Diagnostic reproducibility of tumour budding in colorectal cancer: a multicentre, multinational study using virtual microscopy

Puppa G, Senore C, Sheahan K, Vieth M, Lugli A, Zlobec I, Pecori S, Wang L M, Langner C, Mitomi H, Nakamura T, Watanabe M, Ueno H, Chasle J, Conley S A, Herlin P, Lauwers G Y & Risio M (2012) Histopathology Diagnostic reproducibility of tumour budding in colorectal cancer: a multicentre, multinational study using virtual microscopy Aims:  Despite the established prognostic relevance of tumour budding in colorectal cancer, the reproducibility of the methods reported for its assessment has not yet been determined, limiting its use and reporting in routine pathology practice. Methods and results:  A morphometric system within telepathology was devised to evaluate the reproducibility of the various methods published for the assessment of tumour budding in colorectal cancer. Five methods were selected to evaluate the diagnostic reproducibility among 10 investigators, using haematoxylin and eosin (H&E) and AE1-3 cytokeratin-immunostained, whole-slide digital scans from 50 pT1-pT4 colorectal cancers. The overall interobserver agreement was fair for all methods, and increased to moderate for pT1 cancers. The intraobserver agreement was also fair for all methods and moderate for pT1 cancers. Agreement was dependent on the participants' experience with tumour budding reporting and performance time. Cytokeratin immunohistochemistry detected a higher percentage of tumour budding-positive cases with all methods compared to H&E-stained slides, but did not influence agreement levels. Conclusions:  An overall fair level of diagnostic agreement for tumour budding in colorectal cancer was demonstrated, which was significantly higher in early cancer and among experienced gastrointestinal pathologists. Cytokeratin immunostaining facilitated detection of budding cancer cells, but did not result in improved interobserver agreement.

A New Symbiosis: Municipalities, Private Contractors and Non-Governmental Organisations for the Provision of Local Public Services"

This project considered the second stage of transforming local administration and public service management to reflect democratic forms of government. In Hungary in the second half of the 1990s more and more public functions delegated to local governments have been handed over to the private or civil sectors. This has led to a relative decrease of municipal functions but not of local governments' responsibilities, requiring them to change their orientation and approach to their work so as to be effective in their new roles of managing these processes rather than traditional bureaucratic administration. Horvath analysed the Anglo-Saxon, French and German models of self-government, identifying the differing aspects emphasised in increasing the private sector's role in the provision of public services, and the influence that this process has on the system of public administration. He then highlighted linkages between actors and local governments in Hungary, concluding that the next necessary step is to develop institutional mechanisms, financial incentives and managerial practices to utilise the full potential of this process. Equally important is the need for conscious avoidance of restrictive barriers and unintended consequences, and for local governments to confront the social conflicts that have emerged in parallel with privatisation. A further aspect considered was a widening of the role of functional governance at local level in the field of human services. A number of different special purpose bodies have been set up in Hungary, but the results of their work are unclear and Horvath feels that this institutionalisation of symbiosis is not the right path in Hungary today. He believes that the change from local government to local governance will require the formulation of specific public policy, the relevance of which can be proven by processes supported with actions.

Development of a screening tool predicting the transition from acute to chronic low back pain for patients in a GP setting: protocol of a multinational prospective cohort study

BACKGROUND: Low back pain (LBP) is by far the most prevalent and costly musculoskeletal problem in our society today. Following the recommendations of the Multinational Musculoskeletal Inception Cohort Study (MMICS) Statement, our study aims to define outcome assessment tools for patients with acute LBP and the time point at which chronic LBP becomes manifest and to identify patient characteristics which increase the risk of chronicity. METHODS: Patients with acute LBP will be recruited from clinics of general practitioners (GPs) in New Zealand (NZ) and Switzerland (CH). They will be assessed by postal survey at baseline and at 3, 6, 12 weeks and 6 months follow-up. Primary outcome will be disability as measured by the Oswestry Disability Index (ODI); key secondary endpoints will be general health as measured by the acute SF-12 and pain as measured on the Visual Analogue Scale (VAS). A subgroup analysis of different assessment instruments and baseline characteristics will be performed using multiple linear regression models. This study aims to examine: 1. Which biomedical, psychological, social, and occupational outcome assessment tools are identifiers for the transition from acute to chronic LBP and at which time point this transition becomes manifest. 2. Which psychosocial and occupational baseline characteristics like work status and period of work absenteeism influence the course from acute to chronic LBP. 3. Differences in outcome assessment tools and baseline characteristics of patients in NZ compared with CH. DISCUSSION: This study will develop a screening tool for patients with acute LBP to be used in GP clinics to access the risk of developing chronic LBP. In addition, biomedical, psychological, social, and occupational patient characteristics which influence the course from acute to chronic LBP will be identified. Furthermore, an appropriate time point for follow-ups will be given to detect this transition. The generalizability of our findings will be enhanced by the international perspective of this study. TRIAL REGISTRATION: [Clinical Trial Registration Number, ACTRN12608000520336].

