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BackgroundThe most frequent form of vasculitis in elderly people is giant cell arteritis (GCA) with an annual incidence rate less than 10 per 100,000 persons over the age of 50. Like most vasculitides, GCA is characterized by chronicity and relapses, leading to significant overall morbidity and higher mortality in a subset of patients with aortic involvement and dissection. Most studies carried out so far have been retrospective, used monocentric study designs and small patient cohorts. Therefore, the Joint Vasculitis Registry in German-speaking countries (GeVas) has been established to record patients, who have been recently diagnosed with vasculitis or who have changed their treatment due to a relapse (inception cohort). The GeVas-Registry allows a long-term follow-up of a substantial cohort of vasculitis patients in a prospective and multicenter manner.ObjectivesTo describe the subgroup of GCA and its characteristics within the GeVas registry.MethodsGeVas is a prospective, web-based, multicenter, clinician-driven registry for the documentation of organ manifestations, damage, long-term outcomes, and therapy regimens in various types of vasculitis. Recruitment started in June 2019. By January 2022, 17 centers in Germany were initiated and have begun enrolling patients. Meanwhile, more than 350 patients have been documented in the registry. Sites in Austria and the German-speaking cantons of Switzerland will be integrated soon (1).ResultsBy mid-October 2021, the participating centers recruited 131 GCA patients into the registry. 21.7% of patients (n=28) were enrolled in the registry due to relapse, and 78.3% (n=101) due to a first-time diagnosis. In accordance with long-standing epidemiology data, the majority of patients (67,2%), were female (n=88), and 32.8% (n=43) were male. Mean age was 74 years (max. 92y, min. 52y). The most frequently recorded organ manifestations in GCA patients addressed cranial and ophthalmic symptoms, and the cardiovascular system. However, vascular lung/chest involvement was also observed in 3% of cases (n=4). Out of the 131 patients, 97.7% (n=128) received immunosuppressive therapy, three refused to take any medication. An equal number of patients were treated with glucocorticoid (GC) therapy. While about two equal parts were treated by stable long term oral GC therapy (47,7%, n=62) or by i.v. pulse therapy followed by tapering (49,2%, n=64), only about 2.3% (n=3) were treated by oral GC therapy with intermittent i.v. pulses. 48.5% (n=63) of patients received tocilizumab as additional immunosuppressive therapy, 19.2% (n=25) methotrexate, and 18.5% (n=24) cyclophosphamide i.v. pulses.ConclusionIn June 2019, we successfully established the prospective multicenter vasculitis registry GeVAS. It describes the first systematically recorded prospective GCA cohort in German-speaking countries. Its characteristics correspond to those that can be expected from the literature, with some unexpected finding e.g. the high proportion of patients treated with cyclosphosphamid, probably reflecting a sicker patient population with e.g. aortic or central nervous involvement. After 2.5 years of follow-up documentation, the first long-term results will be systematically evaluated and interpreted. The newly acquired data on disease manifestation, diagnostics and therapy regimens will provide important insights into the treatment of GCA patients in Germany and may generate further research goals.ReferencesTrial registration: German Clinical Trials Register (Deutsches Register Klinischer Studien): DRKS00011866. Registered 10 May 2019. 3[1]C Iking-Konert; P Wallmeier; S Arnold; S Adler; K de Groot; B Hellmich; B Hoyer; K Holl-Ulrich; Ihorst; M Kaufmann; I Kötter; U Müller-Ladner; T Magnus; J. Rech; H. Schulze-Koops; N. Venhoff; T. Wiech; P. Villiger; F. Schubach; P. Lamprecht. The Joint Vasculitis Registry in German-speaking countries (GeVas) – a prospective, multicenter registry for the follow-up of long-term outcomes in vasculitis. BMC Rheumatol. 2021 Jul 31;5(1):40. doi: 10.1186/s41927-021-00206-2.AcknowledgementsGeVas was supported by unrestricted grants by: DGRh, John Grube Foundation, Vifor and Roche PharmaDisclosure of InterestsPia Wallmeier: None declared, Sabrina Arnold: None declared, Fabian Schubach: None declared, Gabriele Ihorst: None declared, Peer Aries: None declared, Raoul Bergner Consultant of: Advisory Board VIFOR, Grant/research support from: John-Grube Research Award 2021, Jan Philip Bremer: None declared, Norman Görl: None declared, Bernhard Hellmich: None declared, Jörg Henes: None declared, Bimba Hoyer: None declared, Antje Kangowski: None declared, Ina Kötter: None declared, Tim Magnus: None declared, Claudia Metzler: None declared, Ulf Müller-Ladner: None declared, Matthias Schaier: None declared, Ulf Schönermark: None declared, Jens Thiel: None declared, Leonore Unger: None declared, Nils Venhoff Speakers bureau: Roche and Vifor, Consultant of: Roche and Vifor, Grant/research support from: John-Grube Research Award 2021, Julia Weinmann-Menke: None declared, Jana Petersen: None declared, Peter Lamprecht Speakers bureau: Lecture fees from: Chugai, GSK, Roche, Consultant of: Consulting & lecture fees from: Chugai, GSK, Roche, and Vifor., Grant/research support from: Research grants for GeVas: DGRh, John Grube Foundation, Roche, and Vifor, Christof Iking-Konert Speakers bureau: lecture fees from: Chugai, GSK, Roche, and Vifor., Consultant of: Consulting fees from: Chugai, GSK, Roche, and Vifor., Grant/research support from: Research grants for GeVas: DGRh, John Grube Foundation, Roche, and Vifor

