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ZUSAMMENFASSUNGChronische anhaltende oder wiederkehrende Schmerzen am Bewegungsapparat über einen Zeitraum von mindestens 3 Monaten sind bei Kindern und Jugendlichen zunehmend zu beobachten. Der Schmerz kann dabei seine Funktion als Warnsignal verlieren und verselbstständigt sich aufgrund von Veränderungen im Schmerzverarbeitungssystem. Die chronische Schmerzstörung mit somatischen und psychischen Faktoren, die anhaltende somatoforme Schmerzstörung und das komplexe regionale Schmerzsyndrom (CRPS) äußern sich in starken Schmerzen, haben einen negativen Einfluss auf das psychische Befinden und beeinträchtigen die jugendgerechte Lebensführung. In Diagnostik, Edukation und Therapie müssen nun andere Schwerpunkte gelegt werden als bei akuten Schmerzen, welche üblicherweise aufgrund von Verletzungen, entzündlichen Vorgängen oder sonstigen somatischen Ursachen auftreten. Eine multiprofessionelle Zusammenarbeit ist sowohl im ambulanten als auch im stationären Setting wünschenswert und wird am Beispiel der stationären interdisziplinären multimodalen Schmerztherapie (IMST) vorgestellt.

ZUSAMMENFASSUNGChronische Schmerzen bei Kindern und Jugendlichen werden oft in Zusammenhang mit Angst, Depression und Verhaltensauffälligkeiten gebracht, zugleich begünstigen diese psychischen Auffälligkeiten eine Chronifizierung. Lebensqualität, Angst-Vermeidungs-Tendenzen, elterliches Verhalten und sozioökonomischer Status modulieren ebenfalls Prozesse der Schmerzchronifizierung. Darüber hinaus müssen Schlafverhalten, operative/invasive Eingriffe, spezielle Schmerzarten und -orte und frühkindliche Schmerzerfahrungen als mögliche Prädiktoren für chronische Schmerzen rechtzeitig in Erwägung gezogen werden. Im klinischen Alltag sollten all diese Faktoren in Anamnese, Edukation und Therapieverlauf einbezogen werden. Ein rechtzeitiges Erkennen und Therapieren psychischer und sozialer Belastungen kann die Gefahr der Chronifizierung von Schmerzen reduzieren.

Aim We aimed to develop a risk score to calculate a person’s individual risk for a severe COVID-19 course (POINTED score) to support prioritization of especially vulnerable patients for a (booster) vaccination. Subject and methods This cohort study was based on German claims data and included 623,363 individuals with a COVID-19 diagnosis in 2020. The outcome was COVID-19 related treatment in an intensive care unit, mechanical ventilation, or death after a COVID-19 infection. Data were split into a training and a test sample. Poisson regression models with robust standard errors including 35 predefined risk factors were calculated. Coefficients were rescaled with a min–max normalization to derive numeric score values between 0 and 20 for each risk factor. The scores’ discriminatory ability was evaluated by calculating the area under the curve (AUC). Results Besides age, down syndrome and hematologic cancer with therapy, immunosuppressive therapy, and other neurological conditions were the risk factors with the highest risk for a severe COVID-19 course. The AUC of the POINTED score was 0.889, indicating very good predictive validity. Conclusion The POINTED score is a valid tool to calculate a person’s risk for a severe COVID-19 course.

Background There is an evidence gap on whether the choice of specialty care beneficially affects health-related quality of life (HRQoL) in patients with chronic obstructive pulmonary disease (COPD). This study analyzes how newly initiated pulmonologist care affects the generic and disease-specific HRQoL in COPD patients over a period of 1 year. Methods We linked claims data with data from two survey waves to investigate the longitudinal effect of specialty care on HRQoL using linear Difference-in-Difference models based on 1:3 propensity score matched data. Generic HRQoL was operationalized by EQ-5D-5L visual analog scale (VAS), and disease-specific HRQoL by COPD assessment test (CAT). Subgroup analyses examined COPD patients with low (GOLD AB) and high (GOLD CD) exacerbation risk. Results In contrast to routine care patients, pulmonologists’ patients (n = 442) experienced no significant deterioration in HRQoL (VAS − 0.0, p = 0.9870; CAT + 0.5, p = 0.0804). Models unveiled a small comparative advantage of specialty care on HRQoL (mean change: CAT − 0.8, VAS + 2.9), which was especially pronounced for GOLD AB (CAT − 0.7; VAS + 3.1). Conclusion The uptake of pulmonologist care had a statistically significant, but not clinically relevant, beneficial impact on the development of HRQoL by slowing down overall HRQoL deterioration within 1 year. Including specialty care more appropriately in COPD management, especially at lower disease stages (GOLD AB), could thus improve patients’ health outcome.

