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Attila Magyar,1,2 Martin Wagner,2–4 Phillip Thomas,1,2 Carolin Malsch,2 Reinhard Schneider,3 Stefan Störk,4,5 Peter U Heuschmann,2,4,6 Rainer G Leyh,1 Mehmet Oezkur1,21Department of Cardiovascular Surgery, University Hospital Würzburg, Würzburg, Germany; 2Institute of Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany; 3Division of Nephrology, Department of Medicine I, University Hospital Würzburg, Würzburg, Germany; 4Comprehensive Heart Failure Center, University of Würzburg, Würzburg, Germany; 5Division of Cardiology, Department of Medicine I, University Hospital Würzburg, Würzburg, Germany; 6Clinical Trial Center Würzburg, University Hospital Würzburg, Würzburg, Germany Background: Acute kidney injury (AKI) is a serious complication after cardiac surgery that is associated with increased mortality and morbidity. Heme oxygenase-1 (HO-1) is an enzyme synthesized in renal tubular cells as one of the most intense responses to oxidant stress linked with protective, anti-inflammatory properties. Yet, it is unknown if serum HO-1 induction following cardiac surgical procedure involving cardiopulmonary bypass (CPB) is associated with incidence and severity of AKI. Patients and methods: In the present study, we used data from a prospective cohort study of 150 adult cardiac surgical patients. HO-1 measurements were performed before, immediately after and 24 hours post-CPB. In univariate and multivariate analyses, the association between HO-1 and AKI was investigated. Results: AKI with an incidence of 23.3% (35 patients) was not associated with an early elevation of HO-1 after CPB in all patients (P=0.88), whereas patients suffering from AKI developed a second burst of HO-1 24 hours after CBP. In patients without AKI, the HO-1 concentrations dropped to baseline values (P=0.031). Furthermore, early HO-1 induction was associated with CPB time (P=0.046), while the ones 24 hours later lost this association (P=0.219). Conclusion: The association of the second HO-1 burst 24 hours after CBP might help to distinguish between the causality of AKI in patients undergoing CBP, thus helping to adapt patient stratification and management. Keywords: acute kidney injury, cardiac surgery, heme oxygenase-1, cardiopulmonary bypass

Abstract Background The risk of breast cancer patients for long-term side effects of therapy such as neurotoxicity and cardiotoxicity as well as late effects regarding comorbidities varies from individual to individual. Personalised follow-up care concepts that are tailored to individual needs and the risk of recurrences, side effects and late effects are lacking in routine care in Germany. Methods We describe the methodology of BETTER-CARE, a parallel-arm cluster-randomised controlled trial conducted at 15 intervention and 15 control centres, aiming to recruit 1140 patients, and the results of the pilot phase. The needs- and risk-adapted complex intervention, based on existing development frameworks, includes a multidisciplinary network and digital platforms for symptom and need documentation and just-in-time adaptive interventions. The control group comprises usual care according to clinical guidelines. The primary outcome is health-related quality of life (EORTC QLQ-C30 global health), and secondary outcomes include treatment adherence. Results The 2-month pilot phase comprising 16 patients in one intervention and one control pilot centre demonstrated the feasibility of the BETTER-CARE approach. Discussion BETTER-CARE is a feasible intervention and study concept, investigating individualised needs- and risk-adapted breast cancer follow-up care in Germany. If successful, the approach could be implemented in German routine care. Trial registration German Clinical Trial Register DRKS00028840. Registered on April 2022.

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.

Background: This article examines discrepancies in the frequency of diagnoses of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents in Germany using information on health care utilisation from both administrative and parent-reported survey data linked at person level. Methods: 5,461 parents of 0- to 17-year-olds insured with DAK-Gesundheit in 2020 and being registered with a confirmed administrative ADHD diagnosis (ICD-10 F90.0-9) in at least one quarter in 2020 (M1Q criterion) were surveyed online on their child’s ADHD diagnosis, utilisation of specialist care and therapeutic service providers. With regard to the presence of a parental report of the child’s documented ADHD diagnosis, administrative data and survey data were bi- and multivariately analysed. Results: The response rate was 21.5 %. ADHD diagnoses were given more frequently in the context of paediatric care, but in the multivariable model with the administrative data only the diagnosis made by mental health professionals (OR = 2.78), in the model with the survey data only utilisation of mental health professionals (OR = 2.99) positively predicted the parental diagnostic report. With regard to the utilisation of therapeutic service providers, only the utilisation of occupational therapy was associated with the parental report of the diagnosis in both data sources. Conclusions: Parental non-reporting of a child’s administrative ADHD diagnosis in survey studies can be in part be explained by utilisation characteristics.

Background: In the project INTEGRATE-ADHD, administrative and parent-reported ADHD diagnosis data of children and adolescents were linked at person level for the first time in Germany. This contribution analyses discrepancies between the data sources, considering sociodemographic characteristics. Methods: Parents of 5,461 0- to 17-year-olds insured with the German statutory health insurance company DAK-Gesundheit in 2020, who had a confirmed administrative diagnosis of ADHD (ICD-10 F90.0-9) in at least one quarter (M1Q criterion), were surveyed online about their child’s ADHD diagnosis and other health and care-related topics. Using logistic regression, associations between the presence of a parental report of the child’s administrative ADHD diagnosis and sociodemographic predictors were analysed. Results: 71.6 % of parents reported their child’s administrative diagnosis of ADHD in the survey. The diagnosis was significantly less likely to be reported by parents of girls, younger children, children with a migration background and children from nuclear families with both biological parents. There were no differences with regard to parental education, urbanisation (urban/rural) or density of care. Bivariate findings were confirmed in the multivariable model. Conclusions: Approximately one third of parents do not report their child’s administrative diagnosis of ADHD. The likelihood of parental reporting varies according to sociodemographic factors. This should be considered when contextualising the data sources in the future.

