Search

Hintergrund Der Gemeinsame Bundesausschuss (G-BA) fuhrt fur alle neu zugelassenen Arzneimittel eine (Zusatz)Nutzenbewertung durch (vgl. § 35a SGB V). Fur Arzneimittel zur Behandlung seltener Erkrankungen (sogenannte Orphan Drugs [OD]) gelten einige Sonderregeln. Methodik Anhand offentlich zuganglicher Dokumente auf der Homepage des G-BA sowie der Fachinformationen erfolgte eine deskriptive Analyse der von September 2011 bis Juni 2016 abgeschlossenen OD Verfahren. Die Datenextraktion umfasste dabei u. a. den Studientyp der zulassungsbegrundenden Studie, den primaren Endpunkt und die Einschatzung dessen Patientenrelevanz, die in der Nutzenbewertung festgestellte Nutzenkategorie (nicht quantifizierbar, gering, betrachtlich, erheblich) sowie die Erfassung der Lebensqualitat. Ergebnisse Insgesamt wurden 36 Verfahren (47 Anwendungsgebiete [AWG]) analysiert. Auf Verfahrensebene dienten 16 der bewerteten ODs der Behandlung von onkologischen Erkrankungen, 11 der Therapie von Stoffwechselkrankheiten, und 9 der Behandlung von sonstigen Erkrankungen. Bei ca. 83% der Verfahren (70% der AWG) lag mind. eine randomisiert kontrollierte Studie vor. Bei 26 Verfahren (29 AWG) bewertete der G-BA den primaren Endpunkt der Zulassungsstudie als nicht patientenrelevant. 64% der OD Zulassungsstudien enthielten Ergebnisse zur Lebensqualitat. Daten zu diesen Endpunkten lagen haufig jedoch eingeschrankt vor. Bei 19 OD Verfahren wurde das Ausmas des Zusatznutzen vom G-BA als nicht quantifizierbar, bei 14 Verfahren als gering und bei einem Verfahren als betrachtlich eingestuft. Bei 2 weiteren Verfahren wurden jeweils 2 Subgruppen unterschieden. In dem ersten Verfahren wurden jeweils ein geringer und ein betrachtlicher Zusatznutzen und in dem zweiten Verfahren wurden ein geringer und ein nicht quantifizierbarer Zusatznutzen festgestellt. Schlussfolgerung Nach den bisherigen Erfahrungen mit der wertung von OD im G-BA zeigt sich, dass fur 70% der zugelassenen Anwendungsgebiete Daten aus RCTs vorliegen, d. h. dass ein randomisiertes Studiendesign auch bei seltenen Erkrankungen moglich ist. Bei unzureichender Evidenzlage, v. a. wenn keine RCTs durchgefuhrt wurden, resultiert oftmals eine Befristung des Beschlusses. Unterschiedliche Auffassungen bestehen derzeit noch bei der Einschatzung der Patientenrelevanz einer Reihe von primaren Endpunkten. Daten zu Lebensqualitats-Endpunkten mussen besser berichtet werden, damit ein Einbezug zur Bestimmung des Zusatznutzens moglich wird. Background The Federal Joint Committee (G-BA) performs an (additional) benefit assessment (see § 35a SGB V) of all newly approved drugs. For drugs treating rare diseases (so-called orphan drugs [OD]), some special rules apply. The legislature has specified that an additional medical benefit is already considered proven upon approval of the drug [and the G-BA only evaluates its extent]. Methodology We conducted an analysis of all OD assessments completed between 09/2011 and 06/2016 using publicly available documents from the G-BA website as well as Summary of Product Characteristics documents. Data extracted included study type of the pivotal studies, the primary endpoint and an assessment of its relevance to patients, the extent of additional benefit as given by the benefit assessment category (non-quantifiable, minor, considerable, major), and the assessment of patient quality of life. Results A total of 36 assessments (47 therapeutic indications) were analyzed. 16 ODs were for treatment of oncological diseases, 11 for metabolic diseases, and 9 for treatment of other diseases. In 83% of the procedures (70% of the therapeutic indications), there was at least one randomized controlled trial. In 26 procedures (29 therapeutic indications), the G-BA assessed the primary endpoint of the pivotal trial as not patient relevant. Almost all OD pivotal studies reported results on quality of life. However, data on these endpoints were often limited. For 19 OD procedures, the extent of the additional benefit as determined by the G-BA was non-quantifiable, 14 procedures had a minor additional benefit and one procedure had a considerable additional benefit. In 2 other procedures, 2 subgroups were distinguished, one with a minor and a considerable additional benefit and the other with a minor and non-quantifiable additional benefit. Conclusion The experience with the evaluation of OD in G-BA shows that about 70% of the approved therapeutic indications have data from RCTs. Thus, a randomized study design is also possible for rare diseases. In case of insufficient evidence, especially when no RCTs were carried out, the decision is often a limited. Pharmaceutical entrepreneurs and the G-BA disagree over the assessment of the relevance to patients of a number of primary endpoints. Data on quality of life endpoints must be better reported in order to enable their inclusion in the benefit assessments.

Der Gemeinsame Bundesausschuss (G-BA) führt für alle neu zugelassenen Arzneimittel eine (Zusatz)Nutzenbewertung durch (vgl. § 35a SGB V). Für Arzneimittel zur Behandlung seltener Erkrankungen (sogenannte Orphan Drugs [OD]) gelten einige Sonderregeln.Anhand öffentlich zugänglicher Dokumente auf der Homepage des G-BA sowie der Fachinformationen erfolgte eine deskriptive Analyse der von September 2011 bis Juni 2016 abgeschlossenen OD Verfahren. Die Datenextraktion umfasste dabei u. a. den Studientyp der zulassungsbegründenden Studie, den primären Endpunkt und die Einschätzung dessen Patientenrelevanz, die in der Nutzenbewertung festgestellte Nutzenkategorie (nicht quantifizierbar, gering, beträchtlich, erheblich) sowie die Erfassung der Lebensqualität.Insgesamt wurden 36 Verfahren (47 Anwendungsgebiete [AWG]) analysiert. Auf Verfahrensebene dienten 16 der bewerteten ODs der Behandlung von onkologischen Erkrankungen, 11 der Therapie von Stoffwechselkrankheiten, und 9 der Behandlung von sonstigen Erkrankungen. Bei ca. 83% der Verfahren (70% der AWG) lag mind. eine randomisiert kontrollierte Studie vor. Bei 26 Verfahren (29 AWG) bewertete der G-BA den primären Endpunkt der Zulassungsstudie als nicht patientenrelevant. 64% der OD Zulassungsstudien enthielten Ergebnisse zur Lebensqualität. Daten zu diesen Endpunkten lagen häufig jedoch eingeschränkt vor. Bei 19 OD Verfahren wurde das Ausmaß des Zusatznutzen vom G-BA als nicht quantifizierbar, bei 14 Verfahren als gering und bei einem Verfahren als beträchtlich eingestuft. Bei 2 weiteren Verfahren wurden jeweils 2 Subgruppen unterschieden. In dem ersten Verfahren wurden jeweils ein geringer und ein beträchtlicher Zusatznutzen und in dem zweiten Verfahren wurden ein geringer und ein nicht quantifizierbarer Zusatznutzen festgestellt.Nach den bisherigen Erfahrungen mit der wertung von OD im G-BA zeigt sich, dass für 70% der zugelassenen Anwendungsgebiete Daten aus RCTs vorliegen, d. h. dass ein randomisiertes Studiendesign auch bei seltenen Erkrankungen möglich ist. Bei unzureichender Evidenzlage, v. a. wenn keine RCTs durchgeführt wurden, resultiert oftmals eine Befristung des Beschlusses. Unterschiedliche Auffassungen bestehen derzeit noch bei der Einschätzung der Patientenrelevanz einer Reihe von primären Endpunkten. Daten zu Lebensqualitäts-Endpunkten müssen besser berichtet werden, damit ein Einbezug zur Bestimmung des Zusatznutzens möglich wird.The Federal Joint Committee (G-BA) performs an (additional) benefit assessment (see § 35a SGB V) of all newly approved drugs. For drugs treating rare diseases (so-called orphan drugs [OD]), some special rules apply. The legislature has specified that an additional medical benefit is already considered proven upon approval of the drug [and the G-BA only evaluates its extent].We conducted an analysis of all OD assessments completed between 09/2011 and 06/2016 using publicly available documents from the G-BA website as well as Summary of Product Characteristics documents. Data extracted included study type of the pivotal studies, the primary endpoint and an assessment of its relevance to patients, the extent of additional benefit as given by the benefit assessment category (non-quantifiable, minor, considerable, major), and the assessment of patient quality of life.A total of 36 assessments (47 therapeutic indications) were analyzed. 16 ODs were for treatment of oncological diseases, 11 for metabolic diseases, and 9 for treatment of other diseases. In 83% of the procedures (70% of the therapeutic indications), there was at least one randomized controlled trial. In 26 procedures (29 therapeutic indications), the G-BA assessed the primary endpoint of the pivotal trial as not patient relevant. Almost all OD pivotal studies reported results on quality of life. However, data on these endpoints were often limited. For 19 OD procedures, the extent of the additional benefit as determined by the G-BA was non-quantifiable, 14 procedures had a minor additional benefit and one procedure had a considerable additional benefit. In 2 other procedures, 2 subgroups were distinguished, one with a minor and a considerable additional benefit and the other with a minor and non-quantifiable additional benefit.The experience with the evaluation of OD in G-BA shows that about 70% of the approved therapeutic indications have data from RCTs. Thus, a randomized study design is also possible for rare diseases. In case of insufficient evidence, especially when no RCTs were carried out, the decision is often a limited. Pharmaceutical entrepreneurs and the G-BA disagree over the assessment of the relevance to patients of a number of primary endpoints. Data on quality of life endpoints must be better reported in order to enable their inclusion in the benefit assessments.

