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Background: High birth weight is associated with overweight later in life, while tobacco exposure in utero is associated with low birth weight, but with later risk of overweight. Aims: To examine whether body mass index (BMI) z-scores of children at age 5 are associated with measurements of mid-abdominal diameter (MAD) in utero comparing smoking and non-smoking mothers. Study Design: Growth in utero was recorded as MAD in mm per days of gestational age (MAD for gestational age) at 17, 25, 33 and 37 weeks of gestation in 561 infants whose mothers participated in a population-based study in Scandinavia (1986-1988). Outcome Measures: The offspring's BMI z-score at 5 years was used as a dependent variable, and MAD for gestational age as well as birth weight divided by gestational age in days were included as explanatory variables in separate linear regression models. Maternal BMI was considered as a potential confounder. Results: At 17 and 25 weeks gestation there were no relevant differences in MAD for gestational age between smokers and non-smokers. At 33 and 37 weeks gestation, children of smoking mothers had less increase in MAD than children of non-smoking mothers. In adjusted models, MAD for gestational age in week 33 and 37 was positively associated with BMI z-score at 5 years of age among children of both smoking and non-smoking mothers. Conclusions: In this study overweight in children exposed to tobacco smoking in utero was apparently not mediated through foetal growth retardation, followed by enhanced fat accretion after birth. [ABSTRACT FROM AUTHOR]

Abstract Background Evidence for protection of preterm born infants from invasive pneumococcal disease (IPD) by 7-valent pneumococcal conjugate vaccination (PCV7) is relatively sparse. Data from randomized trials is based on relatively small numbers of preterm born children. Methods We report data from active prospective surveillance of IPD in children in Germany. The cohorts of preterm born children in 2000 and 2007 and the respective whole birth cohorts are compared regarding occurrence of IPD. Results After introduction of PCV7 we observed a reduction in the rate of IPD in preterm born infants comparing the 2000 and 2007 birth cohort. The rate of IPD among the whole birth cohorts was reduced from 15.0 to 8.5 notifications per 100,000 (P < .001). The impact among the preterm birth cohort was comparable: A reduction in notification rate from 26.1 to 16.7 per 100,000 comparing the 2000 with the 2007 preterm birth cohort (P = .39). Preterm born infants with IPD were either unvaccinated or vaccinated delayed or incomplete. Conclusions This adds to evidence that PCV7 also protects preterm born infants effectively from IPD. Preterm born infants should receive pneumococcal vaccination according to their chronological age.

Abstract Background Attributable fractions (AF) assess the proportion of cases in a population attributable to certain risk factors but are infrequently reported and mostly calculated without considering potential confounders. While logistic regression for adjusted individual estimates of odds ratios (OR) is widely used, similar approaches for AFs are rarely applied. Methods Different methods for calculating adjusted AFs to risk factors of cardiovascular disease (CVD) were applied using data from the National Health and Nutrition Examination Survey (NHANES). We compared AFs from the unadjusted approach using Levin's formula, from Levin's formula using adjusted OR estimates, from logistic regression according to Bruzzi's approach, from logistic regression with sequential removal of risk factors ('sequential AF') and from logistic regression with all possible removal sequences and subsequent averaging ('average AF'). Results AFs following the unadjusted and adjusted (using adjusted ORs) Levin's approach yielded clearly higher estimates with a total sum of more than 100% compared to adjusted approaches with sums < 100%. Since AFs from logistic regression were related to the removal sequence of risk factors, all possible sequences were considered and estimates were averaged. These average AFs yielded plausible estimates of the population impact of considered risk factors on CVD with a total sum of 90%. The average AFs for total and HDL cholesterol levels were 17%, for hypertension 16%, for smoking 11%, and for diabetes 5%. Conclusion Average AFs provide plausible estimates of population attributable risks and should therefore be reported at least to supplement unadjusted estimates. We provide functions/macros for commonly used statistical programs to encourage other researchers to calculate and report average AFs.

Abstract Background Previous studies reported an increase of upper body mass index (BMI) quantiles for formula fed infants compared to breastfed infants, while corresponding mean differences were low. The aim of this study was to assess the impact of known risk factors for childhood obesity on the BMI distribution. Methods Data on 4,884 children were obtained at obligatory school entry health examinations in Bavaria (Germany). Exposure variables were formula feeding, maternal smoking in pregnancy, excessive TV-watching, low meal frequency, poor parental education, maternal overweight and high infant weight gain. Cumulative BMI distributions and Tukey mean-difference plots were used to assess possible shifts of BMI distributions by exposure. Results Maternal overweight and high infant weight gain shifted the entire BMI-distribution with an accentuation on upper quantiles to higher BMI values. In contrast, parental education, formula feeding, high TV consumption, low meal frequency and maternal smoking in pregnancy resulted in a shift of upper quantiles only. Conclusion The single shifts among upper parts of the BMI distribution might be due to effect modification of the corresponding exposures by another environmental exposure or genetic predisposition. Affected individuals might represent a susceptible subpopulation of the exposed.

