An improved soil ionization representation to numerical simulation of impulsive grounding systems

This paper presents a hybrid method based on the transmission line modeling method (TLM) aiming to represent the soil ionization effect for grounding systems simulation. This natural phenomenon can be better represented by taking into account the variation of the conductive components present in the TLM circuit and considering the residual resistivity remaining in the soil. The proposed analytical formulation is developed with a focus on the computational implementation of the method. The model is validated by comparing synthetized test results with measured data and other numerical models (residual resistivity, TLM, and analytical model). High precision together with an easy to implement formulation indicates that the methodology presents potential for real-life applications

Receptor activity-modifying protein dependent and independent activation mechanisms in the coupling of calcitonin gene-related peptide and adrenomedullin receptors to Gs

Calcitonin gene-related peptide (CGRP) or adrenomedullin (AM) receptors are heteromers of the calcitonin receptor-like receptor (CLR), a class B G protein-coupled receptor, and one of three receptor activity-modifying proteins (RAMPs). How CGRP and AM activate CLR and how this process is modulated by RAMPs is unclear. We have defined how CGRP and AM induce Gs-coupling in CLR-RAMP heteromers by measuring the effect of targeted mutagenesis in the CLR transmembrane domain on cAMP production, modeling the active state conformations of CGRP and AM receptors in complex with the Gs C-terminus and conducting molecular dynamics simulations in an explicitly hydrated lipidic bilayer. The largest effects on receptor signaling were seen with H295A5.40b, I298A5.43b, L302A5.47b, N305A5.50b, L345A6.49b and E348A6.52b, F349A6.53b and H374A7.47b (class B numbering in superscript). Many of these residues are likely to form part of a group in close proximity to the peptide binding site and link to a network of hydrophilic and hydrophobic residues, which undergo rearrangements to facilitate Gs binding. Residues closer to the extracellular loops displayed more pronounced RAMP or ligand-dependent effects. Mutation of H3747.47b to alanine increased AM potency 100-fold in the CGRP receptor. The molecular dynamics simulation showed that TM5 and TM6 pivoted around TM3. The data suggest that hydrophobic interactions are more important for CLR activation than other class B GPCRs, providing new insights into the mechanisms of activation of this class of receptor. Furthermore the data may aid in the understanding of how RAMPs modulate the signaling of other class B GPCRs

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The role of networks in establishing an entrepreneurial venture

M.Comm.In South Africa, a disappointingly high number of start-up ventures fail. The success of global entrepreneurs in the South African marketplace is largely attributable to their reliance on sound network relationships prior to entering this market. The purpose of this study was thus to explore the role of networks in establishing an entrepreneurial venture. A literature study, and interviews with respondents who met the criteria of the study, were the chosen means of collecting the data. The study examined, through the literature review, the subjects underpinning the objectives of the research, namely entrepreneurship and networks. Each subject was investigated individually, after which the research literature was evaluated to determine the extent of a relationship between entrepreneurship and networks. In the literature component, a synergy between networks and entrepreneurship was identified. A significant contribution to this relationship was shown to be grounded in the way networks assist entrepreneurs in gaining access to scarce resources, particularly in the start-up phase of new venture development. Through the use of a research methodology which encompassed a qualitative research technique, primary data was gathered through personal in-depth interviews. The questions were aligned with the objectives and propositions set out in the study. The analysis of the data revealed that, although networks were relied upon to overcome resource constraint challenges at the businesses’ inception, networks were as important, if not more important, throughout the other stages of the entrepreneurial process. It was further determined that there are no feasible replacements for the use of networks in any of the stages of the entrepreneurial process. Thus it can be concluded with limitations that networks play a critical role in the establishment of an entrepreneurial venture

Institutionalisation and deinstitutionalisation of children 2: policy and practice recommendations for global, national, and local actors

