A precise performance-based reimbursement model for the multi-centre NAPKON cohorts - development and evaluation.

Fair allocation of funding in multi-centre clinical studies is challenging. Models commonly used in Germany - the case fees ("fixed-rate model", FRM) and up-front staffing and consumables ("up-front allocation model", UFAM) lack transparency and fail to suitably accommodate variations in centre performance. We developed a performance-based reimbursement model (PBRM) with automated calculation of conducted activities and applied it to the cohorts of the National Pandemic Cohort Network (NAPKON) within the Network of University Medicine (NUM). The study protocol activities, which were derived from data management systems, underwent validation through standardized quality checks by multiple stakeholders. The PBRM output (first funding period) was compared among centres and cohorts, and the cost-efficiency of the models was evaluated. Cases per centre varied from one to 164. The mean case reimbursement differed among the cohorts (1173.21€ [95% CI 645.68-1700.73] to 3863.43€ [95% CI 1468.89-6257.96]) and centres and mostly fell short of the expected amount. Model comparisons revealed higher cost-efficiency of the PBRM compared to FRM and UFAM, especially for low recruitment outliers. In conclusion, we have developed a reimbursement model that is transparent, accurate, and flexible. In multi-centre collaborations where heterogeneity between centres is expected, a PBRM could be used as a model to address performance discrepancies.Trial registration: https://clinicaltrials.gov/ct2/show/NCT04768998 ; https://clinicaltrials.gov/ct2/show/NCT04747366 ; https://clinicaltrials.gov/ct2/show/NCT04679584 .

A multicenter, matched case-control analysis comparing burden of illness among patients with tuberous sclerosis complex related epilepsy, generalized idiopathic epilepsy, and focal epilepsy in Germany.

BACKGROUND: Depending on the underlying etiology and epilepsy type, the burden of disease for patients with seizures can vary significantly. This analysis aimed to compare direct and indirect costs and quality of life (QoL) among adults with tuberous sclerosis complex (TSC) related with epilepsy, idiopathic generalized epilepsy (IGE), and focal epilepsy (FE) in Germany. METHODS: Questionnaire responses from 92 patients with TSC and epilepsy were matched by age and gender, with responses from 92 patients with IGE and 92 patients with FE collected in independent studies. Comparisons were made across the main QoL components, direct costs (patient visits, medication usage, medical equipment, diagnostic procedures, ancillary treatments, and transport costs), indirect costs (employment, reduced working hours, missed days), and care level costs. RESULTS: Across all three cohorts, mean total direct costs (TSC: €7602 [median €2620]; IGE: €1919 [median €446], P < 0.001; FE: €2598 [median €892], P < 0.001) and mean total indirect costs due to lost productivity over 3 months (TSC: €7185 [median €11,925]; IGE: €3599 [median €0], P < 0.001; FE: €5082 [median €2981], P = 0.03) were highest among patients with TSC. The proportion of patients with TSC who were unemployed (60%) was significantly larger than the proportions of patients with IGE (23%, P < 0.001) or FE (34%, P = P < 0.001) who were unemployed. Index scores for the EuroQuol Scale with 5 dimensions and 3 levels were significantly lower for patients with TSC (time-trade-off [TTO]: 0.705, visual analog scale [VAS]: 0.577) than for patients with IGE (TTO: 0.897, VAS: 0.813; P < 0.001) or FE (TTO: 0.879, VAS: 0.769; P < 0.001). Revised Epilepsy Stigma Scale scores were also significantly higher for patients with TSC (3.97) than for patients with IGE (1.48, P < 0.001) or FE (2.45, P < 0.001). Overall Quality of Life in Epilepsy Inventory-31 items scores was significantly lower among patients with TSC (57.7) and FE (57.6) than among patients with IGE (66.6, P = 0.004 in both comparisons). Significant differences between patients with TSC and IGE were also determined for Neurological Disorder Depression Inventory for Epilepsy (TSC: 13.1; IGE: 11.2, P = 0.009) and Liverpool Adverse Events Profile scores (TSC: 42.7; IGE: 37.5, P = 0.017) with higher score and worse results for TSC patients in both questionnaires. CONCLUSIONS: This study is the first to compare patients with TSC, IGE, and FE in Germany and underlines the excessive QoL burden and both direct and indirect cost burdens experienced by patients with TSC.

