Mapping the multi-faceted: Determinants of uncertainty in safety-critical projects

© 2016 Elsevier Ltd and Association for Project Management and the International Project Management Association. Project managers tasked with delivering safety-critical projects must demonstrate care, competence and confidence right from the earliest stages of project inception, when levels of uncertainty can be very high. Based on interviews with 30 project management practitioners in civil nuclear and aerospace sectors, this paper builds on work by Saunders et al. (2015), who posited the Uncertainty Kaleidoscope as a framework for identifying uncertainties. Our findings are that the six determinants of project uncertainty are similar across both civil nuclear and aerospace projects. The most commonly mentioned determinant of project uncertainty was the Environment, followed by Complexity, Capability and Information. The impact of Time on project uncertainty and Individual perceptions of uncertainty were mentioned less frequently by respondents. Our key contribution is to validate the Uncertainty Kaleidoscope over a larger data set, thereby enriching our understanding of the sources of project uncertainty in these two important and highly-consequential project environments

Responding to project uncertainty: Evidence for high reliability practices in large-scale safety–critical projects

In large-scale safety–critical projects unforeseen events and uncertainties must be carefully managed to safeguard the integrity of the end product and deliver projects to time and cost. Based on 47 ‘vignettes’ of uncertainty across projects in two safety–critical sectors, this study provides an empirical examination of whether practices consistent with theories of high reliability organising are adopted by project managers as a response to project uncertainty. Our findings are that confronting uncertainties in safety–critical projects do involve many high reliability practices. Respondents expressed a sense of balancing competing demands, and provided evidence of learning, acting mindfully, avoiding over-rigid processes, and of upholding constructive tensions, conceptual slack and close interdisciplinary working. However these practices are often fragile in nature and dependent on key individuals. There are also differences between the two sectors studied, with more widespread evidence of high reliability project organising in civil nuclear than in aerospace projects

Alternative pre-mRNA splicing switches modulate gene expression in late erythropoiesis

Differentiating erythroid cells execute a unique gene expression program that insures synthesis of the appropriate proteome at each stage of maturation. Standard expression microarrays provide important insight into erythroid gene expression but cannot detect qualitative changes in transcript structure, mediated by RNA processing, that alter structure and function of encoded proteins. We analyzed stage-specific changes in the late erythroid transcriptome via use of high-resolution microarrays that detect altered expression of individual exons. Ten differentiation-associated changes in erythroblast splicing patterns were identified, including the previously known activation of protein 4.1R exon 16 splicing. Six new alternative splicing switches involving enhanced inclusion of internal cassette exons were discovered, as well as 3 changes in use of alternative first exons. All of these erythroid stage-specific splicing events represent activated inclusion of authentic annotated exons, suggesting they represent an active regulatory process rather than a general loss of splicing fidelity. The observation that 3 of the regulated transcripts encode RNA binding proteins (SNRP70, HNRPLL, MBNL2) may indicate significant changes in the RNA processing machinery of late erythroblasts. Together, these results support the existence of a regulated alternative pre-mRNA splicing program that is critical for late erythroid differentiation

Solitary metastatic adenocarcinoma of the sternum treated by total sternectomy and chest wall reconstruction using a Gore-Tex patch and myocutaneous flap: a case report

<p>Abstract</p> <p>Introduction</p> <p>The consequences of bone metastasis are often devastating. Although the exact incidence of bone metastasis is unknown, it is estimated that 350,000 people die of bone metastasis annually in the United States. The incidence of local recurrences after mastectomy and breast-conserving therapy varies between 5% and 40% depending on the risk factors and primary therapy utilized. So far, a standard therapy of local recurrence has not been defined, while indications of resection and reconstruction considerations have been infrequently described. This case report reviews the use of sternectomy for breast cancer recurrence, highlights the need for thorough clinical and radiologic evaluation to ensure the absence of other systemic diseases, and suggests the use of serratus anterior muscle flap as a pedicle graft to cover full-thickness defects of the anterior chest wall.</p> <p>Case presentation</p> <p>We report the case of a 70-year-old Caucasian woman who was referred to our hospital for the management of a retrosternal mediastinal mass. She had undergone radical mastectomy in 1999. Computed tomography and magnetic resonance imaging revealed a 74.23 × 37.7 × 133.6-mm mass in the anterior mediastinum adjacent to the main pulmonary artery, the right ventricle and the ascending aorta. We performed total sternectomy at all layers encompassing the skin, the subcutaneous tissues, the right pectoralis major muscle, all the costal cartilages, and the anterior part of the pericardium. The defect was immediately closed using a 0.6 mm Gore-Tex cardiovascular patch combined with a serratus anterior muscle flap. Our patient had remained asymptomatic during her follow-up examination after 18 months.</p> <p>Conclusion</p> <p>Chest wall resection has become a critical component of the thoracic surgeon's armamentarium. It may be performed to treat either benign conditions (osteoradionecrosis, osteomyelitis) or malignant diseases. There are, however, very few reports on the results of full-thickness complete chest wall resections for locally recurrent breast cancer with sufficient safety margins, and even fewer reports that describe the operative technique of using the serratus anterior muscle as a pedicled flap.</p