Background: Attention-deficit/hyperactivity disorder (ADHD) is associated with increased costs for the family, the health care system and the society. Previous cost-of-illness studies in Germany usually focused on prevalent ADHD. This study addressed the research gap on health care resource utilisation and costs of children and adolescents with incident ADHD diagnosis using nationwide claims data from the statutory health insurance DAK-Gesundheit. Methods: A matched-control design (propensity score matching, 1:3 ratio) was used to examine the health care costs of incident ADHD patients compared with a non-ADHD control group, considering an observation period of four quarters. Besides bivariate statistics, multivariate analyses of total costs were used to consider relevant covariates. Results: Total health care costs for children and adolescents with ADHD in the first year after diagnosis exceeded those of the control group by € 1,505.3. According to the multivariate analysis, the group with incident ADHD had significantly higher (2.86-fold) health care costs when compared with non-ADHD peers. Sensitivity analyses proved these findings. In addition, the analyses identified children’s age and comorbidity index to be significantly associated with increased costs. Conclusions: ADHD in children and adolescents is associated with a significant economic burden. The results emphasise the need for social awareness, prevention, appropriate treatment and research efforts.

Background: The study examines the psychometric properties of the ADHD section of the semi-structured diagnostic interview ILF-EXTERNAL, which was conducted online via video chat. Methods: As part of the INTEGRATE-ADHD research project, 202 children and adolescents (age M = 12.87 years, SD = 3.04, 28.2 % female) with an administrative diagnosis of ADHD registered with their health insurance company were clinically assessed for the presence of ADHD according to the German ADHD S3 guideline. Using the ILF-EXTERNAL, one parent and, from the age of eight, also the children themselves were interviewed. A proxy rating by a parent was made using the German FBB-ADHS rating scale. In a subsample (n = 65), an independent blind interviewer rated the videorecordings of the ILF-EXTERNAL parent interview to determine the interrater reliability of the ILF-EXTERNAL. Results: All ADHD symptom scales of the ILF-EXTERNAL showed good to excellent internal consistency (α = 0.89 to 0.93). Interrater reliability was high for both categorical and dimensional analyses (κ = 0.78 and κ = 0.81; ICC(1,1) = 0.97 and 0.98). High correlations of the ILF-EXTERNAL parent interview with the FBB-ADHS (r = 0.79 to r = 0.85) and with the ILF-EXTERNAL child interview (r = 0.60 to r = 0.71) demonstrated convergent validity. Conclusions: Sound psychometric properties of the ILF-EXTERNAL were also confirmed for its use in an online setting. High interrater reliabilities demonstrate the quality of the ADHD diagnostics carried out in the consortium project INTEGRATE-ADHD.

Background: The health-related quality of life (HRQoL) of individuals living with Attention-deficit/hyperactivity disorder (ADHD) is known to be impaired. Identifying factors that influence HRQoL can provide important information for the development of prevention and intervention programmes for affected children and adolescents. The aim of the present study was to investigate health care-related and psychosocial risk and protective factors for HRQoL in children and adolescents with an administrative ADHD diagnosis. Methods: In the consortium project INTEGRATE-ADHD, n = 4,809 parents of children and adolescents aged 7 to 17 years participated in an online survey between October 2021 and August 2022 and answered questions regarding HRQoL (KIDSCREEN-27), health care utilisation, and psychosocial risk and protective factors. Multiple linear regression analyses were conducted to assess the association between these factors and the five HRQoL dimensions of the KIDSCREEN-27. Results: Findings indicate that parental psychopathology and parental burden were risk factors for lower HRQoL in children and adolescents with ADHD. Further, a positive association was found between the five HRQoL dimensions and the psychosocial factors family climate and social support, indicating that these are protective factors. Conclusions: The results highlight the importance of prevention and intervention programmes for individuals with ADHD that consider parental mental health and aim to strengthen resources such as the availability of good family climate and social support.

Juliane Matlach,1,* Matthias Hipp,1,* Martin Wagner,2,3 Peter U Heuschmann,2,3 Thomas Klink,1 Franz Grehn11Department of Ophthalmology, 2Institute of Clinical Epidemiology and Biometry, 3Comprehensive Heart Failure Center, University of Würzburg, Würzburg, Germany*These authors contributed equally to this workPurpose: The objective of the study reported here was to evaluate the outcome of a modified filtering trabeculotomy (FTO) without iridectomy in open-angle glaucoma compared with that of conventional trabeculectomy (trab).Patients and methods: Thirty eyes of 30 patients who underwent modified FTO were prospectively followed for 1 year and were compared with 87 conventional trab patients (87 eyes), matched for age and preoperative intraocular pressure (IOP). The FTO procedure consisted of a deep sclerectomy and trabeculotomy preserving the trabeculo-Descemet membrane, without iridectomy. Main outcome measures were complete success (IOP /=30% IOP reduction, without medication), IOP, visual acuity, medication, complications, and subsequent surgeries.Results: In the conventional trab group, the median preoperative IOP was 23.0 mmHg (interquartile range 20.0–27.0) with 3.0 (2.0–3.0) medications, compared with 23.0 mmHg (20.0–27.0) and 3.0 (2.8–4.0) in the modified FTO group. Median postoperative IOP at 12 months was 12.0 mmHg (10.0–13.0) in the conventional trab and 11.0 mmHg (8.0–14.0) in the modified FTO group (P=0.3). The complete success rate at 1 year was 83.1% and 79.3% in the conventional trab group and modified FTO group, respectively (P=0.8). The complications hypotony (20.7%, 24.1%), choroidal detachment (2.3%, 10.3%), and bleb scarring (17.2%, 13.8%), were present in the conventional trab group and modified FTO group, respectively.Conclusion: The outcomes of reduced IOP and medications in the FTO group were not different to those in the conventional trab group over 1 year, but some complications were more often seen with the modified FTO technique. The new filtration trabeculotomy, however, has the advantage of avoiding iridectomy, thus reducing the risk of cataract formation, and may result in the development of more favorable blebs by controlling the flow over two resistance levels.Keywords: glaucoma surgery, open-angle glaucoma, outflow resistance, iridectomy, trabeculectomy

