mehr ins Blickfeld. Neben allen Schwierigkeiten, wie eingeschrankte Untersuchungsbedingungen im Ultraschall, sollte die kardiale Abklarung bei entsprechenden Symptomen unverzuglich und mit den etablierten Standardmethoden erfolgen.

Background.Data on potential variations in delivery of appropriate stroke care over time are scarce. We investigated temporal changes in the quality of acute hospital stroke care across five national audits in Europe over a period of six years.Methods.Data were derived from national stroke audits in Germany, Poland, Scotland, Sweden, and England/Wales/Northern Ireland participating within the European Implementation Score (EIS) collaboration. Temporal changes in predefined quality indicators with comparable information between the audits were investigated. Multivariable logistic regression analyses were performed to estimate adherence to quality indicators over time.Results.Between 2004 and 2009, individual data from 542,112 patients treated in 538 centers participating continuously over the study period were included. In most audits, the proportions of patients who were treated on a SU, were screened for dysphagia, and received thrombolytic treatment increased over time and ranged from 2-fold to almost 4-fold increase in patients receiving thrombolytic therapy in 2009 compared to 2004.Conclusions.A general trend towards a better quality of stroke care defined by standardized quality indicators was observed over time. The association between introducing a specific measure and higher adherence over time might indicate that monitoring of stroke care performance contributes to improving quality of care.

Background and Purpose— We compared compliance with standards of acute stroke care between 6 European audits and identified factors associated with delivery of appropriate care. Methods— Data were derived from stroke audits in Germany, Poland, Scotland, Catalonia, Sweden, and England/Wales/Northern-Ireland participating within the European Implementation Score (EIS) collaboration. Associations between demographic and clinical characteristics with adherence to predefined quality indicators were investigated by hierarchical logistic regression analyses. Results— In 2007/2008 data from 329 122 patients with stroke were documented. Substantial variations in adherence to quality indicators were found; older age was associated with a lower probability of receiving thrombolytic therapy, anticoagulant therapy, or stroke unit treatment and a higher probability of being tested for dysphagia. Women were less likely to receive anticoagulant or antiplatelet therapy or stroke unit treatment. No major weekend effect was found. Conclusions— Detected variations in performance of acute stroke services were found. Differences in adherence to quality indicators might indicate population subgroups with specific needs for improving care delivery.

PPARalpha (peroxisome-proliferator-activated receptor alpha) regulates the expression of genes that are involved in lipid metabolism, tissue homoeostasis and inflammation. Consistent rodent and human studies suggest a link between PPARalpha function and cardiovascular disease, qualifying PPARalpha [PPARA in HUGO (Human Genome Organisation) gene nomenclature] as a candidate gene for coronary artery disease. In the present study, we comprehensively evaluated common genetic variations within the PPARalpha gene and assessed their association with myocardial infarction. First, we characterized the linkage disequilibrium within the PPARalpha gene in an initial case-control sample of 806 individuals from the Regensburg Myocardial Infarction Family Study using a panel of densely spaced SNPs (single nucleotide polymorphisms) across the gene. Single SNP analysis showed significant association with the disease phenotype [OR (odds ratio)=0.74, P=0.012, 95% CI (confidence interval)=0.61-0.94 for rs135551]. Moreover, we identified a protective three-marker haplotype with an association trend for myocardial infarction (OR=0.76, P=0.067, 95% CI=0.56-1.02). Subsequently, we were able to confirm the single SNP and haplotype association results in an independent second case-control cohort with 667 cases from the Regensburg Myocardial Infarction Family Study and 862 control individuals from the WHO (World Health Organization) MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) Augsburg project (OR=0.87, P=0.046, 95% CI=0.72-0.99 for rs135551 and OR=0.80, P=0.034, 95% CI=0.65-0.98 for the three-marker haplotype respectively). From these cross-sectional association results, we provide evidence that common variations in the PPARalpha gene may influence the risk of myocardial infarction in a European population.