BackgroundGranulomatosis with polyangiitis (GPA) is the second most frequent vasculitis in Germany with an annual incidence of 34 per million and a prevalence of 210 per million [1]. GPA is characterized by its chronic course, frequent relapses, significant overall morbidity and mortality, and substantial socio-economic impact. Multiorgan involvement affecting the respiratory tract, kidney, and other organs is common. Limited variants also occur [2]. So far, prospective long-term observational data on the disease course of GPA are missing in Germany. Therefore, the Joint Vasculitis Registry in German-speaking countries (GeVas) has been established to follow the course of patients recently diagnosed with vasculitis or a change of their treatment due to a relapse (inception cohort). The GeVas registry allows long-term follow-up of a substantial cohort of vasculitis patients in a multicenter setting.ObjectivesTo present the first data on the follow-up of newly diagnosed and relapsing GPA enrolled in the GeVas registry.MethodsGeVas is a prospective, web-based, multicenter, clinician-driven registry for the documentation of organ manifestations, damage, long-term outcomes, and therapy regimens in various types of vasculitis. Recruitment started in June 2019. By January 2022, 17 centers in Germany were initiated and started enrolling patients. Meanwhile, more than 350 patients have been documented in the registry. Sites in Austria and the German-speaking cantons of Switzerland will be integrated soon [3].ResultsBy mid-October 2021, the participating centers included 113 patients with GPA. The majority of patients were PR3-ANCA positive and affected by general symptoms, ENT, lung, renal, and neurological involvement. Patients commonly received cyclophosphamide or rituximab in combination with glucocorticoids for the induction of remission. Fewer patients received methotrexate or other immunosuppressants. Patient characteristics and therapy are summarized in Table 1.Table 1.Patient characteristics (n = 113). *Unless otherwise specified.CategoryFeaturen (%)*AgeAge (years); median [range]60 [51 - 70]GenderMale61 (54.0)Female52 (46.0)Reason for inclusion in the registryNewly diagnosed vasculitis57 (51.4)Relapse56 (49.6)ANCA statusPR3-ANCA99 (87.6)MPO-ANCA4 (3.6)ANCA negative9 (7.9)Organ manifestationGeneral symptoms86 (76.1)ENT69 (61.1)Lung/chest66 (58.4)Renal35 (31.0)Cardiovascular7 (6.2)GI3 (2.7)Neurological27 (23.9)TherapyGlucocorticoid102 (90.3)Rituximab56 (49.6)Cyclophosphamide37 (32.7)Methotrexate and other immunosuppressants, respectively26 (23.0) and 19 (16.8), respectivelyConclusionHere, we present the first interim analysis of the GeVas registry. Clinical manifestations of GPA reported herein show less frequent renal involvement in comparison with a recent report from another European registry (POLVAS) and an UK study [4, 5]. This is potentially related to the predominance of recruiting rheumatology centers thus far. By contrast, respiratory tract involvement is more frequent and PR3-ANCA less common in Japan [5]. Further data are prospectively documented and a follow up analysis is in progress.References[1]Hellmich B, et al. New insights into the epidemiology of ANCA-associated vasculitides in Germany: results from a claims data study. Rheumatology 2021;60:4868-73.[2]Kitching AR, et al. ANCA-associated vasculitis. Nat Rev Dis Primers 2020;6:71.[3]Iking-Konert C, et al. The Joint Vasculitis Registry in German-speaking countries (GeVas) – a prospective, multicenter registry for the follow-up of long-term outcomes in vasculitis. BMC Rheumatol 2021;5:40.[4]Wójcik K, et al. Clinical characteristics of Polish patients with ANCA-asscoiated vasculitides – retrospective analysis of POLVAS registry. Clin Rheumatol 2019;38:2553-63.[5]Furuta S, et al. Comparison of the phenotype and outcome of granulomatosis with polyangiitis between UK and Japanese cohorts. J Rheumatol 2017;44:216-22.AcknowledgementsGeVas was supported by unrestricted grants by: DGRh, John Grube Foundation, Vifor and Roche PharmaDisclosure of InterestsSabrina Arnold: None declared, Pia Wallmeier: None declared, Fabian Schubach: None declared, Gabriele Ihorst: None declared, Peer Aries: None declared, Raoul Bergner Consultant of: VIFOR, Jan Philip Bremer: None declared, Norman Görl: None declared, Bernhard Hellmich: None declared, Jörg Henes: None declared, Bimba Hoyer: None declared, Antje Kangowski: None declared, Ina Kötter: None declared, Claudia Metzler: None declared, Ulf Müller-Ladner: None declared, Matthias Schaier: None declared, Ulf Schönermark: None declared, Jens Thiel: None declared, Leonore Unger: None declared, Nils Venhoff Speakers bureau: Roche and Vifor: speaker honoraries, Consultant of: Roche and Vifor: advisory boards, Grant/research support from: John-Grube Research Award 2021, Julia Weinmann-Menke: None declared, Jana Petersen: None declared, Christof Iking-Konert Speakers bureau: Lecture fees from: Chugai, GSK, Roche, and Vifor, Consultant of: Consulting fees from: Chugai, GSK, Roche, and Vifor, Grant/research support from: Research grants for GeVas: Roche, Vifor, DGRh, John Grube Foundation, Peter Lamprecht Speakers bureau: Chugai, GSK, Roche, and Vifor, Consultant of: Chugai, GSK, Roche, and Vifor, Grant/research support from: DGRh, John Grube Foundation, Roche, and Vifor