Abstract Knowledge about a patient’s physical fitness can aid in medical decision-making, but objective assessment can be challenging and time-consuming. We aimed to investigate the concordance of self-reported health status and physical functioning with the 6 minute walking distance (6MWD) as objective measure of physical performance. The prospective characteristics and course of heart failure stages A/B and determinants of progression (STAAB) cohort study iteratively follows a representative sample of residents of the city of Würzburg, Germany, aged 30–79 years, without a history of heart failure (HF). The 6MWD was measured in 2752 individuals (aged 58 ± 11 years, 51% women) from a population-based cohort under strictly standardized conditions. Self-reported health status and physical functioning were assessed from items of the short form 36 (SF-36). After the respective classification of self-reported health status and physical functioning into ‘good’, ‘moderate’, and ‘poor’, we determined the association of these categories with 6MWD by applying a generalized linear model adjusted for age and sex. Prevalence of self-reported good/moderate/poor general health and physical functioning was 41/52/7% and 45/48/7%, respectively. Mean 6MWD in the respective categories was 574 ± 70/534 ± 76/510 ± 87 m, and 574 ± 72/534 ± 73/490 ± 82 m, with significant sex-specific differences between all categories (all p

Background Oral anticoagulation (OAC) is key in stroke prevention in patients with atrial fibrillation (AF) but there is uncertainty regarding the optimal timing of OAC (re)initiation after stroke, as recent large randomised controlled trials have methodological weaknesses and excluded stroke patients on therapeutic anticoagulation at stroke onset as well as patients started on a vitamin K antagonist after stroke. The ‘1–3–6–12 days rule’, based on expert consensus and referring to stroke severity, was used in clinical practice to initiate OAC after acute ischaemic stroke or transient ischaemic attack (TIA) since publication in 2013.Methods We retrospectively assessed whether compliance to the ‘1–3–6–12 days rule’ was associated with the composite endpoint (recurrent stroke, systemic embolism, myocardial infarction, major bleeding or all-cause death).Results Among 708 registry patients with known AF before stroke and hospitalisation within 72 hours after stroke, 432 were anticoagulated at stroke onset. OAC was started according to the ‘1–3–6–12 days rule’ in 255 (39.2%) patients. Non-adherence to the ‘1–3–6–12 days rule’ was not associated with the composite endpoint within 3 months in 661 patients who (re-)started on OAC (log-rank test: p=0.74).Results were similar for 521 patients (re)started on a non-vitamin K-dependent OAC.Conclusion (Re)starting OAC after stroke followed the ‘1–3–6–12 days rule’ in about 40% of all patients with AF, and more often in those anticoagulated at stroke onset. Adherence to the ‘1–3–6–12 days rule’ did not reduce the composite clinical endpoint, if OAC was restarted within 3 months of stroke/TIA.Trial registration number NCT02306824.

IntroductionRespiratory viral infections (RVIs) are a major global contributor to morbidity and mortality. The susceptibility and outcome of RVIs are strongly age-dependent and show considerable inter-population differences, pointing to genetically and/or environmentally driven developmental variability. The factors determining the age-dependency and shaping the age-related changes of human anti-RVI immunity after birth are still elusive. MethodsWe are conducting a prospective birth cohort study aiming at identifying endogenous and environmental factors associated with the susceptibility to RVIs and their impact on cellular and humoral immune responses against the influenza A virus (IAV), respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The MIAI birth cohort enrolls healthy, full-term neonates born at the University Hospital Würzburg, Germany, with follow-up at four defined time-points during the first year of life. At each study visit, clinical metadata including diet, lifestyle, sociodemographic information, and physical examinations, are collected along with extensive biomaterial sampling. Biomaterials are used to generate comprehensive, integrated multi-omics datasets including transcriptomic, epigenomic, proteomic, metabolomic and microbiomic methods. DiscussionThe results are expected to capture a holistic picture of the variability of immune trajectories with a focus on cellular and humoral key players involved in the defense of RVIs and the impact of host and environmental factors thereon. Thereby, MIAI aims at providing insights that allow unraveling molecular mechanisms that can be targeted to promote the development of competent anti-RVI immunity in early life and prevent severe RVIs.Clinical trial registrationhttps://drks.de/search/de/trial/, identifier DRKS00034278.