Recently, the genetic variant Y402H in the CFH (complement factor H) gene was associated with an increased risk for MI (myocardial infarction) in a prospective Caucasian cohort. In another nested case-control study, however, the CFH -Y402H variant did not carry susceptibility to MI. The aim of the present study was to test for an association between the CFH -Y402H variant and MI in a large case-control sample with a familial background for CAD (coronary artery disease). A total of 2161 individuals from the German MI family study were studied by questionnaire, physical examination and biochemical analyses. MI patients ( n =1188; 51.4±8.6 years at first MI) were recruited from families with at least two members affected by MI and/or severe CAD. Spouses, sisters-in-law and brothers-in-law respectively, without MI/CAD were included as unaffected controls ( n =973; 56.9±9.8 years). Genotyping was performed using a TaqMan assay. The common Y402H variant in the CFH gene was not associated with classical cardiovascular risk factors (diabetes, hypercholesterolaemia, hypertension, obesity, smoking and C-reactive protein serum levels). No association was found between the CFH -Y402H variant and susceptibility to MI. Separate analyses in both men and women revealed no gender-specific influence of the gene variant on cardiovascular risk factors or MI. This investigation was unable to replicate the association between the common CFH -Y402H variant and susceptibility to MI in our large Caucasian population which is enriched for genetic factors. We conclude that the CFH -Y402H variant has no relevant risk-modifying effect in our population.

Background Fabry-associated pain may be the first symptom of Fabry disease (FD) and presents with a unique phenotype including mostly acral burning triggerable pain attacks, evoked pain, pain crises, and permanent pain. We recently developed and validated the first Fabry Pain Questionnaire (FPQ) for adult patients. Here we report on the validation of the self-administered version of the FPQ that no longer requires a face-to-face interview but can be filled in by the patients themselves allowing more flexible data collection. Methods At our Würzburg Fabry Center for Interdisciplinary Treatment, Germany, we have developed the self-administered version of the FPQ by adapting the questionnaire to a self-report version. To do this, consecutive Fabry patients with current or past pain history (n = 56) were first interviewed face-to-face. Two weeks later patients’ self-reported questionnaire results were collected by mail (n = 55). We validated the self-administered version of the FPQ by assessing the inter-rater reliability agreement of scores obtained by supervised administration and self-administration of the FPQ. Results The FPQ contains 15 questions on the different pain phenotypes, on pain development during life with and without therapy, and on impairment due to pain. Statistical analysis showed that the majority of questions were answered in high agreement in both sessions with a mean AC1-statistic of 0.857 for 55 nominal-scaled items and a mean ICC of 0.587 for 9 scores. Conclusions This self-administered version of the first pain questionnaire for adult Fabry patients is a useful tool to assess Fabry-associated pain without a time-consuming face-to-face interview but via a self-reporting survey allowing more flexible usage. Electronic supplementary material The online version of this article (doi:10.1186/s13023-015-0325-7) contains supplementary material, which is available to authorized users.

Background and Purpose— There are no agreed measures of stroke care quality that enable the standardized comparison of stroke care between countries. We aimed to develop a set of measures of quality of acute stroke care involving stroke quality registers in Western Europe. Methods— A multinational working group identified 6 regional or national stroke quality registers in Europe and reviewed their data sets, performance measures, and the method by which these had been developed. Measures used in the registers were presented for discussion to a consensus group of representatives from the quality registers identified, as well as other stroke experts, and the final set of common performance measures was agreed through majority consensus. Results— Thirty final performance measures were agreed by the European consensus group, encompassing the domains of coordination of care (stroke unit–based care), diagnosis (brain imaging, vascular imaging, cardiac arrhythmia detection, and therapy assessment), preservation of neural tissue (thrombolytic therapy and door-to-needle time), prevention of complications (dysphagia screening), initiation of secondary prevention (antiplatelet, anticoagulation, lipid lowering, blood pressure lowering, carotid surgery, time from vascular imaging to carotid surgery, and smoking cessation), survival (90-day poststroke mortality), and functional outcomes (90-day modified Rankin Scale). Conclusions— On the basis of experience of quality registers in Europe, we have proposed a common set of performance measures that will facilitate the international comparison of acute stroke care quality.

