Predicted activity of UGT2B7, ABCB1, OPRM1, and COMT using full-gene haplotypes and their association with the CYP2D6-inferred metabolizer phenotype

The pharmacogene, CYP2D6, is commonly used to infer metabolizer phenotype of many marketed drugs and endogenous toxins in ante- and post-mortem patients but only represents the efficiency of phase 1 metabolism. Downstream metabolic enzymes encoded by UGT2B7, ABCB1, OPRM1, and COMT also have been implicated in variable individual response to drugs due to their activity at different stages of the tramadol ADME (absorption, distribution, metabolism, and excretion) process. While commonly studied as single genes using targeted genotyping approaches, a more comprehensive tramadol metabolism profile has not been evaluated. 1000 Genomes Project data for UGT2B7, ABCB1, OPRM1, and COMT were used to characterize full-gene haplotypes and their effect on protein function using in-house excel-based workbooks, PopART, and TreeView. Population genetic summary statistics and intergenic analyses associated these haplotypes with full-gene CYP2D6-inferred metabolizer phenotype. The findings suggest that UGT2B7, ABCB1, OPRM1, and COMT may contribute to predicted metabolizer phenotype as opposed to relying solely on CYP2D6.Peer reviewe

Regional governance and local school development policy in the process of de- or reconstructing regional structures of educational institutions

Der politikwissenschaftliche und ökonomische Diskurs über Governance und neue Steuerung dominiert seit einigen Jahren auch die schulpolitischen und erziehungswissenschaftlichen Debatten über Schulentwicklung. In dem Beitrag werden die Chancen und Grenzen dieses Politikmodells - sowohl als bildungspolitische Strategie wie auch als analytisches Instrumentarium - an einem konkreten empirischen Fall überprüft und diskutiert. Empirische Grundlage sind ausgewählte Daten und Teilergebnisse eines Forschungsprojekts zur wissenschaftlichen Begleitung von kommunalen Schulentwicklungsinitiativen in Westfalen. Im Prozess des Rück- und Umbaus regionaler Schulangebotsstrukturen, der heute durch den demographischen Wandel erzwungen wird, erweisen sich die interkommunale Standortkonkurrenz und die etablierten kommunalpolitischen Akteure als bestimmende Faktoren, wenn dabei politische Handlungsstrategien verfolgt werden, die als Local Governance bezeichnet werden können. (DIPF/Orig.)For several years now, the political-scientific and economic discourse on governance has also dominated the school-political and educational-scientific debates on school development. Drawing on a concrete empirical example, the authors examine and discuss the opportunities and limitations of this political model - both as an educational-political strategy and as analytical instrument. The study\u27s empirical basis is formed by selected data and partial results from a research project for the scientific monitoring of local school development initiatives in Westphalia. In the process of de- and reconstructing regional structures of educational institutions - a process forced by present-day demographic change - inter-communal competition between locations and the established players on the local political field prove to be the decisive factors if strategies of political action are pursued which can be described as local governance. (DIPF/Orig.

Ground penetrating radar applied to rebar corrosion inspection

In this paper we investigate the use of ground penetrating radar (GPR) to detect corrosion-induced thinning of rebar in concrete bridge structures. We consider a simple pulse/echo amplitude-based inspection, positing that the backscattered response from a thinned rebar will be smaller than the similar response from a fully-intact rebar. Using a commercial 1600-MHz GPR system we demonstrate that, for laboratory specimens, backscattered amplitude measurements can detect a thinning loss of 50% in rebar diameter over a short length. GPR inspections on a highway bridge then identify several rebar with unexpectedly low amplitudes, possibly signaling thinning. To field a practical amplitude-based system for detecting thinned rebar, one must be able to quantify and assess the many factors that can potentially contribute to GPR signal amplitude variations. These include variability arising from the rebar itself (e.g., thinning) and from other factors (concrete properties, antenna orientation and liftoff, etc.). We report on early efforts to model the GPR instrument and the inspection process so as to assess such variability and to optimize inspections. This includes efforts to map the antenna radiation pattern, to predict how backscattered responses will vary with rebar size and location, and to assess detectability improvements via synthetic aperture focusing techniques (SAFT)

Patient-reported physical functioning and quality of life after pelvic ring injury:A systematic review of the literature

Background Pelvic ring injuries are one of the most serious traumatic injuries with large consequences for the patients' daily life. During recent years, the importance of the patients' perception of their functioning and quality of life following injury has increasingly received attention. This systematic review reports on self-reported physical functioning and quality of life after all types of pelvic ring injuries. Methods The online databases MEDLINE-PubMed and Ovid-EMBASE were searched for studies published between 2008 and 2019 to identify published evidence of patient-reported physical functioning and quality of life after which they were assessed for their methodological quality. Results Of the 2577 articles, 46 were reviewed in full-text, including 3049 patients. Most studies were heterogeneous, with small cohorts of patients, a variety of injury types, treatment methods and use of different, often non-validated, outcome measures. The overall methodological quality was moderate to poor. Nine different PROMs were used, of which the Majeed Pelvic Score (MPS), SF-36 and EQ-5D were the most widely used. Mean scores respectively ranged from 75-95 (MPS), 53-69 (SF-36, physical functioning) and 0.63-0.80 (EQ-5D). Conclusions Physical functioning and quality of life following pelvic ring injuries seem fair and tend to improve during follow-up. However, differences in patient numbers, injury definition, treatment strategy, follow-up duration and type of PROMs used between studies hampers to elucidate the actual effects of pelvic ring injuries on a patient's life. Implications of key findings Physicians and researchers should use valid and reliable patient-reported outcome instruments on large cohorts of patients with properly defined injuries to truly evaluate physical functioning and quality of life after pelvic ring injuries. Systematic review registration number PROSPERO International prospective register of systematic reviews; registration number CRD42019129176

