Abstract Children, adolescent and young adults (CAYA) with relapsed high-grade gliomas (rHGG) share a dismal prognosis. Singular immunotherapeutic interventions like therapeutic vaccines have shown safety and immunogenicity, yet limited clinical efficacy. In the HIT-HGG Rez Immunovac phase I/II study (Eudra-CT 2013-000419-26) we optimzed induction and persistance of immune responses by combining upfront Treg-depletion using metronomic cyclophosphamide followed by therapeutic dendritic cell-based vaccines and subsequent checkpoint inibitor blockade (4x Nivolumab 3 mg/kg and Ipilimumab 1 mg/kg q3wk followed by Nivo mono 6 mg/kg q4wk for up to one year). Primary efficacy endpoint was to reach a 6-month post-relapse overall survival (prOS) of at least 82%. Twenty-five CAYAs with a mean age of 13.8 years [4.3-19.5] were enrolled between 2018-2024. Five patients were excluded due to progression before vaccine start or insufficient tumor material, 20 patients received therapy as per protocol. Fifteen SAEs were noted with no unexpected toxicities. The primary end point was confirmed with a 6-month prOS of 84% and one patient being alive after 31.2 months follow-up. PrOS was significantly improved over a historical control group (HCG, n = 87) from the HIT-HGG database (median OS 9.0 months, range 3.3-31.2 vs. 4.98 months, range 0.26-47.77 in Immunovac vs. HCG patients respectively, p=0.0003). Patients with stable disease at the end of vaccination had a better prOS than those relapsing during the vaccine schedule. Immunomonitoring demonstrated a decline in Tregs and a shift from naïve to memory T-cell subsets under treatment. Vaccine-specific CD4+ and CD8+ T-cell responses were observed in almost all patients, including responses against tumor-specific HLA-class I/II epitopes from the respective immunopeptidomes. Furthermore, spatial omics using cyclic immunofluorescence imaging technology at baseline revealed an immune-cold tumor microenvironment (TME) dominated by myeloid cells (∼50%), predominantly M2-polarized macrophages. T- and NK-cells contributed ∼10% and 15%, respectively. Immune effector cells were spatially dispersed, displayed an exhausted phenotype and were typically embedded within immunosuppressive glial niches or stromal compartments. The tumor compartment exhibited aggressive features, including high Ki67, strong GFAP expression, and frequent p53 alterations, but showed robust HLA-class II expression, revealing potential vulnerability to CD4+ T-cell-mediated responses. In conclusion, our data demonstrate safety and clinical efficacy of an optimized immunotherpeutic regime in CAYA with rHGG. Our immunomonitoring data show substantial T-cell responses and changes in the peripheral immune compartments. Together with insights from the TME these results will shape the design of future immunotherapy trials in HGG.

Abstract:In the project INTEGRATE-ADHD, routine data from a German statutory health insurance company (DAK-Gesundheit) was linked with data from an online survey and clinical online diagnostics. The period between the documentation of a child's ADHD diagnosis in the routine data and the parent report of the diagnosis in the survey was at least nine and at most 32 months. Clinical online diagnostics according to the German AWMF-S3 guideline took place between three and five months after the survey. Only about two-thirds of the parents reported the ADHD diagnosis of their child in the survey and only just under two-thirds of the administrative ADHD diagnoses were clinically confirmed. Based on data from 1,355 children and adolescents with incident ADHD diagnosis, this study used descriptive statistics and logistic regression to examine whether the time lag between the date of diagnosis documentation and the parent report in the survey or the diagnosis in the clinical examination could explain the discrepancies between the different diagnosis data, for example, due to parents' recall bias or changes in in the children's symptom presentation. The date when the diagnosis was coded could be approximated with the start and end date of the treatment period in which the diagnosis was coded. Subsequently, the effect of the time lag was analyzed using descriptive and multivariate statistics. Even when the date of diagnostic coding was differently approximated, no statistically significant association was observed between the time lag and discrepancies between the diagnosis data. Accordingly, the present analyses did not provide evidence that a time-dependent recall bias of the parents or changes in the presentation of symptoms were associated with unreported or clinically unconfirmed ADHD diagnoses.