Background: Population-based data, which continuously monitors time trends in stroke epidemiology are limited. We investigated the incidence of pathological and etiological stroke subtypes over a 16 year time period. Methods: Data were collected within the Erlangen Stroke Project (ESPro), a prospective, population-based stroke register in Germany covering a total study population of 105,164 inhabitants (2010). Etiology of ischemic stroke was classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Results: Between January 1995 and December 2010, 3,243 patients with first-ever stroke were documented. The median age was 75 and 55% were females. The total stroke incidence decreased over the 16 year study period in men (Incidence Rate Ratio 1995-1996 vs. 2009-2010 (IRR) 0.78; 95% CI 0.58-0.90) but not in women. Among stroke subtypes, a decrease in ischemic stroke incidence (IRR 0.73; 95% CI 0.57-0.93) and of large artery atherosclerotic stroke (IRR 0.27; 95% CI 0.12-0.59) was found in men and an increase of stroke due to small artery occlusion in women (IRR 2.33; 95% CI 1.39-3.90). Conclusions: Variations in time trends of pathological and etiological stroke subtypes were found between men and women that might be linked to gender differences in the development of major vascular risk factors in the study population.

Background Stroke patients should be cared for in accordance with evidence-based guidelines. The extent of implementation of guidelines for the acute care of stroke patients in Germany has been unclear to date.

Stimulation of immune cells by antigens triggers changes in the transcription of genes encoding cytokines and other proteins; these changes in gene expression are part of the normal immune response. Previous studies have provided evidence that biotin status may affect secretion of cytokines by immune cells. Here we determined whether biotin supplementation affects gene expression in human immune cells. Peripheral blood mononuclear cells were isolated from healthy adults before and after supplementation with 8.8 micro mol biotin/d for 21 d. Cells were cultured ex vivo with concanavalin A for 21 h to simulate stimulation with antigens. Expression of genes that play roles in cytokine metabolism, cell proliferation, signal transduction, stress response, apoptosis and biotin homeostasis was quantified by using DNA microarrays and reverse transcriptase-polymerase chain reaction. The abundance of mRNA encoding interferon-gamma, interleukin-1beta, and 3-methylcrotonyl-CoA carboxylase was 4.3, 5.6 and 8.9 times greater, respectively, after supplementation with biotin compared with before supplementation. In contrast, the abundance of mRNA encoding interleukin-4 was 6.8 times greater before supplementation than after supplementation. These data suggest that biotin supplementation affects gene expression in human immune cells. Effects of biotin on gene expression are likely to modulate the response of immune cells to antigens.

Pain may be the earliest symptom in Fabry disease and presents with a distinct phenotype including triggerable pain attacks, evoked pain, pain crises, and chronic pain. Current pain questionnaires do not reflect the special phenotype of Fabry disease-associated pain, which hampers its systematic evaluation as the basis of correct diagnosis and effective treatment. A questionnaire specifically designed to assess Fabry disease-associated pain is thus urgently needed. At the Wurzburg Fabry Center for Interdisciplinary Therapy (FAZIT), Germany, we developed and validated the first face-to-face Fabry Pain Questionnaire (FPQ) for adult patients. The initial version of the FPQ was tested in a pilot study with 20 consecutive Fabry disease patients. The performance of the revised FPQ was assessed in a first (n=56) and second (n=20) validation phase in consecutive Fabry disease patients. For this, patients were interviewed at baseline and 2 weeks later. We determined the test-retest reliability and validity of the FPQ in comparison to data obtained with the Neuropathic Pain Symptom Inventory. The FPQ contains 15 questions on the 4 pain phenotypes of Fabry disease (pain attacks, pain crises, evoked pain, chronic pain) in childhood and adulthood, on pain development during life with and without enzyme replacement therapy, and on everyday life impairment due to pain. This first disease-specific questionnaire is a valuable tool for baseline and follow-up assessment of pain in Fabry disease patients and may guide treatment in this distinct pain phenotype.