Background The incidental finding of a pericardial effusion (PE) poses a challenge in clinical care. PE is associated with malignant conditions or severe cardiac disease but may also be observed in healthy individuals. This study explored the prevalence, determinants, course, and prognostic relevance of PE in a population‐based cohort. Methods and Results The STAAB (Characteristics and Course of Heart Failure Stages A/B and Determinants of Progression) cohort study recruited a representative sample of the population of Würzburg, aged 30 to 79 years. Participants underwent quality‐controlled transthoracic echocardiography including the dedicated evaluation of the pericardial space. Of 4965 individuals included at baseline (mean age, 55±12 years; 52% women), 134 (2.7%) exhibited an incidentally diagnosed PE (median diameter, 2.7 mm; quartiles, 2.0–4.1 mm). In multivariable logistic regression, lower body mass index and higher NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) levels were associated with PE at baseline, whereas inflammation, malignancy, and rheumatoid disease were not. Among the 3901 participants attending the follow‐up examination after a median time of 34 (30–41) months, PE was found in 60 individuals (1.5%; n=18 new PE, n=42 persistent PE). Within the follow‐up period, 37 participants died and 93 participants reported a newly diagnosed malignancy. The presence of PE did not predict all‐cause death or the development of new malignancy. Conclusions Incidental PE was detected in about 3% of individuals, with the vast majority measuring

Abstract Background After infection with SARS-CoV-2 a relevant proportion of patients complains about persisting symptoms, a condition termed Post-COVID-19-syndrome (PC19S). So far, possible treatments are under investigation. Among others, neurotropic vitamins and anti-inflammatory substances are potential options. Thus, the PreVitaCOV trial aims to assess feasibility, safety, and effectiveness of treating patients in primary care with prednisolone and/or vitamin B1, B6 and B12. Methods The phase IIIb, multi-centre randomised, double-blind, and placebo-controlled PreVitaCOV trial has a factorial design and is planned as a two-phase approach. The pilot phase assessed feasibility and safety and was transformed into a confirmatory phase to evaluate effectiveness since feasibility was proven. Adult patients with PC19S after a documented SARS-CoV-2 infection at least 12 weeks ago are randomly assigned to 4 parallel treatments: prednisolone 20 mg for five days followed by 5 mg for 23 days (trial drug 1), B vitamins (B1 (100 mg OD), B6 (50 mg OD), and B12 (500 µg OD)) for 28 days (trial drug 2), trial drugs 1 and 2, or placebo. The primary outcome of the pilot phase was defined as the retention rate of the first 100 patients. Values of ≥ 85% were considered as confirmation of feasibility, this criterion was even surpassed by a retention rate of 98%. After transformation, the confirmatory phase proceeds by enrolling 240 additional patients. The primary outcome for the study is the change of symptom severity from baseline to day 28 as assessed by a tailored Patient Reported Outcomes Measurement Information System (PROMIS) total score referring to five symptom domains known to be typical for PC19S (fatigue, dyspnoea, cognition, anxiety, depression). The confirmatory trial is considered positive if superiority of any treatment is demonstrated over placebo operationalised by an improvement of at least 3 points on the PROMIS total score (t-score). Discussion The PreVitaCOV trial may contribute to the understanding of therapeutic approaches in PC19S in a primary care context. Trial registration EudraCT: 2022-001041-20. DRKS: DRKS00029617. ClinicalTrials.gov: F001AM02222_1 (registered: 05 Dec 2022).

Abstract Background The number of patients depending on home mechanical ventilation (HMV) has increased substantially in Germany in recent years. These patients receive long-term care in different nursing facilities (nursing home, shared living community, private home). However, there are limited data available on the quality of care of HMV patients. The aim of the OVER-BEAS project was to identify quality indicators (QIs) of HMV care using an evidence-based approach. Methods A multidisciplinary board consisting of professionals and experts of HMV provision compiled a set of QIs between March and September 2019. In a structured, transparent process a set of QIs covering structures, processes and outcome of HMV patient’s care were proposed and evaluated based on the best available evidence. QIs were defined as relevant, reliable and valid measurements of the quality of HMV care and furthermore to be comprehensive and applicable in practice. Results The experts proposed 40 QIs and consented a final set of 26 QIs. Based on the final set, questionnaires to document the QIs were developed: (1) to assess the quality and describe the structure of the nursing facility; and (2) to gather information on patient-related processes and outcomes. The feasibility of the questionnaires was tested in 5 nursing facilities treating HMV patients. The remarks from the nursing specialists were categorised in three groups: (1) term missing accuracy, (2) problem of understanding, and (3) not documented or documented elsewhere. Mean documentation time by the nursing specialists for one patient was 15 min. Based on this feedback, the questionnaires were finalised. Conclusions We proposed a set of QIs relating to long-term HMV care and developed two questionnaires to collect this information. In a pilot study, we found the set of questionnaires to be feasible in assessing the quality of HMV care according to current evidence. The development of standardised evidence-based QIs to evaluate HMV care is a step towards implementing a standardised quality assurance program to document the quality of care of HMV patients.