Writing center handbooks and travel guidebooks : redesigning instructional texts for multicultural, multilingual, and multinational contexts

In an increasingly interconnected world characterized by the accelerating interplay of cultural, linguistic, and national difference, the ability to negotiate that difference in an equitable and ethical manner is a crucial skill for both individuals and larger social groups. This dissertation, Writing Center Handbooks and Travel Guidebooks: Redesigning Instructional Texts for Multicultural, Multilingual, and Multinational Contexts, considers how instructional texts that ostensibly support the negotiation of difference (i.e., accepting and learning from difference) actually promote the management of difference (i.e., rejecting, assimilating, and erasing difference). As a corrective to this focus on managing difference, chapter two constructs a theoretical framework that facilitates the redesign of handbooks, guidebooks, and similar instructional texts. This framework centers on reflexive design practices and is informed by literacy theory (Gee; New London Group; Street), social learning theory (Wenger), globalization theory (Nederveen Pieterse), and composition theory (Canagarajah; Horner and Trimbur; Lu; Matsuda; Pratt). By implementing reflexive design practices in the redesign of instructional texts, this dissertation argues that instructional texts can promote the negotiation of difference and a multicultural/multilingual sensibility that accounts for twenty-first century linguistic and cultural realities. Informed by the theoretical framework of chapter two, chapters three and four conduct a rhetorical analysis of two forms of instructional text that are representative of the larger genre: writing center coach handbooks and travel guidebooks to Hong Kong. This rhetorical analysis reveals how both forms of text employ rhetorical strategies that uphold dominant monolingual and monocultural assumptions. Alternative rhetorical strategies are then proposed that can be used to redesign these two forms of instructional texts in a manner that aligns with multicultural and multilingual assumptions. These chapters draw on the work of scholars in Writing Center Studies (Boquet and Lerner; Carino; DiPardo; Grimm; North; Severino) and Technical Communication (Barton and Barton; Dilger; Johnson; Kimball; Slack), respectively. Chapter five explores how the redesign of coach handbooks and travel guidebooks proposed in this dissertation can be conceptualized as a political act. Ultimately, this dissertation argues that instructional texts are powerful heuristic tools that can enact social change if they are redesigned to foster the negotiation of difference and to promote multicultural/multilingual world views.

Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6)

BACKGROUND: Unlike most antihyperglycaemic drugs, glucagon-like peptide-1 (GLP-1) receptor agonists have a glucose-dependent action and promote weight loss. We compared the efficacy and safety of liraglutide, a human GLP-1 analogue, with exenatide, an exendin-based GLP-1 receptor agonist. METHODS: Adults with inadequately controlled type 2 diabetes on maximally tolerated doses of metformin, sulphonylurea, or both, were stratified by previous oral antidiabetic therapy and randomly assigned to receive additional liraglutide 1.8 mg once a day (n=233) or exenatide 10 microg twice a day (n=231) in a 26-week open-label, parallel-group, multinational (15 countries) study. The primary outcome was change in glycosylated haemoglobin (HbA(1c)). Efficacy analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00518882. FINDINGS: Mean baseline HbA(1c) for the study population was 8.2%. Liraglutide reduced mean HbA(1c) significantly more than did exenatide (-1.12% [SE 0.08] vs -0.79% [0.08]; estimated treatment difference -0.33; 95% CI -0.47 to -0.18; p<0.0001) and more patients achieved a HbA(1c) value of less than 7% (54%vs 43%, respectively; odds ratio 2.02; 95% CI 1.31 to 3.11; p=0.0015). Liraglutide reduced mean fasting plasma glucose more than did exenatide (-1.61 mmol/L [SE 0.20] vs -0.60 mmol/L [0.20]; estimated treatment difference -1.01 mmol/L; 95% CI -1.37 to -0.65; p<0.0001) but postprandial glucose control was less effective after breakfast and dinner. Both drugs promoted similar weight losses (liraglutide -3.24 kg vs exenatide -2.87 kg). Both drugs were well tolerated, but nausea was less persistent (estimated treatment rate ratio 0.448, p<0.0001) and minor hypoglycaemia less frequent with liraglutide than with exenatide (1.93 vs 2.60 events per patient per year; rate ratio 0.55; 95% CI 0.34 to 0.88; p=0.0131; 25.5%vs 33.6% had minor hypoglycaemia). Two patients taking both exenatide and a sulphonylurea had a major hypoglycaemic episode. INTERPRETATION: Liraglutide once a day provided significantly greater improvements in glycaemic control than did exenatide twice a day, and was generally better tolerated. The results suggest that liraglutide might be a treatment option for type 2 diabetes, especially when weight loss and risk of hypoglycaemia are major considerations.