Background Chemotherapy-induced peripheral neuropathy (CIPN) can affect functional performance and quality of life considerably. Since balance training has proven to enhance physical function, it might be a promising strategy to manage CIPN-induced functional impairments. Methods Fifty cancer survivors with persisting CIPN after finishing their treatment were randomly allocated to an intervention (IG) or active control group (CG). The IG did endurance plus balance training, the CG only endurance training (twice weekly over 12 weeks). Pre- and post-assessments included functional performance, cardiorespiratory fitness, vibration sense, and self-reported CIPN symptoms (EORTC QLQ-CIPN20). Results Intention-to-treat analyses (n = 41) did not reveal a significant group difference (CG minus IG) for sway path in semi-tandem stance after intervention (primary endpoint), adjusted for baseline. However, our per-protocol analysis of 37 patients with training compliance ≥70% revealed: the IG reduced their sway path during semi-tandem stance (− 76 mm, 95% CI -141 – -17; CG: -6 mm, 95% CI -52 – 50), improved the duration standing on one leg on instable surface (11 s, 95% CI 8–17; CG: 0 s, 95%CI 0–5) and reported decreased motor symptoms (−8points, 95% CI -18 – 0; CG: -2points 95% CI -6 – 2). Both groups reported reduced overall- (IG: -10points, 95% CI -17 – -4; CG: -6points, 95% CI -11 – -1) and sensory symptoms (IG: -7points, 95% CI -15 – 0; CG: -7points, 95% CI -15 – 0), while only the CG exhibited objectively better vibration sense (knuckle: 0.8points, 95% CI 0.3–1.3; IG: 0.0points, 95% CI -1.1 – 0.9; patella: 1.0points, 95% CI 0.4–1.6: IG: -0.8points, 95% CI -0.2 – 0.0). Furthermore, maximum power output during cardiopulmonary exercise test increased in both groups (IG and CG: 0.1 W/kg, 95% CI 0.0–0.2), but only the CG improved their jump height (2 cm, 95% CI 0.5–3.5; IG: 1 cm, 95% CI -0.4 – 3.2). Conclusion We suppose that endurance training induced a reduction in sensory symptoms in both groups, while balance training additionally improved patients’ functional status. This additional functional effect might reflect the IG’s superiority in the CIPN20 motor score. Both exercises provide a clear and relevant benefit for patients with CIPN. Trial registration German Clinical Trials Register (DRKS) number: DRKS00005419, prospectively registered on November 19, 2013.

Background: New therapeutic options for metastatic pancreatic cancer are urgently needed. In pancreatic cancer, overexpression of the epidermal growth factor receptor 2 (HER2) has been reported in up to 45%. This multicentre phase II study investigated the efficacy and toxicity of the HER2 antibody trastuzumab combined with capecitabine in the patients with pancreatic cancer and HER2 overexpression. Methods: Primary endpoint was progression-free survival (PFS) after 12 weeks. A total of 212 patients were screened for HER2 expression. Results: Immunohistochemical (IHC) HER2 expression was: 83 (40%) grade 0, 71 (34%) grade 1, 31 (15%) grade 2, 22 (11%) grade 3. A total of 17 patients with IHC +3 HER2 expression or gene amplification could be assessed for the treatment response. Grade 3/4 treatment toxicities were: each 7% leucopenia, diarrhoea, nausea and hand-foot syndrome. Progression-free survival after 12 weeks was 23.5%, median overall survival (OS) 6.9 months. Conclusion: This study demonstrates +3 HER2 expression or gene amplification in 11% of patients. Contrary to breast and gastric cancer, only 7 out of 11 (64%) patients with IHC +3 HER2 expression showed gene amplification. Although the therapy was well tolerated, PFS and OS did not perform favourably compared with standard chemotherapy. Together, we do not recommend further evaluation of anti-HER2 treatment in patients with metastatic pancreatic cancer.

The role of suspected or confirmed neonatal sepsis in modifying the risk of atopic disease during childhood was assessed. Children with early-onset neonatal sepsis were identified from a cohort of neonates, hospitalized between 1990 and 1995. Of 196 individuals, 140 were recruited (71.4%). Pre- and postnatal history was ascertained from neonatal medical records. Based on clinical symptoms and a positive blood culture or at least three of initially defined laboratory or bacteriological criteria, they were stratified in either confirmed neonatal sepsis (CS) or suspected sepsis (SS) group. A control group (C) comprised children who were never hospitalized during infancy (n = 696). Primary end-point was the development of atopic dermatitis, bronchial asthma or allergic rhinitis during childhood (mean age 8.4 yr, range 5.7-12.4). CS and SS children had a higher prevalence of atopic dermatitis (CS 15.7%, SS 21.4%) compared with controls (C 5.2%, p0.001). Similarly, children with SS (7.1%), but not with CS (4.3%) had significantly more often a doctor's diagnosis of bronchial asthma compared to controls (1.9%, p = 0.02). No difference in the prevalence of allergic rhinitis was observed (CS 4.3%, SS 10%, C 8.3%). After adjusting for parental history of atopic disease and demographic factors, no significant difference for the risk to develop atopic dermatitis, asthma or allergic rhinitis among the groups was calculated in children with normal birth weight (2500 g). Our data failed to show a possible link between hospital admission with SS and development of atopic disease.

Objective: This study was designed to examine the subjective appraisal of aversive tension under conditions of daily life in patients with borderline personality disorder (BPD). Method: A sample of 63 female subjects with BPD and 40 mentally healthy controls were each given a hand-held computer. For two consecutive days, participants were prompted at hourly intervals to record their current state of aversive tension and prompting events. Results: Compared with controls, states of aversive tension occurred significantly more frequently in BPD patients. The average levels of aversive tension were significantly higher, and the rate of increase in tension was markedly more rapid. Furthermore, states of aversive tension persisted for a longer period. Among BPD subjects three events (rejection, being alone, and failure) account for 39% of all events preceding states of tension. Conclusion: The study provides support for the theory that patients with BPD experience more frequent, stronger, and longer-lasting states of aversive tension.

Summary Background Sensitization to house dust mite (HDM) is an important risk factor for the development of asthma and allergic disease in childhood. Higher levels of HDM allergen are linked to increased sensitization to HDM. Objective To study the effect of mite-impermeable mattress encasings and an educational package on the development of allergies in a newborn cohort. Methods Six hundred and ninety-six newborns at high risk of developing allergies were enrolled in three European countries (Germany, Austria, UK) in a prospective, randomized, controlled birthcohort study. Children were randomly assigned to an intervention and control group. Intervention measures included the use of mite-impermeable mattress encasings for the child’s bed and a simple educational package on allergen avoidance. The control group received basic information about allergies. Children were followed up at age 6, 12, 18 and 24 months. Results 80.9% of the children were followed up to the age of 24 months. No difference in the prevalence of sensitization to HDM (control vs. intervention group: 8.4% vs. 6.1%, P 5 0.33) or the development of symptoms (recurrent wheezing 10.3% vs. 10.7%, nocturnal cough 12.5% vs. 12.5%) or allergic diseases (asthma 3.5% vs. 5.1%, eczema 20.0% vs. 19.6%, rhinitis 28.9% vs. 25.8%) could be found between the control and intervention group. Conclusion In this study, HDM avoidance did not show a protective effect on the development of sensitization to HDM or symptomatic allergy in children at age 24 months.