Summary: Background: Anticipating the burden of intracerebral haemorrhage is crucial for proactive management and building resilience against future health challenges. Prior forecasts are based on population demography and to a lesser extent epidemiological trends. This study aims to utilise selected modifiable risk factors and socio-demographic indicators to forecast the incidence and mortality of intracerebral haemorrhage in Europe between 2019 and 2050. Methods: Three intracerebral haemorrhage risk factors identified in the Global Burden of Diseases, Injuries, and Risk Factors study (GBD 2019)—high systolic blood pressure, high fasting plasma glucose, and high body mass index—were utilised to predict the risk-attributable fractions between 2019 and 2050. Disease burden not attributable to these risk factors was then forecasted using time series models (autoregressive integrated moving average [ARIMA]), incorporating the Socio-demographic Index (SDI) as an external predictor. The optimal parameters of ARIMA models were selected for each age-sex-country group based on the Akaike Information Criterion (AIC). Different health scenarios were constructed by extending the past 85th and 15th percentiles of annualised rates of change in risk factors and SDI across all location-years, stratified by age and sex groups. A decomposition analysis was performed to assess the relative contributions of population size, age composition, and intracerebral haemorrhage risk on the projected changes. Findings: Compared with observed figures in 2019, our analysis predicts an increase in the burden of intracerebral haemorrhage in Europe in 2050, with a marginal rise of 0.6% (95% uncertainty interval [UI], −7.4% to 9.6%) in incident cases and an 8.9% (−2.8% to 23.6%) increase in mortality, reaching 141.2 (120.6–166.5) thousand and 144.2 (122.9–172.2) thousand respectively. These projections may fluctuate depending on trajectories of the risk factors and SDI; worsened trends could result in increases of 16.7% (8.7%–25.3%) in incidence and 31.2% (17.7%–48%) in mortality, while better trajectories may lead to a 10% (16.4%–2.3%) decrease in intracerebral haemorrhage cases with stabilised mortality. Individuals aged ≥80 years are expected to contribute significantly to the burden, comprising 62.7% of the cases in 2050, up from 40% in 2019, and 72.5% of deaths, up from 50.5%. Country-wide variations were noted in the projected changes, with decreases in the standardised rates across all nations but varying crude rates. The largest relative reductions in counts for both incidence and mortality are expected in Latvia, Bulgaria, and Hungary—ranging from −38.2% to −32.4% and −37.3% to −30.2% respectively. In contrast, the greatest increases for both measures were forecasted in Ireland (45.7% and 74.4%), Luxembourg (45% and 70.7%), and Cyprus (44.5% and 74.2%). The modelled increase in the burden of intracerebral haemorrhage could largely be attributed to population ageing. Interpretation: This study provides a comprehensive forecast of intracerebral haemorrhage in Europe until 2050, presenting different trajectories. The potential increase in the number of people experiencing and dying from intracerebral haemorrhage could have profound implications for both caregiving responsibilities and associated costs. However, forecasts were divergent between different scenarios and among EU countries, signalling the pivotal role of public health initiatives in steering the trajectories. Funding: The European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 754517. The National Institute for Health and Care Research (NIHR) under its Programme Grants for Applied Research (NIHR202339).

Summary: Background: Despite the high prevalence and major disability associated with fatigue and cognitive deficits after SARS-CoV-2 infection, little is known about long-term trajectories of these sequelae. We aimed to assess long-term trajectories of these conditions and to identify risk factors for non-recovery. Methods: We analyzed longitudinal data from the population-based COVIDOM/NAPKON-POP cohort in Germany. Participants with confirmed SARS-CoV-2 infection were assessed at least 6 months (baseline) and again at least 18 months (follow-up) after infection using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale (cutoff ≤ 30) and the Montreal Cognitive Assessment (MoCA, cutoff ≤ 25). Predictors of recovery from fatigue or cognitive deficits between assessments were identified through univariate and multivariable logistic regression models. The COVIDOM study is registered at the German registry for clinical studies (DRKS00023742) and at ClinicalTrials.gov (NCT04679584). Findings: Between 15 November 2020 and 9 May 2023, a total of 3038 participants were assessed at baseline (median 9 months after infection) and 83% responded to invitations for follow-up (median 26 months after infection). At baseline, 21% (95% confidence interval (CI) [20%, 23%]) had fatigue and 23% (95% CI [22%, 25%]) had cognitive deficits according to cutoff scores on the FACIT-Fatigue or MoCA. Participants with clinically relevant fatigue (at baseline) showed significant improvement in fatigue scores at follow-up (Hedges’ g [95% CI] = 0.73 [0.60, 0.87]) and 46% (95% CI [41%, 50%]) had recovered from fatigue. Participants with cognitive deficits showed a significant improvement in cognitive scores (g [95% CI] = 1.12 [0.90, 1.33]) and 57% (95% CI [50%, 64%]) had recovered from cognitive deficits. Patients with fatigue exhibiting a higher depressive symptom burden and/or headache at baseline were significantly less likely to recover. Significant risk factors for cognitive non-recovery were male sex, older age and

Abstract We aimed to assess the prognostic value of serum β-synuclein (β-syn), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in patients with moderate-to-severe acute ischemic stroke. We measured β-syn, GFAP and NfL in serum samples collected one day after admission in 30 adult patients with moderate-to-severe ischemic stroke due to middle cerebral artery (MCA) occlusion. We tested the associations between biomarker levels and clinical and radiological scores (National Institute of Health Stroke Scale scores, NIHSS, and Alberta Stroke Program Early CT Score, ASPECTS), as well as measures of functional outcome (modified Rankin Scale, mRS). Serum biomarkers were significantly associated with ASPECTS values (β-syn p = 0.0011, GFAP p = 0.0002) but not with NIHSS scores at admission. Patients who received mechanical thrombectomy and intravenous thrombolysis showed lower β-syn (p = 0.029) und NfL concentrations (p = 0.0024) compared to patients who received only mechanical thrombectomy. According to median biomarker levels, patients with high β-syn, NfL or GFAP levels showed, after therapy, lower clinical improvement (i.e., lower 24-h NIHSS change), higher NIHSS scores during hospitalization and higher mRS scores at 3-month follow-up. Elevated serum concentrations of β-syn (p = 0.016), NfL (p = 0.020) or GFAP (p = 0.010) were significantly associated with 3-month mRS of 3–6 vs. 0–2 even after accounting for age, sex and renal function. In patients with moderate-to-severe acute ischemic stroke, serum β-syn, NfL and GFAP levels associated with clinical and radiological scores at different timepoints and were able to predict short- and middle-term clinical outcomes.