Background: Previous studies reported an increase of upper body mass index (BMI) quantiles for formula fed infants compared to breastfed infants, while corresponding mean differences were low. The aim of this study was to assess the impact of known risk factors for childhood obesity on the BMI distribution.Methods: Data on 4,884 children were obtained at obligatory school entry health examinations in Bavaria (Germany). Exposure variables were formula feeding, maternal smoking in pregnancy, excessive TV-watching, low meal frequency, poor parental education, maternal overweight and high infant weight gain. Cumulative BMI distributions and Tukey mean-difference plots were used to assess possible shifts of BMI distributions by exposure.Results: Maternal overweight and high infant weight gain shifted the entire BMI-distribution with an accentuation on upper quantiles to higher BMI values. In contrast, parental education, formula feeding, high TV consumption, low meal frequency and maternal smoking in pregnancy resulted in a shift of upper quantiles only.Conclusion: The single shifts among upper parts of the BMI distribution might be due to effect modification of the corresponding exposures by another environmental exposure or genetic predisposition. Affected individuals might represent a susceptible subpopulation of the exposed. [ABSTRACT FROM AUTHOR]

In a phase 3 trial (PANAMO, NCT04333420), vilobelimab, a complement 5a (C5a) inhibitor, reduced 28-day mortality in mechanically ventilated COVID-19 patients. This post hoc analysis of 368 patients aimed to explore treatment heterogeneity through unsupervised learning. All available clinical variables at baseline were used as input. Treatment heterogeneity was assessed using latent class analysis (LCA), Ward's hierarchical clustering (HC) and the adjudication to previously described clinical sepsis phenotypes. The primary outcome was 28-day mortality. For LCA, a 2-class latent model was deemed most suitable. In the LCA model, 82 (22%) patients were assigned to class 1 and 286 (78%) to class 2. Class 1 was defined by more severely ill patients with significantly higher mortality. In an adjusted logistic regression, no heterogeneity of treatment effect (HTE) between classes was observed (p = 0.998). For HC, no significant classes were found (p = 0.669). Using the previously described clinical sepsis subtypes, 41 patients (11%) were adjudicated subtype alpha (α), 17 (5%) beta (β), 112 (30%) delta (δ) and 198 (54%) gamma (γ). HTE was observed between clinical subtypes (p = 0.001) with improved 28-day mortality after treatment with vilobelimab for the δ subtype (OR = 0.17, 95% CI 0.07-0.40, p < 0.001). No signal for harm of treatment with vilobelimab was observed in any class or clinical subtype. Overall, treatment effect with vilobelimab was consistent across different classes and subtypes, except for the δ subtype, suggesting potential additional benefit for the most severely ill patients., (© 2024. The Author(s).)

Background: Vilobelimab, a complement 5a (C5a)-specific monoclonal antibody, reduced mortality in critically ill COVID-19 patients in a phase 3 multicentre, randomized, double-blind, placebo-controlled study. As part of the study, vilobelimab concentrations and C5a levels as well as antidrug antibodies (ADAs) to vilobelimab were analysed., Results: From Oct 1, 2020 to Oct 4, 2021, 368 invasively mechanically ventilated COVID-19 patients were randomized: 177 patients were randomly assigned to receive vilobelimab while 191 patients received placebo. Pharmacokinetic sampling was only performed at sites in Western Europe. Blood samples for vilobelimab measurements were available for 93 of 177 (53%) patients in the vilobelimab group and 99 of 191 (52%) patients in the placebo group. On day 8, after three infusions, mean vilobelimab (trough) concentrations ranged from 21,799.3 to 302,972.1 ng/mL (geometric mean 137,881.3 ng/mL). Blood samples for C5a measurements were available for 94 of 177 (53%) patients in the vilobelimab group and 99 of 191 (52%) patients in the placebo group. At screening, C5a levels were highly elevated and comparable between groups. In the vilobelimab group, median C5a levels were 118.3 ng/mL [IQR 71.2-168.2 ng/mL] and in the placebo group, median C5a levels were 104.6 ng/mL [IQR 77.5-156.6 ng/mL]. By day 8, median C5a levels were reduced by 87% in the vilobelimab group (median 14.5 ng/mL [IQR 9.5-21.0 ng/mL], p < 0.001) versus an 11% increase in the placebo group (median 119.2 ng/mL [IQR 85.9-152.1 ng/mL]). Beyond day 8, though plasma sampling was sparse, C5a levels did not reach screening levels in the vilobelimab group while C5a levels remained elevated in the placebo group. Treatment-emergent ADAs were observed in one patient in the vilobelimab group at hospital discharge on day 40 and in one patient in the placebo group at hospital discharge on day 25., Conclusions: This analysis shows that vilobelimab efficiently inhibits C5a in critically ill COVID-19 patients. There was no evidence of immunogenicity associated with vilobelimab treatment. Trial registration ClinicalTrials.gov, NCT04333420. Registered 3 April 2020, https://clinicaltrials.gov/ct2/show/NCT04333420., (© 2023. The Author(s).)

