The genetics of the Lp antigen

The frequency distribution of the quantitative activity of the Lp antigen was found to be bimodal. It is hypothesized that a major genetic factor is operating to determine the modes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66117/1/j.1469-1809.1974.tb01991.x.pd

Expert consensus on neurodevelopmental outcomes in pregnancy pharmacovigilance studies

Background: Exposure in utero to certain medications can disrupt processes of fetal development, including brain development, leading to a continuum of neurodevelopmental difficulties. Recognizing the deficiency of neurodevelopmental investigations within pregnancy pharmacovigilance, an international Neurodevelopmental Expert Working Group was convened to achieve consensus regarding the core neurodevelopmental outcomes, optimization of methodological approaches and barriers to conducting pregnancy pharmacovigilance studies with neurodevelopmental outcomes. Methods: A modified Delphi study was undertaken based on stakeholder and expert input. Stakeholders (patient, pharmaceutical, academic and regulatory) were invited to define topics, pertaining to neurodevelopmental investigations in medication-exposed pregnancies. Experts were identified for their experience regarding neurodevelopmental outcomes following medicinal, substances of misuse or environmental exposures in utero. Two questionnaire rounds and a virtual discussion meeting were used to explore expert opinion on the topics identified by the stakeholders. Results: Twenty-five experts, from 13 countries and professionally diverse backgrounds took part in the development of 11 recommendations. The recommendations focus on the importance of neurodevelopment as a core feature of pregnancy pharmacovigilance, the timing of study initiation and a core set of distinct but interrelated neurodevelopmental skills or diagnoses which require investigation. Studies should start in infancy with an extended period of investigation into adolescence, with more frequent sampling during rapid periods of development. Additionally, recommendations are made regarding optimal approach to neurodevelopmental outcome measurement, comparator groups, exposure factors, a core set of confounding and mediating variables, attrition, reporting of results and the required improvements in funding for potential later emerging effects. Different study designs will be required depending on the specific neurodevelopmental outcome type under investigation and whether the medicine in question is newly approved or already in widespread use. Conclusion: An improved focus on neurodevelopmental outcomes is required within pregnancy pharmacovigilance. These expert recommendations should be met across a complementary set of studies which converge to form a comprehensive set of evidence regarding neurodevelopmental outcomes in pregnancy pharmacovigilance

“Top-Down-Bottom-Up” Methodology as a Common Approach to Defining Bespoke Sets of Sustainability Assessment Criteria for the Built Environment

YesThe top-down-bottom-up (TDBU) methodology for defining bespoke sets of sustainability criteria for specific civil engineering project types is introduced and discussed. The need to define sustainability criteria for specific civil engineering project types occurs mainly in one or both of the following cases: (1) when a more comprehensive and indicative assessment of the sustainability of the project type in question is required; and/or (2) there is no readily available bespoke sustainability assessment tool, or set of criteria, for assessing the sustainability of the project type. The construction of roads, buildings, airports, tunnels, dams, flood banks, bridges, water supply, and sewage systems and their supporting systems are considered to be unique civil engineering/infrastructure project types. The normative definition of sustainable civil engineering/infrastructure projects and the framework for assessing its sustainability is defined and provided by the authors. An example of the TDBU methodology being applied to define sustainability criteria for transport noise reducing devices is presented and discussed. The end result of applying the methodology is a systematically researched and industry validated set of criteria that denotes assessing the sustainability of the civil engineering/infrastructure project type. The paper concludes that the top-down-bottom-up will support stakeholders and managers involved in assessing sustainability to consider all major research methods to define general and unique sustainability criteria to assess and so maximize sustainability

Service evaluation of a nurse-led dental anxiety management service for adult patients

Objective: Evaluate patients’ and professionals’ experiences of a Nurse-led Dental Anxiety Management Service (NDAMS). Design: Service evaluation. Setting: The NDAMS operates as part of Sheffield Salaried Primary Dental Care Service. Subjects and methods: Questionnaire survey of anxious patients and qualitative interviews with patients and professionals Interventions: Dental nurses delivered low-level psychological interventions as part of an Integrated Care Pathway (ICP) for dental anxiety. Main outcome Measures: Dental anxiety and oral health-related quality of life (OHRQoL) questionnaires were completed by patients prior to and following NDAM. Results: A total of 187 patients were assessed as suitable for NDAM (mean age= 33.7, 77% female) and 33 had completed it at the time of the service evaluation. Of those patients who had completed the intervention significant improvements in dental anxiety and OHRQoL were reported. Professionals highlighted the importance of integrated working, adequate support and training and assessing the suitability of patients for NDAM. Conclusion: ICPs that combine pharmacological and psychological management approaches can help meet the needs of dentally anxious patients, however, early identification of patients most likely to benefit from psychological intervention should be a priority