Decision Forest Analysis of 61 Single Nucleotide Polymorphisms in a Case-Control Study of Esophageal Cancer; a novel method

BACKGROUND: Systematic evaluation and study of single nucleotide polymorphisms (SNPs) made possible by high throughput genotyping technologies and bioinformatics promises to provide breakthroughs in the understanding of complex diseases. Understanding how the millions of SNPs in the human genome are involved in conferring susceptibility or resistance to disease, or in rendering a drug efficacious or toxic in the individual is a major goal of the relatively new fields of pharmacogenomics. Esophageal squamous cell carcinoma is a high-mortality cancer with complex etiology and progression involving both genetic and environmental factors. We examined the association between esophageal cancer risk and patterns of 61 SNPs in a case-control study for a population from Shanxi Province in North Central China that has among the highest rates of esophageal squamous cell carcinoma in the world. METHODS: High-throughput Masscode mass spectrometry genotyping was done on genomic DNA from 574 individuals (394 cases and 180 age-frequency matched controls). SNPs were chosen from among genes involving DNA repair enzymes, and Phase I and Phase II enzymes. We developed a novel adaptation of the Decision Forest pattern recognition method named Decision Forest for SNPs (DF-SNPs). The method was designated to analyze the SNP data. RESULTS: The classifier in separating the cases from the controls developed with DF-SNPs gave concordance, sensitivity and specificity, of 94.7%, 99.0% and 85.1%, respectively; suggesting its usefulness for hypothesizing what SNPs or combinations of SNPs could be involved in susceptibility to esophageal cancer. Importantly, the DF-SNPs algorithm incorporated a randomization test for assessing the relevance (or importance) of individual SNPs, SNP types (Homozygous common, heterozygous and homozygous variant) and patterns of SNP types (SNP patterns) that differentiate cases from controls. For example, we found that the different genotypes of SNP GADD45B E1122 are all associated with cancer risk. CONCLUSION: The DF-SNPs method can be used to differentiate esophageal squamous cell carcinoma cases from controls based on individual SNPs, SNP types and SNP patterns. The method could be useful to identify potential biomarkers from the SNP data and complement existing methods for genotype analyses

Liquid and vapour-phase antifungal activities of selected essential oils against candida albicans: microscopic observations and chemical characterization of cymbopogon citratus

<p>Abstract</p> <p>Background</p> <p>Use of essential oils for controlling <it>Candida albicans </it>growth has gained significance due to the resistance acquired by pathogens towards a number of widely-used drugs. The aim of this study was to test the antifungal activity of selected essential oils against <it>Candida albicans </it>in liquid and vapour phase and to determine the chemical composition and mechanism of action of most potent essential oil.</p> <p>Methods</p> <p>Minimum Inhibitory concentration (MIC) of different essential oils in liquid phase, assayed through agar plate dilution, broth dilution & 96-well micro plate dilution method and vapour phase activity evaluated through disc volatilization method. Reduction of <it>C. albicans </it>cells with vapour exposure was estimated by kill time assay. Morphological alteration in treated/untreated <it>C. albicans </it>cells was observed by the Scanning electron microscopy (SEM)/Atomic force microscopy (AFM) and chemical analysis of the strongest antifungal agent/essential oil has been done by GC, GC-MS.</p> <p>Results</p> <p>Lemon grass (<it>Cymbopogon citratus</it>) essential oil exhibited the strongest antifungal effect followed by mentha (<it>Mentha piperita</it>) and eucalyptus (<it>Eucalyptus globulus</it>) essential oil. The MIC of lemon grass essential oil in liquid phase (288 mg/l) was significantly higher than that in the vapour phase (32.7 mg/l) and a 4 h exposure was sufficient to cause 100% loss in viability of <it>C. albicans </it>cells. SEM/AFM of <it>C. albicans </it>cells treated with lemon grass essential oil at MIC level in liquid and vapour phase showed prominent shrinkage and partial degradation, respectively, confirming higher efficacy of vapour phase. GC-MS analysis revealed that lemon grass essential oil was dominated by oxygenated monoterpenes (78.2%); α-citral or geranial (36.2%) and β-citral or neral (26.5%), monoterpene hydrocarbons (7.9%) and sesquiterpene hydrocarbons (3.8%).</p> <p>Conclusion</p> <p>Lemon grass essential oil is highly effective in vapour phase against <it>C. albicans</it>, leading to deleterious morphological changes in cellular structures and cell surface alterations.</p

Design and methods for a randomized clinical trial treating comorbid obesity and major depressive disorder

