Emerging pharmacotherapy of tinnitus

Tinnitus, the perception of sound in the absence of an auditory stimulus, is perceived by about 1 in 10 adults, and for at least 1 in 100, tinnitus severely affects their quality of life. Because tinnitus is frequently associated with irritability, agitation, stress, insomnia, anxiety and depression, the social and economic burdens of tinnitus can be enormous. No curative treatments are available. However, tinnitus symptoms can be alleviated to some extent. The most widespread management therapies consist of auditory stimulation and cognitive behavioral treatment, aiming at improving habituation and coping strategies. Available clinical trials vary in methodological rigor and have been performed for a considerable number of different drugs. None of the investigated drugs have demonstrated providing replicable long-term reduction of tinnitus impact in the majority of patients in excess of placebo effects. Accordingly, there are no FDA or European Medicines Agency approved drugs for the treatment of tinnitus. However, in spite of the lack of evidence, a large variety of different compounds are prescribed off-label. Therefore, more effective pharmacotherapies for this huge and still growing market are desperately needed and even a drug that produces only a small but significant effect would have an enormous therapeutic impact. This review describes current and emerging pharmacotherapies with current difficulties and limitations. In addition, it provides an estimate of the tinnitus market. Finally, it describes recent advances in the tinnitus field which may help overcome obstacles faced in the pharmacological treatment of tinnitus. These include incomplete knowledge of tinnitus pathophysiology, lack of well-established animal models, heterogeneity of different forms of tinnitus, difficulties in tinnitus assessment and outcome measurement and variability in clinical trial methodology. © 2009 Informa UK Ltd.Fil: Langguth, Berthold. Universitat Regensburg; AlemaniaFil: Salvi, Richard. State University of New York; Estados UnidosFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentin

Gender diversity in construction: demystifying the pipeline leaks in Australia, United States, United Kingdom and Brazil

Globally, the construction industry is a key contributor to the gross domestic product. However, compared to the gender diversity performance of the workforce in the world economy, historically, construction has been performing significantly poorly. Literature argued that these consistently poor performances in diversity, equity and inclusion were causing leaks in the education and career pipeline. However, a systematic investigation with evidence base was lacking. In this vacuum, the proposed study aims to explore the evolution of gender dynamics within the construction sector in Australia, United States, United Kingdom, and Brazil through quantitative evidence. This study collected industry gender representation data, gender pay gaps and tertiary degrees conferred from government agencies in four countries: Australia, the United States, the United Kingdom and Brazil. Quantitative data analysis was conducted with an exploration of factual figures, significant trajectories and fluctuations. Results were explored to understand local jurisdictions’ possible causal relationships and interventions. Delving into findings from the education pipeline revealed declining trends and alarming opportunities for the education institutions to take a lead role in moving from a “challenge leaky pipeline” towards a “shared solution space” through international cross-sectorial collaborations with the paradigm shift in the construction industry with the emerging fifth industrial revolution

Differential Pathogenesis of Lung Adenocarcinoma Subtypes Involving Sequence Mutations, Copy Number, Chromosomal Instability, and Methylation

Lung adenocarcinoma (LAD) has extreme genetic variation among patients, which is currently not well understood, limiting progress in therapy development and research. LAD intrinsic molecular subtypes are a validated stratification of naturally-occurring gene expression patterns and encompass different functional pathways and patient outcomes. Patients may have incurred different mutations and alterations that led to the different subtypes. We hypothesized that the LAD molecular subtypes co-occur with distinct mutations and alterations in patient tumors.The LAD molecular subtypes (Bronchioid, Magnoid, and Squamoid) were tested for association with gene mutations and DNA copy number alterations using statistical methods and published cohorts (n = 504). A novel validation (n = 116) cohort was assayed and interrogated to confirm subtype-alteration associations. Gene mutation rates (EGFR, KRAS, STK11, TP53), chromosomal instability, regional copy number, and genomewide DNA methylation were significantly different among tumors of the molecular subtypes. Secondary analyses compared subtypes by integrated alterations and patient outcomes. Tumors having integrated alterations in the same gene associated with the subtypes, e.g. mutation, deletion and underexpression of STK11 with Magnoid, and mutation, amplification, and overexpression of EGFR with Bronchioid. The subtypes also associated with tumors having concurrent mutant genes, such as KRAS-STK11 with Magnoid. Patient overall survival, cisplatin plus vinorelbine therapy response and predicted gefitinib sensitivity were significantly different among the subtypes.The lung adenocarcinoma intrinsic molecular subtypes co-occur with grossly distinct genomic alterations and with patient therapy response. These results advance the understanding of lung adenocarcinoma etiology and nominate patient subgroups for future evaluation of treatment response