Definition of the Post-COVID syndrome using a symptom-based Post-COVID score in a prospective, multi-center, cross-sectoral cohort of the German National Pandemic Cohort Network (NAPKON).

PURPOSE: The objective examination of the Post-COVID syndrome (PCS) remains difficult due to heterogeneous definitions and clinical phenotypes. The aim of the study was to verify the functionality and correlates of a recently developed PCS score. METHODS: The PCS score was applied to the prospective, multi-center cross-sectoral cohort (in- and outpatients with SARS-CoV-2 infection) of the "National Pandemic Cohort Network (NAPKON, Germany)". Symptom assessment and patient-reported outcome measure questionnaires were analyzed at 3 and 12 months (3/12MFU) after diagnosis. Scores indicative of PCS severity were compared and correlated to demographic and clinical characteristics as well as quality of life (QoL, EQ-5D-5L). RESULTS: Six hundred three patients (mean 54.0 years, 60.6% male, 82.0% hospitalized) were included. Among those, 35.7% (215) had no and 64.3% (388) had mild, moderate, or severe PCS. PCS severity groups differed considering sex and pre-existing respiratory diseases. 3MFU PCS worsened with clinical severity of acute infection (p = .011), and number of comorbidities (p = .004). PCS severity was associated with poor QoL at the 3MFU and 12MFU (p < .001). CONCLUSION: The PCS score correlated with patients' QoL and demonstrated to be instructive for clinical characterization and stratification across health care settings. Further studies should critically address the high prevalence, clinical relevance, and the role of comorbidities. TRAIL REGISTRATION NUMBER: The cohort is registered at www. CLINICALTRIALS: gov under NCT04768998.

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.

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.

Ethical and coordinative challenges in setting up a national cohort study during the COVID-19 pandemic in Germany.

With the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), global researchers were confronted with major challenges. The German National Pandemic Cohort Network (NAPKON) was launched in fall 2020 to effectively leverage resources and bundle research activities in the fight against the coronavirus disease 2019 (COVID-19) pandemic. We analyzed the setup phase of NAPKON as an example for multicenter studies in Germany, highlighting challenges and optimization potential in connecting 59 university and nonuniversity study sites. We examined the ethics application process of 121 ethics submissions considering durations, annotations, and outcomes. Study site activation and recruitment processes were investigated and related to the incidence of SARS-CoV-2 infections. For all initial ethics applications, the median time to a positive ethics vote was less than two weeks and 30 of these study sites (65%) joined NAPKON within less than three weeks each. Electronic instead of postal ethics submission (9.5 days (Q1: 5.75, Q3: 17) vs. 14 days (Q1: 11, Q3: 26), p value = 0.01) and adoption of the primary ethics vote significantly accelerated the ethics application process. Each study center enrolled a median of 37 patients during the 14-month observation period, with large differences depending on the health sector. We found a positive correlation between recruitment performance and COVID-19 incidence as well as hospitalization incidence. Our analysis highlighted the challenges and opportunities of the federated system in Germany. Digital ethics application tools, adoption of a primary ethics vote and standardized formal requirements lead to harmonized and thus faster study initiation processes during a pandemic.

Impact of Clinical Study Implementation on Data Quality Assessments - Using Contradictions within Interdependent Health Data Items as a Pilot Indicator.

INTRODUCTION: Contradiction is a relevant data quality indicator to evaluate the plausibility of interdependent health data items. However, while contradiction assessment is achieved using domain-established contradictory dependencies, recent studies have shown the necessity for additional requirements to reach conclusive contradiction findings. For example, the oral or rectal methods used in measuring the body temperature will influence the thresholds of fever definition. The availability of this required information as explicit data items must be guaranteed during study design. In this work, we investigate the impact of activities related to study database implementation on contradiction assessment from two perspectives including: 1) additionally required metadata and 2) implementation of checks within electronic case report forms to prevent contradictory data entries. METHODS: Relevant information (timestamps, measurement methods, units, and interdependency rules) required for contradiction checks are identified. Scores are assigned to these parameters and two different studies are evaluated based on the fulfillment of the requirements by two selected interdependent data item sets. RESULTS: None of the studies have fulfilled all requirements. While timestamps and measurement units are found, missing information about measurement methods may impede conclusive contradiction assessment. Implemented checks are only found if data are directly entered. DISCUSSION: Conclusive contradiction assessment typically requires metadata in the context of captured data items. Consideration during study design and implementation of data capture systems may support better data quality in studies and could be further adopted in primary health information systems to enhance clinical anamnestic documentation.