The number of prescriptions and costs of oral anticancer drugs are increasing. Therapy discontinuation due to, for example, side effects, progression, or death, often lead to medication wastage. While evidence exists for the economic value of wasted injectable chemotherapeutics, there is a lack of data for oral anticancer drugs in Germany.The multicenter AMBORA trial investigated 202 patients, who had been newly started on new oral anticancer drugs, over 12 weeks and analyzed the outpatient prescription data of patients who discontinued treatment. The amount of medicines wasted and their costs were determined using the pharmacy retail price. Defined daily doses and prescription data from the AOK Bayern, a German statutory health care insurance company, were used to extrapolate these costs.Within 12 weeks, 24.8 % of the AMBORA patients discontinued oral anticancer treatment (50 of 202). Prescription data of 34 patients were evaluable. In total, 1,693 tablets/capsules with a value of 112,212 euros were wasted. The approximate extrapolation to the prescription volume of the AOK Bayern resulted in an estimated wastage of 3.49 million euros in 12 weeks.Medication wastage due to discontinuation of new oral anticancer drug therapy leads to a considerable financial burden. Regarding rising prescription numbers and therapy costs in oncology, measures to reduce wastage of oral anticancer drugs should be initiated.Clinical pharmacological / pharmaceutical care including medication reconciliation and review, side effect management and patient counseling to optimize adherence and medication intake behavior, contributes to a reduction of therapy discontinuations, thereby reducing drug wastage. To further reduce drug wastage small (initiation) packages, which are currently not always available for an economic prescription, play an important role. The practice of partial prescription fills, which is already practiced internationally, should also be further discussed in Germany.

Drug-related problems (e.g., adverse drug reactions, ADR) are serious safety issues in patients treated with oral anticancer therapeutics (OAT). The previously published randomized AMBORA trial showed that an intensified clinical pharmacological/pharmaceutical care program within the first 12 weeks of treatment reduces the number and severity of ADR as well as hospitalization rates in 202 patients. The present investigation focused on unscheduled hospitalizations detected within AMBORA and analyzed the characteristics (e.g., frequency, involved OAT) and cost of each hospital stay. To estimate the potential savings of an intensified care program in a larger group, the absolute risk for OAT-related hospitalizations was extrapolated to all insureds of a leading German statutory health insurance company (AOK Bayern). Within 12 weeks, 45 of 202 patients were hospitalized. 50% of all unscheduled hospital admissions were OAT-related (20 of 40) and occurred in 18 patients. The mean cost per inpatient stay was EUR 5873. The intensified AMBORA care program reduced the patients’ absolute risk for OAT-related hospitalization by 11.36%. If this care program would have been implemented in the AOK Bayern collective (3,862,017 insureds) it has the potential to reduce hospitalization rates and thereby cost by a maximum of EUR 4.745 million within 12 weeks after therapy initiation.

BACKGROUND AND OBJECTIVE: Adherence to and persistence with inhaled long-acting bronchodilators (ILAB), is commonly considered to be a relevant driver of perceived health-related quality of life (HRQoL) in chronic obstructive pulmonary disease (COPD), but the topic is rarely studied with real-world data. Using survey and health insurance claims data, this study investigates the effect of adherence to and persistence with ILAB on EQ-5D-5L visual analog scale (VAS) in ILAB users who were enrolled in the German disease management programs (DMP) for COPD. METHODS Included ILAB users were aged ≥ 18 years, continuously insured with AOK Bavaria and enrolled in the DMP for COPD. Adherence to ILAB [proportion of days covered (PDC); PDC ≥ 80%], and persistence (days of uninterrupted ILAB therapy) were assessed in the year preceding the study's HRQoL questionnaire. In a cross-sectional design we applied quasi-Poisson models with log link function and subgroup analyses. The robustness of results was analyzed with comprehensive sensitivity analyses. RESULTS Patients with PDC ≥ 80% had 2.96% higher VAS scores than patients with lower PDCs. From all analyses, patients with GOLD stage III had the highest effects from PDC ≥ 80% (5.33% increased VAS). Patients without heart failure profited significantly more from PDC ≥ 80% (+ 4.34% vs - 2.88%) and from an additional persistent day (+ 0.01% vs - 0.01%) than patients with heart failure. CONCLUSIONS Overall, ILAB users significantly profited from PDC ≥ 80%, but not from continuous PDC or persistent days. In secondary subgroup analyses, patients with GOLD stage III and patients without heart failure particularly profited from PDC ≥ 80%. Only patients without heart failure particularly profited from more persistent days. Because identified effects were small and often not robust, advancing adherence and persistence alone may not improve the German DMP for COPD substantially.

BACKGROUND: Precise individual risk quantification of severe courses of Covid-19 is needed to prioritize protective measures and to assess population risks in a phase of increased immunization. So far, results for the German population are lacking. Furthermore, existing studies pre-specify comorbidity risks by broad categories rather than deriving them from the data using statistical learning techniques. METHODS: Risk factors for severe, critical and lethal courses of Covid-19 are identified from a large German claims dataset covering more than 4 million individuals. To avoid prior grouping and pre-selection of risk factors, fine-grained hierarchical information from medical classification systems for diagnoses, pharmaceuticals and procedures are used, resulting in more than 33,000 covariates. These are processed using a LASSO approach. RESULTS: We identify relevant risk factors, among which hypertensive diseases, heart disease and the corresponding medications are most relevant at population level. Prior use of diuretics is the strongest single medical predictor for severe course (e.g. Torasemide, odds ratio (OR) 1.801), but also for a critical course (OR 2.304) and death (OR 2.523). To assess risk profiles at the individual level, our approach sums up many such factors and has better predictive ability than using pre-specified morbidity groups (AUC for predicting critical course 0.875 versus AUC ≤ 0.865). CONCLUSIONS: The proposed method can help to identify risk factors and assess risk at the individual level for other infectious diseases. The results can be used by administrative data holders to guide protective policies, while a risk index can be applied in clinical studies with a narrower focus.