Introduction: Fluvoxamine is used in children and adolescents (‘youths’) for treating obsessive compulsive disorder (OCD) but also off-label for depressive and anxiety disorders. This study aimed to investigate the relationship between fluvoxamine dose and serum concentrations, independent correlates of fluvoxamine concentrations, and a preliminary therapeutic reference range (TRR) for youths with OCD and treatment response. Methods: Multicenter naturalistic data of a therapeutic drug monitoring service, as well as prospective data of the ‘TDM Vigil study’ (EudraCT 2013-004881-33), were analyzed. Patient and treatment characteristics were assessed by standardized measures, including Clinical Global Impressions—Severity (CGI-S) and —Change (CGI-I), with CGI-I of much or very much improved defining treatment response and adverse drug reactions using the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale. Multivariable regression analysis was used to evaluate the influence of sex, age, body weight, body mass index (BMI), and fluvoxamine dose on fluvoxamine serum concentrations. Results: The study included 70 youths (age = 6.7–19.6 years, OCD = 78%, mean fluvoxamine dose = 140.4 (range = 25–300) mg/d). A weak positive correlation between daily dose and steady-state trough serum concentrations was found (rs = 0.34, p = 0.004), with dose variation explaining 16.2% of serum concentration variability. Multivariable correlates explaining 25.3% of the variance of fluvoxamine concentrations included higher fluvoxamine dose and lower BMI. Considering responders with OCD, the estimated TRR for youths was 55–371 ng/mL, exceeding the TRR for adults with depression of 60–230 ng/mL. Discussion: These preliminary data contribute to the definition of a TRR in youth with OCD treated with fluvoxamine and identify higher BMI as a moderator of lower fluvoxamine concentrations.

Abstract Psychosocial factors affect mental health and health-related quality of life (HRQL) in a complex manner, yet gender differences in these interactions remain poorly understood. We investigated whether psychosocial factors such as social support and personal and work-related concerns impact mental health and HRQL differentially in women and men during the first year of the COVID-19 pandemic. Between June and October 2020, the first part of a COVID-19-specific program was conducted within the “Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB)” cohort study, a representative age- and gender-stratified sample of the general population of Würzburg, Germany. Using psychometric networks, we first established the complex relations between personal social support, personal and work-related concerns, and their interactions with anxiety, depression, and HRQL. Second, we tested for gender differences by comparing expected influence, edge weight differences, and stability of the networks. The network comparison revealed a significant difference in the overall network structure. The male (N = 1370) but not the female network (N = 1520) showed a positive link between work-related concern and anxiety. In both networks, anxiety was the most central variable. These findings provide further evidence that the complex interplay of psychosocial factors with mental health and HRQL decisively depends on gender. Our results are relevant for the development of gender-specific interventions to increase resilience in times of pandemic crisis.

Abstract Background About 25% of all ischaemic strokes are related to cardio-embolism, most often due to atrial fibrillation (AF). Little is known about the extent and standardization of routine cardiac diagnostic work-up at certified stroke-units in Germany. Methods The MonDAFIS study included non-AF patients with acute ischaemic stroke or transient ischaemic attack (TIA) at 38 certified stroke-units in Germany. Here, we analysed routine diagnostic work-up and disregarded study-related Holter-ECG monitoring. We compared duration of stroke-unit stay, number of 24-h Holter-ECGs, and echocardiography performed between university-based comprehensive stroke centres (UCSC, 12 hospitals, 1606 patients), non university-based comprehensive stroke centres (nUCSC, 14 hospitals, 892 patients), and primary stroke centres at non-university hospitals (PCS, 12 hospitals, 933 patients) using multivariable mixed regression analyses. Detection of a first AF episode in-hospital was also compared between hospitals of different stroke-unit levels. Results In 3431 study patients (mean age 66.2 years, 39.5% female, median NIHSS = 2 on admission), median duration of the stroke-unit stay was 72 h (IQR 42–86). Stroke-unit stay was longer (categorised ≤ 24/ > 24- ≤ 72/ > 72 h) for patients with severe stroke (NIHSS score ≥ 5/

Background Vasoregulatory autoantibodies including autoantibodies targeting G‐protein–coupled receptors might play a functional role in vascular diseases. We investigated the impact of vasoregulatory autoantibodies on clinical outcome after ischemic stroke. Methods and Results Data were used from the PROSCIS‐B (Prospective Cohort With Incident Stroke–Berlin). Autoantibody‐targeting receptors such as angiotensin II type 1 receptor (AT1R), endothelin‐1 type A receptor, complement factor‐3 and ‐5 receptors, vascular endothelial growth factor receptor‐1 and ‐2, vascular endothelial growth factor A and factor B were measured. We explored associations of high antibody levels with (1) poor functional outcome defined as modified Rankin Scale >2 or Barthel Index

Background: Anti-NMDA-receptor GluN1 antibodies (NMDAR1-abs) are present in an autoimmune encephalitis with severe neuropsychiatric symptoms. We aimed to estimate the impact of serum NMDAR1-abs on depressive symptoms years after first-ever ischemic stroke (IS). Methods: Data were used from the PROSpective Cohort with Incident Stroke-Berlin (PROSCIS-B; NCT01363856). Serum NMDAR1-abs (IgM/IgA/IgG) were measured within 7 days after IS using cell-based assays. We defined seropositivity as titers ≥1:10, thereof low titers as ≤1:100 and high titers as >1:100. We used the Center for Epidemiological Studies–Depression (CES-D) scale to measure depressive symptoms at year one, two and three following IS. We calculated crude and confounder adjusted weighted generalized linear models to quantify the impact of NMDAR1-abs on CES-D assessed at three annual time-points. Results: NMDAR1-abs were measured in 583 PROSCIS-B IS patients (mean age = 67 [SD = 13]; 42%female; median NIHSS = 2 [IQR = 1–4]) of whom 76 (13%; IgM: n = 49/IgA: n = 43/IgG: n = 2) were seropositive, 55 (9%) with low and 21 (4%) with high titers. CES-D regarded over all follow-up time-points was higher in seropositive patients (βcrude = 2.56 [95%CI = −0.34 to 5.45]; βadjusted = 2.26 [95%CI = −0.68 to 5.20]) and effects were highest in patients with high titer (low titers: βcrude = 1.42 [95%CI = −1.79 to 4.62], βadjusted = 0.53 [95%CI = −2.47 to 3.54]; high titers: βcrude = 5.85 [95%CI = 0.20 to 11.50]; βadjusted = 7.20 [95%CI = 0.98 to 13.43]). Conclusion: Patients with serum NMDAR1-abs (predominantly IgM&IgA) suffer more severe depressive symptoms after mild-to-moderate IS compared to NMDAR1-abs seronegative patients.