This paper aims to describe the study design, methodological approach, conduct, and sample characteristics of the data linkage project INTEGRATE-ADHD. The project was designed to evaluate the concordance and validity of administrative versus epidemiological and clinical ADHD diagnoses, thereby providing insights for health care and health care planning. The assessment of treatment satisfaction among families with children with ADHD, as well as the health economics of ADHD, is also part of the project. A total of 24,880 parents of children and adolescents statutorily insured with DAK-Gesundheit, who had at least one confirmed administrative ADHD diagnosis in one quarter of the 2020 insurance year, were invited to complete an online survey. The survey included questions on ADHD diagnosis, disorder-specific and comorbid psychopathology, health care utilisation, and both the quality of and satisfaction with health care. A random sampling procedure was applied to select 202 participants for a guideline-based clinical online assessment. Administrative, survey, and clinical diagnostic data were subsequently linked at the individual level. Non-responder analyses and sample characteristics were examined with descriptive statistics. Group differences were tested with chi-square and t-tests. Sample representativeness was evaluated. A total of 5,461 parents of youths (mean age = 12.5 years; 25.4

Background Excessive supraventricular ectopic activity (ESVEA) is regarded as a risk marker for later atrial fibrillation (AF) detection. Methods and Results The investigator‐initiated, prospective, open, multicenter MonDAFIS (Impact of Standardized Monitoring for Detection of Atrial Fibrillation in Ischemic Stroke) study randomized 3465 patients with acute ischemic stroke without known AF 1:1 to usual diagnostic procedures for AF detection or additive Holter monitoring in hospital for up to 7 days, analyzed in a core laboratory. Secondary study objectives include the comparison of recurrent stroke, myocardial infarction, major bleeding, and all‐cause death within 24 months in patients with ESVEA (defined as ectopic supraventricular beats ≥480/day or atrial runs of 10–29 seconds or both) versus patients with newly diagnosed AF versus patients without ESVEA or AF (non‐ESVEA/AF), randomized to the intervention group. Overall, 1435 (84.8%) of 1714 patients randomized to the intervention group had analyzable study ECG monitoring of at least 48 hours' duration within the first 72 hours of monitoring. ESVEA was detected in 363 (25.3%) patients, while AF was first detected in 48 (3.3%) patients. Within 24 months, AF was newly detected in 67 (18.5%) patients with ESVEA versus 60 (5.9%) patients without ESVEA/AF‐ ( P <0.001). The composite outcome at 24 months was not different between patients with ESVEA and patients without ESVEA/AF (15.2% versus 12.6%; P =0.242). All‐cause death was numerically higher in patients with ESVEA (6.6% versus 3.2%), but failed statistical significance ( P =0.433) in multivariate analysis (including age, heart failure, stroke severity, and creatinine at baseline). Conclusions ESVEA in the acute phase of ischemic stroke or transient ischemic attack is associated with AF detection during follow‐up and therefore may be used to select patients for prolonged ECG monitoring. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02204267.

Adequate secondary prevention in survivors of intracerebral hemorrhage (ICH) who also have atrial fibrillation (AF) is a long-standing clinical dilemma because these patients are at increased risk of recurrent ICH as well as of ischemic stroke. The efficacy and safety of oral anticoagulation, the standard preventive medication for ischemic stroke patients with AF, in ICH patients with AF are uncertain. PRESTIGE-AF is an international, phase 3b, multi-center, randomized, open, blinded end-point assessment (PROBE) clinical trial that compared the efficacy and safety of direct oral anticoagulants (DOACs) with no DOAC (either no antithrombotic treatment or any antiplatelet drug). Randomization occurred in a 1:1 ratio and stratification was based on ICH location and sex. The two co-primary binary endpoints included ischemic stroke and recurrent ICH which will be analyzed hierarchically according to the intention-to-treat principle. Secondary efficacy endpoints encompassed all-stroke and systemic embolism, all-cause and cardiovascular mortality, major adverse cardiac events, and net clinical benefit. Secondary safety endpoints included any major hemorrhage and intracranial hemorrhage. All outcome events were adjudicated by an independent committee. Results of PRESTIGE-AF are expected to support risk-adjusted secondary prevention in ICH survivors with AF and to inform clinical guideline recommendations.