GRADE suggests that examination of 95% confidence intervals (CIs) provides the optimal primary approach to decisions regarding imprecision. For practice guidelines, rating down the quality of evidence (i.e., confidence in estimates of effect) is required when clinical action would differ if the upper versus the lower boundary of the CI represented the truth. An exception to this rule occurs when an effect is large, and consideration of CIs alone suggests a robust effect, but the total sample size is not large and the number of events is small. Under these circumstances, one should consider rating down for imprecision. To inform this decision, one can calculate the number of patients required for an adequately powered individual trial (termed the "optimal information size" or OIS). For continuous variables, we suggest a similar process, initially considering the upper and lower limits of the CI, and subsequently calculating an OIS. Systematic reviews require a somewhat different approach. If the 95% CI excludes a relative risk (RR) of 1.0 and the total number of events or patients exceeds the OIS criterion, precision is adequate. If the 95% CI includes appreciable benefit or harm (we suggest a RR of under 0.75 or over 1.25 as a rough guide) rating down for imprecision may be appropriate even if OIS criteria are met.

Introduction The Finnish prevention policy as well as the Finnish preventative interventions are widely recognized as a model for other countries. This qualitative interview study has the objective of shedding light on the political, organizational and scientific framework of their success. Methods In 2008, qualitative interviews with twelve experts from political institutions and research institutes from all over Finland were conducted in Helsinki and Tampere. Results Experts point out the close interaction between science and policy as the key element for the success of regional and national prevention campaigns. Furthermore, they refer to the institutional structure as its base, i.e. institutions focus on the prevention and promotion of health under the joint patronage of the Finnish Ministry of Social Affairs and Health. Researchers, health politicians and representatives from the food industry promote dietary recommendations conjointly under the auspices of the National Nutrition Council. Experts also point out a lack of coordination among projects. They regret that too often, projects are done side by side without any coordination. Especially with regard to prevention, experts regret that current campaigns are not tailored to target groups. For the future, experts stress the importance of evaluation and coordination in the area of prevention. Conclusions The administrative structure of health care in Finland facilitates an extensive collaboration of public health policy and public health research. Experts press for a strategy of multisectorial collaboration and connection of existing projects to strengthen prevention at national level. In addition, information material should be tailored to individual target groups.

Background: The role of passive smoking for allergies and asthma in children above the age of 3 years remains unclear and possible interactive effects with parental allergies have not been formally evaluated in long-term studies. To examine the interaction of passive smoking and an allergic predisposition regarding allergic sensitization, allergic airway symptoms and respiratory infections during the first 10 years of life. Methods: In a prospective multicenter birth cohort study with 1314 recruited children in Germany, we assessed serum immunoglobulin E against common allergens at seven time points, and parental smoking and respiratory symptoms annually by using questionnaires. Longitudinal analyses were performed using generalized estimating equation models (stratified by parental allergy status). Results: During the first 10 years, 18% of the children were exposed to regular maternal smoking since pregnancy, 43% to irregular maternal or only paternal smoking. Among children with two allergic parents, a mother who smoked regularly significantly increased the odds for allergic sensitization (adjusted OR 4.8, 95% CI 1.3–18.2) and wheezing (adjusted OR 5.7, 95% CI 1.7–19.0) in her child compared with children who were never exposed. For those with only one allergic parent, the odds were doubled and also statistically significant, whereas in children without allergic parents maternal smoking had no effects. There was no association of maternal smoking with allergic rhinitis or respiratory infections. Conclusions: Our results suggest that regular maternal smoking is a strong risk factor for allergic sensitization and asthma symptoms during the first 10 years of life, but only in children with allergic parents.

Background Coverage decisions determining the benefit baskets of health systems have been increasingly relying on evidence regarding patient benefit and costs. Relevant structures, methodologies, and processes have especially been established for pharmaceuticals but approaches differ. The objective of this work was thus to identify institutions in a broad range of European countries (n = 36) in charge of determining the value of pharmaceuticals for pricing and reimbursement purposes and to map their decision-making process; to examine the different approaches and consider national and supranational possibilities for best practice. Methods Institutions were identified through websites of international networks, ministries, and published literature. Details on institutional practices were supplemented with information from institution websites and linked online sources. Results The type and extent of information available varied considerably across countries. Different types of public regulatory bodies are involved in pharmaceutical coverage decisions, assuming a range of responsibilities. As a rule, the assessment of scientific evidence is kept structurally separate from its appraisal. Recommendations on value are uniformly issued by specific committees within or commissioned by responsible institutions; these institutions often also act as decision-makers on reimbursement status and level or market price. While effectiveness and costs are important criteria in all countries, the latter are often considered on a case-by-case basis. In all countries, manufacturer applications, including relevant evidence, are used as one of the main sources of information for the assessment. Conclusion Transparency of evidence-based coverage decisions should be enhanced. International collaboration can facilitate knowledge exchange, improve efficiency of information production, and strengthen new or developing systems. Electronic supplementary material The online version of this article (doi:10.1186/s12961-015-0028-5) contains supplementary material, which is available to authorized users.

BACKGROUND: The Global Allergy and Asthma European Network (GA2LEN) is a consortium of 26 leading European research centres committed to establish a European research area of excellence in the field of allergy and asthma. AIM: One of the GA2LEN work packages was designed to identify and compare the existing European birth cohort studies on asthma and atopic diseases. The present review compares their subjective and objective outcomes as well as exposure variables. METHODS: A common database was established to assess study characteristics of observational birth cohort studies designed to examine asthma and atopic diseases. Data were collected by visiting most of the participating research teams and interviewing all relevant study personnel. For each study, the type of objective/subjective outcome parameters and potentially influential factors were recorded precisely for every time point during follow-up. RESULTS: Eighteen birth cohort studies on asthma and atopic diseases were identified in eight European countries. Thirteen studies collected data on specific immunoglobulin E (IgE) to various inhalant and food allergens, whereas 12 performed skin prick tests (many at several time points during follow up). Several studies measured lung function, but across the cohorts no comparable standard procedures were used. For subjective evaluation of asthma and allergic rhinitis most studies applied the ISAAC questionnaire (sometimes modified), whereas the assessment of eczema was rather heterogeneous across the studies. CONCLUSION: This GA2LEN initiative established a unique common database of 18 European birth cohorts on asthma and atopic diseases. For selected cohorts, it seems that pooling data and performing common analyses may be possible to examine associations between certain exposure variables (e.g. pet ownership, tobacco smoke exposure and day-care) and selected outcome measures for atopy, asthma or allergic rhinitis (e.g. sensitization assessed by IgE or skin prick tests, doctor's diagnosis of asthma, parental perception regarding asthma/wheezing or hay fever symptoms).