Serious suicidal behaviors: socio-demographic and clinical features in a multinational, multicenter sample

BACKGROUND: Declared suicidal intent and physical danger are both considered important components in defining suicidal behaviors (SB). AIMS: 1) To investigate characteristics of serious suicidal behaviors (SSB), defined by either suicidal intent or lethality; 2) To determine any difference in terms of socio-demographic, clinical and/or service usage variables between SSB and non-serious suicidal behaviors (NSSB). METHODS: A total of 2631 contacts for SB were registered in the context of the MONSUE (Monitoring Suicidal Behavior in Europe) study project. Demographic and clinical information were registered. ICD-10 was used for classifying data about psychiatric diagnoses, methods used for SB and injuries reported. Clear intentionality, high-case fatality methods and serious injuries all defined SSB (n = 1169; 44.4%) RESULTS: SSB were more often preceded by a contact with an inpatient (either psychiatric or somatic) rather than an outpatient service. Among those having a previous history of SB, SSB subjects had fewer contacts with health services before the previous attempt. The strongest predictors for SSB appeared to be older age and not professing a religion. CONCLUSION: Many of the known factors contributing to the risk of completed suicide were also present for SSB. Our findings on service usage by suicide attempters show which aspects of mental health services should be strengthened in order to improve suicide prevention.

Fertility-preservation counselling and treatment for medical reasons: data from a multinational network of over 5000 women.

Fertility-preservation techniques for medical reasons are increasingly offered in national networks. Knowledge of the characteristics of counselled patients and techniques used are essential. The FertiPROTEKT network registry was analysed between 2007 and 2013, and included up to 85 university and non-university centres in Germany, Austria and Switzerland; 5159 women were counselled and 4060 women underwent fertility preservation. In 2013, fertility-preservation counselling for medical reasons increased significantly among nullipara and women aged between 21 and 35 years (n = 1043; P < 0.001). Frequency of GnRH applications slowly decreased, whereas tissue, oocytes and zygote cryopreservation increased. In 2013, women with breast cancer mainly opted for tissue freezing, whereas women with lymphoma opted for GnRH agonist. Women younger than 20 years predominantly opted for GnRH agonists and ovarian tissue cryopreservation; women aged between 20 and 40 years underwent a variety of techniques; and women over 40 years opted for GnRH agonists. The average number of aspirated oocytes per stimulation cycle decreased as age increased (< 30 years: 12.9; 31-35 years: 12.3; 36-46: 9.0; > 41 years: 5.7). For ovarian tissue cryopreservation, removal and cryopreservation of fewer than one ovary was preferred and carried out in 97% of cases in 2013.

A multinational case-control study on childhood brain tumours, anthropogenic factors, birth characteristics and prenatal exposures: A validation of interview data.

Little is known about the aetiology of childhood brain tumours. We investigated anthropometric factors (birth weight, length, maternal age), birth characteristics (e.g. vacuum extraction, preterm delivery, birth order) and exposures during pregnancy (e.g. maternal: smoking, working, dietary supplement intake) in relation to risk of brain tumour diagnosis among 7-19 year olds. The multinational case-control study in Denmark, Sweden, Norway and Switzerland (CEFALO) included interviews with 352 (participation rate=83.2%) eligible cases and 646 (71.1%) population-based controls. Interview data were complemented with data from birth registries and validated by assessing agreement (Cohen's Kappa). We used conditional logistic regression models matched on age, sex and geographical region (adjusted for maternal age and parental education) to explore associations between birth factors and childhood brain tumour risk. Agreement between interview and birth registry data ranged from moderate (Kappa=0.54; worked during pregnancy) to almost perfect (Kappa=0.98; birth weight). Neither anthropogenic factors nor birth characteristics were associated with childhood brain tumour risk. Maternal vitamin intake during pregnancy was indicative of a protective effect (OR 0.75, 95%-CI: 0.56-1.01). No association was seen for maternal smoking during pregnancy or working during pregnancy. We found little evidence that the considered birth factors were related to brain tumour risk among children and adolescents.

