[INTEGRATE-ADHD: Comparison and Integration of Administrative and Epidemiological ADHD Diagnosis Data through Clinical Assessment - Presentation of the Project]. / INTEGRATE-ADHD: Vergleich und Integration administrativer und epidemiologischer ADHS-Diagnosedaten durch klinisches Assessment ­ Vorstellung des Projekts.

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.

Association between self-reported and objectively assessed physical functioning in the general population.

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 < 0.001) as well as significant differences between the respective groups except for the categories 'moderate' and 'poor' health status in men. This cross-sectional analysis revealed a strong association between self-reported health status and physical functioning with the objective assessment of 6MWD, suggesting that physicians can rely on their patients' respective answers. Nevertheless, sex-specific perception and attribution of general health and physical functioning deserve further in-depth investigation. Decision-making based on self-reported health requires prospective evaluation in population-based cohorts as well as adult inpatients.

Innate immune memory after brain injury drives inflammatory cardiac dysfunction.

The medical burden of stroke extends beyond the brain injury itself and is largely determined by chronic comorbidities that develop secondarily. We hypothesized that these comorbidities might share a common immunological cause, yet chronic effects post-stroke on systemic immunity are underexplored. Here, we identify myeloid innate immune memory as a cause of remote organ dysfunction after stroke. Single-cell sequencing revealed persistent pro-inflammatory changes in monocytes/macrophages in multiple organs up to 3 months after brain injury, notably in the heart, leading to cardiac fibrosis and dysfunction in both mice and stroke patients. IL-1ß was identified as a key driver of epigenetic changes in innate immune memory. These changes could be transplanted to naive mice, inducing cardiac dysfunction. By neutralizing post-stroke IL-1ß or blocking pro-inflammatory monocyte trafficking with a CCR2/5 inhibitor, we prevented post-stroke cardiac dysfunction. Such immune-targeted therapies could potentially prevent various IL-1ß-mediated comorbidities, offering a framework for secondary prevention immunotherapy.

Effects of occupational health promotion interventions on health-related outcomes among employees of small businesses and self-employed individuals: A systematic review.

BACKGROUND: Compared to workers of larger companies it is less clear what health promoting interventions might be beneficial for employees of small businesses and self-employed individuals. OBJECTIVE: Our aim was to critically appraise trials investigating health promotion programs among small business workers and self-employed individuals, by means of a systematic review. METHODS: We conducted a search of primary studies using MEDLINE, Web of Science, LIVIVO and the Cochrane library. Our assessment followed the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions and PRISMA. RESULTS: We identified six trials including 5,854 participants from Asia, North America and Australia. Most were of moderate methodological quality, only one was of low quality. Some of the supervised psycho-educational lifestyle programs focusing on individual behavior changes showed benefits in terms of stress reduction and increased physical activity levels among small enterprise employees. CONCLUSIONS: There is a huge knowledge gap on evidence-based health promotion interventions for self-employed and for small business workers, especially in Europe.

Serum Concentration-Dose Relationship and Modulation Factors in Children and Adolescents Treated with Fluvoxamine.

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.

Prognostic Utility of Pericardial Effusion in the General Population: Findings From the STAAB Cohort Study.

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 <10 mm and completely resolving. PE was not associated with inflammation markers, death, incident heart failure, or malignancy. Our findings corroborate the view of current guidelines that a small PE in asymptomatic individuals can be considered an innocent phenomenon and does not require extensive short-term monitoring.

Biomarkers to improve functional outcome prediction after ischemic stroke: Results from the SICFAIL, STRAWINSKI, and PREDICT studies.