Background Gastro-oesophageal reflux disease can be associated with extra-oesophageal reflux disease such as chronic cough or laryngeal symptoms. The aim of this study was to analyse the clinical course of extra-oesophageal reflux disease in a large population with gastro-oesophageal reflux disease and extra-oesophageal reflux disease under routine clinical care. Methods ProGERD is a prospective multicentre cohort study of 6215 outpatients with gastro-oesophageal reflux disease. At baseline all patients underwent endoscopies and were interviewed for extra-oesophageal reflux disease. Initial standardised treatment was esomeprazole for up to 8 weeks. After 2 years of follow-up, reflux symptoms and the prevalence of extra-oesophageal reflux disease were assessed. A multivariate analysis was performed with resolved versus persistent symptoms for chronic cough and laryngeal symptoms as dependent predictors. Independent variables were gender, age, body mass index (BMI), alcohol consumption, cigarette smoking, gastro-oesophageal reflux disease classification, history of gastro-oesophageal reflux disease in the family, duration of gastro-oesophageal reflux disease and proton pump inhibitors medication. Results Four thousand four hundred and four patients (71%) were available for analysis at 2 years, including 570 and 454 patients who had chronic cough and laryngeal disorders at baseline, respectively. In 63% and 74% of the patients, chronic cough and laryngeal disorders had resolved. Patients with persistent respiratory symptoms in year 2 had significantly more reflux symptoms. Further clinically relevant associations were smoking and non-steroidal anti-inflammatory drugs use. According to the multivariate analysis, classification of gastro-oesophageal reflux disease, proton pump inhibitors medication or duration of gastro-oesophageal reflux disease were not associated with the resolution of cough or laryngeal symptoms. Conclusion In most patients with gastro-oesophageal reflux disease and extra-oesophageal reflux disease, respiratory symptoms resolve during long-term routine care. A high reflux symptom load was associated with the persistence of respiratory disorders.

Background: The reasons for the rise in asthma and allergies remain unclear. To identify risk or protective factors, it is essential to carry out longitudinal epidemiological studies, preferably birth cohort studies. In Europe, several birth cohort studies on asthma and atopic diseases have been initiated over the last two decades. Aim: One of the work packages within the Global Allergy and Asthma European Network (GA 2 LEN) project was designed to identify and compare European birth cohorts on asthma and atopic diseases. The present review (part I) describes their objectives, study settings, recruitment process and follow-up rates. A subsequent review (part II) will compare outcome and exposure parameters. Methods: For each birth cohort, we collected detailed information regarding recruitment process, study setting, baseline data (pregnancy, birth, parents/siblings) as well as follow-up rates, outcome and exposure parameters at each time point. Results: We identified and assessed 18 European birth cohorts on asthma, allergic rhinitis and eczema. Six of these studies also focused on food allergies. The birth cohorts were mostly initiated in the 1990s with predominantly urban/ metropolitan settings. Many studies were able to maintain high follow-up rates, even after five or more years. Conclusions: Due to the unique cooperation within the GA 2 LEN project a common database was established containing study characteristics of European birth cohorts on asthma and atopic diseases. This can be used as a basis for evaluating the possibility to pool data and perform meta-analyses, as well as to recommend criteria for conducting future birth cohorts.

Summary Background Gastro-oesophageal reflux disease (GERD) is a common and frequently chronic condition that causes considerable costs. Aim To estimate the economic burden caused by patients with erosive and non-erosive reflux disease, and Barrett's oesophagus. Methods The Progression of Gastro-oesophageal Reflux Disease study includes a total of 6215 patients. At baseline, patients were categorized as non-erosive reflux disease, erosive reflux disease, or Barrett's oesophagus according to endoscopic findings alone or as confirmed by histology. Direct and indirect disease-related costs were calculated based on 5273 patients with complete information in the second year of the study. Results A total of 73% of the Progression of Gastro-oesophageal Reflux Disease patients had taken GERD medication, 61% had visited a doctor, and 2% had been hospitalized because of GERD during the previous 12 months. Of all employed persons, 6% reported days off work because of GERD. This health resource utilization caused direct costs of €342 ± 864 (mean ± s.d.) and indirect costs of €40 ± 473 per patient and year. Total costs for patients with Barrett's oesophagus or erosive reflux disease were higher than those for patients with non-erosive reflux disease. Conclusion Patients with GERD frequently need long-term medication and doctor care. The disorder is associated with a considerable health economic burden to society.

Background: Double-blind, placebo-controlled food challenges are time-consuming, expensive and not without risk to patients. Therefore, an in vitro test that could accurately diagnose food allergy would be of great value. Objective: To evaluate the utility of the ratio of specific immunoglobulin E (IgE)/total IgE compared with specific IgE (sIgE) alone in predicting symptomatic food allergy. Methods: We retrospectively analysed 992 controlled oral food challenges performed in 501 children (median age 13 months). The ratio of sIgE/total IgE was calculated and tested for correlation with the outcome of food challenges. Receiver operator characteristics (ROC)-curves were performed; predicted probabilities and predictive decision points were calculated. Results: A significant correlation was found between the ratio and the outcome of food challenges for cow's milk (CM), hen's egg (HE), and wheat, but not for soy. The ROC and predicted probability curves as well as sensitivity and specificity of the decision points of the ratio were similar to those of sIgE levels for CM, HE and wheat. Conclusion: In view of the greater effort needed to determine the ratio, without benefit compared with the sIgE alone, the calculation of the ratio of sIgE/total IgE for diagnosing symptomatic food allergy offers no advantage for CM, HE, wheat or soy. For the majority of cases controlled oral food challenges still remain the method of choice.

Mortality rates from ischaemic heart disease have consistently been higher in East compared to West Germany both prior to and since reunification. Coronary care is inversely related to mortality from ischaemic heart disease. The objective of the present study was, therefore, to compare cardiovascular medication in East and West German patients following cardiac rehabilitation.East German (n = 530) and West German (n = 1638) patients were included at admission to one of 18 rehabilitation centres. Inclusion criteria were myocardial infarction, coronary artery bypass grafting and percutaneous transluminal coronary angioplasty. The follow-up period was 12 months.At admission, East and West German patients differed with regard to sociodemographic variables, risk factors and medical conditions. At 12 months, a higher percentage of West compared to East German patients were prescribed beta-blockers (71% vs. 65%, P = 0.04) and lipid-lowering agents (64% vs. 55%, P = 0.002). Angiotensin converting enzyme (ACE) inhibitors, on the other hand, were prescribed more frequently in the East compared to the West (60% vs. 48%, P0.001). In multivariable analyses, region of residence remained a significant predictor for the prescription of lipid-lowering agents (East vs. West: OR 0.61, 95% CI 0.46-0.81) and ACE inhibitors (East vs. West: OR 1.78, 95% CI 1.33-2.39).There is a considerable variation in the prescription of cardiovascular medication in secondary prevention within Germany. Some, but not all, of this variation can be explained by differences in patient characteristics.

Objective We describe the validation of a German-language version of the Reflux Disease Questionnaire in what is the first validation study of this patient questionnaire for a non-English speaking population. Gastro-oesophageal reflux disease is one of the most common diseases in primary care and has a significant negative impact on patients' quality of life. There is no gold standard for diagnosing gastro-oesophageal reflux disease, however, so the valid assessment of symptoms is especially important. Design and methods A total of 5689 patients (92%) completed the questionnaire both before treatment and after 2 weeks. The results were tested for validity and reliability. Predictive validity was tested in a pilot study of 100 patients. Convergent validity was examined using the Quality of Life in Reflux and Dyspepsia Questionnaire for the assessment of disease-specific quality of life and the McMaster Overall Treatment Evaluation for the assessment of therapeutic success. Results Principal component analysis suggested a three-factor solution with the subscores heartburn, regurgitation, and dyspepsia. The internal consistencies of the subscores were between 0.84 and 0.86. Item difficulty ranged from 0.33 to 0.53, and corrected item-total correlation from 0.66 to 0.72. Effect sizes were between 0.8 and 1.0. Conclusion The German version of the questionnaire has good psychometric properties and is responsive to changes in health. Thus, we conclude that the German Reflux Disease Questionnaire is suitable for the assessment of heartburn, regurgitation, and treatment response, both in primary care settings and clinical studies.