Background Little is known about how long-term weight gain affects the health perception of COPD patients. Objectives The aim is to evaluate the long-term association of BMI change and health-related quality of life (HRQoL) in obese COPD patients. Methods Claims and survey data from a COPD disease management program were used to match two groups of COPD patients with BMI ≥ 30 who have differing weight trajectories over a 5-year timespan via propensity score and genetic matching. EQ-5D-5L, including visual analog scale (VAS) and COPD Assessment Test (CAT), were used as outcomes of interest. Sociodemographic and disease-based variables were matched. Results Out of 1202 obese COPD patients, 126 with a weight increase of four or more BMI points were matched separately with 252 (propensity score matching) and 197 (genetic matching) control subjects who had relatively stable BMI. For the EQ-5D-5L, patients with BMI increase reported significantly worse health perception for VAS and all descriptive dimensions except pain/discomfort. For the CAT, especially the perception of ability to complete daily activities and overall energy results were significantly worse. VAS differences reach the range of minimal important differences. Stopping smoking and already being in obesity class II were the most influential risk factors for BMI increase. Conclusion Obese COPD patients who gain four or more BMI points over 5 years report significantly lower results in different dimensions of generic and disease-specific HRQoL than their peers with stable BMI. To improve real-world outcomes, tracking and preventing specific BMI trajectories could constitute a clinically relevant aspect of managing COPD patients.

Alisa Stöber,1,2 Johanna I Lutter,1,3 Larissa Schwarzkopf,1,3,4 Florian Kirsch,1 Anja Schramm,5 Claus F Vogelmeier,6 Reiner Leidl1,7 1Institute of Health Economics and Health Care Management, Helmholtz Zentrum München, Neuherberg, Germany; 2Institute for Medical Information Processing, Biometry, and Epidemiology (IBE), Ludwig-Maximilians-University Munich (LMU), Munich, Germany; 3Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany; 4Institute fuer Therapieforschung (IFT), Working Group Therapy and Health Services Research, Munich, Germany; 5AOK Bayern, Service Center of Health Care Management, Regensburg, Germany; 6Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-University Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany; 7Munich Center of Health Sciences (MC-Health), Institute for Health Economics and Management, Ludwig-Maximilians-University Munich (LMU), Munich, GermanyCorrespondence: Alisa StöberInstitute of Health Economics and Health Care Management, Helmholtz Zentrum München, Neuherberg, 85764, GermanyTel +49 89 3187/43572Email alisa.stoeber@helmholtz-muenchen.dePurpose: Real-world evidence on the impact of forced expiratory volume in one second (FEV1) and exacerbations on health-related quality of life (HRQoL) in patients with chronic obstructive pulmonary disease (COPD) is sparse especially with regard to GOLD ABCD groups. This study investigates how changes in FEV1 and exacerbations affect generic and disease-specific HRQoL in COPD patients over one year.Methods: Using German claims data and survey data, we classified 3016 COPD patients and analyzed their health status by GOLD groups AB and CD. HRQoL was measured with the disease-specific COPD assessment test (CAT) and the visual analog scale (VAS) from the generic Euro-Qol 5D-5L. We applied change score models to assess associations between changes in FEV1 (≥ 100 mL decrease/no change/≥ 100 mL increase) or the development of severe exacerbations with change in HRQoL.Results: FEV1 decrease was associated with a significant but not minimal important difference (MID) deterioration in disease-specific HRQoL (mean change [95% CI]: CAT +0.74 [0.15 to 1.33]), while no significant change was observed in the generic VAS. Experiencing at least one severe exacerbation also had a significant impact on CAT deterioration (+1.58 [0.52 to 2.64]), but again not on VAS. Here, GOLD groups AB showed not only a statistically but also a clinically relevant MID deterioration in CAT (+2.1 [0.88 to 3.32]). These particular patient groups were further characterized by a higher probability of being male, having a higher mMRC and Charlson index, and a lower probability of having higher FEV1 or BMI values.Conclusion: FEV1 decline and the occurrence of ≥ 1 severe exacerbation are significantly associated with overall deterioration in disease-specific HRQoL. Preventing severe exacerbations particularly in patients without previous severe exacerbations (ABCD groups A and B) may help to stabilize the key patient-reported outcome HRQoL.Keywords: COPD, health-related quality of life, longitudinal study, real-world evidence, forced expiratory volume in 1 second, exacerbation

Background Body mass index (BMI) is an important parameter associated with mortality and health-related quality of life (HRQoL) in chronic obstructive pulmonary disease (COPD). However, informed guidance on stratified weight recommendations for COPD is still lacking. This study aims to determine the association between BMI and HRQoL across different severity grades of COPD to support patient management. Methods We use conjunct analysis of claims and survey data based on a German COPD disease management program from 2016 to 2017. The EQ-5D-5L visual analog scale (VAS) and COPD Assessment Test (CAT) are used to measure generic and disease-specific HRQoL. Generalized additive models with smooth functions are implemented to evaluate the relationship between BMI and HRQoL, stratified by COPD severity. Results 11,577 patients were included in this study. Mean age was 69.4 years and 59% of patients were male. In GOLD grades 1–3, patients with BMI of around 25 had the best generic and disease-specific HRQoL, whereas in GOLD grade 4, obese patients had the best HRQoL using both instruments when controlled for several variables including smoking status, income, COPD severity, comorbidities, emphysema, corticosteroid use, and days spent in hospital. Conclusion This real-world analysis shows the non-linear relationship between BMI and HRQoL in COPD. HRQoL of obese patients with mild to severe COPD might improve following weight reduction. For very severe COPD, a negative association of obesity and HRQoL could not be confirmed. The results hint at the need to stratify COPD patients by disease stage for optimal BMI management.