BACKGROUND AND AIMS: Acute ischemic stroke (AIS) outcome prognostication remains challenging despite available prognostic models. We investigated whether a biomarker panel improves the predictive performance of established prognostic scores. METHODS: We investigated the improvement in discrimination, calibration, and overall performance by adding five biomarkers (procalcitonin, copeptin, cortisol, mid-regional pro-atrial natriuretic peptide (MR-proANP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP)) to the Acute Stroke Registry and Analysis of Lausanne (ASTRAL) and age/NIHSS scores using data from two prospective cohort studies (SICFAIL, PREDICT) and one clinical trial (STRAWINSKI). Poor outcome was defined as mRS > 2 at 12 (SICFAIL, derivation dataset) or 3 months (PREDICT/STRAWINSKI, pooled external validation dataset). RESULTS: Among 412 SICFAIL participants (median age 70 years, quartiles 59-78; 63% male; median NIHSS score 3, quartiles 1-5), 29% had a poor outcome. Area under the curve of the ASTRAL and age/NIHSS were 0.76 (95% CI 0.71-0.81) and 0.77 (95% CI 0.73-0.82), respectively. Copeptin (0.79, 95% CI 0.74-0.84), NT-proBNP (0.80, 95% CI 0.76-0.84), and MR-proANP (0.79, 95% CI 0.75-0.84) significantly improved ASTRAL score's discrimination, calibration, and overall performance. Copeptin improved age/NIHSS model's discrimination, copeptin, MR-proANP, and NT-proBNP improved its calibration and overall performance. In the validation dataset (450 patients, median age 73 years, quartiles 66-81; 54% men; median NIHSS score 8, quartiles 3-14), copeptin was independently associated with various definitions of poor outcome and also mortality. Copeptin did not increase model's discrimination but it did improve calibration and overall model performance. DISCUSSION: Copeptin, NT-proBNP, and MR-proANP improved modest but consistently the predictive performance of established prognostic scores in patients with mild AIS. Copeptin was most consistently associated with poor outcome in patients with moderate to severe AIS, although its added prognostic value was less obvious.

Heart failure, recurrent vascular events and death in patients with ischemic stroke-results of the MonDAFIS study.

Heart failure (HF) is associated with poor outcome after stroke, but data from large prospective trials are sparse.We assessed the impact of HF on clinical endpoints in patients hospitalized with acute ischemic stroke or transient ischemic attack (TIA) enrolled in the prospective, multicenter Systematic Monitoring for Detection of Atrial Fibrillation in Patients with Acute Ischemic Stroke (MonDAFIS) trial. HF was defined as left ventricular ejection fraction (LVEF) < 55% or a history of HF on admission. The composite of recurrent stroke, major bleeding, myocardial infarction, and all-cause death, and its components during the subsequent 24 months were assessed. We used estimated hazard ratios in confounder-adjusted models. Overall, 410/2562 (16.0%) stroke patients fulfilled the HF criteria (i.e. 381 [14.9%] with LVEF < 55% and 29 [1.9%] based on medical history). Patients with HF had more often diabetes, coronary and peripheral arterial disease and presented with more severe strokes on admission. HF at baseline correlated with myocardial infarction (HR 2.21; 95% CI 1.02-4.79), and all-cause death (HR 1.67; 95% CI 1.12-2.50), but not with major bleed (HR 1.93; 95% CI 0.73-5.06) or recurrent stroke/TIA (HR 1.08; 95% CI 0.75-1.57). The data were adjusted for age, stroke severity, cardiovascular risk factors, and randomization. Patients with ischemic stroke or TIA and comorbid HF have a higher risk of myocardial infarction and death compared with non-HF patients whereas the risk of recurrent stroke or major hemorrhage was similar. Trial registration number Clinicaltrials.gov NCT02204267.

Differences in Preferences for Drug Therapy Between Patients with Metastatic Versus Early-Stage Breast Cancer: A Systematic Literature Review.

INTRODUCTION: Compared with early stages (eBC) metastatic BC (mBC) is incurable. In mBC, aggressive treatment may increase the duration of survival but may also cause severe treatment side effects. A better understanding how patients with BC value different aspects of drug therapy might improve treatment effectiveness, satisfaction and adherence. This systematic review aims to identify and summarise studies evaluating patient preferences for drug therapy of BC and to compare preferences of patients with eBC and mBC. METHODS: The systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The electronic databases PubMed and Web of Science were searched on 22 June 2023. All studies published to this point were considered. Original studies reporting patient preferences on BC drug therapy determined by any type of choice experiment were eligible. A narrative synthesis of the effect measures presented as relative importance ratings, trade-offs (required benefit to make a therapy worthwhile) or monetary values of the treatment attributes was reported for each study. Risk of bias assessment for individual studies was performed using the checklist for observational studies from the STROBE Statement and the checklist from 'Conducting Discrete Choice Experiments to Inform Healthcare Decision Making: A User's Guide'. The study protocol was registered at the PROSPERO database (CRD42022377031). RESULTS: A total of 34 studies met the inclusion criteria were included in the analysis evaluating the preferences of patients with eBC (n = 18), mBC (n = 10) or any stage BC (n = 6) on, for example, chemotherapy, endocrine therapy, hormonal therapy or CKD4/6-inhibitors using different types of choice experiments. Regardless of the stage, most patients valued treatment effectiveness in terms of survival gains higher than potential adverse drug reactions (ADRs). Treatment cost, mode of administration, treatment regimen and monitoring aspects were considered as least important treatment attributes. In addition, preferences concerning 16 different types of ADRs were described, showing high heterogeneity within BC stages. Yet, comparable results across BC stages were observed. CONCLUSIONS: Regardless of the stage, patients with BC consistently valued survival gains as the most important attribute and were willing to accept the risk of potential ADRs. Incorporating patient preferences in shared decision making may improve the effectiveness of interventions by enhancing adherence to drug therapy in patients suffering from BC.