Reprise du travail apres une readaptation cardiologique Objectif: L'objectif de l'etude etait d'analyser la reprise du travail apres une readaptation cardiologique et de determiner les facteurs associes avec la reprise du travail. Methodes: Les patients ont ete inclus a l'admission aux Services pour readaptation participants (n = 18). Les indications primaires pour l'admission etaient un infarctus du myocarde, un pontage aorto-coronaire ou une angioplastie coronaire. Resultats: Parmi les 2441 patients inclus, 1907 etaient de sexe masculin avec un âge moyen de 60 ′ 10 ans, et 534 de sexe feminin avec un âge moyen de 65 ′ 10 ans. Avant la readaptation, 43% des patients travaillaient. Six mois apres l'hospitalisation, 65 % des patients ont repris leur travail et 12 mois apres l'hospitalisation 67%. La reprise du travail apres 12 mois a ete significativement associee avec l'âge jeune, un travail non-physique, un travail independant, une meilleure qualite de vie physique et mentale et un bon resultat de l'epreuve d'effort. Conclusions: La reprise du travail a ete associee avec des facteurs socio-demographiques, la qualite de vie et le resultat de l'epreuve d'effort. La determination des facteurs associes avec la reprise du travail peut faciliter l'identification des patients avec un risque augmente de ne pas reprendre leur travail.

Summary Aims : To determine the impact of gastro-oesophageal reflux disease (GERD) on the quality of life, to assess changes in the quality of life during treatment with esomeprazole and to define factors that can predict these changes. Methods : Patients with GERD (n = 6215) were included in a prospective cohort study (ProGERD). All patients underwent endoscopy and received esomeprazole. At baseline and after 2 weeks of treatment, symptoms and quality of life were assessed. Factors that influenced changes in the quality of life were determined by multiple regression analyses. Results : At baseline, the quality of life in GERD patients was lower than that in the general population, and was similar to that in patients after acute coronary events. No differences in symptoms or quality of life were observed between the subgroups of patients with non-erosive GERD, erosive GERD and Barrett's oesophagus. After treatment with esomeprazole, the symptoms and quality of life were improved in all subscales within 2 weeks (P

Background: Guidelines (GLs) for the management of heart failure (HF) are of great importance in order to define and disseminate therapeutic recommendations based on scientific evidence. The aim was to analyse and to compare the methodological quality of HF GLs as well as to evaluate the consistency of therapeutic recommendations. Methods: Eleven international GLs for the management of chronic HF were identified by search of the internet, electronic databases and references of published literature. Their methodological quality was assessed by two different appraisal instruments: (1) according to the US National Guideline Clearinghouse (NGC) on a scale from 0 to 17 points, (2) according to the German Guideline Clearinghouse (Agency for Quality in Medicine, AQUMED) on a scale from 0 to 44 points. Clinical criteria for assessment of the consistency of the recommendations included diagnostic testing, pharmacological and non-pharmacological treatment. Results: The quality scores of the GLs varied substantially with a range of 1.5–15.5 points (NGC) and 8–30 points (AQUMED). The greatest variation was found in the dimensions ‘development’ and ‘evidence’. Only 3 of the 11 GLs (≈30%) were rated as methodologically well prepared. The recommendations on diagnostic procedures and medical management were rather consistent among the different GLs. Conclusions: Published international GL recommendations on medical management of patients with chronic HF are broadly consistent. The methodological quality of the GLs, however, varies to a great extent. Improvement is needed in most methodological aspects, especially in the dimensions ‘evidence’ and ‘applicability’.

Summary Background and aims: Gastro-oesophageal reflux disease (GERD) can be associated with a variety of extra-oesophageal disorders (EED) such as chronic cough, asthma, laryngeal disorder or chest pain. The aim of the study was to estimate and compare the prevalence of EED in a population with symptomatic GERD presenting as either erosive reflux disease (ERD) or non-erosive reflux disease (NERD). Methods: Baseline data were collected from a prospective, multicentre, open cohort study (ProGERD) in which patients will be followed for 5 years after initial treatment with esomeprazole. Within the framework of this trial, all patients underwent gastroscopy and filled out a questionnaire designed to assess EED. The influence of potential prognostic factors on the prevalence of EED was analysed by multivariate (stepwise logistic regression) analysis. Results: 6215 patients (3303 male, 2912 female; mean age 54 years) presenting with heartburn were included. EED was detected in 32.8% of all patients. The proportion was significantly higher (P = 0.0002) in ERD patients (34.9%) than in NERD patients (30.5%). As judged from the multivariate analysis, female gender, age, oesophagitis of LA grade C/D, duration of GERD disease greater than 1 years and smoking were significantly associated with EED. ERD patients with oesophagitis of LA grade A or B did not have a significantly higher risk of EED than patients with NERD. Conclusions: Patients with GERD have a high probability of experiencing EED, which may be associated with a number of prognostic factors such as duration and severity of GERD. Extra-oesophageal disorders are slightly, but statistically, more prevalent in ERD than in NERD patients.

This article represents the update of ‘European Stroke Initiative Recommendations for Stroke Management’, first published in this Journal in 2000. The recommendations are endorsed by the 3 European societies which are represented in the European Stroke Initiative: the European Stroke Council, the European Neurological Society and the European Federation of Neurological Societies.

Several birth cohort studies have been initiated during the past two decades to study environmental and genetic risk factors for atopic dermatitis, asthma and allergic rhinitis. This article summarizes results from the German Multicentre Allergy Study (MAS), which has followed children (initially 1,314) from birth (in 1990) to the present time. The effects of immunizations, allergen exposure, early sensitization patterns as well as upper airway infections on the subsequent development of asthma and atopy at school age are described. Furthermore, candidate gene studies of atopic dermatitis and increased total serum IgE levels on chromosomes 5q, 12q and 17q in MAS-children and their parents are outlined.

Epidemiological surveys have indicated that there has been a notable increase in the prevalence of both asthma and other allergic symptoms in children and young adults. Since it seems unlikely that genetic factors would contribute to the rising trend, environmental factors might play a major part in the development of childhood asthma. In a prospective birth-cohort study, we assessed the relevance of different exposures such as mite and cat allergen exposure, environmental tobacco smoke (ETS) exposure, early infectious diseases and vaccinations for the development of childhood asthma up to the age of 10 years. Data up to 7 years of age have been evaluated. Of 1314 newborn infants enrolled in five German cities in 1990, follow-up data at age 7 years were available for 939 children (72%). Assessments included repeated measurements of specific IgE to food and inhalant allergens, measurement of indoor allergen exposure at 6 months, 18 months and 3 years of age and yearly interviews by a paediatrician. At age 7 years, pulmonary function was tested and bronchial responsiveness was determined in 645 children. At age 7, the prevalence of wheezing in the past 12 months was 10% (94 out of 938), and 6.1% (57 out of 939) parents reported a doctor's diagnosis of asthma in their children. Sensitisation to indoor allergens was associated with asthma, wheeze and increased bronchial responsiveness. However, no relationship between early indoor allergen exposure and the prevalence of asthma, wheeze and bronchial responsiveness was seen. During the first 3 years of life, intra-uterine tobacco and consistent ETS exposure have an adjuvant effect on allergic sensitisation that is transient and restricted to children with a genetic predisposition for allergy. Children sensitised to any allergen early in life and sensitised to inhalant allergens by the age of 7 years were at a significantly increased risk of being asthmatic at this age (odds ratio (OR) = 10.12; 95% confidence interval (CI) = 3.81-26.88). Children with repeated episodes (> or =2) of runny nose before the age of 1 year were less likely to develop asthma by the age of 7 years (OR = 0.52; 95% CI = 0.29-0.92). Our data do not support the hypothesis that exposure to environmental allergens directly causes asthma in childhood but that induction of specific IgE responses and the development of childhood asthma are determined by independent factors. Indoor allergen avoidance is recommended as first line treatment in secondary and tertiary prevention; however, conclusions should be drawn with caution about the possible effect of primary preventative measures. Since allergic asthma seems to be a Th2-disease, immunomodulating factors such as early childhood infections, LPS-exposure or other factors influencing gene-environment interaction and individual susceptibility seem to be relevant for the development of childhood asthma

Birth cohort studies offer the opportunity to study average risks, rates and occurrence times of disease longitudinally from birth. The effect of genetic and environmental factors and their interactions can be studied. Furthermore, quantity and duration of exposure to environmental agents can be evaluated prospectively. However, prospective birth cohort studies are expensive, labour intensive and take many years to complete. Loss of subjects over time as well as recall bias complicate the interpretation of observations. This paper summarises the potential pitfalls of such studies and discusses the experience of the German Multicentre Allergy Study (MAS), which began in 1990 in five German cities and included 1314 newborns for the study of the natural course of atopic diseases.