Increased circulating fibronectin, depletion of natural IgM and heightened EBV, HSV-1 reactivation in ME/CFS and long COVID.

Myalgic Encephalomyelitis/ Chronic Fatigue syndrome (ME/CFS) is a complex, debilitating, long-term illness without a diagnostic biomarker. ME/CFS patients share overlapping symptoms with long COVID patients, an observation which has strengthened the infectious origin hypothesis of ME/CFS. However, the exact sequence of events leading to disease development is largely unknown for both clinical conditions. Here we show antibody response to herpesvirus dUTPases, particularly to that of Epstein-Barr virus (EBV) and HSV-1, increased circulating fibronectin (FN1) levels in serum and depletion of natural IgM against fibronectin ((n)IgM-FN1) are common factors for both severe ME/CFS and long COVID. We provide evidence for herpesvirus dUTPases-mediated alterations in host cell cytoskeleton, mitochondrial dysfunction and OXPHOS. Our data show altered active immune complexes, immunoglobulin-mediated mitochondrial fragmentation as well as adaptive IgM production in ME/CFS patients. Our findings provide mechanistic insight into both ME/CFS and long COVID development. Finding of increased circulating FN1 and depletion of (n)IgM-FN1 as a biomarker for the severity of both ME/CFS and long COVID has an immediate implication in diagnostics and development of treatment modalities.

Persistent symptoms and risk factors predicting prolonged time to symptom-free after SARS­CoV­2 infection: an analysis of the baseline examination of the German COVIDOM/NAPKON-POP cohort.

PURPOSE: We aimed to assess symptoms in patients after SARS-CoV-2 infection and to identify factors predicting prolonged time to symptom-free. METHODS: COVIDOM/NAPKON-POP is a population-based prospective cohort of adults whose first on-site visits were scheduled ≥ 6 months after a positive SARS-CoV-2 PCR test. Retrospective data including self-reported symptoms and time to symptom-free were collected during the survey before a site visit. In the survival analyses, being symptom-free served as the event and time to be symptom-free as the time variable. Data were visualized with Kaplan-Meier curves, differences were tested with log-rank tests. A stratified Cox proportional hazard model was used to estimate adjusted hazard ratios (aHRs) of predictors, with aHR < 1 indicating a longer time to symptom-free. RESULTS: Of 1175 symptomatic participants included in the present analysis, 636 (54.1%) reported persistent symptoms after 280 days (SD 68) post infection. 25% of participants were free from symptoms after 18 days [quartiles: 14, 21]. Factors associated with prolonged time to symptom-free were age 49-59 years compared to < 49 years (aHR 0.70, 95% CI 0.56-0.87), female sex (aHR 0.78, 95% CI 0.65-0.93), lower educational level (aHR 0.77, 95% CI 0.64-0.93), living with a partner (aHR 0.81, 95% CI 0.66-0.99), low resilience (aHR 0.65, 95% CI 0.47-0.90), steroid treatment (aHR 0.22, 95% CI 0.05-0.90) and no medication (aHR 0.74, 95% CI 0.62-0.89) during acute infection. CONCLUSION: In the studied population, COVID-19 symptoms had resolved in one-quarter of participants within 18 days, and in 34.5% within 28 days. Over half of the participants reported COVID-19-related symptoms 9 months after infection. Symptom persistence was predominantly determined by participant's characteristics that are difficult to modify.

Consistency as a Data Quality Measure for German Corona Consensus Items Mapped from National Pandemic Cohort Network Data Collections.