Preferences of patients with breast cancer for drug therapy play a crucial role in treatment efficacy, satisfaction and adherence. In this systematic review following the PRISMA guidelines, 34 studies were analysed to determine patient preferences at different stages of breast cancer, comparing early stage and metastatic disease. Regardless of stage, patients with breast cancer consistently prioritised survival benefit as the most important treatment feature. This universal emphasis on survival held true even in the face of potential side effects, with patients willing to accept the associated risks. Conversely, factors unrelated to efficacy, such as the cost of treatment, route of administration, characteristics of the treatment regimen and monitoring aspects, were considered less important in treatment decisions. The study revealed a nuanced landscape of patient preferences, with greater variation within breast cancer stages than between them. While survival remained an unwavering priority, the variability in expressed preferences emphasises the individual nature of patient perspectives. In conclusion, incorporating patient preferences, particularly those that emphasise the importance of survival, into shared decision-making processes is a critical factor in improving treatment adherence. This patient-centred approach is likely to improve the overall effectiveness of breast cancer treatment and highlights the need for tailored strategies that take into account the individual preferences of patients at different stages of the disease.

Incremental value of serum neurofilament light chain and glial fibrillary acidic protein as blood-based biomarkers for predicting functional outcome in severe acute ischemic stroke.

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.

Predictors of non-recovery from fatigue and cognitive deficits after COVID-19: a prospective, longitudinal, population-based study.

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 <12 years of school education. Importantly, SARS-CoV-2 reinfection had no significant impact on recovery from fatigue or cognitive deficits. Interpretation: Fatigue and cognitive deficits are common sequelae after SARS-CoV-2 infection. These syndromes improved over time and about half of the patients recovered within two years. The identified risk factors for non-recovery from fatigue and cognitive deficits could play an important role in shaping targeted strategies for treatment and prevention. Funding: Funded by the German Federal Ministry of Education and Research (BMBF; grant number 01KX2121) and German Research Foundation (DFG) Excellence Cluster "Position Medicine in Information".

Depression and fatigue six months post-COVID-19 disease are associated with overlapping symptom constellations: A prospective, multi-center, population-based cohort study.

BACKGROUND: Depression and fatigue are commonly observed sequelae following viral diseases such as COVID-19. Identifying symptom constellations that differentially classify post-COVID depression and fatigue may be helpful to individualize treatment strategies. Here, we investigated whether self-reported post-COVID depression and post-COVID fatigue are associated with the same or different symptom constellations. METHODS: To address this question, we used data from COVIDOM, a population-based cohort study conducted as part of the NAPKON-POP platform. Data were collected in three different German regions (Kiel, Berlin, Würzburg). We analyzed data from >2000 individuals at least six months past a PCR-confirmed COVID-19 disease, using elastic net regression and cluster analysis. The regression model was developed in the Kiel data set, and externally validated using data sets from Berlin and Würzburg. RESULTS: Our results revealed that post-COVID depression and fatigue are associated with overlapping symptom constellations consisting of difficulties with daily activities, perceived health-related quality of life, chronic exhaustion, unrestful sleep, and impaired concentration. Confirming the overlap in symptom constellations, a follow-up cluster analysis could categorize individuals as scoring high or low on depression and fatigue but could not differentiate between both dimensions. LIMITATIONS: The data presented are cross-sectional, consisting primarily of self-reported questionnaire or medical records rather than biometric data. CONCLUSIONS: In summary, our results suggest a strong link between post-COVID depression and fatigue, highlighting the need for integrative treatment approaches.

Population data-based federated machine learning improves automated echocardiographic quantification of cardiac structure and function: the Automatisierte Vermessung der Echokardiographie project.