Background Direct oral anticoagulants (DOACs) reduce the rate of thromboembolism in patients with atrial fibrillation but the benefits and risks in survivors of intracerebral haemorrhage are uncertain. We aimed to determine whether DOACs reduce the risk of ischaemic stroke without substantially increasing the risk of recurrent intracerebral haemorrhage. Methods PRESTIGE-AF is a multicentre, open-label, randomised, phase 3 trial conducted at 75 hospitals in six European countries. Eligible patients were aged 18 years or older with spontaneous intracerebral haemorrhage, atrial fibrillation, an indication for anticoagulation, and a score of 4 or less on the modified Rankin Scale. Patients were randomly assigned (1:1) to a DOAC or no anticoagulation, stratified by intracerebral haemorrhage location and sex. Only the events adjudication committee was masked to treatment allocation. The coprimary endpoints were first ischaemic stroke and first recurrent intracerebral haemorrhage. Hierarchical testing for superiority and non-inferiority, respectively, was performed in the intention-to-treat population. The margin to establish non-inferiority regarding intracerebral haemorrhage was less than 1·735. The safety analysis was done in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT03996772, and is complete. Findings Between May 31, 2019, and Nov 30, 2023, 319 participants were enrolled and 158 were randomly assigned to the DOAC group and 161 to the no anticoagulant group. Patients' median age was 79 years (IQR 73–83). 113 (35%) of 319 patients were female and 206 (65%) were male. Median follow-up was 1·4 years (IQR 0·7–2·3). First ischaemic stroke occurred less frequently in the DOAC group than in the no anticoagulant group (hazard ratio [HR] 0·05 [95% CI 0·01–0·36]; log-rank p<0·0001). The rate of all ischaemic stroke events was 0·83 (95% CI 0·14–2·57) per 100 patient-years in the DOAC group versus 8·60 (5·43–12·80) per 100 patient-years in the no anticoagulant group. For first recurrent intracerebral haemorrhage, the DOAC group did not meet the prespecified HR for the non-inferiority margin of less than 1·735 (HR 10·89 [90% CI 1·95–60·72]; p=0·96). The event rate of all intracerebral haemorrhage was 5·00 (95% CI 2·68–8·39) per 100 patient-years in the DOAC group versus 0·82 (0·14–2·53) per 100 patient years in the no anticoagulant group. Serious adverse events occurred in 70 (44%) of 158 patients in the DOAC group and 89 (55%) of 161 patients in the no anticoagulant group. 16 (10%) patients in the DOAC group and 21 (13%) patients in the no anticoagulant group died. Interpretation DOACs effectively prevent ischaemic strokes in survivors of intracerebral haemorrhage with atrial fibrillation but a part of this benefit is offset by a substantially increased risk of recurrent intracerebral haemorrhage. To optimise stroke prevention in these vulnerable patients, further evidence from ongoing trials and a meta-analysis of randomised data is needed, as well as the evaluation of safer medical or mechanical alternatives for selected patients. Funding European Commission.

Zielsetzung: Die Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) gehört zu den häufigsten kinder- und jugendpsychischen Störungen. Bevölkerungsbezogene ADHS-Diagnosedaten für Kinder und Jugendliche in Deutschland sind einerseits Abrechnungsdaten gesetzlicher Krankenkassen, andererseits aus Elternbefragungen in der KiGGS-Studie des Robert Koch-Instituts. Während administrative Diagnoseprävalenzen in der ersten Dekade des Jahrtausends stark anstiegen, blieben die in der KiGGS-Studie ermittelten Diagnosehäufigkeiten stabil oder waren rückläufig. Ob die Diagnosen leitliniengerecht gestellt wurden, ist für keine der Datenquellen bekannt. Im Rahmen des Data-Linkage-Projekts INTEGRATE-ADHD wurden administrative und epidemiologisch ermittelte ADHS-Diagnosedaten auf Personenebene miteinander verknüpft und mittels einer leitliniengerechten Diagnostik klinisch überprüft. Ziel war es, die verschiedenen Datenquellen zu integrieren, zu einer valideren Prävalenzschätzung der ADHS beizutragen sowie Erkenntnisse zur Versorgungssituation von Kindern und Jugendlichen mit ADHS zu erhalten.

ABSTRACTAimsAtrial fibrillation (AF) accounts for about 20% of all ischemic strokes worldwide. It is known that AF impairs health‐related quality of life (HRQOL) in the general population, but data on HRQOL in stroke patients with newly diagnosed AF are sparse.MethodsPost hoc analysis of the prospective, investigator‐initiated, multicenter MonDAFIS study (NCT02204267) to analyze whether AF‐related oral anticoagulation (OAC), and/or AF‐symptom severity are associated with HRQOL after ischemic stroke or transient ischemic attack (TIA). HRQOL was measured using the EQ‐5D‐3L‐questionnaire (including EQ‐index/EQ‐VAS) at baseline and after 12 months using multivariable linear mixed models. AF symptom severity was assessed using the European Heart Rhythm Association classification and symptom severity score (EHRA score) categorizing patients with no/mild/severe/disabling AF‐related symptoms.ResultsA first episode of AF was detected in 261/2927 (8.9%) patients within 12 months after the index stroke and 227/2920 (7.8%) patients had AF and were anticoagulated at 12 months. HRQOL (measured by EQ‐index, n = 2495 patients) was higher in AF patients on OAC compared to AF patients without OAC at 12 months after stroke (mean difference: MD: –16.8, 95% CI: 5.6 to 28.0), and similar in AF patients under OAC compared with patients without AF (MD: 2.0, 95% CI: –2.2 to 6.3). AF‐related symptoms were negatively associated with HRQOL (measured by EQ‐index) indicating that stroke patients with AF‐related symptoms had a lower HRQOL compared to asymptomatic AF patients (mild vs. asymptomatic: MD: –9.0, 95% CI: –17.7 to –0.3; severe/disabling vs. asymptomatic: MD: –19.1, 95% CI: –34.7 to –3.4).DiscussionStroke patients with newly diagnosed AF are at risk of lower quality of life at 12 months, depending on OAC status and AF symptom severity.