Stroke patients should be cared for in accordance with evidence-based guidelines. The extent of implementation of guidelines for the acute care of stroke patients in Germany has been unclear to date.The regional quality assurance projects that cooperate in the framework of the German Stroke Registers Study Group (Arbeitsgemeinschaft Deutscher Schlaganfall-Register, ADSR) collected data on the care of stroke patients in 627 hospitals in 2012. The quality of the acute hospital care of patients with stroke or transient ischemic attack (TIA) was assessed on the basis of 15 standardized, evidence-based quality indicators and compared across the nine participating regional quality assurance projects.Data were obtained on more than 260 000 patients nationwide. Intravenous thrombolysis was performed in 59.7% of eligible ischemic stroke patients patients (range among participating projects, 49.7-63.6%). Dysphagia screening was documented in 86.2% (range, 74.8-93.1%). For the following indicators, the defined targets were not reached for all of Germany: anti-aggregation within 48 hours, 93.4% (range, 86.6-96.4%); anticoagulation for atrial fibrillation, 77.6% (range, 72.4-80.1%); standardized dysphagia screening, 86.2% (range, 74.8-93.1%); oral and written information of the patients or their relatives, 86.1% (range, 75.4-91.5%). The rate of patients examined or treated by a speech therapist was in the target range.The defined targets were reached for most of the quality indicators. Some indicators, however, varied widely across regional quality assurance projects. This implies that the standardization of care for stroke patients in Germany has not yet been fully achieved.

Rationale Long-term risk of vascular disease is substantially increased after stroke with several models proposed to predict subsequent stroke and other vascular events after an index event. However, recent validation studies demonstrate limited predictive properties of available prognostic models. Aims We aim to determine prediction models of different complexity for the combined vascular end-point of stroke, myocardial infarction, and vascular death at three-years after first-ever stroke. An independent external validation of the developed models will be performed. Design Prospective observational hospital-based cohort study of patients after first-ever stroke. Methods The new predictive models will be developed using the following steps: ( 1 ) Development of a basic score based on clinical history data (e.g. hypertension, myocardial infarction, and atrial fibrillation); ( 2 ) Development of an advanced score including additional factors such as blood-based biomarkers and results of vascular imaging; ( 3 ) Comparing the models fit using different methods (discrimination, calibration); ( 4 ) Assessment of clinical utility of an advanced score using methods based on reclassification tables (e.g. net reclassification improvement, integrated discrimination improvement, decision curve analysis); and ( 5 ) Investigation of external validity. Outcomes Primary outcome is a combined vascular end-point composed of stroke, myocardial infarction, and vascular death at three-years after stroke. Furthermore, each component of the composite end-point will be investigated individually and the patterns and time points of risk transitions between vascular end-points and stroke sub-types will be determined.

Background: Major gender differences exist in cardiovascular diseases and lead to different outcomes in women and men. However, attention and incorporation of sex-/gender-specific research might vary among disciplines. We therefore conducted a systematic review comparing publication characteristics and trends between stroke and myocardial infarction (MI) with respect to sex- and gender-related aspects. Methods: A systematic literature search was performed in PubMed to identify gender-/sex-related articles published for stroke and MI between 1977 and 2008. A specifically designed text mining program was used, and all literature was rated by two independent investigators. Publications were classified according to type of research performed, publication year, funding, geographical location, and gender of first and last authors. Results: 962 articles were retrieved and limited to 405 (42%) gender-relevant publications; 131 on stroke and 274 on MI. Type of performed research differed, especially in disease management, which received little attention (17%) in stroke, while representing the major focus in MI (40%). In both areas, clinical presentation received little attention (3 and 5%). Although publications progressively increased in both fields, an 8- to 10-year time gap emerged for stroke compared to MI. Last authors in both areas were predominantly men, but female last authorship is increasing more significantly over time in the field of stroke. Research on sex and gender differences in MI and stroke is largely underfunded, particularly by the EU. Conclusions: The data demonstrate how sex-/gender-specific research differs between specialties, most likely due to the diverse interest, funding opportunities and authorship distributions identified.