Aim: To compare the effectiveness of Helicobacter pylori eradication in curing peptic ulcer disease in trials involving both gastric ulcer and duodenal ulcer. Methods: Twenty-four relevant randomized controlled trials and randomized comparative trials met the predefined selection criteria. Only proton pump inhibitor-based eradication trials were considered for the evaluation of eradication efficacy and ulcer healing. For the determination of relapse rates, all trials independent of the eradication therapy regimen were considered. Results: Data from 2102 patients were analysed comparing gastric ulcer with duodenal ulcer. No statistical differences between gastric ulcer and duodenal ulcer patients were found with regard to eradication rates (summarized odds ratio, 1.23; 95% confidence interval, 0.98–1.55) or ulcer relapse rates, whether in successfully H. pylori eradicated patients (summarized odds ratio, 0.69; 95% confidence interval, 0.26–1.84) or unsuccessfully H. pylori eradicated patients (summarized odds ratio, 1.48; 95% confidence interval, 0.85–2.56). Owing to heterogeneity, healing rates were not comparable. Conclusions: The eradication of H. pylori infection cures both gastric and duodenal ulcer, and the cure rates are similar. This suggests that H. pylori is the key factor in peptic ulcer disease independent of the ulcer site.

Against the background of the controversial discussion about an increase in allergic rhinitis in recent years, intraindividual longitudinal data is lacking for IgE-mediated seasonal allergic rhinitis (SAR). Little is known about the development of SAR in terms of prevalence and incidence rates from birth to school age.In a prospective birth cohort, we investigated the development of sensitization and symptoms of SAR. SAR should be defined with high specificity, and associated risk factors should be determined.Annual longitudinal data about seasonal allergic symptoms and sensitization was available for 587 children from birth to their seventh birthday. The definition of SAR was based on a combination of exposure-related symptoms and sensitization.Up to 7 years of age, SAR developed in 15% of the children. Incidence and prevalence of symptoms and sensitization were low during early childhood (2%) and increased steadily with age. Children in which SAR had already developed in the second year all were born in spring or early summer, resulting in at least two seasons of pollen exposure before manifestation of SAR. Risk factors assessed by multiple logistic regression analysis were male sex (odds ratio [OR] = 2.4), atopic mothers (OR = 2.6) and fathers (OR = 3.6) having allergic rhinitis themselves, first-born child (OR = 2.0), early sensitization to food (OR = 3.3), and atopic dermatitis (OR = 2.5), whereas early wheezing was not associated with SAR.The development of SAR is characterized by a marked increase in prevalence and incidence after the second year of life. Our longitudinal data further indicate that in combination with the risk of allergic predisposition, at least 2 seasons of pollen allergen exposure are needed before allergic rhinitis becomes clinically manifest.

Background: A positive atopic family history has proved to be one important risk factor for the development of atopic diseases in offspring. However, many epidemiologists are concerned about the accuracy and reliability of data because responses to questionnaires can be biased for many reasons. Objective: The study investigated whether responses of parents questioned about their atopic diseases change depending on the development of atopic symptoms in their children. Methods: During a prospective birth cohort study on atopy in children (the Multicenter Allergy Study) parents filled out questionnaires twice within 2 years about their atopic diseases. Differences between the 2 responses were examined by log-linear and logistic regression models depending on the diagnosed atopy status of the study children. Results: Mothers tended to report more atopic diseases in the second questioning than in the first, indicating a nondifferential misclassification. Fathers were influenced by the development of atopic diseases in their children: they reported significantly more atopic diseases if the child developed atopic illness with atopic dermatitis. Conclusion: In parental questioning about atopic diseases, a recall bias must be considered for the association of atopic family history and atopy in children. Especially in case-control and cross-sectional studies, such misclassifications can result in biased estimates of prognosis and risk factors. (J Allergy Clin Immunol 2000;105:274-8.)

Background: Specific IgE antibody responses to alimentary and environmental allergens are one of the hallmarks of atopic diseases. The knowledge of the time course of allergic sensitization during early life may facilitate measures for preventive interventions. Objective: In a prospective birth cohort study (the Multicenter Allergy Study [MAS]) we investigated annual incidence and prevalence rates of sensitization to food and inhalant allergens during the first 6 years of life. Methods: For 216 children of a prospective birth cohort (MAS), a complete follow-up of specific IgE measurements to 9 food and inhalant allergens was available at 1, 2, 3, 5, and 6 years of age. On the basis of these measurements, sensitization rates were estimated for the reference population of 4082 children by weighted analysis. Results: Annual incidence rates of sensitization to food allergens decreased from 10% at 1 year of age to 3% at the 6 years of age. Incidences of sensitization to inhalant allergen, however, increased with age (from 1.5% at 1 year to 8% at 6 years). Point prevalences of allergic sensitization to at least 1 of the 9 tested allergens increased from 11% at 1 year up to 30% at 6 years. This increase was due to markedly increasing sensitization rates to inhalant allergens (1.5% to at least 1 inhalant allergen at 1 year and 26% at 6 years of age), whereas sensitization rates to food allergens remained stable during the first 6 years of life (10%). Conclusion: The earliest serologic marker for atopic immunoreactivity in infancy is the presence of IgE antibodies to egg, followed by milk. The development of sensitization to inhalant allergens occurs mostly after infancy. Beyond the third birthday annual incidence and prevalence increase markedly with age. Rates for outdoor allergens are twice those for indoor allergens. (J Allergy Clin Immunol 1999;103:1173-9.)

Objective: Total serum IgE percentiles were derived for a population-based sample of 4082 white children from Germany by weighted analysis of measurements from the Multicenter Allergy Study cohort. Methods: The children of a prospective birth cohort were selected from a complete 1-year sample of newborns in 6 obstetric departments in 1990. Total IgE was determined at 1, 2, 3, 5, and 6 years of age in 1160 newborns of the cohort. By weighting these measurements for sex, atopic family history, and elevated cord blood IgE, total serum IgE percentiles were estimated for the original population-based sample of 4082 children. Results: IgE levels increased by age (P < .0001). We found statistically significant higher total IgE values in boys than in girls at each age (P < .05). Within the group of atopic children, this sex difference was not statistically significant. Conclusion: Our estimates of total serum IgE levels for a large population-based sample were lower than most values previously reported. We suggest that for both clinical and epidemiologic and genetic studies, IgE values should be expressed with percentiles. (J Pediatr 1999;134:453-8)

The purpose of the study was to investigate whether the duration of sensitization to food allergens during early childhood is related to later development of IgE mediated hypersensitivity to inhalant allergens and of allergic rhinitis and asthma in 5-year-old children and whether long-lasting food-sensitization may be used to predict subsequent allergic airway diseases. Five hundred and eight children of a prospective birth cohort study with available serum samples at one and two years of age were included and followed up until five years of age. Specific sensitization to food and inhalant allergens and the occurrence of subsequent allergic airway diseases were determined. Children with a long-lasting sensitization to food allergens (persistently sensitized for more than one year) produced significantly higher total IgE and specific IgE levels than children who were only transiently food-sensitized by two years of age. Children persistently sensitized to food had a 3.4 fold higher risk of developing allergic rhinitis and a 5.5 fold higher risk of developing asthma than infants who were only transiently food sensitized. Persistent food sensitization in combination with a positive atopic family history was a strong predictor for the development of allergic rhinitis and asthma at five years of age. The risks for these children are up to 50%, and 67% respectively. Persistently detectable sensitization to food over more than one year in early childhood is a strong prognostic factor for subsequent allergic airway disease. Persistently food-sensitized children especially in atopic families have to be regarded as a high-risk group and should be considered for preventive measures against respiratory atopy.