The use of objective outcome measures that assess airway inflammation in pediatric asthma can provide a good evaluation of asthma severity and treatment response. In this double-blind and randomized study the effects of 200 micro g of budesonide and 800 micro g of budesonide on markers of inflammation (exhaled nitric oxide (eNO), eosinophil protein X (EPX) excretion in urine) and on lung function (FEV (1)) were prospectively investigated in 24 ICS-naive children with mild persistent to moderate persistent asthma over a period of eight weeks. After eight weeks of treatment 200 micro g and 800 micro g of budesonide led to a significant decrease (p < 0.025) in eNO [median (90 % interval): 200 micro g: - 17.2 ppb (- 54.6 to 0.9); 800 micro g: - 13.2 ppb (- 44.6 to - 1.7)]. A significant change in urinary EPX excretion was only observed in the high dose group [200 micro g: - 10.3 micro g/mmol creatinine (- 116.2 to 50.5), p = 0.9; 800 micro g: - 49.2 micro g/mmol creatinine (- 231.0 to 48.7), p = 0.02]. However, a significant difference between the change from baseline after 8 weeks of either group was found neither for eNO (p = 0.66) nor for EPX excretion (p = 0.04). In conclusion, our data demonstrate that 800 micro g budesonide per day did not show any advantage in reduction of airway inflammation, measured by eNO and urinary EPX excretion, in children with mild persistent to moderate persistent asthma.

Summary Objectives: To obtain a reliable estimate of the population size in an epidemiological study concerned with incidence estimation. Methods: In the present case, the population of interest consists of all children attending a certain pediatric practice for any reason and is estimated making use of the number of regularly attended well baby visits. In some cases, exact figures from the practices are available as a reference. A prospective epidemiological study on the estimation of the incidence of lower respiratory tract infections (LRTI) in the German pediatric population (PRI.DE, Parainfluenza- und Respiratory-Syncytial-Virus-Infektionen in Deutschland) is used to demonstrate the procedure. Results: In most cases, the fit can be regarded as good with deviations between 11% and 17%, whereas in a few cases it must be considered as poor (deviations of 60%). Conclusions: The importance of using exact figures whenever obtainable and of appraising the results carefully is emphasized.

Aim: To evaluate a recruitment strategy to identify high risk toddlers for a programme of prevention of allergy. For screening, parents were asked to participate in our study by information form and screening questionnaire on the occasion of routine check-up visits of toddlers scheduled between 20 and 48 months of age in four paediatric practices. As a next step, readiness of parents for implementation of preventive measures was confirmed. Method: Inclusion criteria were age between 20 and 48 months and a positive atopic family history (evaluated by 5 questions regarding asthma, allergic rhino-conjunctivitis and atopic dermatitis) of parents or siblings. This was confirmed by sensitization to an environmental allergen (skin prick test (SPT)) in at least one parent. If these inclusion criteria were fulfilled, the toddlers were randomly allocated to the intervention and control group of the prevention programme. Results: 111 of 175 screening questionnaires (63.4%) were returned. In 76.6% (n = 85) of these 111 questionnaires a positive atopic family history (mother, father, sibling) was noted. All inclusion criteria were fulfilled by only 43 toddlers (age: median 33.6 months, 5-95% quantile: 21.6-48 months). Based on the positive screening questionnaire, history of atopy was confirmed by positive SPT in 70.0% of fathers and 77.8% of mothers. Despite a negative screening questionnaire, history of atopy was detected by a positive SPT in 11.1% of mothers and 47.4% of fathers. Detection of specific IgE against house-dust mite in 9 of 18 serum samples revealed the risk for allergy of the toddlers. A re-evaluation after three months showed that all the elements of the prevention programme as well as the recommendations for the control group had been almost completely accepted by all the families concerned practically without any reservations. Conclusion: The recruitment of toddlers with high risk for developing allergy turned out well and could be validated. The prevention programme was readily accepted by the families and thus can be used for a larger study.

UNLABELLED The practical interpretation of lung function data depends to a very great extent on the quality of reference values. METHODS From a population of n = 2615 schoolchildren between 6 and 12 years of age 15,404 lung function measurements were taken in accordance with commonly accepted guidelines. In the present study the validity of reference equations from the literature is examined with regard to our measured data. RESULTS Employing linear regression analysis, the natural logarithm (ln) of forced vital capacity in ml (FVC) and expiratory volume in one second in ml (FEV1) were explained on the basis of the equation ln y = a + b* ln x (y = FVC, FEV1 (ml); x = height (cm)). Analyses were performed for girls (lnFVC = -4.8789 + 2.5504* lnheight, lnFEV1 = -4.3078 + 2.4070* lnheight) and boys (lnFVC = -4.5241 + 2.4917* lnheight, lnFEV1 = -3.7338 + 2.2985* lnheight), separately. Our coefficients correspond best to the literature dealing with a population of the same age group. On the other hand, for example, if reference values are derived from equations from the literature for the age group 6 to 18 years, they result at 6 years in an underestimation of the volume measured by us (FVC -150 ml) and at 12 years to an overestimation (FVC + 120 ml). CONCLUSIONS The extent of the proven systematic deviations of the reference values from the measured values is of clinical and epidemiological relevance. To avoid misinterpretations, special reference values should be applied for preadolescents, at least with regard to FVC and FEV1.