Aims: Machine-learning (ML)-based automated measurement of echocardiography images emerges as an option to reduce observer variability. The objective of the study is to improve the accuracy of a pre-existing automated reading tool ('original detector') by federated ML-based re-training. Methods and results: Automatisierte Vermessung der Echokardiographie was based on the echocardiography images of n = 4965 participants of the population-based Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression Cohort Study. We implemented federated ML: echocardiography images were read by the Academic Core Lab Ultrasound-based Cardiovascular Imaging at the University Hospital Würzburg (UKW). A random algorithm selected 3226 participants for re-training of the original detector. According to data protection rules, the generation of ground truth and ML training cycles took place within the UKW network. Only non-personal training weights were exchanged with the external cooperation partner for the refinement of ML algorithms. Both the original detectors as the re-trained detector were then applied to the echocardiograms of n = 563 participants not used for training. With regard to the human referent, the re-trained detector revealed (i) superior accuracy when contrasted with the original detector's performance as it arrived at significantly smaller mean differences in all but one parameter, and a (ii) smaller absolute difference between measurements when compared with a group of different human observers. Conclusion: Population data-based ML in a federated ML set-up was feasible. The re-trained detector exhibited a much lower measurement variability than human readers. This gain in accuracy and precision strengthens the confidence in automated echocardiographic readings, which carries large potential for applications in various settings.

Feasibility, safety and effectiveness of prednisolone and vitamin B1, B6, and B12 in patients with post-COVID-19-syndrome (PreVitaCOV) - protocol of a randomised, double-blind, placebo-controlled multicentre trial in primary care (phase IIIb).

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).

Determinants and reference values of the 6-min walk distance in the general population-results of the population-based STAAB cohort study.

AIMS: The 6-min walk test is an inexpensive, safe, and easy tool to assess functional capacity in patients with cardiopulmonary diseases including heart failure (HF). There is a lack of reference values, which are a prerequisite for the interpretation of test results in patients. Furthermore, determinants independent of the respective disease need to be considered when interpreting the 6-min walk distance (6MWD). METHODS: The prospective Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB) cohort study investigates a representative sample of residents of the City of Würzburg, Germany, aged 30 to 79 years, without a history of HF. Participants underwent detailed clinical and echocardiographic phenotyping as well as a standardized assessment of the 6MWD using a 15-m hallway. RESULTS: In a sample of 2762 participants (51% women, mean age 58 ± 11 years), we identified age and height, but not sex, as determinants of the 6MWD. While a worse metabolic profile showed a negative association with the 6MWD, a better systolic and diastolic function showed a positive association with 6MWD. From a subgroup of 681 individuals without any cardiovascular risk factors (60% women, mean age 52 ± 10 years), we computed age- and height-specific reference percentiles. CONCLUSION: In a representative sample of the general population free from HF, we identified determinants of the 6MWD implying objective physical fitness associated with metabolic health as well as with cardiac structure and function. Furthermore, we derived reference percentiles applicable when using a 15-m hallway.

Development and pilot-testing of an evidence-based quality indicator set for home mechanical ventilation care: the OVER-BEAS project.

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.

Analysis of acute COVID-19 including chronic morbidity: protocol for the deep phenotyping National Pandemic Cohort Network in Germany (NAPKON-HAP).

BACKGROUND: The severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) pandemic causes a high burden of acute and long-term morbidity and mortality worldwide despite global efforts in containment, prophylaxis, and therapy. With unprecedented speed, the global scientific community has generated pivotal insights into the pathogen and the host response evoked by the infection. However, deeper characterization of the pathophysiology and pathology remains a high priority to reduce morbidity and mortality of coronavirus disease 2019 (COVID-19). METHODS: NAPKON-HAP is a multi-centered prospective observational study with a long-term follow-up phase of up to 36 months post-SARS-CoV-2 infection. It constitutes a central platform for harmonized data and biospecimen for interdisciplinary characterization of acute SARS-CoV-2 infection and long-term outcomes of diverging disease severities of hospitalized patients. RESULTS: Primary outcome measures include clinical scores and quality of life assessment captured during hospitalization and at outpatient follow-up visits to assess acute and chronic morbidity. Secondary measures include results of biomolecular and immunological investigations and assessment of organ-specific involvement during and post-COVID-19 infection. NAPKON-HAP constitutes a national platform to provide accessibility and usability of the comprehensive data and biospecimen collection to global research. CONCLUSION: NAPKON-HAP establishes a platform with standardized high-resolution data and biospecimen collection of hospitalized COVID-19 patients of different disease severities in Germany. With this study, we will add significant scientific insights and provide high-quality data to aid researchers to investigate COVID-19 pathophysiology, pathology, and chronic morbidity.

Associations of C-reactive protein with depressive symptoms over time after mild to moderate ischemic stroke in the PROSCIS-B cohort.