Background: Vilobelimab, an anti-C5a monoclonal antibody, was shown to be safe in a phase 2 trial of invasively mechanically ventilated patients with COVID-19. Here, we aimed to determine whether vilobelimab in addition to standard of care improves survival outcomes in this patient population., Methods: This randomised, double-blind, placebo-controlled, multicentre phase 3 trial was performed at 46 hospitals in the Netherlands, Germany, France, Belgium, Russia, Brazil, Peru, Mexico, and South Africa. Participants aged 18 years or older who were receiving invasive mechanical ventilation, but not more than 48 h after intubation at time of first infusion, had a PaO 2 /FiO 2 ratio of 60-200 mm Hg, and a confirmed SARS-CoV-2 infection with any variant in the past 14 days were eligible for this study. Eligible patients were randomly assigned (1:1) to receive standard of care and vilobelimab at a dose of 800 mg intravenously for a maximum of six doses (days 1, 2, 4, 8, 15, and 22) or standard of care and a matching placebo using permuted block randomisation. Treatment was not continued after hospital discharge. Participants, caregivers, and assessors were masked to group assignment. The primary outcome was defined as all-cause mortality at 28 days in the full analysis set (defined as all randomly assigned participants regardless of whether a patient started treatment, excluding patients randomly assigned in error) and measured using Kaplan-Meier analysis. Safety analyses included all patients who had received at least one infusion of either vilobelimab or placebo. This study is registered with ClinicalTrials.gov, NCT04333420., Findings: From Oct 1, 2020, to Oct 4, 2021, we included 368 patients in the ITT analysis (full analysis set; 177 in the vilobelimab group and 191 in the placebo group). One patient in the vilobelimab group was excluded from the primary analysis due to random assignment in error without treatment. At least one dose of study treatment was given to 364 (99%) patients (safety analysis set). 54 patients (31%) of 177 in the vilobelimab group and 77 patients (40%) of 191 in the placebo group died in the first 28 days. The all-cause mortality rate at 28 days was 32% (95% CI 25-39) in the vilobelimab group and 42% (35-49) in the placebo group (hazard ratio 0·73, 95% CI 0·50-1·06; p=0·094). In the predefined analysis without site-stratification, vilobelimab significantly reduced all-cause mortality at 28 days (HR 0·67, 95% CI 0·48-0·96; p=0·027). The most common TEAEs were acute kidney injury (35 [20%] of 175 in the vilobelimab group vs 40 [21%] of 189 in the placebo), pneumonia (38 [22%] vs 26 [14%]), and septic shock (24 [14%] vs 31 [16%]). Serious treatment-emergent adverse events were reported in 103 (59%) of 175 patients in the vilobelimab group versus 120 (63%) of 189 in the placebo group., Interpretation: In addition to standard of care, vilobelimab improves survival of invasive mechanically ventilated patients with COVID-19 and leads to a significant decrease in mortality. Vilobelimab could be considered as an additional therapy for patients in this setting and further research is needed on the role of vilobelimab and C5a in other acute respiratory distress syndrome-causing viral infections., Funding: InflaRx and the German Federal Government., Competing Interests: Declaration of interests NCR and RG are founders, active officers, and executive directors of the board, and hold shares and stock options in InflaRx. KP is the chief clinical development officer and holds stock options in InflaRx. RZ is the program director and holds stock options in InflaRx. SR is an employee of Metronomia Clinical Research and a contracted statistical service provider for InflaRx. MW receives grants from the German Research Foundation (SFB-TR84 C6, SFB-TR84 C9, and SFB 1449 B02) and German Ministry of Education and Research (e:Med CAPSyS [01ZX1304B], SYMPATH [01ZX1906A], NUM-NAPKON [01KX2021], and PROVID [01KI20160A]). APJV received consulting fees from InflaRx for advisory work, paid to the institution. GM received honoraria for lecturing and consulting from B Braun, 4TEEN4, Adrenomed, and Philips. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Recently, we reported the phase II portion of the adaptive phase II/III PANAMO trial exploring potential benefit and safety of selectively blocking C5a with the monoclonal antibody vilobelimab (IFX-1) in patients with severe coronavirus disease 2019 (COVID-19). The potent anaphylatoxin C5a attracts neutrophils and monocytes to the infection site, causes tissue damage by oxidative radical formation and enzyme releases, and leads to activation of the coagulation system. Results demonstrated that C5a inhibition with vilobelimab was safe and secondary outcomes appeared in favor of vilobelimab. We now report the pharmacokinetic/pharmacodynamic (PK/PD) analysis of the phase II study. Between March 31 and April 24, 2020, 30 patients with severe COVID-19 pneumonia confirmed by real-time polymerase chain reaction were randomly assigned 1:1 to receive vilobelimab plus best supportive care or best supportive care only. Samples for measurement of vilobelimab, C3a and C5a blood concentrations were taken. Vilobelimab predose (trough) drug concentrations in plasma ranged from 84,846 to 248,592 ng/ml (571 to 1674 nM) with a geometric mean of 151,702 ng/ml (1022 nM) on day 2 and from 80,060 to 200,746 ng/ml (539 to 1352 nM) with a geometric mean of 139,503 ng/ml (939 nM) on day 8. After the first vilobelimab infusion, C5a concentrations were suppressed in the vilobelimab group (median 39.70 ng/ml 4.8 nM, IQR 33.20-45.55) as compared to the control group (median 158.53 ng/ml 19.1 nM, IQR 60.03-200.89, p = 0.0006). The suppression was maintained on day 8 (p = 0.001). The current PK/PD analysis shows that vilobelimab efficiently inhibits C5a in patients with severe COVID-19., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The pneumococcal conjugate vaccine is recommended since July 2006 for all children up to 24 months by the Standing Committee on Vaccination (STIKO) in Germany. Immunisation includes 4 doses; a single dose should be administered at completed 2, 3, 4 months and 11-14 months of age. To analyse the immunization coverage, timeliness and completeness of vaccinations, a claims data analysis was conducted. The evaluation was based on routine claims data of a statutory health insurance covering the period from May 2008-September 2009. Overall, 81.2% (5 484/6 755) of all live births of mothers and fathers of the insurance received at least one vaccination dose. In 91.3% and 72.0% of these cases, the second and third dose was administered, respectively. A vaccination cycle of 4 doses was often not completed and the recommended time points for vaccination were not met in two-thirds of all children. Due to the limited and relatively short observation period, a conclusion about the rate of fully completed vaccination cycles was not possible., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: The duration of protection after hepatitis B vaccination in early infancy is unclear and may be related to vaccination schedule, dosage, vaccine type and population characteristics. Factors potentially influencing waning immunity were assessed., Methods: A systematic review was performed. The main outcomes were prevalence of anti-hepatits B antibodies ≥ 10 mIU/mL after primary or booster vaccination. Factors potentially influencing protection were assessed in an adjusted random-effects meta-analysis model by age for both outcomes. Results of both meta-analyses were combined in a prognostic model., Results: Forty-six studies reporting on the anti-hepatits B antibodies ≥ 10 mIU/mL 5 to 20 years after primary immunization and 29 on booster response were identified. The adjusted meta-analyses identified maternal carrier status (odds ratio [OR]: 2.37 [1.11; 5.08]), lower vaccine dosage than presently recommended (OR: 0.14 [0.06; 0.30]) and gap time between last and preceding dose of the primary vaccine series (OR: 0.44 [0.22; 0.86]) as determinants for persistence of anti-hepatits B antibodies ≥ 10. A lower vaccine dosage was also associated with failure to respond to booster (OR: 0.20 [0.10; 0.38]). The prognostic model predicted long-term protection of 90% [77%; 100%] at the age of 17 years for offspring of noncarrier mothers vaccinated with a presently recommended dose and vaccination schedule., Conclusions: Based on meta-analyses, predictors of waning immunity after hepatitis B vaccination in infancy could be identified. A prognostic model for long-term protection after hepatitis B vaccination in infancy was developed.