BACKGROUND: In order to investigate, whether atopic and nonatopic children show differences in their specific IgE and IgG4 immune responses to tetanus (T) and diphtheria (D) antigens, we studied 538 children who had been followed from birth on and from whom records had been kept of all immunizations. METHODS: The prevalence of eczema and asthma was registered at regular intervals and the cumulative incidence of symptoms was determined at 24 months of age. Total serum IgE and specific IgE to a panel of nine allergens as well as T- and D-specific IgE and IgG4 were determined from the 24-months blood samples. RESULTS: Our results show that both atopic and nonatopic children are capable of mounting high levels of toxoid-specific IgE antibody responses. Children with cord blood IgE > 0.9 kU/1, serum IgE 10-100 kU/1 and > 100 kU/1 and at least one sensitization to an allergen at 24 months of age have significantly higher IgE responses to T and D (p

GRADE suggests that examination of 95% confidence intervals (CIs) provides the optimal primary approach to decisions regarding imprecision. For practice guidelines, rating down the quality of evidence (i.e., confidence in estimates of effect) is required when clinical action would differ if the upper versus the lower boundary of the CI represented the truth. An exception to this rule occurs when an effect is large, and consideration of CIs alone suggests a robust effect, but the total sample size is not large and the number of events is small. Under these circumstances, one should consider rating down for imprecision. To inform this decision, one can calculate the number of patients required for an adequately powered individual trial (termed the "optimal information size" or OIS). For continuous variables, we suggest a similar process, initially considering the upper and lower limits of the CI, and subsequently calculating an OIS. Systematic reviews require a somewhat different approach. If the 95% CI excludes a relative risk (RR) of 1.0 and the total number of events or patients exceeds the OIS criterion, precision is adequate. If the 95% CI includes appreciable benefit or harm (we suggest a RR of under 0.75 or over 1.25 as a rough guide) rating down for imprecision may be appropriate even if OIS criteria are met.

Aluminium nitride powder was synthesized via a high-temperature gas-phase reaction process of aluminium trichloride with ammonia in flowing nitrogen atmosphere in a graphite reactor at 1600–1800°C. After purification of the reaction product by sublimation of ammonium chloride at 900–1100°C and calcination at 1500–1700°C in nitrogen atmosphere a high-purity aluminium nitride powder with low residual chlorine (

INTRODUCTION: Patients with metastatic rhabdomyosarcoma (RMS) have a poor prognosis. The aim of this systematic review is to investigate whether high-dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation (HSCT) in patients with metastatic RMS has additional benefit or harm compared to standard chemotherapy. METHODS: Systematic literature searches were performed in MEDLINE, EMBASE, and The Cochrane Library. All databases were searched from inception to February 2010. PubMed was searched in June 2010 for a last update. In addition to randomized and non-randomized controlled trials, case series and case reports were included to complement results from scant data. The primary outcome was overall survival. A meta-analysis was performed using the hazard ratio as primary effect measure, which was estimated from Cox proportional hazard models or from summary statistics of Kaplan Meier product-limit estimations. RESULTS: A total of 40 studies with 287 transplant patients with metastatic RMS (age range 0 to 32 years) were included in the assessment. We identified 3 non-randomized controlled trials. The 3-year overall survival ranged from 22% to 53% in the transplant groups vs. 18% to 55% in the control groups. Meta-analysis on overall survival in controlled trials showed no difference between treatments. Result of meta-analysis of pooled individual survival data of case series and case reports, and results from uncontrolled studies with aggregate data were in the range of those from controlled data. The risk of bias was high in all studies due to methodological flaws. CONCLUSIONS: HDCT followed by autologous HSCT in patients with RMS remains an experimental treatment. At present, it does not appear justifiable to use this treatment except in appropriately designed controlled trials.

To cite this article: Keil T, McBride D, Grimshaw K, Niggemann B, Xepapadaki P, Zannikos K, Sigurdardottir ST, Clausen M, Reche M, Pascual C, Stanczyk AP, Kowalski ML, Dubakiene R, Drasutiene G, Roberts G, Schoemaker A-FA, Sprikkelman AB, Fiocchi A, Martelli A, Dufour S, Hourihane J, Kulig M, Wjst M, Yazdanbakhsh M, Szepfalusi Z, van Ree R, Willich SN, Wahn U, Mills ENC, Beyer K. The multinational birth cohort of EuroPrevall: background, aims and methods. Allergy 2010; 65: 482–490. Abstract Background/aim: The true prevalence and risk factors of food allergies in children are not known because estimates were based predominantly on subjective assessments and skin or serum tests of allergic sensitization to food. The diagnostic gold standard, a double-blind placebo-controlled food provocation test, was not performed consistently to confirm suspected allergic reactions in previous population studies in children. This protocol describes the specific aims and diagnostic protocol of a birth cohort study examining prevalence patterns and influential factors of confirmed food allergies in European children from different regions. Methods: Within the collaborative translational research project EuroPrevall, we started a multi-center birth cohort study, recruiting a total of over 12 000 newborns in nine countries across Europe in 2005–2009. In addition to three telephone interviews during the first 30 months, parents were asked to immediately inform the centers about possible allergic reactions to food at any time during the follow-up period. Results: All children with suspected food allergy symptoms were clinically evaluated including double-blind placebo-controlled food challenge tests. We assessed sensitization to different food allergens by measurements of specific serum immunoglobulin E and skin prick tests, collect blood, saliva or buccal swabs for genetic tests, breast milk for measurement of food proteins/cytokines, and evaluate quality-of-life and economic burden of families with food allergic children. Conclusions: This birth cohort provides unique data on prevalence, risk factors, quality-of-life, and costs of food allergies in Europe, leading to the development of more informed and integrated preventative and treatment strategies for children with food allergies.

Aqueous silicon nitride suspensions with solid volume fractions of 0.2 –0.5 were prepared from preoxidized and electrosterically stabilized powder mixtures. The filtration kinetics during pressure casting with constant filtration rate up to a maximum pressure of 10 MPa into porous steel molds were examined. Resulting from the constant filtration rate the hydrodynamic conditions for particle incorporation in the growing cake surface remain independent of the cake thickness. Thus, gradient-free green compacts with a fractional density of 0.6 were obtained which could be further densified by isostatic compression up to 0.74. Significantly higher matrix densities than for cold isostatically pressed samples could also be obtained for composite materials containing up to 20 vol.% of SiC platelets.

