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Purpose: Non-functioning pituitary neuroendocrine tumors are challengingly diagnosed tumors in the clinic. Transsphenoidal surgery remains the first-line treatment. Despite the development of state-of-the-art techniques, no drug therapy is currently approved for the treatment. There are also no randomized controlled trials comparing therapeutic strategies or drug therapy for the management after surgery. Therefore, novel therapeutic interventions for the therapeutically challenging NF-PitNETs are urgently needed. Methods: We integrated epigenome and transcriptome data (both coding and non-coding) that elucidate disease-specific signatures, in addition to biological and pharmacological data, to utilize rational pathway and drug prioritization in NF-PitNETs. We constructed an epigenome- and transcriptome-based PPI network and proposed hub genes. The signature-based drug repositioning based on the integration of multi-omics data was performed. Results: The construction of a disease-specific network based on three different biological levels revealed DCC, DLG5, ETS2, FOXO1, HBP1, HMGA2, PCGF3, PSME4, RBPMS, RREB1, SMAD1, SOCS1, SOX2, YAP1, ZFHX3 as hub proteins. Signature-based drug repositioning using hub proteins yielded repositioned drug candidates that were confirmed in silico via molecular docking. As a result of molecular docking simulations, palbociclib, linifanib, trametinib, eplerenone, niguldipine, and zuclopenthixol showed higher binding affinities with hub genes compared to their inhibitors and were proposed as potential repositioned therapeutics for the management of NF-PitNETs. Conclusion: The proposed systems’ biomedicine-oriented multi-omics data integration for drug repurposing to provide promising results for the construction of effective clinical therapeutics. To the best of our knowledge, this is the first study reporting epigenome- and transcriptome-based drug repositioning for NF-PitNETs using in silico confirmations.

AbstractWhile the firm-level distributional consequences of market liberalization are well understood, previous studies have paid only limited attention to how variations in domestic institutions across countries affect the winners and losers from opening up to trade. We argue that the presence of coordinated wage-bargaining institutions, which impose a ceiling on wage increases, and state-subsidized vocational training, which creates a large supply of highly skilled workers, generate labor market frictions. Upward wage rigidity, in particular, helps smaller firms weather the rising competition and increasing labor costs triggered by trade liberalization. We test this hypothesis using a firm-level data set of European Union countries, which includes more than 800,000 manufacturing firms between 2003 and 2014. We find that, for productive firms, gains from trade are 20 percent larger in countries with liberal market economies than they are in coordinated market economies. Symmetrically, less productive firms in coordinated market economies experience significantly smaller revenue losses compared to liberal market economies. We show that both the presence of an institutionalized wage ceiling and the availability of subsidized vocational training are key mechanisms for reducing the reallocation of revenue from unproductive to productive firms in coordinated market economies compared to liberal market economies. In line with our theory, we find that wages and employment in liberalized industries increase differentially across both types of labor markets. Finally, we provide suggestive evidence that trade liberalization triggers a differential demand for redistribution at the individual level across different labor markets, which is in line with our firm-level analysis.

AbstractSustainable development provisions have become an integral part of the European Union's (EU's) ‘new generation’ trade agreements. Yet, a growing number of empirical works show that their design varies significantly, even in the trade agreements signed with countries at similar (low) levels of development. We contend that this variation can be accounted for by discussing how the growing integration of the EU economy with specific developing countries across global value chains (GVCs) affects the domestic politics of regulatory export in the EU. European firms that operate within GVCs rely on imports of inputs produced in low-labor cost countries. These firms tend to oppose the export of those regulatory burdens that generate an increase in their imports' variable costs. The political mobilization of these actors weakens domestic coalitions supporting regulatory export strategies, which explains why the EU adopts a more lenient approach over the inclusion of sustainable development provisions in Preferential Trade Agreement negotiations with some developing countries.

AbstractThis article aims to account for the variation in the time it takes for WTO Members to bring compliance following adverse panel rulings. It seeks to answer the question: under what conditions do defendants swiftly implement adverse rulings of WTO panels? I demonstrate that defendants are more likely to comply without delay when the targeted measures involve firms that are integrated into regional and global value chains. When a dispute touches upon the interests of these firms and targets import-restricting measures, they are triggered to mobilize and press for compliance because they rely on foreign imports. In effect, the mobilization of these firms changes the domestic political conditions in favor of timely implementation. I show the plausibility of my argument in a comparative design with four case studies in which the US and Canada acted as defendants in WTO disputes. I control for a number of political factors and also consider legal sources of variation – i.e. the complexity of the form of implementation – that may impact WTO Members’ record of compliance.