As one of the most frequently diagnosed mental disorders in children and adolescents with sometimes serious individual, family and social consequences, attention deficit/hyperactivity disorder (ADHD) is highly relevant to society and health policy. In Germany, data from statutory health insurance companies has reported increasing ADHD diagnosis prevalence rates over years, while epidemiological data has shown constant and recently even decreasing prevalence rates. The clinical validity of diagnoses from either data sources is unknown. In the framework of the consortium project INTEGRATE-ADHD, 5461 parents of children aged 0 to 17 years with a confirmed administrative ADHD diagnosis insured with the third-largest German statutory health insurance provider (DAK-Gesundheit) in at least one quarter of 2020 were surveyed with the questionnaires from the epidemiological German Health Interview and Examination Survey (KiGGS study) and its in-depth module on child mental health (BELLA study) on their child's ADHD diagnosis and symptoms and on other topics, including comorbidity, utilisation of healthcare services, quality of care and satisfaction, psychosocial risk and protective factors and health-related quality of life. In addition, a subsample of 202 children and adolescents with a clinical diagnosis based on the AMWF S3 guideline on ADHD was analysed. An important aim of the project is to use data linkage on person-level to identify possible causes for the often divergent prevalence estimates from epidemiological and administrative data and to integrate and validate the data sources using a guideline-based clinical diagnosis, thereby contributing to a more accurate population-based prevalence estimate of ADHD in children and adolescents and clarifying actual or supposed contradictions between the data sources. The INTEGRATE-ADHD data linkage project combines administrative, epidemiological and clinical ADHD diagnosis data to create a "three-dimensional view" of the ADHD diagnosis. The results will be used to identify fields of action for healthcare policy and self-administration in the German healthcare system and to derive recommendations for the actors and stakeholders in the field of ADHD. The first results will be published in 2024.

Background: The consortium project INTEGRATE-ADHD compared administrative data on the presence of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents with the results of a parent survey and a comprehensive clinical assessment based on the S3 guideline of the Association of the Scientific Medical Societies in Germany (AWMF). Due to the COVID-19 pandemic, the clinical assessment was carried out online. Methods: The article describes how a guideline-based clinical assessment of ADHD can be implemented in an online setting. A specially developed diagnostic matrix is presented to illustrate the assessment procedures and the diagnostic decision-making process. The matrix is intended to help the diagnostician to gain an overview of the numerous individual findings that have been collected using different assessment perspectives and methods (e.g. diagnostic interviews, rating scales, performance tests) in order to make a well-founded and transparent diagnostic decision. Discussion: The consortium project INTEGRATE-ADHD has shown that an online assessment can be implemented in a guideline-compliant manner and allows a valid clinical decision. The diagnostic strategy is discussed with reference to international guidelines and recommendations for online diagnostics (e.g. aspects of feasibility, acceptability and safety of the assessment procedures). The challenges and opportunities of using online assessments in clinical practice are also described.

Introduction: Blood-based biomarkers may improve prediction of functional outcome in patients with acute ischemic stroke. The role of neurofilament light chain (NfL) and glial fibrillary acidic (GFAP) as potential biomarkers especially in severe stroke patients is unknown. Patients and Methods: Prospective, monocenter, cohort study including consecutive patients with severe ischemic stroke in the anterior circulation on admission (NIHSS score ⩾ 6 points or indication for mechanical thrombectomy). Outcome was assessed 3 months after the index stroke by the modified Rankin Scale (mRS). Serum biomarkers levels of NfL and GFAP were determined by ultrasensitive ELISA. Univariate and multivariate logistic regression models were performed to determine the association of biomarker levels and functional disability. Discrimination, calibration, and overall performance were analyzed in different models via AUROC, calibration plots (with Emax and Eavg), Brier-score and R2 using variables, identified as important covariates for functional outcome in previous studies. Results: Between 06/2020 and 08/2021, 213 patients were included [47% female, mean age 76 (SD ± 12) years, median NIHSS score 13 (interquartile range, IQR 9; 17)]. Biomarker serum levels were measured at a median of 1 [IQR, 1; 2] day after admission. Compared to patients with mRS 0–2 at 3 months, patients with mRS 3–6 had higher serum levels of NfL (median: 136 pg/ml vs 41 pg/ml; p < 0.0001) and GFAP (700 ng/ml vs 9.6 ng/ml; p < 0.0001). Both biomarkers were significantly associated with functional outcome [adjusted logistic regression, odds ratio (95% CI) for NfL: 2.63 (1.62; 4.56), GFAP: 2.16 (1.58; 3.09)]. In all models the addition of serum NfL led to a significant improvement in the AUROC, as did the addition of serum GFAP. Calibration plots showed high agreement between the predicted and observed outcomes and after addition of the two blood-based biomarkers there was an improvement of the overall performance. Conclusion: Prediction of functional outcome after severe acute ischemic stroke was improved by the blood-based biomarkers serum NfL and GFAP, measured in the acute phase of stroke. These findings have to be replicated in independent external cohorts. Study registration: DRKS00022064