Better protection against hepatitis B infection in offspring of carrier mothers has been postulated because of a booster effect by close maternal contact. Empirical evidence, however, is inconclusive. Immunologic markers for protection against hepatitis B are anti-HBs ≥ 10 mIU/ml or response to booster in case anti-HBs had fallen below 10 mIU/ml. The objective of this paper was to asses whether immunologic markers suggest a higher protection after hepatitis B vaccination in offspring of carrier mothers. A systematic review was performed in order to identify all studies in offspring of carrier and non-carrier mothers reporting the proportions of individuals with anti-HBs ≥ 10 mIU/ml after infant hepatitis B vaccination with a presently recommended dose in children aged 5 years or older or response to a booster dose in case anti-HBs was below 10 mIU/ml. Associations between carrier status and the proportions of anti-HBs ≥ 10 mIU/ml or booster response were analysed by random effects models with adjustment for age and potential confounders. We identified 19 studies providing proportions of anti-HBs ≥ 10 mIU/ml with explicit information regarding the maternal carrier status. These studies reported 3245 children of carrier mothers aged up to 20 years and 4602 children of non-carrier mothers aged up to 14 years. Antibody titres ≥ 10 mIU/ml were detected in 75.8% of children of carrier and 63.6% of non-carrier mothers. A random effects model with adjustment for confounding yielded an odds ratio of 2.43 (95% CI 1.24-4.75) suggesting a markedly higher probability of anti-HBs ≥ 10 mIU/ml in offspring of carrier compared to non-carrier mothers. The distribution of proportions of individuals with post booster increase of anti-HBs titres ≥ 10 mIU/ml stratified by age at booster (≤ 10 years and >10 years) showed no differences between offspring of carrier and non carrier mothers up to the age of 10 years and only marginal differences thereafter. In conclusion the proportions of anti-HBs ≥ 10 mIU/ml were clearly higher in offspring of carrier mothers years after infant vaccination but there appeared to be no clinically relevant difference in response to booster. It is unclear to which extent higher proportions of breakthrough infections contribute to the higher proportions of protective antibody titres in offspring of carrier mothers., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objectives: To assess the effectiveness of general ultrasound screening to prevent first operative procedures of the hip., Study Design: We conducted a case-control study in a population in which general ultrasound screening supplementing clinical screening is recommended and offered free of charge for all children. Participation in ultrasound screening before week 7 as recommended in Germany was the exposure of interest. Case ascertainment was based on active surveillance in orthopedic hospitals. The case definition was: first operative procedure for developmental dysplasia of the hip (closed reduction, open reduction, or osteotomy) in children >9 weeks old and <5 years old and born between 1996 and 2001. Control subjects from the same birth cohorts were recruited in telephone surveys., Results: Cases of first operative procedures for developmental dysplasia of the hip (n = 446) were compared with 1173 control subjects for ultrasound screening. Effectiveness of ultrasound screening to prevent first operative procedures for developmental dysplasia of the hip was estimated as 52% (95% CI, 32-67). Effectiveness did not vary substantially for closed and open reductions and osteotomy., Conclusions: General ultrasound screening reduces the rate of operative procedures for developmental dysplasia of the hip; the impact on developmental dysplasia of the hip. Treatment rates and avascular necrosis need further assessment to balance the benefit against potential overtreatment and adverse effects., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Pneumococcal conjugate vaccines have been successfully used in infant vaccination programs. While most countries have used vaccination schedules with three primary immunisations and one booster dose, some countries have implemented schedules with only two primary immunisations and a booster dose. This systematic review aims to summarize evidence on immunogenicity of pneumococcal conjugate vaccines in infants comparing two and three primary immunisations before a booster dose is given. We systematically reviewed papers published between 1999 and 2011. Results from individual studies were pooled in a meta-analysis with the difference in proportion of children achieving serotype-specific ELISA antibody levels of ≥0.35 μg/ml. We estimated that about 10% less children achieve ELISA antibody levels of ≥0.35 μg/ml after two primary immunisations compared to three primary immunisations for most of serotypes included in one of the licensed pneumococcal conjugate vaccines. This difference in proportion was higher for serotypes 6B and 23F, where -49.4% (-66.0; -32.9%) and -26.9% (-37.2%; -16.6%) less children achieved protective antibody levels. These results support the notion that the majority of children are protected by two primary immunisations with pneumococcal conjugate vaccines in the first year of life. However, for serotypes 6B and 23F protection may be reduced., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