Assessing the effectiveness of protected areas for conserving range‐restricted rain forest butterflies in Sabah, Borneo

Rain forests on Borneo support exceptional concentrations of endemic insect biodiversity, but many of these forest‐dependent species are threatened by land‐use change. Totally protected areas (TPAs) of forest are key for conserving biodiversity, and we examined the effectiveness of the current TPA network for conserving range‐restricted butterflies in Sabah (Malaysian Borneo). We found that mean diurnal temperature range and precipitation of the wettest quarter of the year were the most important predictors of butterfly distributions (N = 77 range‐restricted species), and that species richness increased with elevation and aboveground forest carbon. On average across all species, TPAs were effective at conserving ~43% of species’ ranges, but encompassed only ~40% of areas with high species richness (i.e., containing at least 50% of our study species). The TPA network also included only 33%–40% of areas identified as high priority for conserving range‐restricted species, as determined by a systematic conservation prioritization analysis. Hence, the current TPA network is reasonably effective at conserving range‐restricted butterflies, although considerable areas of high species richness (6,565 km2) and high conservation priority (11,152–12,531 km2) are not currently protected. Sabah's remaining forests, and the range‐restricted species they support, are under continued threat from agricultural expansion and urban development, and our study highlights important areas of rain forest that require enhanced protection. Abstract in Malay is available with online material

Integration of multiple data sources to prioritize candidate genes using discounted rating system

Background: Identifying disease gene from a list of candidate genes is an important task in bioinformatics. The main strategy is to prioritize candidate genes based on their similarity to known disease genes. Most of existing gene prioritization methods access only one genomic data source, which is noisy and incomplete. Thus, there is a need for the integration of multiple data sources containing different information. Results: In this paper, we proposed a combination strategy, called discounted rating system (DRS). We performed leave one out cross validation to compare it with N-dimensional order statistics (NDOS) used in Endeavour. Results showed that the AUC (Area Under the Curve) values achieved by DRS were comparable with NDOS on most of the disease families. But DRS worked much faster than NDOS, especially when the number of data sources increases. When there are 100 candidate genes and 20 data sources, DRS works more than 180 times faster than NDOS. In the framework of DRS, we give different weights for different data sources. The weighted DRS achieved significantly higher AUC values than NDOS. Conclusion: The proposed DRS algorithm is a powerful and effective framework for candidate gene prioritization. If weights of different data sources are proper given, the DRS algorithm will perform better

Integrative Genomics Reveals Novel Molecular Pathways and Gene Networks for Coronary Artery Disease

The majority of the heritability of coronary artery disease (CAD) remains unexplained, despite recent successes of genome-wide association studies (GWAS) in identifying novel susceptibility loci. Integrating functional genomic data from a variety of sources with a large-scale meta-analysis of CAD GWAS may facilitate the identification of novel biological processes and genes involved in CAD, as well as clarify the causal relationships of established processes. Towards this end, we integrated 14 GWAS from the CARDIoGRAM Consortium and two additional GWAS from the Ottawa Heart Institute (25,491 cases and 66,819 controls) with 1) genetics of gene expression studies of CAD-relevant tissues in humans, 2) metabolic and signaling pathways from public databases, and 3) data-driven, tissue-specific gene networks from a multitude of human and mouse experiments. We not only detected CAD-associated gene networks of lipid metabolism, coagulation, immunity, and additional networks with no clear functional annotation, but also revealed key driver genes for each CAD network based on the topology of the gene regulatory networks. In particular, we found a gene network involved in antigen processing to be strongly associated with CAD. The key driver genes of this network included glyoxalase I (GLO1) and peptidylprolyl isomerase I (PPIL1), which we verified as regulatory by siRNA experiments in human aortic endothelial cells. Our results suggest genetic influences on a diverse set of both known and novel biological processes that contribute to CAD risk. The key driver genes for these networks highlight potential novel targets for further mechanistic studies and therapeutic interventions