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) imposes a significant burden on Westernized regions. The Western diet, high in salt intake, significantly contributes to disease development. However, there are a lack of data on salt literacy and salt intake among MASLD patients in Germany. Our study aims to analyze daily salt intake and salt-intake-related behavior in MASLD patients. Methods: 234 MASLD patients were prospectively included. Daily salt intake and salt-intake-related behavior were assessed via a food frequency questionnaire (FFQ—DEGS) and a salt questionnaire (SINU). Statistical analyses were performed using SPSS. Results: Mean daily salt intake was higher in men than in women (7.3 ± 5 g/d vs. 5.3 ± 4 g/d; p < 0.001). There was significant agreement between increased daily salt intake (>6 g/d) and the behavioral salt index (SI) (p < 0.001). Men exhibited higher SI scores compared to women, indicating lower awareness of salt in everyday life. Multivariate analysis identified specific salt-intake-related behaviors impacting daily salt consumption. Conclusions: Our study reveals a strong link between daily salt intake and salt-intake-related behavior, highlighting sex-specific differences in an MASLD cohort. To enhance patient care in high-cardiovascular-risk populations, specific behavioral approaches may be considered, including salt awareness, to improve adherence to lifestyle changes, particularly in male patients.

Background In patients with acute ischemic stroke, little is known regarding the frequency of abnormal ECG findings other than atrial fibrillation and their association with cardiovascular outcomes. We aim to analyze the frequency and type of abnormal ECG findings, subsequent changes in medical treatment, and their association with cardiovascular outcomes in patients with acute ischemic stroke. Methods and Results In the investigator‐initiated multicenter MonDAFIS (impact of standardized monitoring for detection of atrial fibrillation in ischemic stroke) study, 3465 patients with acute ischemic stroke or transient ischemic attack and without known atrial fibrillation were randomized 1:1 to receive Holter‐ECG for up to 7 days in‐hospital with systematic evaluation in a core cardiology laboratory (intervention group) or standard diagnostic care (control group). Outcomes included predefined abnormal ECG findings (eg, pauses, atrial fibrillation, brady‐/tachycardias), medical management in the intervention group, and combined vascular end point (recurrent stroke, myocardial infarction, major bleeds, or all‐cause death) and mortality at 24 months in both randomization groups. Predefined abnormal ECG findings were detected in 326 of 1693 (19.3%) patients in the intervention group. Twenty of these 326 patients (6.1%) received a pacemaker, and 62 of 326 (19.0%) patients had newly initiated or discontinued β‐blocker medication. Discontinuation of β‐blockers was associated with a higher death rate in the control group than in the intervention group during 24 months after enrollment (adjusted hazard ratio, 11.0 [95% CI, 2.4–50.4]; P=0.025 for interaction). Conclusions Systematic in‐hospital Holter ECG reveals abnormal findings in 1 of 5 patients with acute stroke, and mortality was lower at 24 months in patients with systematic ECG recording in the hospital. Further studies are needed to determine the potential impact of medical management of abnormal ECG findings. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02204267.