A number of cross-sectional and prospective studies suggested a priming effect of maternal smoking in pregnancy on offspring's obesity. It has been hypothesized that this association might be explained by low birth weight and subsequent catch-up growth in the causal pathway. We therefore examined the role of birth weight in children exposed versus not exposed to cigarette smoking in utero on later body mass index (BMI). Using data of 12,383 children and adolescents (3-17 years of age) recorded in a German population-based survey (KiGGS), we assessed mean body mass index standard deviation scores (BMI-SDS) in different birth weight SDS categories, stratified for children with smoking and non-smoking mothers. We calculated spline regression models with BMI-SDS as outcome variable, cubic splines of birth weight SDS, and potential confounding factors. Children whose mothers had been smoking during pregnancy had lower birth weight SDS and higher BMI-SDS at interview compared to children of non-smoking mothers. However, we observed a linear association between birth weight SDS and BMI-SDS in crude analyses for both groups. Similarly, almost linear effects were observed in adjusted spline regression analyses, except for children with very low birth weight. The respective 95% confidence bands did not preclude a linear effect for the whole birth weight SDS distribution. Our findings suggest that low birth weight is unlikely to be the main cause for the association between intrauterine nicotine exposure and higher BMI in later life. Alternative mechanisms, such as alterations in the noradrenergic system or increased food efficiency, have to be considered.

Background: We determined antibodies to the pandemic influenza A (H1N1) 2009 virus in children to assess: the incidence of (H1N1) 2009 infections in the 2009/2010 season in Germany, the proportion of subclinical infections and to compare titers in vaccinated and infected children., Methodology/principal Findings: Eight pediatric hospitals distributed over Germany prospectively provided sera from in- or outpatients aged 1 to 17 years from April 1(st) to July 31(st) 2010. Vaccination history, recall of infections and sociodemographic factors were ascertained. Antibody titers were measured with a sensitive and specific in-house hemagglutination inhibition test (HIT) and compared to age-matched sera collected during 6 months before the onset of the pandemic in Germany. We analyzed 1420 post-pandemic and 300 pre-pandemic sera. Among unvaccinated children aged 1-4 and 5-17 years the prevalence of HI titers (≥1∶10) was 27.1% (95% CI: 23.5-31.3) and 53.5% (95% CI: 50.9-56.2) compared to 1.7% and 5.5%, respectively, for pre-pandemic sera, accounting for a serologically determined incidence of influenza A (H1N1) 2009 during the season 2009/2010 of 25,4% (95% CI : 19.3-30.5) in children aged 1-4 years and 48.0% (95% CI: 42.6-52.0) in 5-17 year old children. Of children with HI titers ≥1∶10, 25.5% (95% CI: 22.5-28.8) reported no history of any infectious disease since June 2009. Among vaccinated children, 92% (95%-CI: 87.0-96.6) of the 5-17 year old but only 47.8% (95%-CI: 33.5-66.5) of the 1-4 year old children exhibited HI titers against influenza A virus (H1N1) 2009., Conclusion: Serologically determined incidence of influenza A (H1N1) 2009 infections in children indicates high infection rates with older children (5-17 years) infected twice as often as younger children. In about a quarter of the children with HI titers after the season 2009/2010 subclinical infections must be assumed. Low HI titers in young children after vaccination with the AS03(B)-adjuvanted split virion vaccine need further scrutiny.

Background: The 92 capsular serotypes of Streptococcus pneumoniae differ greatly in nasopharyngeal carriage prevalence, invasiveness, and disease incidence. There has been some debate, though, regarding whether serotype independently affects the outcome of invasive pneumococcal disease (IPD). Published studies have shown variable results with regard to case-fatality ratios for specific serotypes and the role of host factors in affecting these relationships. We evaluated whether risk of death due to IPD is a stable serotype-associated property across studies and then compared the pooled effect estimates with epidemiologic and biological correlates., Methods: We performed a systematic review and meta-analysis of serotype-specific disease outcomes for patients with pneumonia and meningitis. Study-specific estimates of risk of death (risk ratio [RR]) were pooled from 9 studies that provided serotype-specific data on pneumonia and meningitis using a random-effects method with serotype 14 as the reference. Pooled RRs were compared with RRs from adults with low comorbidity scores to evaluate potential confounding by host factors., Results: Significant differences were found in the RR estimates among serotypes in patients with bacteremic pneumonia. Overall, serotypes 1, 7F, and 8 were associated with decreased RRs, and serotypes 3, 6A, 6B, 9N, and 19F were associated with increased RRs. Outcomes among meningitis patients did not differ significantly among serotypes. Serotypes with increased RRs had a high carriage prevalence, had low invasiveness, and were more heavily encapsulated in vitro., Conclusions: These results suggest that IPD outcome, like other epidemiologic measures, is a stable serotype-associated property.