Chronic Obstructive Pulmonary Disease (COPD) is characterized by persistent respiratory symptoms and airflow limitation, which is progressive and not fully reversible. In patients with COPD, body mass index (BMI) is an important parameter associated with health outcomes, e.g. mortality and health-related quality of life. However, so far no study evaluated the association of BMI and health care expenditures across different COPD severity grades. We used claims data and documentation data of a Disease Management Program (DMP) from a statutory health insurance fund (AOK Bayern). Patients were excluded if they had less than 4 observations in the 8 years observational period. Generalized additive mixed models with smooth functions were used to evaluate the association between BMI and health care expenditures, stratified by severity of COPD, indicated by GOLD grades 1–4. We included 30,682 patients with overall 188,725 observations. In GOLD grades 1–3 we found an u-shaped relation of BMI and expenditures, where patients with a BMI of 30 or slightly above had the lowest and underweight and obese patients had the highest health care expenditures. Contrarily, in GOLD grade 4 we found an almost linear decline of health care expenditures with increasing BMI. In terms of expenditures, the often reported obesity paradox in patients with COPD was clearly reflected in GOLD grade 4, while in all other severity grades underweight as well as severely obese patients caused the highest health care expenditures. Reduction of obesity may thus reduce health care expenditures in GOLD grades 1–3.

Sabrina Mueller,1 Antje Groth,1 Stefan G Spitzer,2,3 Anja Schramm,4 Andreas Pfaff,5 Ulf Maywald6 1Institute for Pharmacoeconomics and Medication Logistics, University of Wismar, Wismar, Germany; 2Praxisklinik Herz und Gefäße Dresden, Academic Educational Practice Clinic, TU Dresden, Dresden, Germany; 3Institute of Medical Technology, Brandenburg University of Technology Cottbus–Senftenberg, Senftenberg, Germany; 4AOK Bayern, Regensburg, Germany; 5AOK Baden-Württemberg, Stuttgart, Germany; 6AOK PLUS, Dresden, Germany Objective: To compare the real-world effectiveness and safety of non-vitamin-K-antagonist oral anticoagulant (NOAC) treatment in atrial fibrillation (AF) patients with a vitamin-K-antagonist (VKA)-based treatment. Methods: This was a retrospective analysis of an anonymized claims dataset from 3 German health insurance funds covering the period from January 01, 2010 to June 30, 2014, with a minimum observation time of 12 months. All continuously insured patients with at least 2 outpatient AF diagnoses and/or 1 inpatient respective diagnosis who received at least 1 outpatient prescription of a NOAC or VKA were included. Outcomes and measures: Death, ischemic strokes (IS), non-specified strokes, transient ischemic attacks (TIAs), myocardial infarctions (MIs), arterial embolism (AE), hemorrhagic strokes, severe bleedings, and composite outcomes. Main comparisons were done based on propensity score-matched (PSM) cohorts. Results were reported as incidence rate ratios and hazard ratios (HRs). Results: We assigned 37,439 AF patients to each PSM cohort (NOAC cohort: mean age 78.2 years, mean CHA2DS2VASc score 2.96, mean follow-up 348.5 days; VKA cohort: mean age 78.2 years, mean CHA2DS2VASc 2.95, mean follow-up 365.5 days). NOAC exposure was associated with significantly higher incidence rate ratios; 95% CI/HRs; 95% CI for the following outcomes: death (1.22; 1.17–1.28/1.22; 1.17–1.28), IS (1.90; 1.69–2.15/1.92; 1.69–2.19), non-specified strokes (2.04; 1.16–3.70/1.93; 1.13–3.32), TIAs (1.52; 1.29–1.79/1.44; 1.21–1.70), MIs (1.26; 1.10–1.15/1.31; 1.13–1.52), AE (1.75; 1.32–2.32/1.81; 1.36–2.34) and severe bleeding (1.92; 1.71–2.15/1.95; 1.74–2.20). Multivariable Cox regression analyses and additional sensitivity analysis, including analysis of PSM-matched NOAC/VKA treatment-naive patients, only confirmed the above results. The study was documented under clinicaltrials.gov (NCT02657616). Conclusion and relevance: A VKA therapy seems to be more effective and safer than a NOAC therapy in a real-world cohort of German AF patients. Keywords: atrial fibrillation, AF, anticoagulation, NOAC, VKA, cohort study

Background Evidence on the economic impact of chronic obstructive pulmonary disease (COPD) for third-party payers and society based on large real world datasets are still scarce. Therefore, the aim of this study was to estimate the economic impact of COPD severity and its comorbidities, stratified by GOLD grade, on direct and indirect costs for an unselected population enrolled in the structured German Disease Management Program (DMP) for COPD. Methods All individuals enrolled in the DMP COPD were included in the analysis. Patients were only excluded if they were not insured or not enrolled in the DMP COPD the complete year before the last DMP documentation (at physician visit), had a missing forced expiratory volume in 1 s (FEV1) measurement or other missing values in covariates. The final dataset included 39,307 patients in GOLD grade 1 to 4. We used multiple generalized linear models to analyze the association of COPD severity with direct and indirect costs, while adjusting for sex, age, income, smoking status, body mass index, and comorbidities. Results More severe COPD was significantly associated with higher healthcare utilization, work absence, and premature retirement. Adjusted annual costs for GOLD grade 1 to 4 amounted to €3809 [€3691–€3935], €4284 [€4176–€4394], €5548 [€5328–€5774], and €8309 [€7583-9065] for direct costs, and €11,784 [€11,257–€12,318], €12,985 [€12,531-13,443], €15,805 [€15,034–€16,584], and €19,402 [€17,853–€21,017] for indirect costs. Comorbidities had significant additional effects on direct and indirect costs with factors ranging from 1.19 (arthritis) to 1.51 (myocardial infarction) in direct and from 1.16 (myocardial infarction) to 1.27 (cancer) in indirect costs. Conclusion The findings indicate that more severe GOLD grades in an unselected COPD population enrolled in a structured DMP are associated with tremendous additional direct and indirect costs, with comorbidities significantly increase costs. In direct cost category hospitalization and in indirect cost category premature retirement were the main cost driver. From a societal perspective prevention and interventions focusing on disease control, and slowing down disease progression and strengthening the ability to work would be beneficial in order to realize cost savings in COPD.