Abstract Background Randomized controlled trials (RCT) on the treatment of severe space-occupying infarction of the middle cerebral artery (malignant MCA infarction) showed that early decompressive hemicraniectomy (DHC) is life saving and improves outcome without promoting most severe disablity in patients aged 18–60 years. It is, however, unknown whether the results obtained in the randomized trials are reproducible in a broader population in and apart from an academical setting and whether hemicraniectomy has been implemented in clinical practice as recommended by national and international guidelines. In addition, they were not powered to answer further relevant questions, e.g. concerning the selection of patients eligible for and the timing of hemicraniectomy. Other important issues such as the acceptance of disability following hemicraniectomy, the existence of specific prognostic factors, the value of conservative therapeutic measures, and the overall complication rate related to hemicraniectomy have not been sufficiently studied yet. Methods/Design DESTINY-R is a prospective, multicenter, open, controlled registry including a 12 months follow-up. The only inclusion criteria is unilateral ischemic MCA stroke affecting more than 50% of the MCA-territory. The primary study hypothesis is to confirm the results of the RCT (76% mRS ≤ 4 after 12 months) in the subgroup of patients additionally fulfilling the inclusion cirteria of the RCT in daily routine. Assuming a calculated proportion of 0.76 for successes and a sample size of 300 for this subgroup, the width of the 95% CI, calculated using Wilson's method, will be 0.096 with the lower bound 0.709 and the upper bound 0.805. Discussion The results of this study will provide information about the effectiveness of DHC in malignant MCA infarction in a broad population and a real-life situation in addition to and beyond RCT. Further prospectively obtained data will give crucial information on open questions and will be helpful in the plannig of upcomming treatment studies. Trial registration (ICTRP and DRKS): DRKS00000624

Abstract Background Regular exercise is beneficial for cardiovascular health but a recent meta-analysis indicated a relationship between extensive endurance sport and a higher risk of atrial fibrillation, an independent risk factor for stroke. However, data on the frequency of cardiac arrhythmias or (clinically silent) brain lesions during and after marathon running are missing. Methods/ Design In the prospective observational “Berlin Beat of Running” study experienced endurance athletes underwent clinical examination (CE), 3 Tesla brain magnetic resonance imaging (MRI), carotid ultrasound imaging (CUI) and serial blood sampling (BS) within 2-3 days prior (CE, MRI, CUI, BS), directly after (CE, BS) and within 2 days after (CE, MRI, BS) the 38th BMW BERLIN-MARATHON 2011. All participants wore a portable electrocardiogram (ECG)-recorder throughout the 4 to 5 days baseline study period. Participants with pathological MRI findings after the marathon, troponin elevations or detected cardiac arrhythmias will be asked to undergo cardiac MRI to rule out structural abnormalities. A follow-up is scheduled after one year. Results Here we report the baseline data of the enrolled 110 athletes aged 36-61 years. Their mean age was 48.8 ± 6.0 years, 24.5% were female, 8.2% had hypertension and 2.7% had hyperlipidaemia. Participants have attended a mean of 7.5 ± 6.6 marathon races within the last 5 years and a mean of 16 ± 36 marathon races in total. Their weekly running distance prior to the 38th BMW BERLIN-MARATHON was 65 ± 17 km. Finally, 108 (98.2%) Berlin Beat-Study participants successfully completed the 38th BMW BERLIN-MARATHON 2011. Discussion Findings from the “Berlin Beats of Running” study will help to balance the benefits and risks of extensive endurance sport. ECG-recording during the marathon might contribute to identify athletes at risk for cardiovascular events. MRI results will give new insights into the link between physical stress and brain damage. Trial registration clinicaltrials.gov NCT01428778

Abstract Background Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with increasing incidence mainly in high-income countries. One explanation of this phenomenon may be a higher prevalence of allergic and autoimmune diseases in industrialized countries as a consequence of otherwise beneficial advances in sanitation (hygiene hypothesis). We investigated environmental factors in early childhood associated with MS. Methods A case-control study was performed of 245 MS patients and 296 population-based controls in Berlin. The study participants completed a standardized questionnaire on environmental factors in childhood and youth, including aspects of personal and community hygiene. Multivariable logistic regression analysis was performed to investigate factors in childhood and youth associated with the occurrence of MS. Results Mean age was 46 years (range, 20-80) in the MS group and 42 years (range 18-80) in the control group, of which 73.9% in the MS and 61.5% in the control group were female. The multivariable analysis showed that having at least two older siblings (OR 0.54; p = 0.05, for individuals with two older siblings compared to individuals without older siblings), attending a day-care center (OR 0.5; p = 0.004) and growing up in an urban center with more than 100, 000 inhabitants (OR 0.43; p = 0.009) were factors independently associated with a lower chance for MS. Conclusions The hygiene hypothesis may play a role in the occurrence of MS and could explain disease distribution and increasing incidence.