Efficacy of 7-valent pneumococcal conjugate vaccination has been shown in randomized controlled trials using 4 dose vaccination schedules in children under 2 years of age. A case-control study from the US showed considerable protection from IPD for reduced vaccination schedules and even some protection from only one dose. In Germany, delayed and incomplete vaccination is a major issue. We assessed efficacy of PCV7 using data on cases of IPD from active surveillance and applying the indirect cohort design proposed by Broome, comparing cases of IPD with a vaccine serotype with cases with a non-vaccine serotype. Efficacy of at least one dose of PCV7 was estimated to be 88.3% (95% CI: 64.0-96.6). Estimates of efficacy for one, two, and three doses in the first 7 months of life were 78.1% (3.4-96.1), 89.8% (20.6-100.0), and 94.6% (69.7-99.5) respectively. Our study adds to evidence of good protection from IPD by reduced vaccination schedules with PCV7, e.g. with two doses as primary series, in a setting where a high proportion of children receives vaccination delayed., (Copyright 2010. Published by Elsevier Ltd.)

Background: Evidence for protection of preterm born infants from invasive pneumococcal disease (IPD) by 7-valent pneumococcal conjugate vaccination (PCV7) is relatively sparse. Data from randomized trials is based on relatively small numbers of preterm born children., Methods: We report data from active prospective surveillance of IPD in children in Germany. The cohorts of preterm born children in 2000 and 2007 and the respective whole birth cohorts are compared regarding occurrence of IPD., Results: After introduction of PCV7 we observed a reduction in the rate of IPD in preterm born infants comparing the 2000 and 2007 birth cohort. The rate of IPD among the whole birth cohorts was reduced from 15.0 to 8.5 notifications per 100,000 (P < .001). The impact among the preterm birth cohort was comparable: A reduction in notification rate from 26.1 to 16.7 per 100,000 comparing the 2000 with the 2007 preterm birth cohort (P = .39). Preterm born infants with IPD were either unvaccinated or vaccinated delayed or incomplete., Conclusions: This adds to evidence that PCV7 also protects preterm born infants effectively from IPD. Preterm born infants should receive pneumococcal vaccination according to their chronological age.

Background: Prenatal and postnatal tobacco exposure have been reported to be associated with behavioral problems. However, the magnitude of the association with tobacco exposure at specific periods of exposure is unclear., Objective: We assessed the relative risk of behavioral problems in children who had been exposed to tobacco smoke in utero and postnatally., Methods: We analyzed data from a prospective birth cohort study in two cities in Germany: the German Infant Nutrition Intervention. Our sample included 5,991 children born between 1995 and 1998 as well as their parents. We measured behavioral problems using the Strength and Difficulties Questionnaire (SDQ) at follow-up 10 years after birth. According to prespecified SDQ cutoff values, children were classified as "normal," "borderline," or "abnormal" according to the subscales "emotional symptoms," "conduct problems," "hyperactivity/inattention," "peer-relationship problems," and a total difficulties score. Smoke exposure and further covariates were assessed using parent questionnaires., Results: Compared with children not exposed to tobacco smoke, children exposed both pre- and postnatally to tobacco smoke had twice the estimated risk [95% confidence interval (CI), 1.4-3.1] of being classified as abnormal according to the total difficulties score of the SDQ at 10 years of age. Children who were only prenatally exposed had a 90% higher relative risk (95% CI, 0.9-4.0), whereas children who were only postnatally exposed had a 30% higher relative risk (95% CI, 0.9-1.9). These results could not be explained by confounding by parental education, father's employment, child's time spent in front of computer or television screen, being a single father or mother, or mother's age., Conclusions: Prenatal exposure to tobacco smoke is associated with behavioral problems in school-age children. Although our findings do not preclude the influence of postnatal exposure, prenatal exposure seems to be more important.

Aims: To assess the association between peer relationship problems and childhood overweight and obesity., Methods: Data on 4718 preschool children were obtained at the obligatory school entry health examination in Bavaria. Parentally reported peer relationship problems ('normal', 'borderline' or 'abnormal') were assessed from the Strengths and Difficulties Questionnaire. Overweight and obesity were defined according to age- and gender-specific BMI cut-off points. Multivariate logistic regression analysis was performed to control potential confounders., Results: The prevalence of overweight and obesity was higher among children with 'borderline' or 'abnormal' peer relationship problems compared to 'normal' children. The association of 'abnormal' peer relationship problems was still significant in the final logistic regression model for girls [odds ratio (OR) for overweight 2.0; 95% confidence interval (CI): 1.4-3.0; OR for obesity 2.6; 95% CI: 1.3-5.0]. Among boys the adjusted odds ratio were lower and no longer significant., Conclusion: The significantly increased prevalence of overweight and obesity among preschool children with peer relationship problems could not be explained by confounding. It seems evident that there is a relevant co-morbidity of peer relationship problems and obesity in pre-school children pointing to the need of interventions focusing on both physical as well as psychosocial health.

