Potential risk factors for reduced quality of life and increased health care utilization in ARDS survivors: results from the multicenter cohort study DACAPO.

AIM: To analyze the association of individual pre-ICU risk factors (obesity, physical and mental comorbidity, smoking status) on the long-term recovery process in survivors of the acute respiratory distress syndrome (ARDS; outcomes: health related quality of life, health care utilization; measured at 12, 24, and 36 months after ICU discharge). FINDINGS: Results show a possible causal link between pre-ICU risk factors and subsequent recovery of survivors of ARDS, especially with regard to mental health related quality of life. PURPOSE: Identifying relevant pre-existing risk factors, such as mental health problems, will enable the identification of at-risk patients, thus aiding in the improvement of long-term healthcare for survivors of critical illness.

M9657 Is a Bispecific Tumor-Targeted Anti-CD137 Agonist That Induces MSLN-Dependent Antitumor Immunity without Liver Inflammation.

The costimulatory receptor CD137 (also known as TNFRSF9 or 4-1BB) sustains effective cytotoxic T-cell responses. Agonistic anti-CD137 cancer immunotherapies are being investigated in clinical trials. Development of the first-generation CD137-agonist monotherapies utomilumab and urelumab was unsuccessful due to low antitumor efficacy mediated by the epitope recognized on CD137 or hepatotoxicity mediated by Fcγ receptors (FcγR) ligand-dependent CD137 activation, respectively. M9657 was engineered as a tetravalent bispecific antibody (mAb2) in a human IgG1 backbone with LALA mutations to reduce binding to FCγRs. Here, we report that M9657 selectively binds to mesothelin (MSLN) and CD137 with similar affinity in humans and cynomolgus monkeys. In a cellular functional assay, M9657 enhanced CD8+ T cell-mediated cytotoxicity and cytokine release in the presence of tumor cells, which was dependent on both MSLN expression and T-cell receptor/CD3 activation. Both FS122m, a murine surrogate with the same protein structure as M9657, and chimeric M9657, a modified M9657 antibody with the Fab portion replaced with an anti-murine MSLN motif, demonstrated in vivo antitumor efficacy against various tumors in wild-type and human CD137 knock-in mice, and this was accompanied by activated CD8+ T-cell infiltration in the tumor microenvironment. The antitumor immunity of M9657 and FS122m depended on MSLN expression density and the mAb2 structure. Compared with 3H3, a murine surrogate of urelumab, FS122m and chimeric M9657 displayed significantly lower on-target/off-tumor toxicity. Taken together, M9657 exhibits a promising profile for development as a tumor-targeting immune agonist with potent anticancer activity without systemic immune activation and associated hepatotoxicity.

Epigenome-Wide Association Studies of the Fractional Exhaled Nitric Oxide and Bronchodilator Drug Response in Moderate-to-Severe Pediatric Asthma.

Asthma is the most prevalent pediatric chronic disease. Bronchodilator drug response (BDR) and fractional exhaled nitric oxide (FeNO) are clinical biomarkers of asthma. Although DNA methylation (DNAm) contributes to asthma pathogenesis, the influence of DNAm on BDR and FeNO is scarcely investigated. This study aims to identify DNAm markers in whole blood associated either with BDR or FeNO in pediatric asthma. We analyzed 121 samples from children with moderate-to-severe asthma. The association of genome-wide DNAm with BDR and FeNO has been assessed using regression models, adjusting for age, sex, ancestry, and tissue heterogeneity. Cross-tissue validation was assessed in 50 nasal samples. Differentially methylated regions (DMRs) and enrichment in traits and biological pathways were assessed. A false discovery rate (FDR) < 0.1 and a genome-wide significance threshold of p < 9 × 10-8 were used to control for false-positive results. The CpG cg12835256 (PLA2G12A) was genome-wide associated with FeNO in blood samples (coefficient= -0.015, p = 2.53 × 10-9) and nominally associated in nasal samples (coefficient = -0.015, p = 0.045). Additionally, three CpGs were suggestively associated with BDR (FDR < 0.1). We identified 12 and four DMRs associated with FeNO and BDR (FDR < 0.05), respectively. An enrichment in allergic and inflammatory processes, smoking, and aging was observed. We reported novel associations of DNAm markers associated with BDR and FeNO enriched in asthma-related processes.

Identification of M4205─A Highly Selective Inhibitor of KIT Mutations for Treatment of Unresectable Metastatic or Recurrent Gastrointestinal Stromal Tumors.