This study estimates the healthcare costs associated with breast cancer (BC) for different treatment phases (initial, intermediate, terminal) in Germany from the payer’s perspective. The analysis uses claims data from the AOK Bayern covering 2011–2014 for continuously insured BC patients identified through inpatient and outpatient diagnoses. We calculate the healthcare costs attributable to BC using a control group design comparing the target population to a 1:2 matched control group adjusted for age, gender, and comorbidities. For incident and prevalent BC cases, we calculate age-standardized phase-specific incremental costs stratified by cost domain. The initial, intermediate, and terminal phases comprise 3841, 28,315, and 1767 BC cases, respectively. BC-related incremental costs follow a u-shaped curve, with costs highest near diagnosis and death, and lower in between. With average costs of €33,237 per incident and €28,211 per prevalent case in the remaining 11 months before death, the highest BC-related incremental healthcare costs can be found in the terminal phase. In the initial phase, there were mean incremental costs of €21,455 the first 11 months after diagnosis. In the intermediate phase, incremental costs totaled €2851 per incident and €2387 per prevalent case per year. Healthcare costs decreased with age in most phases. The cost drivers depend on the treatment phase, with cytostatic drugs and inpatient treatment showing the highest economic impact in most phases. The study concludes that BC care costs impose a relevant economic burden on statutory health insurance and vary substantially depending on the treatment phase.

Objective Acute myocardial infarction (AMI) carries increased risk of mortality and excess costs. Disease Management Programs (DMPs) providing guideline-recommended care for chronic diseases seem an intuitively appealing way to enhance health outcomes for patients with chronic conditions such as AMI. The aim of the study is to compare adherence to guideline-recommended medication, health care expenditures and survival of patients enrolled and not enrolled in the German DMP for coronary artery disease (CAD) after an AMI from the perspective of a third-party payer over a follow-up period of 3 years. Methods The study is based on routinely collected data from a regional statutory health insurance fund (n = 15,360). A propensity score matching with caliper method was conducted. Afterwards guideline-recommended medication, health care expenditures, and survival between patients enrolled and not enrolled in the DMP were compared with generalized linear and Cox proportional hazard models. Results The propensity score matching resulted in 3870 pairs of AMI patients previously and continuously enrolled and not enrolled in the DMP. In the 3-year follow-up period the proportion of days covered rates for ACE-inhibitors (60.95% vs. 58.92%), anti-platelet agents (74.20% vs. 70.66%), statins (54.18% vs. 52.13%), and β-blockers (61.95% vs. 52.64%) were higher in the DMP group. Besides that, DMP participants induced lower health care expenditures per day (€58.24 vs. €72.72) and had a significantly lower risk of death (HR: 0.757). Conclusion Previous and continuous enrollment in the DMP CAD for patients after AMI is a promising strategy as it enhances guideline-recommended medication, reduces health care expenditures and the risk of death.

Objectives: Patients with chronic obstructive pulmonary disease (COPD) show impairments in health-related quality of life (HRQL). We aimed to find a disease-specific questionnaire for routine application in large cohorts and to assess its additional explanatory power to generic HRQL tool (EQ-5D-5L). Methods: 1,350 participants of the disease management program COPD received the EQ-5D-5L combined with one of the three disease-specific tools: COPD Assessment Test (CAT), Clinical COPD Questionnaire (CCQ) or St. George’s Respiratory Disease Questionnaire (SGRQ) (450 participants each). We compared metric properties and evaluated the Germany-specific experience-based values (EBVS) and utilities in comparison to the Visual Analogue Scale (VAS). We calculated the additional explanatory power of the identified disease-specific tool on VAS through regression analysis. Results: 344 patients returned the questionnaire. CAT, CCQ, and SGRQ group did not differ regarding baseline characteristics. The questionnaire specific response rates were 33.7% for CAT, 30.5% for CCQ, and 34.6% SGRQ, thereof 94.0%, 94.3%, and 65.6% valid answers, respectively. EBVS was better suited to reflect VAS than utilities. CAT increased the explanatory power by 10%. Conclusion: CAT outperformed CCQ and SGRQ, and it increased the explanatory power of VAS. EBV combined with CAT seems superior to only generic or disease-specific approaches.

Evodiae fructus is a widely used herbal drug in traditional Chinese medicine. Evodia extract was found to inhibit hERG channels. The aim of the current study was to identify hERG inhibitors in Evodia extract and to investigate their potential proarrhythmic effects. Dehydroevodiamine (DHE) and hortiamine were identified as I

Inhibition of the human ether-a-go-go-related gene channel is the single most important risk factor leading to acquired long QT syndrome. Drug-induced QT prolongation can cause severe cardiac complications, including arrhythmia, and is thus a liability in drug development. Considering the importance of the human ether-a-go-go-related gene channel as an antitarget and the daily intake of plant-derived foods and herbal products, surprisingly few natural products have been tested for channel blocking properties. In an assessment of possible human ether-a-go-go-related gene liabilities, a selection of widely used herbal medicines and edible plants (vegetables, fruits, and spices) was screened by means of a functional two-microelectrode voltage-clamp assay with Xenopus oocytes. The human ether-a-go-go-related gene channel blocking activity of selected extracts was investigated with the aid of a high-performance liquid chromatography-based profiling approach, and attributed to tannins and alkaloids. Major European medicinal plants and frequently consumed food plants were found to have a low risk for human ether-a-go-go-related gene toxicity.