BACKGROUND: As a national effort to better understand the current pandemic, three cohorts collect sociodemographic and clinical data from coronavirus disease 2019 (COVID-19) patients from different target populations within the German National Pandemic Cohort Network (NAPKON). Furthermore, the German Corona Consensus Dataset (GECCO) was introduced as a harmonized basic information model for COVID-19 patients in clinical routine. To compare the cohort data with other GECCO-based studies, data items are mapped to GECCO. As mapping from one information model to another is complex, an additional consistency evaluation of the mapped items is recommended to detect possible mapping issues or source data inconsistencies. OBJECTIVES: The goal of this work is to assure high consistency of research data mapped to the GECCO data model. In particular, it aims at identifying contradictions within interdependent GECCO data items of the German national COVID-19 cohorts to allow investigation of possible reasons for identified contradictions. We furthermore aim at enabling other researchers to easily perform data quality evaluation on GECCO-based datasets and adapt to similar data models. METHODS: All suitable data items from each of the three NAPKON cohorts are mapped to the GECCO items. A consistency assessment tool (dqGecco) is implemented, following the design of an existing quality assessment framework, retaining their-defined consistency taxonomies, including logical and empirical contradictions. Results of the assessment are verified independently on the primary data source. RESULTS: Our consistency assessment tool helped in correcting the mapping procedure and reveals remaining contradictory value combinations within COVID-19 symptoms, vital signs, and COVID-19 severity. Consistency rates differ between the different indicators and cohorts ranging from 95.84% up to 100%. CONCLUSION: An efficient and portable tool capable of discovering inconsistencies in the COVID-19 domain has been developed and applied to three different cohorts. As the GECCO dataset is employed in different platforms and studies, the tool can be directly applied there or adapted to similar information models.

Statistical biases due to anonymization evaluated in an open clinical dataset from COVID-19 patients.

Anonymization has the potential to foster the sharing of medical data. State-of-the-art methods use mathematical models to modify data to reduce privacy risks. However, the degree of protection must be balanced against the impact on statistical properties. We studied an extreme case of this trade-off: the statistical validity of an open medical dataset based on the German National Pandemic Cohort Network (NAPKON), which was prepared for publication using a strong anonymization procedure. Descriptive statistics and results of regression analyses were compared before and after anonymization of multiple variants of the original dataset. Despite significant differences in value distributions, the statistical bias was found to be small in all cases. In the regression analyses, the median absolute deviations of the estimated adjusted odds ratios for different sample sizes ranged from 0.01 [minimum = 0, maximum = 0.58] to 0.52 [minimum = 0.25, maximum = 0.91]. Disproportionate impact on the statistical properties of data is a common argument against the use of anonymization. Our analysis demonstrates that anonymization can actually preserve validity of statistical results in relatively low-dimensional data.

Culturally adapted cognitive behavioural group therapy for mental disorders in refugees plus problem solving training (ReTreat): study protocol for a multicentre randomised controlled trial.

INTRODUCTION: Since a high proportion of refugees in Germany suffer from mental disorders, culturally adapted treatments are needed that target a broad range of symptoms. There is much evidence for the efficacy of culturally adapted cognitive behavioural therapy (CA-CBT). Given the promising results of CA-CBT, the combination with problem solving training (CA-CBT+) represents a novel approach that potentially improves the refugees' ability to cope actively with psychosocial problems. This randomised controlled trial evaluates the efficacy of 12-session outpatient CA-CBT+ compared with to treatment as usual (TAU) in a sample of refugees suffering from at least one DSM-5 disorder. METHODS AND ANALYSIS: The present study will be carried out as two-group randomised trial with 1:1 individual allocation to either (1) culturally adapted cognitive behavioural therapy in a group setting (CA-CBT+) or (2) TAU. The study takes place at four sites in Germany, randomising in total 138 adult refugees with at least one primary DSM-5 diagnosis to the treatment conditions. In CA-CBT+ the patients receive 12 sessions of 120 min duration over the course of 12 weeks providing psychoeducation, meditation and other techniques of emotional regulation, stretching and problem solving training. The primary outcome is treatment response operationalised by a clinically significant change in General Health Questionnaire (GHQ-28) score. Follow-up visits will take place 3 and 9 months after the end of the intervention. Secondary outcomes include changes in psychopathological symptoms, somatic symptoms and quality of life. Intention-to-treat analysis will be performed. Adverse and serious adverse events will be analysed. Further, healthcare usage and economic outcomes will be assessed and analysed. Primary and secondary outcomes will be analysed using appropriate statistical methods. ETHICS AND DISSEMINATION: The study has been approved by the Ethics Commission of the German Psychological Society (ref: StangierUlrich2019-1018VA). Results will be disseminated via presentations, publication in international journals, and national outlets for clinicians. Furthermore, intervention materials will be available, and the existing network will be used to disseminate and implement the interventions into routine healthcare. TRIAL REGISTRATION NUMBER: DRKS00021536.