Objective: Physical activity is an important determinant of energy balance. However, its impact on overweight/obesity has proved difficult to measure in pre-school children and few studies have found significant associations. A set of simple questions was used to distinguish pre-school children with high and low physical activity, and the association of this classification with childhood overweight/obesity and performance in an established motor test was investigated., Design: Survey, cross-sectional., Setting and Subjects: Weight and height were measured in 12,556 children taking part in the obligatory school entrance health examination 2004-5 and 2005-6 in three urban and three rural Bavarian regions. Their parents were asked to answer a questionnaire with a set of questions on physical activity., Results: The mean age of the children evaluated was 5.78 (sd 0.43) years, 6535 (52.1 %) were boys. Physically active children were less likely to be overweight (OR = 0.786, 95 % CI 0.687, 0.898) or obese (OR = 0.655, 95 % CI 0.506, 0.849) and achieved 6.7 (95 % CI 5.8, 7.7) % more jumps per 30 s than less active children in a motor test, adjusted for a number of potentially confounding variables., Conclusions: Classification of pre-school children as physically active or not, based on a small set of questions, revealed significant associations with overweight/obesity and a motor test. Once further validated, this classification might provide a valuable tool to assess the impact of physical activity on the risk of childhood overweight and obesity.

General vaccination with the 7-valent pneumococcal conjugate vaccine was recommended in Germany in July 2006 for all children <2 years. The proportion of reported invasive pneumococcal disease (IPD) caused by vaccine serotypes before vaccine introduction was considerably lower than in the US. We report data from nationwide surveillance of IPD in children with two reporting sources, pediatric hospitals and microbiological laboratories in Germany. Incidence rates with regard to age groups and pneumococcal serotypes are based on capture recapture estimates combining the two reporting sources. Between July 1, 1997 and June 30, 2003, 2680 cases (an average 447 yearly cases) of IPD were observed in children <16 years in Germany compared to 223 cases between July 1, 2007 and June 30, 2008. A significant reduction in overall incidence (4/100,000-3.2/100,000) was attributed to significant reductions in children younger than 2 years (20.0/100,000-11.0/100,000). While the incidence of all serotypes included in the vaccine was reduced in the age group <2 years, the incidence of non-vaccine serotypes remained stable. These data show a first success of the pneumococcal vaccination program in Germany. Further changes in incidence and serotype distribution of IPD are subject to future surveillance.

Background: Invasive pneumococcal disease (IPD) in children may manifest as bacteremia/sepsis, bacteremic pneumonia, or meningitis, with serious outcomes that include hospitalization, neurologic sequelae, or death. The risk of severe or fatal outcome of disease is associated with host-related factors, such as age or comorbid conditions. Furthermore, there is an ongoing discussion about organism-related factors, such as the pneumococcal serotype., Methods: Data on 494 children aged <16 years hospitalized for IPD between 1997 and 2003 in pediatric hospitals in Germany were analyzed. Serotype specific case-fatality rates and rates of severe outcome were compared using standardized mortality ratios (SMR). The risk of severe or fatal outcome for the serotype with the highest case-fatality rate was further analyzed using multivariate logistic regression adjusting for age younger than 1 year, meningitis, sex, and immunocompromised status as potential confounders., Results: The overall case-fatality rate was 5.3% and the rate of severe outcome was 17.0%. Serotype 7F had the highest case-fatality rate (14.8%, SMR 3.1), followed by serotypes 23F (8.3%, SMR 1.7) and 3 (8.3%, SMR 1.7). The highest rate of severe outcome was also observed for 7F (40.7%, SMR 2.4). Multivariate analysis showed an odds ratio of 4.3 (1.3-14.7) for fatal outcome and 4.0 (1.6-10.4) for severe outcome comparing 7F to all other serotypes., Conclusions: In this study population, serotype 7F accounted for a higher risk of severe and fatal outcome than other serotypes of Streptococcus pneumoniae. In describing the epidemiology of IPD, the serotype-specific risk for severe or fatal outcome is an important complement to other serotype-specific aspects like incidence and antibiotic resistance pattern.

Background: Attributable fractions (AF) assess the proportion of cases in a population attributable to certain risk factors but are infrequently reported and mostly calculated without considering potential confounders. While logistic regression for adjusted individual estimates of odds ratios (OR) is widely used, similar approaches for AFs are rarely applied., Methods: Different methods for calculating adjusted AFs to risk factors of cardiovascular disease (CVD) were applied using data from the National Health and Nutrition Examination Survey (NHANES). We compared AFs from the unadjusted approach using Levin's formula, from Levin's formula using adjusted OR estimates, from logistic regression according to Bruzzi's approach, from logistic regression with sequential removal of risk factors ('sequential AF') and from logistic regression with all possible removal sequences and subsequent averaging ('average AF')., Results: AFs following the unadjusted and adjusted (using adjusted ORs) Levin's approach yielded clearly higher estimates with a total sum of more than 100% compared to adjusted approaches with sums < 100%. Since AFs from logistic regression were related to the removal sequence of risk factors, all possible sequences were considered and estimates were averaged. These average AFs yielded plausible estimates of the population impact of considered risk factors on CVD with a total sum of 90%. The average AFs for total and HDL cholesterol levels were 17%, for hypertension 16%, for smoking 11%, and for diabetes 5%., Conclusion: Average AFs provide plausible estimates of population attributable risks and should therefore be reported at least to supplement unadjusted estimates. We provide functions/macros for commonly used statistical programs to encourage other researchers to calculate and report average AFs.