Abstract Background Levels of the cardiac muscle regulatory protein troponin T (cTnT) are frequently elevated in patients with acute ischemic stroke and elevated cTnT predicts poor outcome and mortality. The pathomechanism of troponin release may relate to co-morbid coronary artery disease and myocardial ischemia or, alternatively, to neurogenic cardiac damage due to autonomic activation after acute ischemic stroke. Therefore, there is uncertainty about how acute ischemic stroke patients with increased cTnT levels should be managed regarding diagnostic and therapeutic workup. Methods/Design The primary objective of the prospective observational trial TRELAS (TRoponin ELevation in Acute ischemic Stroke) is to investigate the frequency and underlying pathomechanism of cTnT elevation in acute ischemic stroke patients in order to give guidance for clinical practice. All consecutive patients with acute ischemic stroke admitted within 72 hours after symptom onset to the Department of Neurology at the Campus Benjamin Franklin of the University Hospital Charité will be screened for cTnT elevations (i.e. >= 0.05 μg/l) on admission and again on the following day. Patients with increased cTnT will undergo coronary angiography within 72 hours. Diagnostic findings of coronary angiograms will be compared with age- and gender-matched patients presenting with Non-ST-Elevation myocardial infarction to the Department of Cardiology. The primary endpoint of the study will be the occurrence of culprit lesions in the coronary angiogram indicating underlying co-morbid obstructive coronary artery disease. Secondary endpoints will be the localization of stroke in the cerebral imaging and left ventriculographic findings of wall motion abnormalities suggestive of stroke-induced global cardiac dysfunction. Discussion TRELAS will prospectively determine the frequency and possible etiology of troponin elevation in a large cohort of ischemic stroke patients. The findings are expected to contribute to clarify pathophysiologic concepts of co-morbid cardiac damage in ischemic stroke patients and also to provide a basis for clinical recommendations for cardiac workup of such patients. Trial registration clinicaltrials.gov NCT01263964

Abstract Background Guidelines recommend maintaining the heart rate (HR) of acute stroke patients within physiological limits; data on the frequency and predictors of significant deviations from these limits are scarce. Methods Demographical data, stroke risk factors, NIH stroke scale score, lesion size and location, and ECG parameters were prospectively assessed in 256 patients with ischemic stroke. Patients were continuously monitored for at least 24 hours on a certified stroke unit. Tachycardia (HR ≥120 bpm) and bradycardia (HR Results HR ≥120 bpm occurred in 39 patients (15%). Stroke severity (larger lesion size/higher NIHSS-score on admission), atrial fibrillation and HR on admission predicted its occurrence. HR Conclusions Significant tachycardia and bradycardia are frequent phenomena in acute stroke; however they do not independently predict clinical course or outcome. Continuous monitoring allows detecting rhythm disturbances in stroke patients and allows deciding whether urgent medical treatment is necessary.

Abstract Background Catheter ablation of the pulmonary veins has become accepted as a standard therapeutic approach for symptomatic paroxysmal atrial fibrillation (AF). However, there is some evidence for an ablation associated (silent) stroke risk, lowering the hope to limit the stroke risk by restoration of rhythm over rate control in AF. The purpose of the prospective randomized single-center study "Mesh Ablator versus Cryoballoon Pulmonary Vein Ablation of Symptomatic Paroxysmal Atrial Fibrillation" (MACPAF) is to compare the efficacy and safety of two balloon based pulmonary vein ablation systems in patients with symptomatic paroxysmal AF. Methods/Design Patients are randomized 1:1 for the Arctic Front® or the HD Mesh Ablator® catheter for left atrial catheter ablation (LACA). The predefined endpoints will be assessed by brain magnetic resonance imaging (MRI), neuro(psycho)logical tests and a subcutaneously implanted reveal recorder for AF detection. According to statistics 108 patients will be enrolled. Discussion Findings from the MACPAF trial will help to balance the benefits and risks of LACA for symptomatic paroxysmal AF. Using serial brain MRIs might help to identify patients at risk for LACA-associated cerebral thromboembolism. Potential limitations of the study are the single-center design, the existence of a variety of LACA-catheters, the missing placebo-group and the impossibility to assess the primary endpoint in a blinded fashion. Trial registration clinicaltrials.gov NCT01061931

Abstract Long-term sequelae in hospitalized Coronavirus Disease 2019 (COVID-19) patients may result in limited quality of life. The current study aimed to determine health-related quality of life (HRQoL) after COVID-19 hospitalization in non-intensive care unit (ICU) and ICU patients. This is a single-center study at the University Hospital of Wuerzburg, Germany. Patients eligible were hospitalized with COVID-19 between March 2020 and December 2020. Patients were interviewed 3 and 12 months after hospital discharge. Questionnaires included the European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L), patient health questionnaire-9 (PHQ-9), the generalized anxiety disorder 7 scale (GAD-7), FACIT fatigue scale, perceived stress scale (PSS-10) and posttraumatic symptom scale 10 (PTSS-10). 85 patients were included in the study. The EQ5D-5L-Index significantly differed between non-ICU (0.78 ± 0.33 and 0.84 ± 0.23) and ICU (0.71 ± 0.27; 0.74 ± 0.2) patients after 3- and 12-months. Of non-ICU 87% and 80% of ICU survivors lived at home without support after 12 months. One-third of ICU and half of the non-ICU patients returned to work. A higher percentage of ICU patients was limited in their activities of daily living compared to non-ICU patients. Depression and fatigue were present in one fifth of the ICU patients. Stress levels remained high with only 24% of non-ICU and 3% of ICU patients (p = 0.0186) having low perceived stress. Posttraumatic symptoms were present in 5% of non-ICU and 10% of ICU patients. HRQoL is limited in COVID-19 ICU patients 3- and 12-months post COVID-19 hospitalization, with significantly less improvement at 12-months compared to non-ICU patients. Mental disorders were common highlighting the complexity of post-COVID-19 symptoms as well as the necessity to educate patients and primary care providers about monitoring mental well-being post COVID-19.