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 registration https://clinicaltrials.gov/ct2/show/NCT04768998 . https://clinicaltrials.gov/ct2/show/NCT04747366 . https://clinicaltrials.gov/ct2/show/NCT04679584

Einleitung Die Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) ist eine der am häufigsten diagnostizierten psychischen Störungen bei Kindern und Jugendlichen in Deutschland. Daten zur Prävalenz der ADHS sowie zu deren Versorgung liegen für Deutschland einerseits aus der epidemiologischen KiGGS-Studie des Robert Koch-Instituts und aus dessen Vertiefungsmodul zur psychischen Gesundheit (BELLA-Studie des Uniklinikums Hamburg-Eppendorf), andererseits aus Abrechnungsdaten der Routineversorgung der gesetzlichen Krankenkassen vor. In der Vergangenheit wurden allerdings steigende administrative Prävalenzzahlen für ADHS-Diagnosen aus Abrechnungsdaten für Krankenkassen berichtet, während epidemiologische Studien auf gleichbleibende, zuletzt sogar sinkende Prävalenzen verweisen. Darüber hinaus ist bisher nur wenig über die klinische Validität administrativer und epidemiologischer ADHS-Diagnosen bekannt. Im Konsortialprojekt INTEGRATE-ADHD werden administrative Daten einer bundesweiten Krankenversicherung und epidemiologische Daten hinsichtlich der Häufigkeit von ADHS bei Kindern und Jugendlichen verglichen und mit einer an der aktuellen AWMF-S3-Leitlinie orientierten klinischen Diagnostik validiert.

We aimed to analyze prevalence and predictors of NOAC off-label under-dosing in AF patients before and after the index stroke. The post hoc analysis included 1080 patients of the investigator-initiated, multicenter prospective Berlin Atrial Fibrillation Registry, designed to analyze medical stroke prevention in AF patients after acute ischemic stroke. At stroke onset, an off-label daily dose was prescribed in 61 (25.5%) of 239 NOAC patients with known AF and CHA2DS2-VASc score ≥ 1, of which 52 (21.8%) patients were under-dosed. Under-dosing was associated with age ≥ 80 years in patients on rivaroxaban [OR 2.90, 95% CI 1.05–7.9, P = 0.04; n = 29] or apixaban [OR 3.24, 95% CI 1.04–10.1, P = 0.04; n = 22]. At hospital discharge after the index stroke, NOAC off-label dose on admission was continued in 30 (49.2%) of 61 patients. Overall, 79 (13.7%) of 708 patients prescribed a NOAC at hospital discharge received an off-label dose, of whom 75 (10.6%) patients were under-dosed. Rivaroxaban under-dosing at discharge was associated with age ≥ 80 years [OR 3.49, 95% CI 1.24–9.84, P = 0.02; n = 19]; apixaban under-dosing with body weight ≤ 60 kg [OR 0.06, 95% CI 0.01–0.47, P < 0.01; n = 56], CHA2DS2-VASc score [OR per point 1.47, 95% CI 1.08–2.00, P = 0.01], and HAS-BLED score [OR per point 1.91, 95% CI 1.28–2.84, P < 0.01]. At stroke onset, off-label dosing was present in one out of four, and under-dosing in one out of five NOAC patients. Under-dosing of rivaroxaban or apixaban was related to old age. In-hospital treatment after stroke reduced off-label NOAC dosing, but one out of ten NOAC patients was under-dosed at discharge. NCT02306824.

BackgroundSystematic electrocardiogram (ECG) monitoring improves detection of covert atrial fibrillation in stroke survivors but the effect on secondary prevention is unknown. We aimed to assess the effect of systematic ECG monitoring of patients in hospital on the rate of oral anticoagulant use after 12 months.MethodsIn this investigator-initiated, randomised, open-label, parallel-group multicentre study with masked endpoint adjudication, we recruited patients aged at least 18 years with acute ischaemic stroke or transient ischaemic attack without known atrial fibrillation in 38 certified stroke units in Germany. Patients were randomly assigned (1:1) to usual diagnostic procedures for atrial fibrillation detection (control group) or additional Holter-ECG recording for up to 7 days in hospital (intervention group). Patients were stratified by centre using a random permuted block design. The primary outcome was the proportion of patients on oral anticoagulants at 12 months after the index event in the intention-to-treat population. Secondary outcomes included the number of patients with newly diagnosed atrial fibrillation in hospital and the composite of recurrent stroke, major bleeding, myocardial infarction, or death after 6 months, 12 months, and 24 months. This trial was registered with ClinicalTrials.gov, NCT02204267, and is completed and closed for participants.FindingsBetween Dec 9, 2014, and Sept 11, 2017, 3465 patients were randomly assigned, 1735 (50·1%) to the intervention group and 1730 (49·9%) to the control group. Oral anticoagulation status was available in 2920 (84·3%) patients at 12 months (1484 [50·8%] in the intervention group and 1436 [49·2%] in the control group). For the primary outcome, at 12 months, 203 (13·7%) of 1484 patients in the intervention group versus 169 (11·8%) of 1436 in the control group were on oral anticoagulants (odds ratio [OR] 1·2 [95% CI 0·9–1·5]; p=0·13). Atrial fibrillation was newly detected in patients in hospital in 97 (5·8%) of 1714 in the intervention group versus 68 (4·0%) of 1717 in the control group (hazard ratio [HR] 1·4 [95% CI 1·0–2·0]; p=0·024). The composite of cardiovascular outcomes and death did not differ between patients randomly assigned to the intervention group versus the control group at 24 months (232 [13·5%] of 1714 vs 249 [14·5%] of 1717; HR 0·9 [0·8–1·1]; p=0·43). Skin reactions due to study ECG electrodes were reported in 56 (3·3%) patients in the intervention group. All-cause death occured in 73 (4·3%) patients in the intervention group and in 103 (6·0%) patients in the control group (OR 0·7 [0·5–0·9]).InterpretationSystematic core centrally reviewed ECG monitoring is feasible and increases the detection rate of atrial fibrillation in unselected patients hospitalised with acute ischaemic stroke or transient ischaemic attack, if added to usual diagnostic care in certified German stroke units. However, we found no effect of systematic ECG monitoring on the rate of oral anticoagulant use after 12 months and further efforts are needed to improve secondary stroke prevention.FundingBayer Vital.TranslationFor the German translation of the abstract see Supplementary Materials section.