Severity, predictors and clinical correlates of Post-COVID syndrome (PCS) in Germany: A prospective, multi-centre, population-based cohort study.

Background: Post-COVID syndrome (PCS) is an important sequela of COVID-19, characterised by symptom persistence for >3 months, post-acute symptom development, and worsening of pre-existing comorbidities. The causes and public health impact of PCS are still unclear, not least for the lack of efficient means to assess the presence and severity of PCS. Methods: COVIDOM is a population-based cohort study of polymerase chain reaction (PCR) confirmed cases of SARS-CoV-2 infection, recruited through public health authorities in three German regions (Kiel, Berlin, Würzburg) between November 15, 2020 and September 29, 2021. Main inclusion criteria were (i) a PCR confirmed SARS-CoV-2 infection and (ii) a period of at least 6 months between the infection and the visit to the COVIDOM study site. Other inclusion criteria were written informed consent and age ≥18 years. Key exclusion criterion was an acute reinfection with SARS-CoV-2. Study site visits included standardised interviews, in-depth examination, and biomaterial procurement. In sub-cohort Kiel-I, a PCS (severity) score was developed based upon 12 long-term symptom complexes. Two validation sub-cohorts (Würzburg/Berlin, Kiel-II) were used for PCS score replication and identification of clinically meaningful predictors. This study is registered at clinicaltrials.gov (NCT04679584) and at the German Registry for Clinical Studies (DRKS, DRKS00023742). Findings: In Kiel-I (n = 667, 57% women), 90% of participants had received outpatient treatment for acute COVID-19. Neurological ailments (61·5%), fatigue (57·1%), and sleep disturbance (57·0%) were the most frequent persisting symptoms at 6-12 months after infection. Across sub-cohorts (Würzburg/Berlin, n = 316, 52% women; Kiel-II, n = 459, 56% women), higher PCS scores were associated with lower health-related quality of life (EQ-5D-5L-VAS/-index: r = -0·54/ -0·56, all p < 0·0001). Severe, moderate, and mild/no PCS according to the individual participant's PCS score occurred in 18·8%, 48·2%, and 32·9%, respectively, of the Kiel-I sub-cohort. In both validation sub-cohorts, statistically significant predictors of the PCS score included the intensity of acute phase symptoms and the level of personal resilience. Interpretation: PCS severity can be quantified by an easy-to-use symptom-based score reflecting acute phase disease burden and general psychological predisposition. The PCS score thus holds promise to facilitate the clinical diagnosis of PCS, scientific studies of its natural course, and the development of therapeutic interventions. Funding: The COVIDOM study is funded by the Network University Medicine (NUM) as part of the National Pandemic Cohort Network (NAPKON).

The German National Pandemic Cohort Network (NAPKON): rationale, study design and baseline characteristics.

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

Trends in resource utilization and cost of illness in patients with active epilepsy in Germany from 2003 to 2020.

OBJECTIVE: This study was undertaken to calculate epilepsy-related direct, indirect, and total costs in adult patients with active epilepsy (ongoing unprovoked seizures) in Germany and to analyze cost components and dynamics compared to previous studies from 2003, 2008, and 2013. This analysis was part of the Epi2020 study. METHODS: Direct and indirect costs related to epilepsy were calculated with a multicenter survey using an established and validated questionnaire with a bottom-up design and human capital approach over a 3-month period in late 2020. Epilepsy-specific costs in the German health care sector from 2003, 2008, and 2013 were corrected for inflation to allow for a valid comparison. RESULTS: Data on the disease-specific costs for 253 patients in 2020 were analyzed. The mean total costs were calculated at €5551 (±€5805, median = €2611, range = €274-€21 667) per 3 months, comprising mean direct costs of €1861 (±€1905, median = €1276, range = €327-€13 158) and mean indirect costs of €3690 (±€5298, median = €0, range = €0-€11 925). The main direct cost components were hospitalization (42.4%), antiseizure medication (42.2%), and outpatient care (6.2%). Productivity losses due to early retirement (53.6%), part-time work or unemployment (30.8%), and seizure-related off-days (15.6%) were the main reasons for indirect costs. However, compared to 2013, there was no significant increase of direct costs (-10.0%), and indirect costs significantly increased (p < .028, +35.1%), resulting in a significant increase in total epilepsy-related costs (p < .047, +20.2%). Compared to the 2013 study population, a significant increase of cost of illness could be observed (p = .047). SIGNIFICANCE: The present study shows that disease-related costs in adult patients with active epilepsy increased from 2013 to 2020. As direct costs have remained constant, this increase is attributable to an increase in indirect costs. These findings highlight the impact of productivity loss caused by early retirement, unemployment, working time reduction, and seizure-related days off.