The treatment of gastrointestinal stromal tumors (GISTs) driven by activating mutations in the KIT gene is a prime example of targeted therapy for treatment of cancer. The approval of the tyrosine kinase inhibitor imatinib has significantly improved patient survival, but emerging resistance under treatment and relapse is observed. Several additional KIT inhibitors have been approved; still, there is a high unmet need for KIT inhibitors with high selectivity and broad coverage of all clinically relevant KIT mutants. An imidazopyridine hit featuring excellent kinase selectivity was identified in a high-throughput screen (HTS) and optimized to the clinical candidate M4205 (IDRX-42). This molecule has a superior profile compared to approved drugs, suggesting a best-in-class potential for recurrent and metastatic GISTs driven by KIT mutations.

Prevalences of cardiometabolic risk and lifestyle factors in young parents: evidence from a German birth cohort study.

BACKGROUND: Studies show that parents significantly impact their children's health through their cardiometabolic risk profile and health behavior. There is only little information about the prevalence of cardiometabolic risk factors and lifestyle factors among new parents yet. The aims of this study are therefore to evaluate the prevalences of cardiometabolic risk factors in parents of infants in Germany and to examine their lifestyle and health behavior. METHODS: In the KUNO-Kids health study, an ongoing birth cohort, parents (n = 930 mothers and 769 fathers) were asked about cardiometabolic risk factors (obesity/hypertension/type 2 diabetes mellitus) and lifestyle factors (dietary/sports/smoking habits/alcohol consumption) during the first year after the birth of their children via questionnaires. Chi-square as well as fisher exact tests were conducted to analyse associations between lifestyle factors and cardiometabolic risk factors. RESULTS: 34.2% of mothers and 58.5% of fathers were overweight or obese. In 11.8% of the families, at least one parent suffered from hypertension, in 2.4% from type 2 diabetes mellitus. One year after delivery, 8.5% of mothers were smoking, 6.9% showed a risky alcohol consumption (> 10 g/d). 16.0% of fathers were smoking 4 weeks after childbirth, 10.7% showed risky alcohol consumption (> 20 g/d). 21.6% of mothers carried out sports activity for more than 2 h a week then. Parental hypertension was linked to a higher prevalence of risky alcohol consumption, obesity to a lower prevalence of daily fruits consumption. CONCLUSIONS: Cardiometabolic risk factors were widespread among new parents with obesity and overweight having the highest prevalences. A considerable number of parents also practiced an unhealthy lifestyle showing that there is potential for improvement to promote the healthy development of their children.

Utilisation of supplementary prenatal screening and diagnostics in Germany: cross-sectional study using data from the KUNO Kids Health Study.

BACKGROUND: Appropriate health system utilisation during pregnancy is fundamental for maintaining maternal and child's health. To study the use and determinants of supplementary prenatal screening and diagnostics in Germany this study provides comprehensive data. METHODS: We obtained data from a recently established prospective German birth cohort study, the KUNO Kids Health Study. Analyses are based on Andersen's Behavioural Model of health system use, which distinguishes between predisposing (e.g. country of birth), enabling (e.g. health insurance) and need factors (e.g. at-risk pregnancy). We examined bi- and multivariate association with the use of supplementary prenatal screening and diagnostics using logistic regression. RESULTS: The study has a sample size of 1886 participating mothers. One fifth of the mothers investigated did not use any supplementary prenatal screening or diagnostics. Notably, the chance of using supplementary prenatal screening and diagnostics more than doubled if the pregnant woman had a private health insurance (OR 2.336; 95% CI 1.527-3.573). Higher maternal age (OR 1.038; 95% CI 1.006-1.071) and environmental tobacco smoke exposure (OR 1.465 95% CI 1.071-2.004) increased the use of supplementary prenatal screening and diagnostics. However, regarding need factors only having an at-risk-pregnancy (OR 1.688; 95% CI 1.271-2.241) showed an independent association. CONCLUSION: The important role of the type of health insurance and the relatively small influence of need factors was surprising. Especially with respect to equity in accessing health care, this needs further attention.

A model for estimating the lifelong exposure to PM2.5 and NO2 and the application to population studies.

Numerous epidemiological studies have confirmed the negative influences of air pollutants on human health, where fine particles (PM2.5) and nitrogen dioxide (NO2) cause the highest health risks. However, the traditional studies have only involved the ambient concentration for a short to medium time period, which ignores the influence of indoor sources, the individual time-activity pattern, and the fact that the health status is impacted by the long-term accumulated exposure. The aim of this paper is to develop a methodology to simulate the lifelong exposure (rather than outdoor concentration) to PM2.5 and NO2 for individuals in Europe. This method is realized by developing a probabilistic model that integrates an outdoor air quality model, a model estimating indoor air pollution, an exposure model, and a life course trajectory model for predicting retrospectively the employment status. This approach has been applied to samples of two population studies in the frame of the European Commission FP7-ENVIRONMENT research project HEALS (Health and Environment-wide Associations based on Large Population Surveys), where socioeconomic data of the participants have been collected. Results show that the simulated exposures to both pollutants for the samples are influenced by socio-demographic characteristics, including age, gender, residential location, employment status and smoking habits. Both outdoor concentrations and indoor sources play an important role in the total exposure. Moreover, large variances have been observed among countries and cities. The application of this methodology provides valuable insights for the exposure modelling, as well as important input data for exploring the correlation between exposure and health impacts.