Dehydroevodiamine (DHE) is a major bioactive constituent in the traditional Chinese herbal drug Evodiae fructus (Wu zhu yu). The compound has been shown to possess pronounced cardiovascular and neuropharmacological activities in vitro and in vivo. For quality control purposes and follow-up studies assessing potential safety risks of DHE, we developed a simple and efficient two-step protocol for gram-scale purification of DHE. An alkaloidal fraction was obtained by cation-exchange solid phase extraction, and DHE and the minor alkaloid hortiamine were purified by isocratic preparative RP-HPLC. The DHE content in different commercial batches of Evodiae fructus, and in a series of commercially available Evodia-containing TCM products was assessed. A daily intake of up to mg amounts of DHE was calculated from recommended doses of these products. A method for the selective removal of quaternary indoloquinazoline alkaloids from Evodia extracts was developed.

Background: Germany provides a wide range of highly developed mental health care to its citizens. The aim of this study was to identify factors influencing the voluntariness of admissions to psychiatric hospitals. Especially the impact of demographic factors of the region, characteristics of the psychiatric hospitals and characteristics of the psychosocial services was analyzed. Method: A retrospective analysis of hospital admission registers from 13 German adult psychiatric hospitals in 2009 was conducted. Public data on the regional psychiatric accommodation and demographic situation were added. Hospitals were dichotomously divided according to their index of involuntary admissions. Group comparisons were performed between the clinics with low and high involuntary admission indices. Analysis was conducted with clinical, psychiatric provision and demographic data related to inpatients in the Landschaftsverbands Westfalen-Lippe (LWL)-PsychiatryNetwork. Results: Especially the range of services provided by the social-psychiatric services in the region such as number of supervised patients and home visits had an influence on the proportion of involuntary admissions to a psychiatric hospital. Some demographic characteristics of the region such as discretionary income showed further influence. Contrary to our expectations, the characteristics of the individual hospital seem to have no influence on the admission rate. Conclusion: Social-psychiatric services show a preventive impact on involuntary acute psychiatry interventions. Sociodemographic factors and patient variables play a role with regard to the number of involuntary hospitalizations, whereas characteristics of hospitals seemed to play no role.

Ziel: In dieser Studie wurden 40 untergebrachte Patienten durchschnittlich 3 Wochen nach erfolgter Zwangsmasnahme zu ihrem Erleben befragt. Methode: Der Fragebogen umfasste 31 Items zu demografischen und krankheitsbezogenen Daten, Modalitaten der Unterbringung, Zwangsmasnahmen im Rahmen der Unterbringung und ihre Empfindung sowie Patientenzufriedenheit. Letzteres wurde bisher nicht detailliert untersucht. Schlussfolgerung: Als fuhrende Emotionen in der Zwangssituation wurden Wut, Arger und Verzweiflung benannt, retrospektiv jedoch auch Verstandnis. Klinisch stabilere Patienten bewerteten das Erlebte insgesamt negativer.

An ethyl acetate extract of Curcuma kwangsiensis S.G. Lee & C.F. Liang (Zingiberaceae) rhizomes (100 μg/ml) enhanced the GABA-induced chloride current ( I GABA ) through GABA A receptors of the α 1 β 2 γ 2S subtype by 79.0 ± 7.0%. Potentiation of I GABA was measured using the two-microelectrode voltage-clamp technique and Xenopus laevis oocytes. HPLC-based activity profiling of the crude extract led to the identification of 11 structurally related labdane diterpenoids, including four new compounds. Structure elucidation was achieved by comprehensive analysis of on-line (LC-PDA-ESI-TOF-MS) and off-line (microprobe 1D and 2D NMR) spectroscopic data. The absolute configuration of the compounds was established by comparison of experimental and calculated ECD spectra. Labdane diterpenes represent a new class of plant secondary metabolites eliciting positive GABA A receptor modulation. The highest efficiency was observed for zerumin A (maximum potentiation of I GABA by 309.4 ± 35.6%, and EC 50 of 24.9 ± 8.8 μM).

Neisseria meningitidis serogroup B strains are responsible for most meningococcal cases in the industrialized countries, and strains belonging to the clonal complex ST-41/44 are among the most prevalent serogroup B strains in carriage and disease. Here, we report the first genome and transcriptome comparison of a serogroup B carriage strain from the clonal complex ST-41/44 to the serogroup B disease strain MC58 from the clonal complex ST-32. Both genomes are highly colinear, with only three major genome rearrangements that are associated with the integration of mobile genetic elements. They further differ in about 10% of their gene content, with the highest variability in gene presence as well as gene sequence found for proteins involved in host cell interactions, including Opc, NadA, TonB-dependent receptors, RTX toxin, and two-partner secretion system proteins. Whereas housekeeping genes coding for metabolic functions were highly conserved, there were considerable differences in their expression pattern upon adhesion to human nasopharyngeal cells between both strains, including differences in energy metabolism and stress response. In line with these genomic and transcriptomic differences, both strains also showed marked differences in their in vitro infectivity and in serum resistance. Taken together, these data support the concept of a polygenic nature of meningococcal virulence comprising differences in the repertoire of adhesins as well as in the regulation of metabolic genes and suggest a prominent role for immune selection and genetic drift in shaping the meningococcal genome.