Multicenter, cross-sectional study of the costs of illness and cost-driving factors in adult patients with epilepsy.

OBJECTIVE: This study was undertaken to quantify epilepsy-related costs of illness (COI) in Germany and identify cost-driving factors. METHODS: COI were calculated among adults with epilepsy of different etiologies and severities. Multiple regression analysis was applied to determine any epilepsy-related and sociodemographic factors that serve as cost-driving factors. RESULTS: In total, 486 patients were included, with a mean age of 40.5 ± 15.5 years (range = 18-83 years, 58.2% women). Mean 3-month COI were estimated at €4911, €2782, and €2598 for focal, genetic generalized, and unclassified epilepsy, respectively. The mean COI for patients with drug-refractory epilepsy (DRE; €7850) were higher than those for patients with non-DRE (€4720), patients with occasional seizures (€3596), or patients with seizures in remission for >1 year (€2409). Identified cost-driving factors for total COI included relevant disability (unstandardized regression coefficient b = €2218), poorer education (b = €2114), living alone (b = €2612), DRE (b = €1831), and frequent seizures (b = €2385). Younger age groups of 18-24 years (b = -€2945) and 25-34 years (b = -€1418) were found to have lower overall expenditures. A relevant disability (b = €441), DRE (b = €1253), frequent seizures (b = €735), and the need for specialized daycare (b = €749) were associated with higher direct COI, and poorer education (b = €1969), living alone (b = €2612), the presence of a relevant disability (b = €1809), DRE (b = €1831), and frequent seizures (b = €2385) were associated with higher indirect COI. SIGNIFICANCE: This analysis provides up-to-date COI data for use in further health economics analyses, highlighting the high economic impacts associated with disease severity, disability, and disease-related loss of productivity among adult patients with epilepsy. The identified cost drivers could be used as therapeutic and socioeconomic targets for future cost-containment strategies.

The Structured Delegation of Medical Care Services for Patients With Inflammatory Rheumatic Diseases.

BACKGROUND: In some areas of Germany, there is a shortage of specialist physicians for patients with inflammatory rheumatic diseases. Delegating certain medical care services to qualified, specialized rheumatological assistants (SRAs) might be an effective way to supplement the available capacity for specialized medical care. METHODS: Patients under stable treatment for rheumatoid arthritis (RA) or psoriatic arthritis (PsA) were included in this trial, which was designed to demonstrate, in a first step, the non-inferiority of a form of care involving delegation of physicians' tasks to SRAs (team-based care), in comparison to standard care, with respect to changes in disease activity at one year. "Non-inferiority," in this context, means either superiority or else an irrelevant extent of inferiority. In a second step, in case non-inferiority could be shown, the superiority of team-based care with respect to changes in patients' health-related quality of life would be tested as well. Disease activity was measured with the Disease Activity Score 28, and health-related quality of life with the EQ-5D-5L. This was a randomized, multicenter, rater-blinded trial with two treatment arms (team-based care and standard care). The statistical analysis was performed with mixed linear models (DRKS00015526). RESULTS: From September 2018 to June 2019, 601 patients from 14 rheumatological practices and 3 outpatient rheumatological clinics in the German states of North Rhine-Westphalia and Lower Saxony were randomized to either team-based or standard care. Team-based care was found to be non-inferior to standard care with respect to changes in disease activity (adjusted difference = -0.19; 95% confidence interval [-0.36; -0.02]; p <0.001 for non-inferiority). Superiority with respect to health-related quality of life was not demonstrated (adjusted difference = 0.02 [-0.02; 0.05], p = 0.285). CONCLUSION: Team-based care, with greater integration of SRAs, is just as good as standard care in important respects. Trained SRAs can effectively support rheumatologists in the care of stable patients with RA or PsA.