Summary. To evaluate the importance of a past history of asthma-like symptoms over a period of 2 years and current bronchial hyperreactivity (BHR), 538 randomly selected schoolchildren, initially aged 7–8 years, were examined. At yearly intervals, three standardized questionnaires, including items from the ISAAC panel, were answered by parents. Following the last questionnaire, BHR to 4.5% hypertonic saline (HS) was recorded. In survey 1, lifetime prevalence of asthma was 4.9%. During the 12-month period, prevalence of wheeze and dyspnea ranged between 9.3 and 5.2% (Survey 1) and 5.9% and 4.4% (Survey 2). Among children with wheeze or dyspnea in Survey 3, BHR (defined as a fall of baseline FEV1 ≥ 15%) was significantly more frequent (50.0% and 60.7%, respectively) than among children without these symptoms (12.8%, P

There is a general consensus that short term exposure to ozone (O3) causes a decrease in lung function parameters such as forced vital capacity (FVC) and forced expiratory volume in one second (FEV1). The objective of this study was to assess the reproducibility of lung function decrements after ambient O3 exposure over a two-summer period. The authors studied 797 children with a mean age of 8.2 yrs (95% confidence interval: 6.9-9.5) from the second and third grades of ten elementary schools in Austria and southwestern Germany. At the outset the various study locations were stratified into three groups with low (L), medium (M) and high (H) O3 exposure (range of mean O3 concentration in the locations April-October 1994: 24-30 (L); 33-38 (M); 44-52 (H) parts per billion (ppb)). Four lung function tests were performed on each child between March 1994 and November 1995. The increases in FVC and FEV1 recorded from one test period to the next were expressed as mL x day(-1). A significantly lower FVC and FEV1 increase was observed in children exposed to high ambient O3 concentration during the summer season. (FVC in summer 1994: 0.83 (L); 0.56 (M); 0.55 (H) mL x day(-1); p=0.004; and summer 1995: 0.80 (L); 0.63 (M); 0.56 (H) mL x day(-1); p=0.011; FEV1 in summer 1994: 0.48 (L); 0.34 (M); 0.18 (H) mL x day(-1); p=0.004 and summer 1995: 0.68 (L); 0.45 (M); 0.41 (H) mL x day(-1), p=0.006). There was no significant difference in FVC or FEV1 increase between the groups during the winter period. Adjusting for sex, age, height and passive smoke exposure, linear regression revealed a statistically significant negative association of average ambient O3 concentration with the FVC and FEV1 increase in both summers. During the winter period no association of O3 with FVC or FEV1 was observed. In conclusion, in two consecutive summer periods the authors found reproducible lung function decrements in children exposed to high levels of ambient ozone. Reoccurrence of ozone associated lung function deficits might increase the likelihood of persisting effects on the childrens' airways.

In asthmatic children sputum-induction with hypertonic saline is useful to quantify the eosinophilic inflammation. However, only few data are available about feasibility and safety of the procedure in children. Therefore, taking 9 non-atopic healthy control children (mean age 11.8 years) and 34 asthmatic children (mean age 11.4 years), inhaling n = 25 Budesonid (400-1200 micrograms/die) and n = 9 DNCG (60 mg/die), sputum induction was performed twice within 6 weeks. Briefly, 10 minutes after inhalation of 200 micrograms salbutamol subjects inhaled hypertonic saline (3, 4 and 5%) for in all 30 minutes, while all 5 minutes lung function was checked and expectoration of sputum was supported. Adequate sputum plugs were separated from contaminating saliva and processed immediately employing native chamber and cytospin cell count as well as measurement of eosinophilic cationic protein (ECP). Sputum-induction could be performed in 84 out of 86 planed tests (97.7%) without any objective clinical adverse effects. The mean fall in FEV1 was 3.0%, the maximum 11.0%. The reproducibility of eosinophil, neutrophil and lymphocyte differential cell count (5-95%-values Test1: 0.0-4.2%, 0.8-11.4%, and 3.2-35.1%, respectively) was moderate for eosinophils and neutrophils (Intraclass-Correlation-Coefficient (ICC) 0.41) as well as for lymphocytes (ICC = 0.49). For ECP 5-95%-values Test1: 39.8-8000.0 micrograms/l) only a fair reproducibility (ICC = 0.24) was found. The ICC levels for total cell count (ICC = 0.31) and for weight of the sputum plug (ICC = 0.30) were also fair. Based on the procedure presented induced sputum is a feasible and safe method in childhood. The differential sputum cell count of eosinophils, neutrophils and lymphocytes can be recommended as parameters with moderate reproducibility.

In unserer Studie sollten mogliche Kurzzeiteffekte der sommerlichen Ozonexposition auf lungenmechanische Mesgrosen von Kindern erfast werden. Fur Kinder ohne Pollenallergie ergaben sich dabei statistisch signifikante, negative Assoziationen der Ozonexposition und der Mesgrosen “Forcierte Vitalkapazitat” und “Einsekundenkapazitat”. Aktuelle Ozonexpositionen sind bei Kindern mit einer Einschrankung der Lungenvolumina assoziiert. Das gesundheitliche Risiko der chronischen Ozonexposition mus noch geklart werden.

To investigate the effect of natural exposure to ambient ozone over time, a follow-up study of school-aged children was performed in two small towns in southwestern Germany (Freudenstadt and Villingen) between March and October of 1994. Ozone half-hour mean concentrations were measured continuously and pulmonary function was tested in each child on four occasions (April, June, August, and September). To obtain an average short-term ozone effect, we first analyzed the data from the four time points separately and then constructed a model that included all information. During the study period the median (5th to 95th percentile) of all half-hour values of the ozone concentration was 101 micrograms/m3 or 50.6 ppb (45-179 micrograms/m3 or 22.5-89.8 ppb) in Freudenstadt and 64 micrograms/m3 or 32.1 ppb (1 to 140 micrograms/m3 or 0.5-70.1 ppb) in Villingen. To assess the effects of an individual ozone exposure we related the highest ozone concentration in the respective 24 hours before lung function testing to the results of the subconcentration in the respective 24 hours before lung function testing to the results of the subsequent pulmonary function tests. In the lung function test following the highest ozone exposure, the results of our cross-sectional linear regression analysis showed a significant negative correlation (P = 0.0181) between ozone exposure and forced vital capacity (FVC). In the longitudinal linear regression model we observed a negative statistical correlation between ozone exposure and lung function for the subpopulation living in the town with the high ozone levels (Freudenstadt). The association was more pronounced in boys than girls. For the children in Freudenstadt the decrement of FVC was -12.31 ml/10 micrograms/m3 ozone and the decrease in the forced expiratory volume in 1 second (FEV1) was -11.29 ml/10 micrograms/m3 ozone.

