A population-based analysis of germline BAP1 mutations in melanoma

Germline mutation of the BRCA1 associated protein-1 (BAP1) gene has been linked to uveal melanoma, mesothelioma, meningioma, renal cell carcinoma and basal cell carcinoma. Germline variants have also been found in familial cutaneous melanoma pedigrees, but their contribution to sporadic melanoma has not been fully assessed. We sequenced BAP1 in 1,977 melanoma cases and 754 controls and used deubiquitinase assays, a pedigree analysis, and a histopathological review to assess the consequences of the mutations found. Sequencing revealed 30 BAP1 variants in total, of which 27 were rare (ExAc allele frequency <0.002). Of the 27 rare variants, 22 were present in cases (18 missense, one splice acceptor, one frameshift and two near splice regions) and 5 in controls (all missense). A missense change (S98R) in a case that completely abolished BAP1 deubiquitinase activity was identified. Analysis of cancers in the pedigree of the proband carrying the S98R variant and in two other pedigrees carrying clear loss-of-function alleles showed the presence of BAP1-associated cancers such as renal cell carcinoma, mesothelioma and meningioma, but not uveal melanoma. Two of these three probands carrying BAP1 loss-of-function variants also had melanomas with histopathological features suggestive of a germline BAP1 mutation. The remaining cases with germline mutations, which were predominantly missense mutations, were associated with less typical pedigrees and tumours lacking a characteristic BAP1-associated histopathological appearances, but may still represent less penetrant variants. Germline BAP1 alleles defined as loss-of-function or predicted to be deleterious/damaging are rare in melanoma

Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial

Background: Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. Methods: In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. Findings: Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88–1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90–1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41–0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22–3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31–0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64–0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37–3·91], p=0·771) was similar. Interpretation: In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status

Thirty Years After Michael E. Porter: What Do We Know About Business Exit?

Although a business exit is an important corporate change initiative, the buyer’s side seems to be more appealing to management researchers than the seller’s because acquisitions imply growth, i.e., success. Yet from an optimistic viewpoint, business exit can effectively create value for the selling company. In this paper we attempt to bring the relevance of the seller’s side back into our consciousness by asking: What do we know about business exit? We start our exploration with Porter (1976), focusing on literature that investigates the antecedents of, barriers to, and outcomes of business exit. We also include studies from related fields such as finance and economics.1 Through this research we determine three clusters of findings: factors promoting business exit, exit barriers, and exit outcomes. Overall, it is the intention of this paper to highlight the importance of business exit for research and practice. Knowing what we know about business exits and their high financial value we should bear in mind that exit need not mean failure but a new beginning for a corporation

Processing of ultrafine-size particulate metal matrix composites by advanced shear technology

Copyright @ 2009 ASM International. This paper was published in Metallurgical & Materials Transactions A 40A(3) and is made available as an electronic reprint with the permission of ASM International. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplications of any material in this paper for a fee or for commercial purposes, or modification of the content of this paper are prohibited.Lack of efficient mixing technology to achieve a uniform distribution of fine-size reinforcement within the matrix and the high cost of producing components have hindered the widespread adaptation of particulate metal matrix composites (PMMCs) for engineering applications. A new rheo-processing method, the melt-conditioning high-pressure die-cast (MC-HPDC) process, has been developed for manufacturing near-net-shape components of high integrity. The MC-HPDC process adapts the well-established high shear dispersive mixing action of a twin-screw mechanism to the task of overcoming the cohesive force of the agglomerates under a high shear rate and high intensity of turbulence. This is followed by direct shaping of the slurry into near-net-shape components using an existing cold-chamber die-casting process. The results indicate that the MC-HPDC samples have a uniform distribution of ultrafine-sized SiC particles throughout the entire sample in the as-cast condition. Compared to those produced by conventional high-pressure die casting (HPDC), MC-HPDC samples have a much improved tensile strength and ductility.EP-SR

Appointing Women to Boards: Is There a Cultural Bias?