EuroQOL-5D-3L does not adequately map quality-of-life deterioration in severely affected patients with epilepsy.

INTRODUCTION: The steadily increasing impact of health-related quality of life (HRQOL) on reasonable diagnostic and therapeutic decisions makes the correct mapping of HRQOL indispensable in modern epileptology. The aim of this study was to address the reliability of the often-used generic HRQOL screening questionnaire EuroQOL 5-dimension, 3-level (EQ-5D-3L) by comparing its normalized index value (calculated via the time trade-off method) and visual analog scale (VAS) to the gold standard of the extensive Quality of Life in Epilepsy Inventory (QOLIE-31). QOLIE-10 scores were compared with the extensive QOLIE-31 and EQ-5D-3L TTO. METHODS: We conducted a retrospective analysis of a monocentric study of 184 patients with epilepsy. Bivariate Spearman correlation analysis and Fisher's r-to-z transformation were used to compare the strengths of correlations of EQ-5D-3L, QOLIE-10 and QOLIE-31 with different epilepsy-specific domains (disease severity, drug interactions, emotional well-being, stigmatization, seizure-related anxiety, cognitive impairment). RESULTS: The different metrics of EQ-5D-3L, QOLIE-10 and QOLIE-31 showed moderate to very strong intra- and inter-metric correlations for overall HRQOL. Quality of Life in Epilepsy Inventory-31 VAS and EQ-5D-3L VAS did not show any significantly different strengths of correlations with respect to the domains studied. In contrast, the correlation strength of the normalized EQ-5D-3L index value differed significantly from the QOLIE-31 T-score for several domains, for example, for drug-related adverse events, neuropsychological deficits, symptoms of depression and seizure worry. In seizure-free patients, EQ-5D-3L VAS and EQ-5D-3L index values correlated significantly less with the domain of "cognitive impairment" than the QOLIE-31 T-score. In patients without relevant neuropsychological deficits, the strengths of correlations with the assessed domains did not differ significantly between EQ-5D-3L metrics and the QOLIE-31 T-score. The HRQOL mapping probability of QOLIE-10 was inferior to QOLIE-31 and comparable to EQ-5D-3L regarding the analyzed domains. CONCLUSION: In contrast to the EQ-5D-3L VAS, EQ-5D-3L index values do not adequately map health-related quality of life in severely affected patients with epilepsy and therefore should not be used as screening tools. The QOLIE-31 T-score remains the gold standard for HRQOL assessment in patients with epilepsy.

Efficacy of a Low-threshold, Culturally-Sensitive Group Psychoeducation Programme for Asylum Seekers (LoPe): study protocol for a multicentre randomised controlled trial.

INTRODUCTION: Despite high levels of mental distress, accessing psychological treatment is difficult for asylum seekers in Western host countries due to a lack of knowledge about mental disorders, and the health system, as well as due to cultural and language barriers. This study aims to investigate whether brief culturally sensitive and transdiagnostic psychoeducation is effective in increasing mental health literacy. METHODS AND ANALYSIS: The study is a parallel two-group randomised controlled trial with 1:1 individual allocation to either culturally sensitive, low-threshold psychoeducation ('Tea Garden' (TG)) or a waitlist (WL) control group. It takes place at four study sites in Germany. A total of 166 adult asylum seekers who report at least mild mental distress will be randomly assigned. The TG consists of two 90 min group sessions and provides information about mental distress, resources and mental health services in a culturally sensitive manner. The primary outcome is the percentage of participants in the TG, as compared with the WL, achieving an increase in knowledge concerning symptoms of mental disorders, individual resources and mental healthcare from preintervention to postintervention. The further trajectory will be assessed 2 and 6 months after the end of the intervention. Secondary outcomes include changes in mental distress, openness towards psychotherapy and resilience. Furthermore, healthcare utilisation and economics will be assessed at all assessment points. ETHICS AND DISSEMINATION: The study has been approved by the Ethics Commission of the German Psychological Society (ref: WeiseCornelia2019-10-18VA). Results will be disseminated via presentations, publication in international journals and national outlets for clinicians. Furthermore, intervention materials will be available, and the existing network will be used to disseminate and implement the interventions into routine healthcare. TRIAL REGISTRATION NUMBER: DRKS00020564; Pre-results. PROTOCOL VERSION: 2020-10-06, version number: VO2F.