Mushrooms contain very little or any vitamin D(2) but are abundant in ergosterol, which can be converted into vitamin D(2) by ultraviolet (UV) irradiation. Our objective was to investigate the bioavailability of vitamin D(2) from vitamin D(2)-enhanced mushrooms by UV-B in humans, and comparing it with a vitamin D(2) supplement.Fresh mushrooms were irradiated with an UV-B dose of 1.5 J/cm(2), increasing vitamin D(2) content from1 to 491 μg/100 g and made to an experimental soup. In this 5-week, single-blinded, randomized, placebo-controlled trial, 26 young subjects with serum 25-hydroxyvitamin D (25OHD) ≤ 50 nmol/l were randomly assigned into three groups ((a) mushroom, (b) supplement and (c) placebo). They received during winter (a) 28,000 IU (700 μg) vitamin D(2) via the experimental soup, or (b) 28,000 IU vitamin D(2) via a supplement or (c) placebo, respectively.After 2 weeks, serum 25OHD was significantly higher in the mushroom than in the placebo group (P=0.001). The serum 25OHD concentrations in the mushroom and supplement groups rose significantly and similarly over the study period by 3.9 nmol/l (95% confidence interval (95% CI): 2.9, 4.8) and by 4.7 nmol/l per week (95% CI: 3.8, 5.7), respectively.We are the first to demonstrate in humans that the bioavailability of vitamin D(2) from vitamin D(2)-enhanced button mushrooms via UV-B irradiation was effective in improving vitamin D status and not different to a vitamin D(2) supplement. This trial was registered at http://germanctr.de as DRKS00000195.

Cochlear implantation (CI) is a new form of treatment in the rehabilitation of single-sided deafness. The patient requires thorough initial examination and a full explanation of alternative treatment options prior to determining the indication for CI treatment. To date, we have treated 28 patients with CI, of whom data are available for 11 after 12 months. We examined speech comprehension in background noise and localisation ability 12 months after CI implantation compared to conventional CROS (contralateral routing of signal) hearing aids, BAHA (bone-anchored hearing aid) and hearing in untreated patients. In addition, we determined the subjective handicap (HHIE, hearing handicap inventory for the elderly) and the subjective success (IOI-HA, international outcome inventory for hearing aids; SSQ, spatial and qualities of hearing scale) of each treatment option. After 12 months' experience, the results show a significantly better localisation ability and an improvement in speech comprehension in background noise with CI than with the other treatment options. Subjective results also show a clear benefit with CI. Careful patient selection is a decisive factor for successful treatment of this patient group. Under these conditions, CI is a treatment option with which significant improvement in speech comprehension and localization ability in single-sided deafness is possible.

In his recent paper, Ali (1991) has shown that the mixed regression estimator, when data contain mean-shift or variance inflation outliers, is uniformly superior to the ordinary least squares estimator in terms of scalar-valued mean square error. However, when using the matrix-valued mean square error criterion, this dominance fails to hold in general. The subsequent investigation gives a complete characterization of the situation where the mixed estimator is superior to the LS-estimator when the comparison is made with respect to this stronger MSE-property. Vice versa, the LS-estimator never dominates the mixed estimator relative to this criterion.

Findings regarding cytokine levels in neonates and their impact on the development of allergic diseases are controversial. This might be attributed to different laboratory approaches. To compare cytokine levels in supernatants of whole blood (WB) and mononuclear cell (MC) cultures in response to unspecific and allergen specific stimuli. A total population of n = 25 healthy full-term neonates and n = 25 adults was recruited. WB was diluted 1 in 5 and incubated with phytohaemagglutinine (PHA; 20 mug/ml) and the cows' milk protein betalactoglobulin (BLG) for 24 and 120 h. In parallel, cord blood mononuclear cells (CBMC) and peripheral blood mononuclear cells (PBMC) were isolated, and cells were cultured with PHA and BLG in the same concentrations in a medium supplemented with fetal calf serum (FCS) and in a serum- free medium (only PBMC from adults). The cytokines interferon-gamma (IFN-gamma), interleukin-10 (IL-10), and IL-13 in the cell culture supernatants were measured using the ELISA technique. IFN-gamma and IL-10 levels in response to PHA in supernatants of MC of neonates were significantly lower compared to that in adults (p < 0.05, Wilcoxon two-sample test). IL-13 levels were significantly higher in response to PHA in neonates. In adults, only levels of IL-10 were significantly correlated in WB and PBMC cultures (PHA: r(S) 0.6; p = 0.002; BLG: r(S) 0.54; p = 0.005). In neonates, IL-10 (PHA: r(S) 0.77; p < 0.001; BLG: r(S) 0.63; p < 0.001) and IFN-gamma (PHA: r(S) 0.48; p = 0.02; BLG: r(S) 0.4; p < 0.047) were significantly correlated. Supernatants of PBMC cultured with an FCS-supplemented medium showed a significant lower IFN-gamma release (PHA 1297 pg/ml; BLG 2762 pg/ml) compared to serum-free cell cultures (PHA 6592.5 pg/ml, p < 0.0001; BLG 14228 pg/ml, p = 0.04). IFN-gamma and IL-13 levels in WB and MC supernatants revealed significant differences. Our data indicate the need for thoroughly defined and standardized culture conditions for the detection of in vitro cytokine levels.

For two given estimators of a parameter vector the covariance structure of their difference is used to compare them in terms of their mean square error matrices. The results obtained are applied to the covariance adjustment technique and regression

To obtain a reliable estimate of the population size in an epidemiological study concerned with incidence estimation.In the present case, the population of interest consists of all children attending a certain pediatric practice for any reason and is estimated making use of the number of regularly attended well baby visits. In some cases, exact figures from the practices are available as a reference. A prospective epidemiological study on the estimation of the incidence of lower respiratory tract infections (LRTI) in the German pediatric population (PRI.DE, Parainfluenza- und Respiratory-Syncytial-Virus-Infektionen in Deutschland) is used to demonstrate the procedure.In most cases, the fit can be regarded as good with deviations between 11% and 17%, whereas in a few cases it must be considered as poor (deviations of 60%).The importance of using exact figures whenever obtainable and of appraising the results carefully is emphasized.