A pathway-driven predictive model of tramadol pharmacogenetics

Predicting metabolizer phenotype (MP) is typically performed using data from a single gene. Cytochrome p450 family 2 subfamily D polypeptide 6 (CYP2D6) is considered the primary gene for predicting MP in reference to approximately 30% of marketed drugs and endogenous toxins. CYP2D6 predictions have proven clinically effective but also have well-documented inaccuracies due to relatively high genotype-phenotype discordance in certain populations. Herein, a pathway-driven predictive model employs genetic data from uridine diphosphate glucuronosyltransferase, family 1, polypeptide B7 (UGT2B7), adenosine triphosphate (ATP)-binding cassette, subfamily B, number 1 (ABCB1), opioid receptor mu 1 (OPRM1), and catechol-O-methyltransferase (COMT) to predict the tramadol to primary metabolite ratio (T:M1) and the resulting toxicologically inferred MP (t-MP). These data were then combined with CYP2D6 data to evaluate performance of a fully combinatorial model relative to CYP2D6 alone. These data identify UGT2B7 as a potentially significant explanatory marker for T:M1 variability in a population of tramadol-exposed individuals of Finnish ancestry. Supervised machine learning and feature selection were used to demonstrate that a set of 16 loci from 5 genes can predict t-MP with over 90% accuracy, depending on t-MP category and algorithm, which was significantly greater than predictions made by CYP2D6 alone.Peer reviewe

Exploring the 1000 Genomes Project haplotype reporting for the CYP2D6 pharmacogene

Non peer reviewe

Low-Intensity Electromagnetic Millimeter Waves for Pain Therapy

Millimeter wave therapy (MWT), a non-invasive complementary therapeutic technique is claimed to possess analgesic properties. We reviewed the clinical studies describing the pain-relief effect of MWT. Medline-based search according to review criteria and evaluation of methodological quality of the retrieved studies was performed. Of 13 studies, 9 of them were randomized controlled trials (RCTs), only three studies yielded more than 3 points on the Oxford scale of methodological quality of RCTs. MWT was reported to be effective in the treatment of headache, arthritic, neuropathic and acute postoperative pain. The rapid onset of pain relief during MWT lasting hours to days after, remote to the site of exposure (acupuncture points), was the most characteristic feature in MWT application for pain relief. The most commonly used parameters of MWT were the MW frequencies between 30 and 70 GHz and power density up to 10 mW cm(−2). The promising results from pilot case series studies and small-size RCTs for analgesic/hypoalgesic effects of MWT should be verified in large-scale RCTs on the effectiveness of this treatment method

Feasibility Study for Detection and Quantification of Corrosion in Bridge Barrier Rails

Technical challenges exist with infrastructure that can be addressed by nondestructive evaluation (NDE) methods, such as detecting corrosion damage to reinforcing steel that anchor concrete bridge railings to bridge road decks. Moisture and chloride ions reach the anchors along the cold joint between the rails and deck, causing corrosion that weakens the anchors and ultimately the barriers. The Center for Nondestructive Evaluation at Iowa State University has experience in development of measurement techniques and new sensors using a variety of interrogating energies. This research evaluated feasibility of three technologies—x-ray radiation, ground-penetrating radar (GPR), and magnetic flux leakage (MFL)—for detection and quantification of corrosion of embedded reinforcing steel. Controlled samples containing pristine reinforcing steel with and without epoxy and reinforcing steel with 25 percent and 50 percent section reduction were embedded in concrete at 2.5 in. deep for laboratory evaluation. Two of the techniques, GPR and MFL, were used in a limited field test on the Iowa Highway 210 Bridge over Interstate 35 in Story County. The methods provide useful and complementary information. GPR provides a rapid approach to identify reinforcing steel that has anomalous responses. MFL provides similar detection responses but could be optimized to provide more quantitative correlation to actual condition. Full implementation could use either GPR or MFL methods to identify areas of concern, followed by radiography to give a visual image of the actual condition, providing the final guidance for maintenance actions

Full-gene haplotypes refine CYP2D6 metabolizer phenotype inferences

CYP2D6 is a critical pharmacogenetic target, and polymorphisms in the gene region are commonly used to infer enzyme activity score and predict resulting metabolizer phenotype: poor, intermediate, extensive/normal, or ultrarapid which can be useful in determining cause and/or manner of death in some autopsies. Current genotyping approaches are incapable of identifying novel and/or rare variants, so CYP2D6 star allele definitions are limited to polymorphisms known a priori. While useful for most predictions, recent studies using massively parallel sequencing data have identified additional polymorphisms in CYP2D6 that are predicted to alter enzyme function but are not considered in current star allele nomenclature. The 1000 Genomes Project data were used to produce full-gene haplotypes, describe their distribution in super-populations, and predict enzyme activity scores. Full-gene haplotypes generated lower activity scores than current approaches due to inclusion of additional damaging polymorphisms in the star allele. These findings are critical for clinical implementation of metabolizer phenotype prediction because a fraction of the population may be incorrectly considered normal metabolizers but actually may be poor or intermediate metabolizers.Peer reviewe