DNA microarray technology has already revolutionized basic research in infectious diseases, and whole-genome sequencing efforts have allowed for the fabrication of tailor-made spotted microarrays for an increasing number of bacterial pathogens. However, the application of microarrays in diagnostic microbiology is currently hampered by the high costs associated with microarray experiments and the specialized equipment needed. Here, we show that a thorough bioinformatic postprocessing of the microarray design to reduce the amount of unspecific noise also allows the reliable use of spotted gene expression microarrays for gene content analyses. We further demonstrate that the use of only single-color labeling to halve the costs for dye-labeled nucleotides results in only a moderate decrease in overall specificity and sensitivity. Therefore, gene expression microarrays using only single-color labeling can also reliably be used for gene content analyses, thus reducing the costs for potential routine applications such as genome-based pathogen detection or strain typing.

Inhibition of the cardiac human ether-a-go-go-related gene channel is a problematic off-target pharmacological activity and, hence, a major safety liability in clinical practice. Several non-cardiac drugs have been restricted in their use, or even removed from the market due to this potentially fatal adverse effect. Comparatively little is known about the human ether-a-go-go-related gene inhibitory potential of plant-derived compounds. In the course of an ongoing human ether-a-go-go-related gene in vitro study, a total of 32 structurally diverse alkaloids of plant origin as well as two semi-synthetically obtained protoberberine derivatives were screened by means of an automated Xenopus oocyte assay. Protopine, (+)-bulbocapnine, (+)-N-methyllaurotetanine, (+)-boldine, (+)-chelidonine, (+)-corynoline, reserpine, and yohimbine reduced the human ether-a-go-go-related gene current by ≥ 50 % at 100 µM, and were submitted to concentration-response experiments. Our data show that some widely occurring plant-derived alkaloids carry a potential risk for human ether-a-go-go-related gene toxicity.

As a part of the health care reform 2007 the German risk structure compensation scheme was extended so as to connect the financial cash flow towards the payers to morbidity information from ambulatory care. Within this context, morbidity information consists of prescriptions as well as coded ambulatory diagnoses. Accordingly, a high quality of coding is essential for a morbidity compatible allocation of funds. The aim of this study was to evaluate coding quality via qualifying characters as well as to identify future challenges. It focuses on diagnoses which are qualified as "assured" or "post-treatment" from about 350 million diagnoses of about 11 k practitioners' treatment of 2.7 million AOK PLUS insurants in Saxony and Thuringia during the years 2007-2010. The practitioners' documented diagnoses were aggregated within several groups according to the code of specialisation which is attached to the practitioner's 9-digit lifelong identification number (LANR). As a result, the number of "assured" diagnoses generally rose from year to year. Furthermore, diagnoses marked as "assumption" or "exclusion" remain constant over time. We identified a lack of diagnosis coding precision regarding the condition after certain medical events. In particular, general practitioners tend to use diagnosis codes qualified as "post-treatment" instead of using correct "assured" diagnoses qualified for conditions after certain events. Consequently, we expect adverse effects evaluating the cost of diseases as only "assured" diagnoses are considered within the risk transfer compensation scheme.

This study evaluated involuntarily admitted psychiatric patients' and their perception of coercive measures (i. e. involuntary admission and physical or pharmacological restraint) by asking retrospectively which emotions were induced during the process of coercion.Interviews were carried out around 3 weeks after coercion. The interview consisted of 31 items categorized into demographic, nosological and coercion-related themes. Patients were also asked about their subjective experiences of the coercion. 40 patients were recruited, with 72 % suffering from psychosis-related and 21 % with affective disorders. For 22.5 % of the patients, this was their first psychiatric hospitalization. The most frequently reported emotions were rage, anger and despair. Patients who were more stable, according to the Clinical Global Impressions scale (CGI), generally evaluated the coercion as being worse.More than half of the patients were satisfied with the treatment received during hospitalization. The potential suffering caused as a result of patients' perceptions of the coercion, and the impact of this on the course of the disease should be taken into account when developing new treatment strategies.

As in many other areas of basic and applied biology, research in infectious diseases has been revolutionized by two recent developments in the field of genome biology: first, the sequencing of the human genome as well as that of many pathogen genomes; and second, the development of high-throughput technologies such as microarray technology, proteomics, and metabolomics. Microarray studies enable a deeper understanding of genetic evolution of pathogens and investigation of determinants of pathogenicity on a whole-genome scale. Host studies in turn permit an unprecedented holistic appreciation of the complexities of the host cell responses at the molecular level. In combination, host-pathogen studies allow global analysis of gene expression in the infecting bacterium as well as in the infected host cell during pathogenesis providing a comprehensive picture of the intricacies of pathogen-host interactions. This chapter briefly explains the principles underlying DNA microarrays including major points to consider when planning and analyzing microarray experiments and highlights in detail their practical application using the interaction of Neisseria meningitidis with endothelial cells as an example.