Das Institut fur Qualitat und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) hat den gesetzlichen Auftrag, den Nutzen von medizinischen Methoden, Verfahren und Leistungen zu bewerten. In der (Fach)Offentlichkeit werden diese Nutzenbewertungen und die zugrunde liegende Methodik oftmals sehr kontrovers diskutiert, was auf folgenden Missverstandnissen und Fehlinterpretationen beruhen kann. Hierzu einige Beispiele: Der medizinische Nutzen wird entsprechend den Vorgaben des §35b des SGB V anhand patientenbezogener Endpunkte bewertet. Die zentralen Nutzendimensionen sind hierbei Mortalitat, Morbiditat, Lebensqualitat. Dies darf nicht zwangslaufig mit Wirksamkeitsbewertungen gleichgesetzt werden. Eine signifikante Veranderung eines Blutwertes oder eine detailliertere Darstellung eines Befundes aufgrund eines (diagnostischen) bildgebenden Verfahrens muss noch keinen unmittelbaren patientenrelevanten Nutzen bedeuten. In die Bewertungen einfliesende Zielgrosen mussen also eindeutig patientenrelvant sein. Die Nutzenbewertungen haben zudem lt. GKV-Wettbewerbsstarkungsgesetz (2007) auf der Basis international anerkannter Standards der evidenzbasierten Medizin (ebM) zu erfolgen. Entsprechend diesen Standards gilt sowohl fur Wirksamkeitsprufungen als auch fur Nutzenbewertungen das Kausalitatsprinzip fur den Nachweis eines Effektes. Dies ist erforderlich, damit bei einem Unterschied zwischen Gruppen dieser Effekt kausal auf die zu prufende (therapeutische) Intervention zuruckgefuhrt werden kann. International unstrittige ebM-Standards setzen hierzu u. a. eine moglichst hohe Strukturgleichheit in den zu vergleichenden Gruppen hinsichtlich bekannter wie unbekannter Storgrosen voraus. Die bisher beste verfugbare Technik das Ziel der Strukturgleichheit zu erreichen ist die Randomisierung. Diesbezugliche kontroverse Einschatzungen konnen auf der Fehlinterpretation beruhen, dass andere — oftmals statistische — Verfahren, die in nicht-randomisierten Studien angewandt werden, mogliche Strukturungleichheiten verlasslich ausbalancieren konnten. Aufgrund der Uberschatzung der Ausbalancierungsmoglichkeiten von solchen Adjustierungsverfahren wird immer wieder das Argument bemuht, neben der Evidenzstufe 1 auch nicht-randomisierte Interventionsstudien den Nutzenbewertungen zugrunde legen zu wollen. Es findet sich jedoch unter den Organisationen, die Nutzenbewertungen durchfuhren, keine die dieser Argumentation folgen. Mit anderen Worten: Wenn Studien auf hochstem Evidenzgrad moglich sind und vorliegen, ermoglichen Studien auf niedrigerer Evidenzstufe keinen Zuwachs an Ergebnissicherheit der Nutzenbewertung. Das Institut und der Gemeinsame Bundesausschuss (G-BA) sind sich jedoch bewusst, dass Studien hochster Evidenz nicht immer verfugbar sind, wie beispielsweise bei sehr seltenen Krankheitsbildern. Das IQWiG schliest gemas seinem Methodenpapier niedrigere Evidenzstufen per se nicht aus, und kann in begrundeten Fallen vom Studieneinschlusskriterium der hochsten Evidenzstufe abweichen. Gerade bei Bewertungen nicht-medikamentoser Verfahren hat das Institut auch Studien niedrigerer Evidenzstufe eingeschlossen. Hierzu bedarf es jedoch einer expliziten Begrundung und dem Bewusstsein, dass die Verlasslichkeit der Bewertung („Ergebnissicherheit“) kaum derjenigen unter Einbezug von hochster Evidenz entsprechen kann. Da die Empfehlungen des IQWiGs als Entscheidungsgrundlage fur den Gemeinsamen Bundesausschusses dienen, steht es wohl auser Frage, eine hohe Ergebnissicherheit der Nutzenbewertung fur die Gesundheitsversorgung und damit fur den Schutz der Patienten zu fordern. Dies wird auch durch die Verfahrensordnung des G-BA in §20 geregelt: „Die Anerkennung des medizinischen Nutzens einer Methode auf (...) einer niedrigeren Evidenzstufe bedarf jedoch (...) zum Schutz der Patienten umso mehr einer Begrundung, je weiter von der Evidenzstufe 1 abgewichen wird.“ Als letztes Beispiel moglicher Missverstandnisse kann der nicht selten geauserte Vorwurf mangelnder Transparenz, insbesondere der Prufkriterien genannt werden. Das Institut entspricht auch hier dem gesetzlichen Auftrag [GKV-Wettbewerbsstarkungsgesetz 2007, Anderung § 35b (1): „Das Institut gewahrleistet ... hohe Verfahrenstransparenz und angemessene Beteiligung der in § 35 Abs. 2 und § 139a Abs. 5 Genannten. Das Institut veroffentlicht die jeweiligen Methoden und Kriterien im Internet“; vgl. IQWiG 2009], indem es seine Methoden (Allgemeine Methoden und Berichtsplane) publiziert bzw. zur Diskussion stellt. Ebenso werden die vorlaufigen Ergebnisse einer Nutzenbewertung im Internet veroffentlicht (Vorbericht), zu denen Stellung genommen werden kann. Die Stellungnahmen werden dementsprechend bei der Erstellung des Abschlussberichts gewurdigt. Beim Stellungnahmeverfahren konnen auch Studien niedrigerer Evidenz eingereicht werden. In begrundeten Fallen, wie beispielsweise dem Nachweis eines dramatischen Effektes, konnen diese dann in die Nutzenbewertung mit einfliesen.

Background: It is unclear which exposures may cause or modify the adverse effect of rapid weight gain on fat mass development in term children whose birth weight is appropriate-for-gestational age (AGA). Objective: To determine which intrauterine or postnatal exposures increase the risk of or modify the effect of rapid weight gain on body fat percentage (BF%) and body mass index (BMI) trajectories between 2 and 6 y of age. Design: Term AGA singletons (n = 370) from the German Multicenter Allergy Study (MAS-90), a longitudinal birth cohort study, with repeated anthropometric measurements until 6 y, and data on breastfeeding status, exposure to smoking during pregnancy, and maternal anthropometric and socioeconomic characteristics were included in this analysis. Results: A shorter gestation [multivariate-adjusted odds ratio (OR): 5.12; 95% CI: 2.22, 11.82; P = 0.0001], being firstborn (OR: 2.01; 95% CI: 1.10, 3.69; P = 0.02), and having been bottle-fed (OR: 3.02; 95% CI: 1.68, 5.43; P = 0.0002) all significantly increased a child's risk of gaining weight rapidly, whereas a larger BMI at birth was protective (OR: 0.54; 95% CI: 0.38, 0.77; P = 0.0006). Multilevel model analyses showed that rapid growers exposed to tobacco in utero subsequently gained more BF% between 2 and 6 y than did rapid growers who had not been exposed ((3 SE: 0.78 +/- 0.28%/y; P = 0.005). Similarly, change in BF% was greater in rapid growers with an overweight mother than in those with a normal-weight mother (1.01 +/- 0.30%/y; P = 0.0007). Conclusions: The occurrence of rapid weight gain between birth and 2 y and the magnitude of its effect on BF% development in AGA children is influenced by both intrauterine and postnatal exposures.

All European countries are facing common challenges for delivering appropriate, evidence-based care to patients with cancer. Despite tangible improvements in diagnosis and treatment, marked differences in cancer survival exist throughout Europe. The reliable translation of new research evidence into consistent patient-oriented strategies is a key endeavour to overcome inequalities in healthcare. Clinical-practice guidelines are important tools for improving quality of care by informing professionals and patients about the most appropriate clinical practice. Guideline programmes in different countries use similar strategies to achieve similar goals. This results in unnecessary duplication of effort and inefficient use of resources. While different initiatives at the international level have attempted to improve the quality of guidelines, less investment has been made to overcome existing fragmentation and duplication of effort in cancer guideline development and research. To provide added value to existing initiatives and foster equitable access to evidence-based cancer care in Europe, CoCanCPG will establish cooperation between cancer guideline programmes. CoCanCPG is an ERA-Net coordinated by the French National Cancer Institute with 17 partners from 11 countries. The CoCanCPG partners will achieve their goal through an ambitious, step-wise approach with a long-term perspective, involving: 1. implementing a common framework for sharing knowledge and skills; 2. developing shared activities for guideline development; 3. assembling a critical mass for pertinent research into guideline methods; 4. implementing an appropriate framework for cooperation. Successful development of joint activities involves learning how to adopt common quality standards and how to share responsibilities, while taking into account the cultural and organisational diversity of the participating organisations. Languages barriers and different organisational settings add a level of complexity to setting up transnational collaboration. Through its activities, CoCanCPG will make an important contribution towards better access to evidence-based cancer practices and thus contribute to reducing inequalities and improving care for patients with cancer across Europe.

Background: Some studies have suggested that supplementation of food with lactobacilli may prevent or improve atopic dermatitis in children. This study was designed to investigate the therapeutic effect of Lactobacillus rhamnosus GG (LGG) as a food supplement in infants suffering from atopic dermatitis. Methods: Infants aged 3–12 months suffering from mild-to-moderate atopic dermatitis (severity scoring of atopic dermatitis or SCORAD index of 15–40) without current antiinflammatory treatment were randomized to receive LGG (5 × 109 colony forming units b.i.d.) or placebo as a food supplement for 12 weeks. Severity scoring of atopic dermatitis index and use of hydrocortisone 1% ointment as rescue medication (2 points per application) were recorded at 4, 8, and 12 weeks of treatment and combined as symptom load (SL). Results: Fifty-four infants (LGG group, mean ± SD SCORAD index 24.6 ± 8.8) and 48 infants (placebo group, SCORAD index 23.6 ± 7.8) were randomized and completed the treatment period (intention-to-treat analysis). Symptom load generally improved over time at 4 weeks (LGG vs placebo, 23.8 ± 12.4 vs 20.6 ± 9.9), 8 weeks (22.5 ± 14.6 vs 17.9 ± 13.1), and 12 weeks (19.6 ± 15.4 vs 15.1 ± 12.1), without statistically significant group differences. When stratified for age, eczema severity or use of rescue medication, no statistically significant group differences, in improvement, were found. No significant group differences were found for the use of rescue medication (0.8 ± 45.0 g vs 3.5 ± 29.8 g), increase in mean logarithmic total serum IgE (0.17 ± 0.30 kU/l vs 0.26 ± 0.45 kU/l), and newly developed allergic sensitization against hen’s egg or cow’s milk (18.8%vs 10.0%). Conclusion: This placebo-controlled trial showed no therapeutic effect of LGG against mild-to-moderate atopic dermatitis in infancy.