<p>Abstract</p> <p>Background</p> <p>Obesity is often comorbid with depression and individuals with this comorbidity fare worse in behavioral weight loss treatment. Treating depression directly prior to behavioral weight loss treatment might bolster weight loss outcomes in this population, but this has not yet been tested in a randomized clinical trial.</p> <p>Methods and design</p> <p>This randomized clinical trial will examine whether behavior therapy for depression administered prior to standard weight loss treatment produces greater weight loss than standard weight loss treatment alone. Obese women with major depressive disorder (N = 174) will be recruited from primary care clinics and the community and randomly assigned to one of the two treatment conditions. Treatment will last 2 years, and will include a 6-month intensive treatment phase followed by an 18-month maintenance phase. Follow-up assessment will occur at 6-months and 1- and 2 years following randomization. The primary outcome is weight loss. The study was designed to provide 90% power for detecting a weight change difference between conditions of 3.1 kg (standard deviation of 5.5 kg) at 1-year assuming a 25% rate of loss to follow-up. Secondary outcomes include depression, physical activity, dietary intake, psychosocial variables and cardiovascular risk factors. Potential mediators (e.g., adherence, depression, physical activity and caloric intake) of the intervention effect on weight change will also be examined.</p> <p>Discussion</p> <p>Treating depression before administering intensive health behavior interventions could potentially boost the impact on both mental and physical health outcomes.</p> <p>Trial registration</p> <p>NCT00572520</p

The Effects of Warming-Shifted Plant Phenology on Ecosystem Carbon Exchange Are Regulated by Precipitation in a Semi-Arid Grassland

BACKGROUND: The longer growing season under climate warming has served as a crucial mechanism for the enhancement of terrestrial carbon (C) sink over the past decades. A better understanding of this mechanism is critical for projection of changes in C cycling of terrestrial ecosystems. METHODOLOGY/PRINCIPAL FINDINGS: A 4-year field experiment with day and night warming was conducted to examine the responses of plant phenology and their influences on plant coverage and ecosystem C cycling in a temperate steppe in northern China. Greater phenological responses were observed under night than day warming. Both day and night warming prolonged the growing season by advancing phenology of early-blooming species but without changing that of late-blooming species. However, no warming response of vegetation coverage was found for any of the eight species. The variances in species-level coverage and ecosystem C fluxes under different treatments were positively dependent upon the accumulated precipitation within phenological duration but not the length of phenological duration. CONCLUSIONS/SIGNIFICANCE: These plants' phenology is more sensitive to night than day warming, and the warming effects on ecosystem C exchange via shifting plant phenology could be mediated by precipitation patterns in semi-arid grasslands

Conditionally Replicating Adenovirus Expressing TIMP2 Increases Survival in a Mouse Model of Disseminated Ovarian Cancer

Ovarian cancer remains difficult to treat mainly due to presentation of the disease at an advanced stage. Conditionally-replicating adenoviruses (CRAds) are promising anti-cancer agents that selectively kill the tumor cells. The present study evaluated the efficacy of a novel CRAd (Ad5/3-CXCR4-TIMP2) containing the CXCR4 promoter for selective viral replication in cancer cells together with TIMP2 as a therapeutic transgene, targeting the matrix metalloproteases (MMPs) in a murine orthotopic model of disseminated ovarian cancer. An orthotopic model of ovarian cancer was established in athymic nude mice by intraperitonal injection of the human ovarian cancer cell line, SKOV3-Luc, expressing luciferase. Upon confirmation of peritoneal dissemination of the cells by non-invasive imaging, mice were randomly divided into four treatment groups: PBS, Ad-ΔE1-TIMP2, Ad5/3-CXCR4, and Ad5/3-CXCR4-TIMP2. All mice were imaged weekly to monitor tumor growth and were sacrificed upon reaching any of the predefined endpoints, including high tumor burden and significant weight loss along with clinical evidence of pain and distress. Survival analysis was performed using the Log-rank test. The median survival for the PBS cohort was 33 days; for Ad-ΔE1-TIMP2, 39 days; for Ad5/3-CXCR4, 52.5 days; and for Ad5/3-CXCR4-TIMP2, 63 days. The TIMP2-armed CRAd delayed tumor growth and significantly increased survival when compared to the unarmed CRAd. This therapeutic effect was confirmed to be mediated through inhibition of MMP9. Results of the in vivo study support the translational potential of Ad5/3-CXCR4-TIMP2 for treatment of human patients with advanced ovarian cancer

Opposing Roles for Membrane Bound and Soluble Fas Ligand in Glaucoma-Associated Retinal Ganglion Cell Death

Glaucoma, the most frequent optic neuropathy, is a leading cause of blindness worldwide. Death of retinal ganglion cells (RGCs) occurs in all forms of glaucoma and accounts for the loss of vision, however the molecular mechanisms that cause RGC loss remain unclear. The pro-apoptotic molecule, Fas ligand, is a transmembrane protein that can be cleaved from the cell surface by metalloproteinases to release a soluble protein with antagonistic activity. Previous studies documented that constitutive ocular expression of FasL maintained immune privilege and prevented neoangeogenesis. We now show that FasL also plays a major role in retinal neurotoxicity. Importantly, in both TNFα triggered RGC death and a spontaneous model of glaucoma, gene-targeted mice that express only full-length FasL exhibit accelerated RGC death. By contrast, FasL-deficiency, or administration of soluble FasL, protected RGCs from cell death. These data identify membrane-bound FasL as a critical effector molecule and potential therapeutic target in glaucoma