The most prominent determinant of acquired long QT syndrome is inhibition of the hERG potassium channel. Drug-induced QT prolongation can cause undesirable cardiac side effects and has led to several drug withdrawals in the past. In contrast to synthetic drugs, little is known about hERG channel inhibitors of natural origin. For assessing the risk of natural products on hERG channel inhibition, extracts obtained from frequently consumed spices, food, and medicinal plants were submitted to a broad in vitro screening. We established an HPLC-based activity profiling approach for this target by combining HPLC-microfractionation with on-line and off-line spectroscopy, and an automated two-microelectrode voltage clamp assay with transfected Xenopus laevis oocytes. Among the extracts tested, the methanolic extract of the TCM herbal drug Evodiae Fructus (Evodia rutaecarpa [Juss.] Benth., Rutaceae) reduced the peak tail hERG current by 60.9±6.9% at 100µg/mL. HPLC-based activity profiling of the crude extract led to the identification of dehydroevodiamine and hortiamine, two indoloquinazoline alkaloids, as the active principles. First information on structure activity relationships revealed that both the methyl group at position 14 and the double bond between C(13b) and N(14) are essential for the inhibitory effect of this compound class. We developed a method for removal of both inhibitory alkaloids by filtration over a cation exchange resin (Lewatit® MonoPlus SP 112). The resulting extract was devoid of hERG channel blocking activity. Moreover, we determined the dehydroevodiamine content in different commercial batches of Evodiae Fructus and in various processed TCM products. Keywords: hERG channel inhibition, herbal extracts, Evodia rutaecarpa, Rutaceae, HPLC-based activity profiling, indoloquinazoline alkaloids

Inhibition of the hERG channel delays repolarization and prolongs the QT interval and cardiac action potential which can lead to sudden death. Several drugs have been withdrawn from the market due to hERG channel inhibition. In the search of hERG channel inhibitors of natural origin, we established an HPLC-based profiling approach which combines HPLC-microfractionation and bioactivity testing on Xenopus laevis oocytes. The methanolic extract of the TCM herbal drug Coptidis rhizoma (Coptis chinensis Franch., Ranunculaceae) reduced the peak tail hERG current by 31.7 ± 2.0% at 100 µg/mL. HPLC-based activity profiling pointed towards berberine as the active constituent. However, hERG inhibition by 100 µM of a reference sample of berberine (16.3 ± 1.6%) was less pronounced than previously reported. Subsequent LC-PDA-MS analysis showed that berberine collected by microfractionation of the Coptis extract had been, in part, transformed to active dihydroberberine. Formic acid added to the HPLC mobile phase to reduce peak tailing of protoberberine alkaloids acted as a reducing reagent according to the mechanism of the Leuckart-Wallach reaction. Among other structurally related protoberberines tested, dihydroberberine (30.1 ± 10.1% at 100 µM) was the most potent hERG inhibitor.

Neisseria meningitidis is a leading cause of infectious childhood mortality worldwide. Most research efforts have hitherto focused on disease isolates belonging to only a few hypervirulent clonal lineages. However, up to 10% of the healthy human population is temporarily colonized by genetically diverse strains mostly with little or no pathogenic potential. Currently, little is known about the biology of carriage strains and their evolutionary relationship with disease isolates. The expression of a polysaccharide capsule is the only trait that has been convincingly linked to the pathogenic potential of N. meningitidis . To gain insight into the evolution of virulence traits in this species, whole-genome sequences of three meningococcal carriage isolates were obtained. Gene content comparisons with the available genome sequences from three disease isolates indicate that there is no core pathogenome in N. meningitidis . A comparison of the chromosome structure suggests that a filamentous prophage has mediated large chromosomal rearrangements and the translocation of some candidate virulence genes. Interspecific comparison of the available Neisseria genome sequences and dot blot hybridizations further indicate that the insertion sequence IS 1655 is restricted only to N. meningitidis ; its low sequence diversity is an indicator of an evolutionarily recent population bottleneck. A genome-based phylogenetic reconstruction provides evidence that N. meningitidis has emerged as an unencapsulated human commensal from a common ancestor with Neisseria gonorrhoeae and Neisseria lactamica and consecutively acquired the genes responsible for capsule synthesis via horizontal gene transfer.

localized sources that are possible targets for radiofrequency ablation (RFA). However, accurate identification of AF drivers in the 3D atrial structure may require simultaneous epi/endocardial (Epi/Endo) mapping. Methods: Coronary perfused human right atria (RA, n 1⁄4 6, 35–72 years) were optically mapped simultaneously by 3 high-resolution CMOS cameras (2 aligned Epi/Endo views, 3.3 3.3 cm, and 1 entire Endo view, 9 9 cm) with near-infrared dye. Sustained AF was induced by burst pacing during 10– 100 mM pinacidil (n 1⁄4 6). The AF driver was defined in the area of highest dominant frequency as a stable repetitive source of fibrillatory conduction. Results: Dual-sided intramural mapping revealed the common mechanism of sustained AF (430 minutes) in all 6 RA was a single, spatially and temporally stable, leading reentrant driver in the pectinate muscle region. Reentrant circuits (11.7 5 3.1 2 5.0 3 mm, 93 44 ms cycle length [CL]) had 2 limbs and intramural pivot points or “U turns” in conduction, creating stable patterns seen from sub-Endo but not sub-Epi. Endo RFA through pivot points consecutively organized (þ10% CL, n 1⁄4 5) and/or terminated AF (n 1⁄4 11). Attempts to reinduce AF resulted in slower AF drivers in different locations (0–2 per RA) or macroreentrant AT around the ablation lesion that was terminated by further ablation (n 1⁄4 3). Conclusions: Our integrative mapping study demonstrates, for the first time, that stable intramural reentry may drive AF in the human heart. Furthermore, this study represents a proof of concept that targeted ablation of localized drivers may successfully treat AF.