The use of objective outcome measures that assess airway inflammation in pediatric asthma can provide a good evaluation of asthma severity and treatment response. In this double-blind and randomized study the effects of 200 micro g of budesonide and 800 micro g of budesonide on markers of inflammation (exhaled nitric oxide (eNO), eosinophil protein X (EPX) excretion in urine) and on lung function (FEV (1)) were prospectively investigated in 24 ICS-naive children with mild persistent to moderate persistent asthma over a period of eight weeks. After eight weeks of treatment 200 micro g and 800 micro g of budesonide led to a significant decrease (p0.025) in eNO [median (90 % interval): 200 micro g: - 17.2 ppb (- 54.6 to 0.9); 800 micro g: - 13.2 ppb (- 44.6 to - 1.7)]. A significant change in urinary EPX excretion was only observed in the high dose group [200 micro g: - 10.3 micro g/mmol creatinine (- 116.2 to 50.5), p = 0.9; 800 micro g: - 49.2 micro g/mmol creatinine (- 231.0 to 48.7), p = 0.02]. However, a significant difference between the change from baseline after 8 weeks of either group was found neither for eNO (p = 0.66) nor for EPX excretion (p = 0.04). In conclusion, our data demonstrate that 800 micro g budesonide per day did not show any advantage in reduction of airway inflammation, measured by eNO and urinary EPX excretion, in children with mild persistent to moderate persistent asthma.

The effects of semi-annual and 3.5 yr mean ozone (O 3 ) concentrations on children9s forced vital capacity (FVC) and forced expiratory volume in one second (FEV 1 ) were assessed over a study period of 3.5 yrs in 2,153 schoolchildren from 15 study sites in South Western Germany and Lower Austria. Spirometric parameters were assessed twice a year, and differences between consecutive measurements divided by days were considered as a measure of lung growth. Exposure was analysed in four classes, separately for winter and summer (semi-annual mean O 3 concentrations 22–30, 30–38, 38–46, 46–54 parts per billion (ppb) in summer and 4–12, 12–20, 20–28, 28–36 ppb in winter). Regression methods for repeated measurements were used, and these revealed a significantly lower FVC (FEV 1 ) increase estimated at −19.2 (−18.5) mL·100 days −1 for semi-annual mean O 3 exposure in summer between 46 and 54 ppb compared to exposure between 22 and 30 ppb. However, in winter, the estimated difference in FVC (FEV 1 ) was 16.4 (10.9) mL·100 days −1 between the semi-annual O 3 class 28–36 ppb and the 4–12 ppb class. By means of linear regression the study found that there was no association between growth rates and mean summer O 3 for FVC and FEV 1 over a 3.5 yr period. The authors conclude that medium-term effects on schoolchildren9s lung growth are possibly present, but are in the long-term not detectable for forced vital capacity and forced expiratory volume in one second over a 3.5 yr period due to partial reversibility.

Previous adult studies demonstrated the clinical efficacy of an additional treatment with leukotriene receptor antagonists on steroid-dependent asthma, but there is little knowledge about anti-inflammatory add-on effects within the lung. In this study, we hypothesized that steroid-treated children exhibit a decrease in bronchial inflammation in induced sputum under additional treatment with montelukast. Twenty-five asthmatic children aged 6 to 14 y, who had been taking inhaled corticosteroids (400-800 microg/d budesonide) regularly for at least 12 wk, were randomized to receive additional treatment with either montelukast (5 mg orally, once daily) or placebo over a 4-wk period. As primary efficacy variable, eosinophil cationic protein (ECP) in induced sputum as direct measurement of bronchial inflammation was assessed before and after treatment. To assure a baseline level of inflammation, an ECP concentration above 100 microg/L was required. Sputum eosinophil count, concentration of exhaled nitric oxide, urinary excretion of eosinophil protein X, and quality-of-life items were considered as secondary outcome variables. After treatment with montelukast, ECP in sputum was significantly reduced (montelukast: median -975 microg/L [5 to 95% confidence interval: -4295 to 583 microg/L]; placebo: 561 microg/L [-1335 to 3320 microg/L]; p0.01) and the quality-of-life score had significantly improved (p0.05) compared with placebo. Partly explained by low baseline levels, no statistically significant change in concentration of exhaled nitric oxide (p0.05), urinary excretion of eosinophil protein X (p0.05), or eosinophil count (p0.05) was found. In conclusion, add-on treatment with montelukast can suppress sputum ECP in children with steroid-dependent asthma, while at the same time an improvement in quality of life items occurs.

Background: In order to prevent pollen asthma by immunotherapy it is mandatory to know the best time to initiate it. Children with hay fever complaints are at considerable risk of developing pollen asthma. Population-based data on their natural history is urgently needed. Methods: A longitudinal cohort study was conducted over four years in six rural towns in Baden-Wu¨rttemberg, Germany. A questionnaire with questions taken from the International Study of Asthma and Allergies in childhood (ISAAC) was filled in every spring and autumn. Hay fever complaints, asthma defining symptoms and new doctors' diagnosis of hay fever and asthma were recorded. Additionally a skin prick test with pollen allergens was performed every autumn. Results: In 1996, 19.7% of 1101 elementary school children (age: 8.1–9.9 years (5–95%)) were found to be sensitized to pollen and 8.7% had already been diagnosed as having hay fever. In a pooled analysis of 2478 children-summers, children with positive pollen sensitization had a significantly higher risk of developing hay fever symptoms (2.63; 2.17–3.10 odds ratio (OR); 95% confidence interval (CI)) and of being diagnosed as suffering from hay fever (7.88; 4.70–13.20). Furthermore, although their OR for the development of asthma symptoms during the pollen season was 3.88 (2.48–6.07 CI), it was only 0.69 (0.24–2.01 CI) for doctors' diagnosis of pollen asthma. Conclusion: >Children of elementary school age with pollen sensitization and a history of hay fever are at considerable risk of getting pollen asthma, but they are not quickly diagnosed as such. Specific immunotherapy might be a means of preventing asthma completely in such a situation. Our data helps to estimate the sample size for intervention studies of this kind.