AimsThe aim of this study was to establish what happens to patients in the long term after endoprosthetic replacement for a primary malignant tumour of bone. Patients and MethodsWe conducted a retrospective analysis of a prospectively maintained database to identify all patients who had undergone an endoprosthetic replacement more than 25 years ago and who were still alive. Their outcomes were investigated with reference to their complications and need for further surgery. A total of 230 patients were identified. Their mean age at diagnosis was 20.7 years (five to 62). The most common diagnosis was osteosarcoma (132). The most common site was the distal femur (102). ResultsThe mean follow-up was 29.4 years (25 to 43). A total of 610 further operations were undertaken, an average of 2.7 further operations per patient. A total of 42 patients (18%) still had the original prosthesis in place. The risk of amputation was 16% at 30 years (31 patients). Those without infection had a mean of 2.1 further operations (one to nine) while those with infection had a mean of 4.6 further operations (two to 11). The risk of infection persisted throughout the life of the prosthesis with a mean of 1% per year becoming infected. Of the 60 patients who developed an infection, 21 (35%) developed this following the primary procedure at a mean of 50 months, but another 19 developed this within a year of another surgical procedure. The risk of infection after any further surgery was 2.7%. The site with the highest risk of infection was the proximal tibia (43.3%).Take home message: This study highlights the inevitable need for further surgery following first-generation endoprosthetic reconstruction, although in most cases, limb salvage is maintained. Late complications, especially infection, continue for the lifetime of the implant.Cite this article: Bone Joint J2016;98-B:857–64.

We address the problem of mining spatiotemporal co-occurrence patterns (STCOPs) in solar datasets with extended polygon-based geometric representations. Specifically designed spatiotemporal indexing techniques are used in the mining of STCOPs. These include versions of two well-known spatiotemporal trajectory indexing techniques: the scalable and efficient trajectory index and Chebyshev polynomial indexing. We present a framework, Stcop-Miner, implementing a filter-and-refine STCOP mining algorithm, with the indexing techniques mentioned for efficiently performing data analysis.

As the popularity of the personal watercraft (PWC) or Jet Ski increases, injuries suffered from the usage of them become more common. Most severe injuries in this setting are typically related to blunt head trauma. Here we present an unusual case of hydrostatic injury to the rectum and sigmoid colon due to exposure to a high-pressure jet stream of water in a passenger thrown from the rear of a PWC. In addition, a review of the literature of similar cases is briefly discussed. (Hong Kong j.emerg.med. 2014;21:322-325)

As the popularity of the personal watercraft (PWC) or Jet Ski increases, injuries suffered from the usage of them become more common. Most severe injuries in this setting are typically related to blunt head trauma. Here we present an unusual case of hydrostatic injury to the rectum and sigmoid colon due to exposure to a high-pressure jet stream of water in a passenger thrown from the rear of a PWC. In addition, a review of the literature of similar cases is briefly discussed. (Hong Kong j.emerg.med. 2014;21:322-325)

Hydrodynamische Studien in Rieselbettreaktoren unter erhöhten Drücken und Temperaturen beschäftigen sich hauptsächlich mit koaleszierenden, also nichtschäumenden, Systemen. Obwohl in zahlreichen industriellen Prozessen schäumende Flüssigkeiten eingesetzt werden, ist keine aussagekräftige Datenbasis vorhanden. Für die verlässliche Auslegung und den sicheren Betrieb von Reaktoren wurden die Effekte von Temperatur und Druck auf die hydrodynamischen Kenngrößen für newtonsche und nichtnewtonsche schaumbildende Systeme untersucht. Außerdem wurde eine neue operative Methode entwickelt, bei der der Rieselbettreaktor alternierend zyklisch betrieben wird und die ohne die Dosierung von chemischen Zusätzen effektiv zur Begrenzung der Schaumbildung eingesetzt werden kann.

Purpose To determine the safety and efficacy of perioperative dexmedetomidine (Dex) sedation on patient comfort and surgeon satisfaction during cataract surgery under topical anesthesia.Methods Forty-four patients having routine clear corneal phacoemulsification surgery under topical anesthesia were included in the study Patients were randomly divided into two groups: Dex group (n=22) and control group (n=22). Patients in the Dex group were to receive intravenous Dex using an infusion pump and those in the control group were to receive 0.9% saline infusion. Primary outcome measures were patient comfort, surgeon satisfaction, and patient pain perception.Results There was no significant difference between the groups in terms of baseline characteristics including age, sex, eye side, pupil diameter, and vital signs (p>0.05 for all). Patient comfort and surgeon satisfaction in Dex group was better than in control group (p=0.042 and p=0.003, respectively). The mean pain perception score was lesser in the Dex group (1.23±1.72) than control group (3.64±1.43), (p<0.001). The mean surgical time and intraoperative complications were similar in both groups (p>0.05). There was no significant effect of the Dex sedation on vital signs perioperatively (p>0.05 for all).Conclusions Dex sedation improved patient and surgeon satisfaction and decreased patients' pain perception while undergoing cataract surgery under topical anesthesia. It appears to be a safe and suitable choice of sedation for cataract surgery.