PURPOSE:Evidence shows that genetic and non-genetic risk factors for breast cancer (BC) differ relative to the molecular subtype. This analysis aimed to investigate associations between epidemiological risk factors and immunohistochemical subtypes in a cohort of postmenopausal, hormone receptor-positive BC patients.METHODS:The prospective, single-arm, multicenter phase IV PreFace study (Evaluation of Predictive Factors Regarding the Effectivity of Aromatase Inhibitor Therapy) included 3529 postmenopausal patients with hormone receptor-positive early BC. Data on their epidemiological risk factors were obtained from patients' diaries and their medical histories. Data on estrogen receptor, progesterone receptor, and HER2 receptor status were obtained from pathology reports. Patients with incomplete information were excluded. Data were analyzed using conditional inference regression analysis, analysis of variance, and the chi-squared test.RESULTS:In a cohort of 3392 patients, the strongest association with the molecular subtypes of BC was found for hormone replacement therapy (HRT) before diagnosis of early BC. The analysis showed that patients who took HRT at diagnosis had luminal A-like BC more often (83.7%) than those who had never taken HRT or had stopped taking it (75.5%). Luminal B-like BC and HER2-positive BC were diagnosed more often in women who had never taken HRT or had stopped taking it (13.3% and 11.2%, respectively) than in women who were taking HRT at diagnosis of BC (8.3% and 8.0%, respectively).CONCLUSIONS:This analysis shows an association between HRT and the distribution of molecular subtypes of BC. However, no associations between other factors (e.g., age at diagnosis, body mass index, smoking status, age at menopause, number of deliveries, age at first delivery, breastfeeding history, or family history) were noted.

Zusammenfassung Ziel der Studie Ziel der Studie war es, die gesundheitsbezogene Lebensqualitat sowie die Zufriedenheit wahrend der Teilnahme am einjahrigen Diabetes-Praventionsprogramm GLICEMIA zu erheben. Methodik GLICEMIA besteht aus drei individuellen Beratungen sowie funf Gruppenschulungen zur Lebensstilanderung. Im Rahmen einer cluster-randomisierten Studie wurden die Teilnehmer von GLICEMIA mit einer Kontrollgruppe verglichen, welche eine schriftliche Standardinformation erhielt. Nach 12 Monaten wurde die Entwicklung des 10-Jahres-Diabetes-Risikos der Teilnehmer mithilfe des FINDRISK beurteilt. Weiterhin wurde die Veranderung der gesundheitsbezogenen Lebensqualitat anhand des Short Form Health Survey SF-12 sowie die Zufriedenheit der beiden Gruppen verglichen. Ergebnisse Insgesamt wurden die Daten von 1087 Studienteilnehmern bei der Intention-to-treat-Analyse ausgewertet. Wahrend der Teilnahme an GLICEMIA reduzierten 38,9% ihren FINDRISK, wohingegen dies von 20,9% der Kontrollgruppe erreicht wurde. Hierbei verbesserte sich die korperliche Lebensqualitat in der Interventionsgruppe im Vergleich zur Kontrollgruppe signifikant (adjustierte Effektgro ss e: 2,39 Punkte; 95%-Konfidenzintervall 1,43-3,34). Die Teilnehmer von GLICEMIA, welche ihr Diabetes-Risiko reduzierten, hatten nach einem Jahr eine verbesserte psychische und korperliche Lebensqualitat. Dies konnte in der Kontrollgruppe nicht beobachtet werden. Gesamtnutzen und Zufriedenheit mit dem Programm wurden in der Interventionsgruppe als sehr hoch eingestuft. Schlussfolgerung Die Teilnehmer von GLICEMIA hatten mit einem signifikant niedrigeren 10-Jahres-Diabetes-Risiko sowie einer verbesserten korperlichen und psychischen Lebensqualitat einen hohen Nutzen vom Programm. Dieser hohe Gesamtnutzen spiegelt sich auch in der Zufriedenheit der Teilnehmer wider. Ein flachendeckendes Angebot des Programms sollte angestrebt werden. Abstract Objectives We aimed to assess the health-related quality of life as well as participant satisfaction during the pharmacy-based diabetes prevention program GLICEMIA. Methods GLICEMIA comprises 3 individual counseling sessions and 5 group-based lectures addressing a lifestyle modification. In a cluster-randomized controlled trial, GLICEMIA was compared with reduced standard information in the control group. After 12 months, the groups were compared regarding the diabetes risk score FINDRISC, health-related quality of life with the 12-item Short Form health survey (SF-12) and participant satisfaction. Results In total, the data of 1,087 participants were analyzed. During GLICEMIA, 38.9% reduced their FINDRISC whereas 20.9% reached this goal in the control group. Moreover, the physical quality of life improved significantly in the intervention group compared with the control group (adjusted effect size: 2.39 points, 95% CI 1.43-3.34). Participants of GLICEMIA who reduced their diabetes risk had enhanced mental and physical quality of life after one year. This was not observed in the control group. The overall benefit and satisfaction were rated very high in the intervention group. Conclusion Participation in GLICEMIA results in a significant reduction of the diabetes risk according to the FINDRISC, as well as an improved physical and mental quality of life. The high satisfaction of the participants reflects the overall benefit. Nationwide implementation of the program is recommended.