To evaluate a recruitment strategy to identify high risk toddlers for a programme of prevention of allergy. For screening, parents were asked to participate in our study by information form and screening questionnaire on the occasion of routine check-up visits of toddlers scheduled between 20 and 48 months of age in four paediatric practices. As a next step, readiness of parents for implementation of preventive measures was confirmed.Inclusion criteria were age between 20 and 48 months and a positive atopic family history (evaluated by 5 questions regarding asthma, allergic rhino-conjunctivitis and atopic dermatitis) of parents or siblings. This was confirmed by sensitization to an environmental allergen (skin prick test (SPT)) in at least one parent. If these inclusion criteria were fulfilled, the toddlers were randomly allocated to the intervention and control group of the prevention programme.111 of 175 screening questionnaires (63.4 %) were returned. In 76.6 % (n = 85) of these 111 questionnaires a positive atopic family history (mother, father, sibling) was noted. All inclusion criteria were fulfilled by only 43 toddlers (age: median 33.6 months, 5-95 % quantile: 21.6-48 months). Based on the positive screening questionnaire, history of atopy was confirmed by positive SPT in 70.0 % of fathers and 77.8 % of mothers. Despite a negative screening questionnaire, history of atopy was detected by a positive SPT in 11.1 % of mothers and 47.4 % of fathers. Detection of specific IgE against house-dust mite in 9 of 18 serum samples revealed the risk for allergy of the toddlers. A re-evaluation after three months showed that all the elements of the prevention programme as well as the recommendations for the control group had been almost completely accepted by all the families concerned practically without any reservations.The recruitment of toddlers with high risk for developing allergy turned out well and could be validated. The prevention programme was readily accepted by the families and thus can be used for a larger study.

The practical interpretation of lung function data depends to a very great extent on the quality of reference values.From a population of n = 2615 schoolchildren between 6 and 12 years of age 15,404 lung function measurements were taken in accordance with commonly accepted guidelines. In the present study the validity of reference equations from the literature is examined with regard to our measured data.Employing linear regression analysis, the natural logarithm (ln) of forced vital capacity in ml (FVC) and expiratory volume in one second in ml (FEV1) were explained on the basis of the equation ln y = a + b* ln x (y = FVC, FEV1 (ml); x = height (cm)). Analyses were performed for girls (lnFVC = -4.8789 + 2.5504* lnheight, lnFEV1 = -4.3078 + 2.4070* lnheight) and boys (lnFVC = -4.5241 + 2.4917* lnheight, lnFEV1 = -3.7338 + 2.2985* lnheight), separately. Our coefficients correspond best to the literature dealing with a population of the same age group. On the other hand, for example, if reference values are derived from equations from the literature for the age group 6 to 18 years, they result at 6 years in an underestimation of the volume measured by us (FVC -150 ml) and at 12 years to an overestimation (FVC + 120 ml).The extent of the proven systematic deviations of the reference values from the measured values is of clinical and epidemiological relevance. To avoid misinterpretations, special reference values should be applied for preadolescents, at least with regard to FVC and FEV1.

In order to investigate nasal inflammation and subsequent adaptation after ambient ozone exposure, nasal lavage (NL) fluid was collected from 170 schoolchildren on 11 occasions (time points) between March and October. Eosinophil cationic protein (ECP), albumin and leukocytes were quantified as markers of nasal inflammation. The highest half-hour outdoor O3 concentration for each individual on the day prior to the NL was used as a measure of exposure (O3indiv). To avoid confounding with exposure to common environmental allergens, the study population was restricted to children without sensitization to inhalant allergens. In the initial period of increased O3 levels in May (time point 4), with a median O3indiv of 135 microg x m(-3) (5th-95th percentile 100-184 microg x m(-3)), the highest medians of all 11 leukocyte and ECP measurements were observed. The highest O3indiv were observed in June at time point 7 (O3indiv 173 microg x m(-3), 5th-95th percentile 120-203 microg x m(-3)). Cross-sectional analysis of all 11 time points revealed no significant association of O3indiv on the one hand and ECP, albumin and leukocyte levels on the other. A multivariable model estimated using generalized estimating equations showed a statistically significant association of O3indiv and leukocytes and ECP as the dependent variable, when time points 1-4 were analysed (p

The relationship between nitric oxide in exhaled air, levels of sputum eosinophils, sputum eosinophil cationic protein (ECP) and urinary eosinophil protein X (EPX) excretion has not yet been investigated in corticosteroid-dependent childhood asthma. Therefore, taking 25 children with stable asthma (mean age 11.2 yrs) treated with inhaled corticosteroids and nine nonatopic healthy control children (mean age 12.8 yrs) the level of exhaled NO was measured by means of a chemiluminescence analyser before and after sputum induction. This was conducted as a slow vital capacity manoeuvre under standardized conditions with a target flow of 70 mL x s(-1) against a resistance of 100 cm H2O x L(-1) x s. Sputum induction was performed by inhalation of hypertonic saline (3, 4, and 5%) in a standardized manner and a single sample of urine was collected. Exhaled NO (p = 0.01), absolute eosinophil cell counts in sputum (p = 0.02), sputum ECP (p = 0.09) and urinary EPX excretion (p = 0.02) were higher in asthmatics compared to control children. Exhaled NO was positively correlated with sputum ECP (r(s) = 0.59, p = 0.002), urinary EPX (r(s) = 0.42, p = 0.03), and sputum eosinophils (r(s) = 0.30, p = 0.15) in the asthmatic children. These correlations appeared to be pronounced after sputum induction, where NO values had decreased (p = 0.01). None of the correlations were observed in the group of nonatopic control subjects. Additionally there were significant correlations between sputum ECP and sputum eosinophils (r(s) = 0.69, p