Background: The completeness of a compulsory reporting system of systemic Haemophilus influenzae infections in children in Germany is studied by means of cross-linking registry data from three sources and applying capture-recapture methods., Methods: Cases were collected for the years 2001-05 by three national data sources: a passive administration registry (SurvNet@RKI), an active hospital surveillance system and an active laboratory surveillance system. The case definition required cultural detection of H. influenzae in blood or cerebrospinal fluid. Linkage was carried out by month and year of birth, sex, geographical region and date of disease onset. Capture-recapture models were used to estimate the incidence of invasive H. influenzae infections., Results: SurvNet@RKI reported 113 H. influenzae and 38 H. influenzae type b (Hib) cases, compared to a total of 231 and 68 cases, respectively, reported by all three sources combined. Best-fitting 3-source capture-recapture estimations amounts to 258 (95% confidence interval: 247-276) H. influenzae and 71 (69-74) Hib cases. SurvNet@RKI data depicted a similar decrease in annual H. influenzae cases as the capture-recapture estimates but failed to detect the underlying decrease in Hib cases which was observed in the capture-recapture estimates due to a considerable annual variability of ascertainment of serotyped cases in SurvNet@RKI ranging from 14% to 69%., Conclusions: Because of small variability of ascertainment, the compulsory passive reporting system depicted trends in H. influenzae incidence, although less than half of the cases were ascertained. However, time trend in Hib cases could not be depicted, because of highly variable serotyping proportions.

Based on active prospective surveillance, we report the incidence and serotype distribution for invasive pneumococcal disease in German children between 1997 and 2003. While incidence of meningitis cases was stable over time, there was an increase in non-meningitis cases. In absence of a general pneumococcal conjugate vaccination program, there were considerable and significant changes in serotype distribution over time. These should be considered when discussing the effect of vaccination programs and related changes in serotype distribution.

Aim of the Study: Differences in health care in Germany have rarely been analysed. Recent research, however, indicates that subjects of the lower social class participate in cancer screening less frequently., Methods: Participation in screening for cervical cancer among women older than 20 years has been analysed using billing information of the KVB (Kassenärztlichen Vereinigung Bayern) for the period from 2002-2005. Women were assigned to one of the 96 Bavarian districts based on their postal code. The following variables were used: Participation rate in cervical cancer screening; age; average household income; gynaecologists per 10,000 women. Multivariate analyses were based on age-stratified linear regressions., Results: There are considerable regional differences in participation in screening for cancer among older women. Participation rates are lower in districts with lower average household income. The correlation between participation rates and average household income shows an almost linear dependence on the level of districts. This association could not be explained by the variable "gynaecologists per 10,000 women"., Conclusion: In order to provide social equality in health care, regional differences in cancer screening participation should be targeted. This is especially important in districts with lower average household incomes.

Objective of the Study: Cervical cancer rates are higher in Germany than in comparable European countries. While other European countries have implemented invitation programs, Germany relied on annual free access only. Are sufficient screening participation rates achieved?, Methods: We analyzed data from 2,223,135 Bavarian women between 2002/3 and 2005/4 in a retrospective cohort, to evaluate screening participation, frequency, age dependencies and regional differences., Results: The highest screening participation was amongst women between 20 and 29 (54.6% had at least one visit after one year, 84% within three years) and decreased progressively with increasing age. Participation was lowest for women above 70 in rural areas (in some regions less than 20% had at least one screening within three years)., Conclusion: Poor participation rates in general are unlikely to account for the high cervical cancer rates in Germany. Low participation rates in elderly women, particularly those in rural regions might contribute to the well-known peak of cervical cancer in elderly women.

Objective: A number of individual risk factors for childhood obesity have been identified, but only some of these are amenable to prevention. To assess the amount of cases in a general population attributable to these risk factors, adjusted population-attributable fractions were estimated., Design: Cross-sectional study., Setting: Obligatory school entry examination in 2001/2002 in six Bavarian communities (Germany)., Subjects: 5472 children at age 5-6 years., Measures: Anthropometric measures were ascertained by public health nurses, and measures concerning sociodemographics, lifestyle and child behaviour such as child's daily meal frequency were obtained with self-administered parental questionnaires. Obesity was defined according to sex- and age-specific body mass index cut-off points proposed by the International Obesity Task Force. Adjusted population-attributable fractions were calculated based on logistic regression., Results: A combination of the risk factors low meal frequency, decreased physical activity, watching television >1 h day- 1, formula feeding and smoking in pregnancy accounted for 48.2% of obese children. This combination yielded a maximal achievable prevalence reduction of 1.5% for obesity (3.2% observed prevalence)., Conclusions: A modification of five known risk factors for childhood overweight and obesity could reasonably lower obesity prevalences at school entry. These risk factors should be particularly considered in decision making on preventive measures.