Epidemiological studies revealed an increasing prevalence of and a steep increase in obesity, a risk factor for cardiovascular disease. Because significant influence of a polymorphism, rs7566605, near the INSIG2 gene on BMI has been shown in the general population and in obesity cohorts, we hypothesized that this polymorphism might also act through an elevated BMI on the development of coronary artery disease (CAD) or myocardial infarction (MI). We pursued two strategies: First, the polymorphism rs7566605 was investigated for association with BMI, CAD/MI, and cardiovascular risk factors in a large German cohort at high risk for CAD and MI (n = 1,460 MI patients) as compared to unrelated healthy controls (n = 1,215); second, we extended our analyses on the families of MI patients and performed family-based association testing (n = 5,390 individuals). The polymorphism rs7566605 was analyzed using TaqMan technology. No deviation from Hardy–Weinberg equilibrium could be observed, and the call rate was 98.2%. No significant associations of rs7566605 with CAD/MI, BMI, and classical cardiovascular risk factors could be detected in the full sample size or in the subgroups. A total of 6,878 individuals were investigated in a population of German MI patients and their family members. Although the number of individuals was large enough, no influence of the rs7566605 INSIG2 polymorphism was detected on BMI and CAD/MI. We therefore conclude that in our sample the SNP rs7566605 near the INSIG2 gene does not influence BMI and is not associated directly with CAD/MI or indirectly through cardiovascular risk factors.

Myocardial infarction (MI) is a complex disease. Multiple genes and their interaction with various environmental factors influence the pathogenesis of MI that is thought to be tightly regulated by inflammatory pathways. Recent progress in genetic analysis includes the use of large-scale genome-wide association studies that have proven to be powerful tools even in the analysis of multifactorial phenotypes. However, certain genes are only sparsely represented on the available gene chips and additional candidate gene approaches are necessary. One such example is the CNR2 gene, encoding the cannabinoid receptor 2 (CB2), which has been implicated in mediating anti-inflammatory and anti-atherosclerotic effects in vivo. We therefore hypothesized that genetic variations within the CNR2 gene are associated with the development of MI or classic cardiovascular risk factors. In a large case-control study, 1,968 individuals from the German MI family study were examined with 13 single nucleotide polymorphisms (SNPs) covering CNR2 and the adjacent genes. The association of these SNPs with MI or cardiovascular risk factors, such as arterial hypertension, obesity, hypercholesterolemia and diabetes mellitus, was determined. In allelic and genotypic models, none of the SNPs showed a significant association with MI. Separate analyses for men and women revealed no gender-specific relationship between common genetic variations within the CNR2 gene and MI. Moreover, no significant association between CNR2 gene variants and common cardiovascular risk factors was observed. We therefore provide evidence in a large German population that common polymorphisms within the CNR2 gene confer no susceptibility to MI or to cardiovascular risk factors.

Background Serum uric acid (UA) levels have recently been shown to be genetically influenced by common polymorphisms in the GLUT9 gene in two genome-wide association analyses of Italian and British populations. Elevated serum UA levels are often found in conjunction with the metabolic syndrome. Hyperuricemia is the major risk factor for gout and has been associated with increased cardiovascular morbidity and mortality. The aim of the present study was to further elucidate the association of polymorphisms in GLUT9 with gout and coronary artery disease (CAD) or myocardial infarction (MI). To test our hypotheses, we performed two large case-control association analyses of individuals from the German MI Family Study. Methods and Findings First, 665 patients with gout and 665 healthy controls, which were carefully matched for age and gender, were genotyped for four single nucleotide polymorphisms (SNPs) within or near the GLUT9 gene. All four SNPs demonstrated highly significant association with gout. SNP rs6855911, located within intron 7 of GLUT9, showed the strongest signal with a protective effect of the minor allele with an allelic odds ratio of 0.62 (95% confidence interval 0.52–0.75; p = 3.2*10−7). Importantly, this finding was not influenced by adjustment for components of the metabolic syndrome or intake of diuretics. Secondly, 1,473 cases with severe CAD or MI and 1,241 healthy controls were tested for the same four GLUT9 SNPs. The analyses revealed, however, no significant association with CAD or with MI. Additional screening of genome-wide association data sets showed no signal for CAD or MI within the GLUT9 gene region. Conclusion Thus, our results provide compelling evidence that common genetic variations within the GLUT9 gene strongly influence the risk for gout but are unlikely to have a major effect on CAD or MI in a German population.