BACKGROUND AND PURPOSE: C-reactive protein serves as a marker of inflammation and is linked to depression in the general population. We aimed to assess whether elevated baseline levels of high-sensitivity C-reactive protein (hs-CRP) are associated with depressive symptoms over time in a prospective cohort of mild-to-moderate first-ever ischemic stroke patients. METHODS: Data were obtained from the Prospective Cohort with Incident Stroke Berlin (NCT01363856). Depressive symptoms were assessed with the Center for Epidemiologic Studies Depression Scale (CES-D) at three annual follow-up points. We assessed the association of elevated levels of hs-CRP with CES-D scores over time via linear mixed models. In a subgroup analysis, we explored an interaction effect with sex. RESULTS: We included 585 ischemic stroke patients with baseline data on CRP levels. The mean age was 67 (13 SD), 39% (n = 226) were female, and the median National Institutes of Health Stroke Scale (NIHSS) was 3 (IQR 1-4). Twenty percent of survivors showed evidence for depressive symptoms one year after stroke with CES-D ≥ 16, 21% at year two, and 17% at year three. Higher log-transformed baseline hs-CRP levels were associated with higher CES-D Scores over time in the adjusted linear mixed model (ß = 1.28; (95% CI 0.22-2.34)). The subgroup analysis revealed an interaction effect of hs-CRP on depressive symptoms in women (ß = 2.33; (95% CI 0.71-3.95)). CONCLUSION: In our cohort with mild-to-moderate first-ever ischemic stroke patients, hs-CRP levels were associated with more depressive symptoms over time, with an interaction effect for the female sex. STUDY REGISTRATION: https://clinicaltrials.gov ; Unique identifier: NCT01363856.

Heart rate variability, interoceptive accuracy and functional connectivity in middle-aged and older patients with depression.

BACKGROUND AND OBJECTIVE: Major depressive disorder (MDD) is associated with increased cardiac morbidity. Reduced heart rate variability (HRV) as well as lower interoceptive accuracy (IAc) have been observed in MDD as possible sympathomimetic mechanisms related to insula activity. The salience network (SN) anchored by the insula has been posited as a crucial functional network for cardiac sensations and the default mode network (DMN) for MDD. This study aimed to investigate the relation between insula-centered and depression-related brain networks, IAc and HRV in patients with depression as a possible mechanism by which MDD increases cardiac morbidity. METHODS: 30 depressed inpatients and 30 healthy subjects (derived from the population-based "Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression" cohort study, STAAB) all over 50 years were examined. HRV and IAc were assessed via electrocardiogram and a heartbeat perception task prior to a 3 T resting-state functional magnetic resonance imaging. Seed-to-voxel resting-state functional connectivity (FC) analysis was conducted with six seeds in the insula and two seeds in the DMN. RESULTS: Depressed patients on the one hand showed decreased FC between insula cortex and frontal as well occipital cortical brain regions compared to controls. Depressed patients on the other hand exhibited higher FC between the medial prefrontal cortex and the insula cortex compared to controls. However, depressed patients did not differ in HRV nor in IAc compared to controls. CONCLUSION: Thus, differences in insula-related brain networks in depression in our study were not mirrored by differences in HRV and IAc. Future research is needed to define the mechanism by which depression increases cardiac morbidity.

Vasoregulatory Autoantibodies and Clinical Outcome After Ischemic Stroke-PROSCIS-B.

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 <60 at 1 year after stroke, (2) Barthel Index scores over time using general estimating equations, and (3) secondary vascular events (recurrent stroke, myocardial infarction) or death up to 3 years using Cox proportional hazard models. We included 491 patients with ischemic stroke with data on autoantibody levels and outcome. In models adjusted for demographics and vascular risk factors, high autoantibody concentrations (quartile 4) targeting complement factor C3a receptor, vascular endothelial growth factor receptor-2, and vascular endothelial growth factor B were associated with poor functional outcome at 1 year: (odds ratio, 2.0 [95% CI, 1.1-3.6]; odds ratio, 1.8 [95% CI, 1.1-3.2]; and odds ratio, 2.1 [95% CI, 1.2-3.6], respectively) and with lower Barthel Index scores over 3 years (complement factor C3a receptor: adjusted ß=-3.3 [95% CI, -5.7 to -0.5]; VEGF-B: adjusted ß=-2.4 [95% CI, -4.8 to -0.06]). Patients with high autoantibody levels were not at higher risk for secondary vascular events or death. CONCLUSIONS: High levels of autoantibodies against vascular endothelial growth factor receptor-2, vascular endothelial growth factor B, and complement factor C3a receptor measured are associated with poor functional outcome after stroke but not with recurrent vascular events or death. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01363856.