[Role of Institutional Review Boards for multi-centre studies in national health services research - a cross-sectional study of the effort to obtain secondary ethical approvals for the DACAPO study]. / Die Rolle von Ethikkommissionen für die nationale Versorgungsforschung - eine Querschnittsstudie des Aufwandes zur Erlangung von Sekundärvoten anhand der DACAPO-Studie.

BACKGROUND: Health services research (HSR) is of fundamental importance for the continuous improvement of preventive, diagnostic or therapeutic measures. The conduct of multi-centre HSR studies requires that ethical approval by Institutional review boards (IRB's) is obtained. We documented the effort, the complexity and the man power necessary to obtain secondary ethical approval for a national HSR in Germany ("Surviving the Acute Respiratory Distress Syndrome" [DACAPO-study]). METHODS: Having obtained a primary ethical approval by the IRB of Regensburg University, the time, correspondence, necessity for amendments, corrections, or additional costs by 34 IRB's for 64 participating study centers was documented. RESULTS: The complete obtainment was found to be time consuming and associated with a high workload and man power. A time span of seven month was needed to receive votes from all IRB's. The median time span was 25,5 days (25 %/75 % percentile 13 and 42 days, respectively). Requirements in terms of corrections or amendments were inhomogeneous and frequent changes were necessary. There were additional fees for secondary votes of 4328,40 €. Total costs for the study center Regensburg were 21.193,40 € (2,6 % of the grant volume). CONCLUSION: Obtaining all ethical approvals for a multi-centre observational HSR study in Germany is complex and time consuming. Various and inhomogeneous formalities may delay the plan and realization of HSR. A Homogenization and simplification of the procedure of ethics votes should be discussed.

Overweight prevention implemented by primary school teachers: a randomised controlled trial.

OBJECTIVE: To describe the effects of URMEL-ICE, a German school-based intervention for overweight prevention, on children's BMI and other measures of fat mass. METHODS: A cluster-randomised controlled design was used. The intervention which focused on physical activity, TV time and soft drink consumption was integrated into a second-grade curriculum and was implemented by classroom teachers themselves. It comprised 29 teaching lessons, 2 short exercise blocks per day and 6 family homework lessons. BMI was assessed as primary outcome measure, waist circumference and skinfold thickness as secondary outcomes. Data of 945 children were analysed. RESULTS: Multivariate analyses adjusted for baseline values showed no statistically significant effect of the intervention on BMI, but on waist circumference (-0.85; 95% confidence interval (95% CI) -1.59 to -0.12) and subscapular skinfold thickness (-0.64; 95% CI -1.25 to -0.02). After additional adjustment for individual time lag between baseline and follow-up, these effects were reduced to -0.60 (95% CI -1.25 to 0.05) and -0.61 (95% CI -1.26 to 0.04) and lost their statistical significance. CONCLUSION: This study contributes to the field of randomised school-based studies on overweight prevention and shows that within a 1-year, integrated intervention no effect on BMI, but a tendency towards effects on fat mass can be achieved.

Determinants of obesity in the Ulm Research on Metabolism, Exercise and Lifestyle in Children (URMEL-ICE).

We investigated the prevalence of overweight and obesity in German schoolchildren and analyzed determinants of overweight. In the context of a randomized intervention study, a baseline cross-sectional assessment was carried out in 2006. During a physical examination, height, weight, skin fold thickness, and upper arm and waist circumferences were measured according to a standardized protocol among 1.079 children aged 6-9 years. Overweight and obesity were classified according to the definitions of the International Obesity Task Force. Parents completed a questionnaire on potential determinants of overweight. Logistic regression models were calculated for determinants of overweight and obesity. The prevalence of overweight was 16.5% in boys and 17.3% in girls and of obesity 3.5% and 3.6%, respectively. Migration (29.4 %) was correlated with overweight and obesity. In particular, among boys with migration background, overweight (24.0%) and obesity (6.6%) were highly prevalent. Higher obesity prevalence was associated with maternal smoking during pregnancy, parental overweight, and low parental education. Indicators for physical inactivity such as watching television more than 1 h per weekday, participation in club sports less than once a week, consumption of sweetened drinks (>or=3 times per week), and skipping breakfast before school were associated with childhood obesity. Our results provide further evidence that parental factors such as migration background and education are strongly associated with body mass of the offspring. Physically inactive children with regular consumption of sweetened drinks and no breakfast were prone to be overweight or obese. Changes of these lifestyle factors as targets of interventions are promising to prevent childhood obesity.