OBJECTIVE— Lipin, a novel molecular protein expressed by adipocytes, has marked effects on adipose tissue mass, insulin sensitivity, and glucose homeostasis. Thus, we hypothesized that genetic variants within LPIN1 are associated with traits of the metabolic syndrome. RESEARCH DESIGN AND METHODS— A total of 15 single nucleotide polymorphisms (SNPs) covering the LPIN1 gene region were genotyped in an age- and sex-stratified sample of the general population (Monitoring Trends and Determinants on Cardiovascular Diseases Study Augsburg; DNA and phenotypes of 1,416 Caucasians). Ten SNPs were also genotyped for replication in an independent sample of 1,030 subjects recruited throughout Germany. The metabolic syndrome was defined via the sum of its core components and, additionally, by a factor score derived from factor analysis. Permutation-based methods were used to test the association between genetic LPIN1 variants and metabolic traits for empirical significance. RESULTS— Linkage disequilibrium (LD) analysis revealed three LD blocks encompassing LPIN1. We identified three associated three-marker haplotypes: one common haplotype (26.8% frequency) increases the risk for the metabolic syndrome (odds ratio 1.6 [95% CI 1.2–2.2]), while the other two, being less common (5.7 and 4.0%), are strongly associated with lower blood pressure levels (systolic blood pressure 127 ± 18 vs. 135 ± 20 mmHg; P = 0.0001), a lower BMI (24.6 ± 3.6 vs. 26.9 ± 4.1 kg/m2; P = 3.7 × 10−7) and waist circumference (82 ± 12 vs. 90 ± 12 cm; P = 3.2 × 10−8), lower A1C levels (5.1 ± 0.7 vs. 5.3 ± 0.9%; P = 0.0002), as well as a lower metabolic syndrome factor score (−0.67 ± 1.00 vs. 0.04 ± 1.24; P = 1.4 × 10−7). Furthermore, the frequencies of arterial hypertension (23.7 vs. 46.4%; P = 0.00001), obesity (12.9 vs. 30.8%; P = 0.0003), diabetes (2.2 vs. 8.2%; P = 0.041), and the presence of three or more metabolic syndrome components (3.3 vs. 13.7%; P = 0.002) were significantly lower than in subjects not carrying one of these protective haplotypes. Strong associations were also observed in the replication sample using the same haplotypes but with effects in the opposite direction. CONCLUSIONS— These data suggest that allelic variants of the LPIN1 gene have significant effects in human metabolic traits and thus implicate lipin in the pathophysiology of the metabolic syndrome.

Lipin, a molecular protein expressed by adipocytes, has marked effects on adipose tissue mass, insulin sensitivity, and glucose homeostasis. Genetic variants within the lipin gene, LPIN1 , may be associated with traits of the metabolic syndrome (MetS) as we have shown previously in a sample of the general population. Methods: 15 SNPs densely covering the LPIN1 gene region were genotyped in an age- and sex- stratified sample of the general population (MONICA study Augsburg, DNA and phenotypes of 1,416 Caucasians). Ten of these SNPs were also genotyped for replication in an independent sample of 1,030 subjects recruited throughout Germany. The MetS was defined via the sum of its core components and additionally by a factor score derived from factor analysis. Permutation based methods were used to test the association between genetic LPIN1 variants and metabolic traits for empirical significance. Results: Linkage disequilibrium (LD) analysis revealed three LD blocks encompassing LPIN1 . We identified three associated three-marker haplotypes: one common haplotype (26.8% frequency) increases the risk for the MetS (OR=1.6, 95% CI[1.2–2.2]), while the other two being less common (5.7% and 4.0%) are strongly associated with lower blood pressure (p Conclusion: These data confirm that allelic variants of the LPIN1 gene have significant effects in human metabolic traits and highlight the importance of lipin in the pathophysiology of the MetS. Permutation-based low p-values and the consistent findings in several populations across multiple phenotypes of the MetS reflect the robustness of these results.