Companies that are serious about corporate governance and business ethics are turning their attention to gender diversity at the most senior levels of business (Institute of Business Ethics, Business Ethics Briefing 21:1, 2011). Board gender diversity has been the subject of several studies carried out by international organizations such as Catalyst (Increasing gender diversity on boards: Current index of formal approaches, 2012), the World Economic Forum (Hausmann et al., The global gender gap report, 2010), and the European Board Diversity Analysis (Is it getting easier to find women on European boards? 2010). They all lead to reports confirming the overall relatively low proportion of women on boards and the slow pace at which more women are being appointed. Furthermore, the proportion of women on corporate boards varies much across countries. Based on institutional theory, this study hypothesizes and tests whether this variation can be attributed to differences in cultural settings across countries. Our analysis of the representation of women on boards for 32 countries during 2010 reveals that two cultural characteristics are indeed associated with the observed differences. We use the cultural dimensions proposed by Hofstede (Culture’s consequences: International differences in work-related values, 1980) to measure this construct. Results show that countries which have the greatest tolerance for inequalities in the distribution of power and those that tend to value the role of men generally exhibit lower representations of women on boards

Floods and climate: emerging perspectives for flood risk assessment and management

Flood estimation and flood management have traditionally been the domain of hydrologists, water resources engineers and statisticians, and disciplinary approaches abound. Dominant views have been shaped; one example is the catchment perspective: floods are formed and influenced by the interaction of local, catchment-specific characteristics, such as meteorology, topography and geology. These traditional views have been beneficial, but they have a narrow framing. In this paper we contrast traditional views with broader perspectives that are emerging from an improved understanding of the climatic context of floods. We come to the following conclusions: (1) extending the traditional system boundaries (local catchment, recent decades, hydrological/hydraulic processes) opens up exciting possibilities for better understanding and improved tools for flood risk assessment and management. (2) Statistical approaches in flood estimation need to be complemented by the search for the causal mechanisms and dominant processes in the atmosphere, catchment and river system that leave their fingerprints on flood characteristics. (3) Natural climate variability leads to time-varying flood characteristics, and this variation may be partially quantifiable and predictable, with the perspective of dynamic, climate-informed flood risk management. (4) Efforts are needed to fully account for factors that contribute to changes in all three risk components (hazard, exposure, vulnerability) and to better understand the interactions between society and floods. (5) Given the global scale and societal importance, we call for the organization of an international multidisciplinary collaboration and data-sharing initiative to further understand the links between climate and flooding and to advance flood research

emerging perspectives for flood risk assessment and management

Flood estimation and flood management have traditionally been the domain of hydrologists, water resources engineers and statisticians, and disciplinary approaches abound. Dominant views have been shaped; one example is the catchment perspective: floods are formed and influenced by the interaction of local, catchment-specific characteristics, such as meteorology, topography and geology. These traditional views have been beneficial, but they have a narrow framing. In this paper we contrast traditional views with broader perspectives that are emerging from an improved understanding of the climatic context of floods. We come to the following conclusions: (1) extending the traditional system boundaries (local catchment, recent decades, hydrological/hydraulic processes) opens up exciting possibilities for better understanding and improved tools for flood risk assessment and management. (2) Statistical approaches in flood estimation need to be complemented by the search for the causal mechanisms and dominant processes in the atmosphere, catchment and river system that leave their fingerprints on flood characteristics. (3) Natural climate variability leads to time-varying flood characteristics, and this variation may be partially quantifiable and predictable, with the perspective of dynamic, climate-informed flood risk management. (4) Efforts are needed to fully account for factors that contribute to changes in all three risk components (hazard, exposure, vulnerability) and to better understand the interactions between society and floods. (5) Given the global scale and societal importance, we call for the organization of an international multidisciplinary collaboration and data-sharing initiative to further understand the links between climate and flooding and to advance flood research

Quasi-probability representations of quantum theory with applications to quantum information science

This article comprises a review of both the quasi-probability representations of infinite-dimensional quantum theory (including the Wigner function) and the more recently defined quasi-probability representations of finite-dimensional quantum theory. We focus on both the characteristics and applications of these representations with an emphasis toward quantum information theory. We discuss the recently proposed unification of the set of possible quasi-probability representations via frame theory and then discuss the practical relevance of negativity in such representations as a criteria for quantumness.Comment: v3: typos fixed, references adde

Econometric estimation of Armington import elasticities for a regional CGE model of the Illinois economy

One of the main concerns associated with the development and use of regional CGE models is the determination of key parameter values, particularly substitution and other price elasticities. A common problem is the lack of appropriate regional data for econometric estimation. Consequently, it is important to identify key parameters that are likely to be important in determining quantitative results and then to prioritize these for estimation where appropriate data are available. In this paper, the focus is on the estimation of the regional trade (import) substitution parameters, which tend to be important in analysis for regional economies (given their openness to trade). Here, commodity import elasticities for the Illinois economy are estimated and tested in a single region CGE model of the Illinois economy. In our econometric estimation, we apply a model that takes account of market size and distance in estimating the substitutability between commodities produced in Illinois and other US states