Summary Background Proton pump inhibitor therapy has been reported to reduce proliferative changes of the oesophagus significantly in gastro-oesophageal reflux disease (GERD). Aim To assess the histological effects of esomeprazole treatment on the oesophagus. Methods Data were derived from a subgroup of patients participating in the proGERD study, who had either erosive reflux disease (n = 720) or non-erosive reflux disease (n = 35) and who had biopsy data from two sites [(i) 2 cm above the z-line and (ii) at the z-line], obtained at baseline and following treatment with esomeprazole. Proliferative changes of the squamous epithelium were assessed histologically by measuring thickness of the basal cell layer and elongation of the papillae as a percentage of the whole epithelial thickness. Results In erosive reflux disease patients, the thickness of the basal cell layer and length of the papillae pretreatment were associated with the severity of oesophagitis (P

Background/Aims: There are still ongoing controversies as to which histological parameters allow the diagnosis of gastroesophageal reflux disease (GERD). The aim of the present analysis was to relate histological changes of the esophageal squamous epithelium to different severities of GERD. Methods: Data were obtained from patients participating in the ProGERD study, who had either erosive reflux disease (ERD, n = 3,245) or non-erosive reflux disease (NERD, n = 2,970). 1,475 patients fulfilled our requirement of having complete biopsy data from two sites (2 cm above the z-line and at the z-line). Changes in the squamous epithelium were assessed by measuring the thickness of the basal cell layer and elongation of the papillae as a percentage of the whole epithelial thickness and counting interepithelial inflammatory cells. Results: The most useful parameters for histological assessment of GERD (given as means, 2 cm above the z-line and at the z-line, respectively) were elongation of the papillae: NERD 40.7 and 48.9%; ERD 46.1 and 54.9% and basal cell hyperplasia: NERD 12.7 and 17.9%; ERD 15.7 and 23.0%. The occurrence of intraepithelial lymphocytic infiltrates, however, is dependent on the severity of GERD, and they are more common than neutrophilic and eosinophilic granulocytes. Conclusion: This study shows that both NERD and ERD can be diagnosed histologically if biopsies are obtained from the distal esophagus or from the z-line. Intraepithelial inflammatory cells are rare and show a high specificity, but very low sensitivity.

Gastroesophageal reflux disease can be divided into three categories: nonerosive GERD (NERD), erosive GERD (ERD), and Barrett's esophagus. A shift among these categories rarely occurs. The aim of the present study was to elucidate potential patient-associated risk factors associated with ERD.A total of 6,215 patients with troublesome heartburn were recruited to a large, prospective, multicenter open cohort study comprising an initial treatment phase and a 5-yr follow-up phase. Each center planned to recruit an equal number of patients with NERD and ERD. All patients underwent an interview based on standardized questionnaires, a physical examination, and endoscopy with biopsies. Data were analyzed by multiple logistic regression analysis.Risk factor analysis was performed on 5,289 patients (NERD: n = 2,834; ERD: n = 2,455), which was the intent-to-treat population excluding patients with suspected/proven complicated reflux disease. Stepwise regression analysis identified the following independent predictors of ERD: male gender, overweight, regular use of alcohol, a history of GERD1 yr, and smoker or ex-smoker. A higher level of education and a positive Helicobacter pylori (H. pylori) status were associated with a lower risk of ERD.Some patient-associated factors increase the risk of erosive esophagitis as opposed to nonerosive reflux disease. However, no single factor or combination of factors is capable of predicting mucosal damage with clinically sufficient certainty. Thus, endoscopy is still required in all GERD patients if valid information on the state of the esophageal mucosa is needed.

Background: Specific immunotherapy (SIT) and treatment with anti-immunoglobulin (Ig)E antibody are complementary approaches to treat allergic rhinoconjunctivitis, which may be used for single or combined treatment. Objective: A randomized, double-blind, placebo-controlled trial was conducted to compare the efficacy of single and combined treatment with SIT and anti-IgE (Omalizumab) in reducing symptom severity and rescue medication use. Methods: A total of 221 subjects with birch and grass pollen allergic rhinoconjunctivitis aged 6–17 years were analysed during the grass pollen season. Group A (SITbirch + placebo) served as a reference group obtaining no effective treatment for grass pollen allergy. Group B received anti-IgE monotherapy during grass pollen season, group C SIT grass pollen monotherapy, and group D the combined treatment of SIT and Omalizumab. Results: Preseasonal treatment with grass pollen SIT alone compared with SIT with the nonrelated allergen did not reduce symptoms or rescue medication use. Anti-IgE monotherapy significantly diminished rescue medication use and number of symptomatic days. The combined treatment with SIT and anti-IgE showed superior efficacy on symptom severity compared with anti-IgE alone. Conclusions: Co-seasonal Omalizumab therapy showed considerable effects in children with seasonal allergic rhinitis. The combination of SIT plus Omalizumab was clinically superior to each treatment alone during the first year of observation.

The aim of the present study was to assess change in health-related quality of life (HRQoL) after cardiac rehabilitation in the usual care setting, and to determine predictors for change. In the Post Infarction Care Study, 2441 patients were consecutively included at admission to 18 inpatient cardiac rehabilitation centres following coronary events. HRQoL was assessed with the SF-36 questionnaire at baseline as well as 6 and 12 months after discharge. HRQoL improved significantly in patients after coronary artery bypass grafting (CABG) but not in patients after myocardial infarction. Significant baseline predictors for change of the SF-36 physical component summary (PCS) score were the exercise ECG result at admission (0.59 absolute change/10-watt increase; 95% CI: 0.39, 0.79), an incomeor = 1750 euros (1.64; 95% CI: 0.35, 2.93), baseline PCS score (-0.63; 95% CI: -0.69, -0.57), and CABG as indication for admission (3.65; 95% CI: 2.27, 5.04). Significant predictors for change of the mental component summary (MCS) score were age (1.28/10-year increase; 95% CI: 0.62, 1.94), East Germany as area of residence (2.62; 95% CI: 1.32, 3.91), baseline MCS score (-0.58; 95% CI: -0.63, -0.52), and CABG as indication for admission (1.68; 95% CI: 0.36, 3.01). The identification of predictors of HRQoL in the present study may aid in the further development and evaluation of cardiac rehabilitation programmes.

The objectives of the present study were to determine prospectively return to work and its predictors in patients after cardiac rehabilitation.Patients were enrolled at admission to inpatient cardiac rehabilitation centres (n = 18). Primary indications for admission were myocardial infarction, coronary artery bypass grafting or percutaneous transluminal coronary angioplasty.We included 2441 consecutive patients (1907 men, mean age: 60 +/- 10 years; 534 women, mean age: 65 +/- 10 years). A total of 43% of all patients had been actively employed before the event. Of these patients, 65% had returned to work six months and 67% 12 months after cardiac rehabilitation. Successful return to work after 12 months was significantly predicted by younger age, non-manual work, self-employment, a higher physical and mental quality of life, and a better exercise ECG result.Return to work is predicted by sociodemographic factors, quality of life, and the exercise ECG at the rehabilitation centre. The determination of early predictors for return to work may aid to identify patients particularly at risk for failure to return to work.

Previous reports of a circadian variation of angina pectoris were based primarily on selected patients of clinical studies. The present ESCVA Study (European Survey on Circadian Variation of Angina Pectoris) was designed to determine the timing of angina pectoris attacks in outpatients, the association of wake time and possible external triggers with angina attacks, and the influence of cardiac medication on the circadian pattern. Inclusion criteria were stable angina pectoris for at least 3 months, average frequency of two or more attacks per week, and treatment with on-demand nitrates. Standardized self-administered questionnaires were provided to all participating physicians to obtain medical information and to their patients to obtain prospective recordings of angina attacks during the 7 subsequent days. From January 1998 to March 1999, 1,333 patients (60% male, 65 ± 10 years, 40% female, 68 ± 10 years) were enrolled in 243 centers of six European countries and reported a total of 4,293 angina pectoris attacks (range 0–48 per patient). The occurrence of angina pectoris demonstrated a significant circadian variation (p < 0.001) with a primary morning peak from 09:00 to 12:00 o’clock (relative risk 2.9, 95% confidence interval 2.6–3.2, compared to other times of day) and a secondary afternoon peak from 15:00 to 18:00 o’clock (relative risk 1.5, 95% confidence interval 1.3–1.7). Of all angina attacks 50% occurred within the initial 6 h after awakening, and 74% were associated with possible external triggers such as physical activity or anger. The study demonstrated a marked wake time-related circadian variation in the occurrence of angina pectoris attacks. To improve preventive strategies, type, dosage and particularly timing of cardiac medication appear of importance, as may be behavior modification.