Data from both experimental models and humans provide evidence that ghrelin and its receptor, the growth hormone secretagogue receptor (ghrelin receptor, GHSR), possess a variety of cardiovascular effects. Thus, we hypothesized that genetic variants within the ghrelin system (ligand ghrelin and its receptor GHSR) are associated with susceptibility to myocardial infarction (MI) and coronary artery disease (CAD). Seven single nucleotide polymorphisms (SNPs) covering the GHSR region as well as eight SNPs across the ghrelin gene (GHRL) region were genotyped in index MI patients (864 Caucasians, ‘index MI cases’) from the German MI family study and in matched controls without evidence of CAD (864 Caucasians, ‘controls’, MONICA Augsburg). In addition, siblings of these MI patients with documented severe CAD (826 ‘affected sibs’) were matched likewise with controls (n = 826 Caucasian ‘controls’) and used for verification. The effect of interactions between genetic variants of both genes of the ghrelin system was explored by conditional classification tree models. We found association of several GHSR SNPs with MI [best SNP odds ratio (OR) 1.7 (1.2–2.5); P = 0.002] using a recessive model. Moreover, we identified a common GHSR haplotype which significantly increases the risk for MI [multivariate adjusted OR for homozygous carriers 1.6 (1.1–2.5) and CAD OR 1.6 (1.1–2.5)]. In contrast, no relationship between genetic variants and the disease could be revealed for GHRL. However, the increase in MI/CAD frequency related to the susceptible GHSR haplotype was abolished when it coincided with a common GHRL haplotype. Multivariate adjustments as well as permutation-based methods conveyed the same results. These data are the first to demonstrate an association of SNPs and haplotypes within important genes of the ghrelin system and the susceptibility to MI, whereas association with MI/CAD could be identified for genetic variants across GHSR, no relationship could be revealed for GHRL itself. However, we found an effect of GHRL dependent upon the presence of a common, MI and CAD susceptible haplotype of GHSR. Thus, our data suggest that specific haplotypes of the ghrelin ligand and its receptor act epistatically to affect susceptibility or tolerance to MI and/or CAD.

Background and Purpose— Quality indicators serve as standards of care by which performance of individual hospitals is measured. Although several audits for monitoring quality of stroke care have been established in Europe, there is currently no consensus on quality indicators for acute stroke care or for methodology for collecting information on these measures. Methods— An up-to-date inventory on European stroke audits in place in 2006 was performed in the course of a project funded by the European Union (European Implementation Score Collaboration [EIS]). Two regional (Flanders, Belgium; Catalonia, Spain) and 4 national (Germany, Scotland, Sweden, England/Wales/Northern Ireland) stroke audits took part. Between November 2009 and July 2010, 2 standardized surveys and a series of interviews were performed to determine characteristics, methods, and content of these quality initiatives. For quality purposes, all summarized information was validated by representatives of the respective audits. Results— Overall, 123 quality indicators (91 process, 24 outcome, and 8 structural indicators) were identified. Anticoagulants in patients with atrial fibrillation and brain imaging were the only quality indicators used in all, whereas another 13 indicators were used in at least 2 of the quality initiatives. Substantial variations were found across the audits in terms of the development process of quality indicators, inclusion criteria, participation, population coverage, data documentation, follow-ups, benchmarking, and feedback of results to participants. Conclusions— There is a huge variety in measuring performance of acute stroke care in Europe, hampering valid comparisons of acute stroke care. Common standards for defining quality indicators and collecting information required for these measures should be defined in Europe.