Deceptive Advertising with Rational Buyers

We study a Bertrand game where two sellers supplying products of different and unverifiable qualities can outwit potential clients through their (costly) deceptive advertising. We characterize a class of pooling equilibria where sellers post the same price regardless of their quality and low quality ones deceive buyers. Although in these equilibria low quality goods are purchased with positive probability, the buyer (expected) utility can be higher than in a fully separating equilibrium. It is also argued that low quality sellers invest more in deceptive advertising the better is their reputation vis-à-vis potential clients — i.e., firms that are better trusted by customers, have greater incentives to invest in deceptive advertising when they produce a low quality product. Finally, we characterize the optimal monitoring effort exerted by a regulatory agency who seeks to identify and punish deceptive practices. When the objective of this agency is to maximize consumer surplus, its monitoring effort is larger than under social welfare maximization

Co-targeting of convergent nucleotide biosynthetic pathways for leukemia eradication

Pharmacological targeting of metabolic processes in cancer must overcome redundancy in biosynthetic pathways. Deoxycytidine (dC) triphosphate (dCTP) can be produced both by the de novo pathway (DNP) and by the nucleoside salvage pathway (NSP). However, the role of the NSP in dCTP production and DNA synthesis in cancer cells is currently not well understood. We show that acute lymphoblastic leukemia (ALL) cells avoid lethal replication stress after thymidine (dT)-induced inhibition of DNP dCTP synthesis by switching to NSP-mediated dCTP production. The metabolic switch in dCTP production triggered by DNP inhibition is accompanied by NSP up-regulation and can be prevented using DI-39, a new high-affinity small-molecule inhibitor of the NSP rate-limiting enzyme dC kinase (dCK). Positron emission tomography (PET) imaging was useful for following both the duration and degree of dCK inhibition by DI-39 treatment in vivo, thus providing a companion pharmacodynamic biomarker. Pharmacological co-targeting of the DNP with dT and the NSP with DI-39 was efficacious against ALL models in mice, without detectable host toxicity. These findings advance our understanding of nucleotide metabolism in leukemic cells, and identify dCTP biosynthesis as a potential new therapeutic target for metabolic interventions in ALL and possibly other hematological malignancies

Regional differences in portion size consumption behaviour: Insights for the global food industry

Abstract: Given the influence of globalization on consumer food behaviour across the world, the purpose of this paper is to contribute to the theoretical discourse around food portion size as a global consumption-related symbol and its underlying socio-economic drivers for food industry strategy. Overall, 25,000 global food consumers were surveyed across 24 countries to elicit insight on portion size consumption behaviour as well as consumer perception on eating and drinking small portion size within selected socio-economic classes. The data was quantitatively analysed to answer the pertinent research objectives. In 20 out of the 24 global markets surveyed, large food portion size was statistically established as a prevalent consumption-related symbol. The paper found that there are regional differences in portion size food consumption behaviour, and further disparities exist across age, gender and income status in 24 countries covering all regions, including Australia, China, Mexico, South Africa, United Kingdom and United States of America. The outlined food industry implications reveal that adaptation and standardisation strategies are still relevant in global food and nutrition strategy as revealed by the variations in the preference for food portion sizes across various countries of the world

Modeling three-party interactional risks in the governance of public-private partnerships

Public-private partnerships (PPPs) involve a variety of project governance structures. Common among all these varied structures is the long-term contractual period between multiple public and private entities. The increased uncertainty of a long-term contract duration coupled with the involvement of multiple stakeholders proves to be a challenge to the development of risk strategies for PPPs. Therefore, it is necessary to systematically frame the risks associated with these projects and explore their dynamics. These risks often arise due to the organizational dynamics from the interactions between stakeholders in varied risk scenarios. In this paper, a methodology is proposed to systematically identify risks in PPP projects, model the organizational dynamics associated with interactional risks using game theory, and simulate these models to observe a range of potential outcomes. The proposed combined approach can help planners prepare for a range of complex and uncertain scenarios and enable stakeholder management in PPP projects. The current literature is extended in this paper by (1) integrating risk identification and framing with modeling and simulation, and (2) expanding the analysis of interactions from the current focus on two parties to three. A case study of the Indiana Toll Road is performed to showcase the application of the proposed approach