tinib prevents acute graft-versus-host disease in patients with myelofibrosis undergoing allogenic stem cell transplantation. Biology of Blood and Marrow Transplantation, 24, 2152–2156. Marchetti, M., Barosi, G., Cervantes, F., Birgeg ard, G., Griesshammer, M., Harrison, C., Hehlmann, R., Kiladjian, J.J., Kr€ oger, N., McMullin, M.F., Passamonti, F., Vannucchi, A. & Barbui, T. (2017) Which patients with myelofibrosis should receive ruxolitinib therapy? ELN-SIE evidence-based recommendations. Leukemia, 31, 882–888. Shantzer, L., Berger, K. & Pu, J.J. (2017) Primary myelofibrosis and its targeted therapy. Annals of Hematology, 96, 531–535. Spoerl, S., Mathew, N.R., Bscheider, M., SchmittGraeff, A., Chen, S., Mueller, T., Verbeek, M., Fischer, J., Otten, V., Schmickl, M., Maas-Bauer, K., Finke, J., Peschel, C., Duyster, J., Poeck, H., Zeiser, R. & von Bubnoff, N. (2014) Activity of therapeutic JAK 1/2 blockade in graft-versushost disease. Blood, 123, 3832–3842. Swerdlow, S.H., Campo, E., Harris, N.L., Jaffe, E.S., Pileri, S.A., Stein, H. & Thiele, J. (2008) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised, 4th edn. IARC, Lyon, France. Tefferi, A., Cervantes, F., Mesa, R., Passamonti, F., Verstovsek, S., Vannucchi, A.M., Gotlib, J., Dupriez, B., Pardanani, A., Harrison, C., Hoffman, R., Gisslinger, H., Kr€ oger, N., Thiele, J., Barbui, T. & Barosi, G. (2013) Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood, 122, 1395–1398. Zeiser, R., Burchert, A., Lengerke, C., Verbeek Maas-Bauer, K., Metzelder, S.K., Spoerl, S., Ditschkowski, M., Ecsedi, M., Sockel, K., Ayuk, F., Ajib, S., de Fontbrune, F.S., Na, I.K., Penter, L., Holtick, U., Wolf, D., Schuler, E., Meyer, E., Apostolova, P., Bertz, H., Marks, R., L€ ubbert, M., W€asch, R., Scheid, C., St€ olzel, F., Ordemann, R., Bug, G., Kobbe, G., Negrin, R., Brune, M., Spyridonidis, A., Schmitt-Gr€aff, A., van der Velden, W., Huls, G., Mielke, S., Grigoleit, G.U., Kuball, J., Flynn, R., Ihorst, G., Du, J., Blazar, B.R., Arnold, R., Kr€ oger, N., Passweg, J., Halter, J., Soci e, G., Beelen, D., Peschel, C., Neubauer, A., Finke, J., Duyster, J. & von Bubnoff, N. (2015) Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia, 29, 2062–2068.