An Approach to Support the Performance Management of Public Health Authorities using an IT based Modeling Method

In this paper we describe a modeling method for supportingperformance management by building upon the currentchallenges of public health authorities. Through focusingon the performance management requirements of nationalcompetent authorities (NCA) that fulll several duties inregard to the marketing authorization of medicinal products,we derive a modeling language, an according modeling procedureand mechanisms and algorithms. Thereby, particularrequirements in regard to the compliance to legal regulations,the competition of NCAs within the European Union, theallocation of resources under uncertainty, and the specichuman resource requirements of NCAs have to be taken intoaccount. The modeling language is formally described usinga meta model based approach and implemented on a metamodeling platform. For the evaluation, the modeling methodhas been applied in a scientic study with the Austriannational competent authority AGES PharmMed

AKT1 (E17K) mutation profiling in breast cancer: prevalence, concurrent oncogenic alterations, and blood-based detection.

BACKGROUND: The single hotspot mutation AKT1 [G49A:E17K] has been described in several cancers, with the highest incidence observed in breast cancer. However, its precise role in disease etiology remains unknown. METHODS: We analyzed more than 600 breast cancer tumor samples and circulating tumor DNA for AKT1 (E17K) and alterations in other cancer-associated genes using Beads, Emulsions, Amplification, and Magnetics digital polymerase chain reaction technology and targeted exome sequencing. RESULTS: Overall AKT1 (E17K) mutation prevalence was 6.3 % and not correlated with age or menopausal stage. AKT1 (E17K) mutation frequency tended to be lower in patients with grade 3 disease (1.9 %) compared with those with grade 1 (11.1 %) or grade 2 (6 %) disease. In two cohorts of patients with advanced metastatic disease, 98.0 % (n = 50) and 97.1 % (n = 35) concordance was obtained between tissue and blood samples for the AKT1 (E17K) mutation, and mutation capture rates of 66.7 % (2/3) and 85.7 % (6/7) in blood versus tissue samples were observed. Although AKT1-mutant tumor specimens were often found to harbor concurrent alterations in other driver genes, a subset of specimens harboring AKT1 (E17K) as the only known driver alteration was also identified. Initial follow-up survival data suggest that AKT1 (E17K) could be associated with increased mortality. These findings warrant additional long-term follow-up. CONCLUSIONS: The data suggest that AKT1 (E17K) is the most likely disease driver in certain breast cancer patients. Blood-based mutation detection is achievable in advanced-stage disease. These findings underpin the need for a further enhanced-precision medicine paradigm in the treatment of breast cancer

The chemistry of sulfur and nitrogen species in a fog system A multiphase approach

Concentration and phase distribution of sulfur and nitrogen species during a particular fog episode in the Po Valley are experimentally described in this paper. Chemical measurements were carried out simultaneously at different heights within the fog layer, up to 50 m. Microphysical and meteorological parameters necessary for the description of the fog multiphase system were also concurrently measured as a function of height. The fog cycle (formation, evolution, dissipation) is described in terms of the total acidity of a unit volume of air containing gas species, interstitial aerosol particles and fog droplets. The fog system was not closed and input of acidic and basic components was observed during fog evolution. The driving force which determines the acidity of the fog multiphase atmospheric system was found to be the presence of NH 3 and its partitioning among the different phases. A strong decrease of fog water pH (from 5.6 down to 2.8) was observed during fog evolution and was attributed to a HNO 3 input to the system. These acidic and basic inputs are described in terms of a titration/back-titration process of the fog system. The SO 2 oxidation process in fog water was found to be of minor importance in determining the SO 4 = concentration within the fog system, due to both low SO 2 concentration and limited oxidant availability during the experiment. DOI: 10.1034/j.1600-0889.1992.t01-4-00005.

Modulation of Genetic Associations with Serum Urate Levels by Body-Mass-Index in Humans

We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, P-inter= 2.6 x 10(-8)). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDAR-ADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10(-8)), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10(-8)), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10(-4)). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.Peer reviewe

Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease

Peer reviewe

Sensors / Evaluation of Aerosol Electrospray Analysis of Metal-on-Metal Wear Particles from Simulated Total Joint Replacement

Wear is a common cause for aseptic loosening in artificial joints. The purpose of this study was to develop an automated diagnostical method for identification of the number and size distribution of wear debris. For this purpose, metal debris samples were extracted from a hip simulator and then analyzed by the electrospray method combined with a differential mobility analyzer, allowing particle detection ranging from several nanometers up to 1 m. Wear particles were identified with a characteristic peak at 15 nm. The electrospray setup was successfully used and validated for the first time to characterize wear debris from simulated total joint replacement. The advantages of this diagnostic method are its time- and financial efficiency and its suitability for testing of different materials.(VLID)491881

Maternal Vitamin B12 Deficiency Detected by Newborn Screening—Evaluation of Causes and Characteristics

Vitamin B12 deficiency, mostly of maternal origin in newborns, is a well-treatable condition but can cause severe neurologic sequelae in infants. Early detection of vitamin B12 deficiency allows the pre-symptomatic treatment of affected children. This evaluation assesses the characteristics of maternal vitamin B12 deficiency detected by newborn screening. In a prospective single-center study, a systematic screening strategy for vitamin B12 deficiency using a combination of two second-tier strategies was applied. In addition to confirmatory diagnostics in children, the systematic work-up of vitamin B12 status was also performed for their mothers. Maternal characteristics were assessed including ethnic origin, diet, and vitamin supplementation during pregnancy. For affected mothers, a work-up by internal medicine was recommended. In total, 121 mother–infant couples were analyzed. 66% of mothers adhered to a balanced diet including meat. The cause of maternal vitamin B12 deficiency was unknown in 56% of cases, followed by dietary causes in 32%, and organic causes in 8%. All mothers following a vegan diet and most mothers with a vegetarian diet took vitamin preparations during pregnancy, whereas only 55.8% of mothers with a balanced diet took folic acid or other vitamins. Maternal vitamin B12, folic acid, and homocysteine levels were significantly correlated with the child’s folic acid levels, and with homocysteine, methylmalonic, and methylcitric acid levels in first and second NBS dried blood spots. Most children had normal blood counts and showed normocytosis. Although 36.7% of mothers showed anemia, only one presented with macrocytosis. Adherence to vitamin supplementation in pregnancy is low despite the recommendation for supplementation of folic acid. Ideally, the evaluation of mothers for vitamin B12 levels and appropriate therapy should be initiated in early pregnancy. In infants detected through newborn screening, the multidisciplinary assessment and therapy of both children and mothers should be performed