Transfer Pricing in the Decentralized Multinational Corporation

This paper considers how the multinational corporation's transfer price responds to changes in international corporate effective tax rates. It extends the decentralized decision-making analysis of transfer pricing in the context of different tax rates. It adopts and extends Bond's (1980) model of the decentralized multinational corporation that assumes centralized transfer pricing. The direction of transfer price change is as expected, while the magnitude of change is likely to be less than predicted by the Horst (1971), centralized decision-making model. The paper extends the model further by assuming negotiated transfer pricing, where the analysis is partitioned into perfect and imperfect information cases. The negotiated transfer pricing result reverts to the Horst (1971), or centralized decision-making, result, under perfect information. Under imperfect information, the centralized decision-making result obtains when top management successfully informs division general managers or it successfully implements a non-monetary reward scheme to encourage division general managers to cooperate. Under simplifying assumptions, centralized decision-making dominates decentralized decision-making, while negotiated transfer pricing weakly dominates centralized transfer pricing.

International Transfer Pricing for Goods and Intangible Asset Licenses in a Decentralized Multinational Corporation: Review and Extensions

We review and extend the core literature on international transfer price manipulation to avoid or evade taxes. Under negotiated transfer pricing with a viable bargaining structure, including performance evaluation disconnected from the transfer price, divisions voluntarily exchange accurate information to obtain firm-wide optimality, a result not dependent on restraint from exercising internal market power. For intangible licenses, a larger optimal profit shift for a given tax rate change strengthens incentives for transfer pricing abuse. In practice, an intangible's arm's length range is viewed as a guideline, a context where incentives for abuse materialize. Transfer pricing for intangibles obliges greater tax authority scrutiny.

The determinants of offshore production by Multinational Corporations (MNCs) : a comparison of Japanese and US MNCs

This study employs confidential affiliate-level panel data to improve measures of foreign affiliate activities of Japanese firms in manufacturing sectors. Combining existing data on U.S. MNCs with the Japanese data, we illustrate the pattern and determinant of their foreign affiliate sales by destination market across countries and industries for the period 1989-2005. Among our results, Japanese and U.S. MNCs are similar in the substantial growth of their foreign affiliate sales and the importance of sales to local markets. However, Japanese MNCs are distinctive from U.S. MNCs in that Japanese affiliate sales in Asia were prominently higher in host markets with lower educational attainment.

Location choice of multinational enterprises in China : comparison between Japan and Taiwan

This paper examines and compares the location choice of Japanese and Taiwanese MNEs in China. Furthermore, we investigate the relationship between location choice and firm characteristics, specifically firms' productivity. Due to Taiwan's linguistic and cultural advantages in China, it is expected that the location choice mechanics are different between Japanese and Taiwanese MNEs. As a result, our main findings are that, while the less productive Japanese firms prefer a location in an area with a larger agglomeration of Japanese affiliates or in an area closer to Japan, the more productive Taiwanese firms prefer a location in an area with a larger agglomeration of Taiwanese affiliates or in an area closer to Taiwan.

Tax differentials and inflow of foreign direct investments : evidence from foreign operations of U.S. multinational companies

This paper concerns the measurement of the impact of tax differentials across countries on inflow of Foreign Direct Investment (FDI) by using comprehensive data on the foreign operations of U.S. multinational corporations that has been collected by the Bureau of Economic Analysis (BEA), the U.S. Department of Commerce. In particular, this research focuses on examining: (1) how responsive FDI locations are to tax differentials across countries, (2) how different the tax effect on FDI inflow is between developed and developing countries, and (3) whether investment location decisions have become more or less sensitive to tax differences between countries over time ranging from the late 1990s to the early 2000s. Estimation results suggest that high rates of corporate income taxation are associated with reduced foreign assets of U.S. multinational firms in all industries by decreasing the return to foreign asset investment. Further, foreign assets of U.S. multinationals in all industries have become more responsive to non-income tax differentials across countries than to income tax differences from 1999 to 2004. Empirical estimates also indicate that foreign investment by American firms is associated with higher tax sensitivity more in developed countries than in those that are developing.

Simulating heterogeneous multinational firms

This paper develops a micro-simulation framework for multinational entry and sales activities across countries. The model is based on Eaton, Kortum, and Kramarz's (2010) quantitative trade model adapted towards multinational production. Using micro data on Japanese manufacturing firms, we first stylize the empirical regularities of multinational entry and sales activity and estimate the model's structural parameters with simulated method of moments. We then demonstrate that our adapted model is able to replicate important dimensions of the in-sample moments conditioned in our estimation strategy. Importantly, it is able to replicate activity under an economic period with a far different level of FDI barriers than was conditioned upon in our estimation sample. Overall, our research highlights the richness of the simulation framework for performing counterfactual analysis of various FDI policies.