Worldwide, millions of children live in institutions, which runs counter to both the UN-recognised right of children to be raised in a family environment, and the findings of our accompanying systematic review of the physical, neurobiological, psychological, and mental health costs of institutionalisation and the benefits of deinstitutionalisation of child welfare systems. In this part of the Commission, international experts in reforming care for children identified evidence-based policy recommendations to promote family-based alternatives to institutionalisation. Family-based care refers to caregiving by extended family or foster, kafalah (the practice of guardianship of orphaned children in Islam), or adoptive family, preferably in close physical proximity to the biological family to facilitate the continued contact of children with import ant individuals in their life when this is in their best interest. 14 key recommendations are addressed to multinational agencies, national governments, local authorities, and institutions. These recommendations prioritise the role of families in the lives of children to prevent child separation and to strengthen families, to protect children without parental care by providing high-quality family-based alternatives, and to strengthen systems for the protection and care of separated children. Momentum for a shift from instit-utional to family-based care is growing internationally—our recom mend ations provide a template for further action and criteria against which progress can be assessed

Pan-Canadian Evaluation of Irreversible Compression Ratios (“Lossy” Compression) for Development of National Guidelines

New technological advancements including multislice CT scanners and functional MRI, have dramatically increased the size and number of digital images generated by medical imaging departments. Despite the fact that the cost of storage is dropping, the savings are largely surpassed by the increasing volume of data being generated. While local area network bandwidth within a hospital is adequate for timely access to imaging data, efficiently moving the data between institutions requires wide area network bandwidth, which has a limited availability at a national level. A solution to address those issues is the use of lossy compression as long as there is no loss of relevant information. The goal of this study was to determine levels at which lossy compression can be confidently used in diagnostic imaging applications. In order to provide a fair assessment of existing compression tools, we tested and compared the two most commonly adopted DISCOM compression algorithms: JPEG and JPEG-2000. We conducted an extensive pan-Canadian evaluation of lossy compression applied to seven anatomical areas and five modalities using two recognized techniques: objective methods or diagnostic accuracy and subjective assessment based on Just Noticeable Difference. By incorporating both diagnostic accuracy and subjective evaluation techniques, enabled us to define a range of compression for each modality and body part tested. The results of our study suggest that at low levels of compression, there was no significant difference between the performance of lossy JPEG and lossy JPEG 2000, and that they are both appropriate to use for reporting on medical images. At higher levels, lossy JPEG proved to be more effective than JPEG 2000 in some cases, mainly neuro CT. More evaluation is required to assess the effect of compression on thin slice CT. We provide a table of recommended compression ratios for each modality and anatomical area investigated, to be integrated in the Canadian Association of Radiologists standard for the use of lossy compression in medical imaging

CGRP receptor antagonists: design and screening

Importance of the field: Calcitonin gene-related peptide (CGRP) receptor antagonists have recently come to attention with the development of olcegepant and telcagepant for the treatment of migraine. The availability of high-affinity, non-peptide antagonists opens the way for trials of these compounds in other conditions where CGRP antagonism might be useful, such as septic shock and inhibition of angiogenesis. Areas covered in this review: This review summarises knowledge about the structure and signalling properties of the CGRP receptor. The clinical ramifications of targeting the CGRP receptor, the profiles of existing antagonists and the requirements for screening new compounds will be discussed. What the reader will gain: Readers will gain an overview of how current non-peptide antagonists seem to bind similar epitopes contributed by both calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1), the main CGRP receptor subunits. We will discuss how current antagonists have low bioavailability, limiting their use. For selectivity at CGRP receptors, it will be necessary to target parts of the receptor influenced by both RAMP1 and CLR. Take home message: For the design of radically new antagonists, more structural information on the receptor is needed. Current screens are largely based on measuring CGRP-mediated changes in cAMP. CGRP receptors can influence other signalling pathways and pathway-selective allosteric antagonists may be useful, but more information is needed about the mechanism of action of CGRP to assess the value of this