Clinical trial designs for rare diseases: Studies developed and discussed by the International Rare Cancers Initiative

BACKGROUND: The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research.

SETTINGS: The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional--usually randomized--clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed.

RESULTS: The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design.

INTERPRETATION: Trials can be designed using a wide array of possibilities. There is no 'one size fits all' solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases.

Uses and abuses of fractal methodology in ecology

Fractals have found widespread application in a range of scientific fields, including ecology. This rapid growth has produced substantial new insights, but has also spawned confusion and a host of methodological problems. In this paper, we review the value of fractal methods, in particular for applications to spatial ecology, and outline potential pitfalls. Methods for measuring fractals in nature and generating fractal patterns for use in modelling are surveyed. We stress the limitations and the strengths of fractal models. Strictly speaking, no ecological pattern can be truly fractal, but fractal methods may nonetheless provide the most efficient tool available for describing and predicting ecological patterns at multiple scales.

Coherence and discontinuity in the scaling of species' distribution patterns

The spatial distribution of a species can be characterized at many different spatial scales, from fine-scale measures of local population density to coarse-scale geographical-range structure. Previous studies have shown a degree of correlation in species' distribution patterns across narrow ranges of scales, making it possible to predict fine-scale properties from coarser-scale distributions. To test the limits of such extrapolation, we have compiled distributional information on 16 species of British plants, at scales ranging across six orders of magnitude in linear resolution (1 in to 100 km). As expected, the correlation between patterns at different spatial scales tends to degrade as the scales become more widely separated. There is, however, an abrupt breakdown in cross-scale correlations across intermediate (ca. 0.5 km) scales, suggesting that local and regional patterns are influenced by essentially non-overlapping sets of processes. The scaling discontinuity may also reflect characteristic scales of human land use in Britain, suggesting a novel method for analysing the 'footprint' of humanity on a landscape.

The Carnian Humid Episode of the late Triassic: A Review

From 1989 to 1994 a series of papers outlined evidence for a brief episode of climate change from arid to humid, and then back to arid, during the Carnian Stage of the late Triassic. This time of climate change was compared to marine and terrestrial biotic changes, mainly extinction and then radiation of flora and fauna. Subsequently termed, albeit incorrectly, the Carnian Pluvial Event (CPE) by successive authors, interest in this episode of climatic change has increased steadily, with new evidence being published as well as several challenges to the theory. The exact nature of this humid episode, whether reflecting widespread precipitation or more local effects, as well as its ultimate cause remains equivocal. Bed-by-bed sampling of the Carnian in the Southern Alps (Dolomites), shows the episode began with a negative carbon isotope excursion that lasted for only part of one ammonoid zone (A. austriacum). However, that the Carnian Humid Episode represents a significantly longer period, both environmentally and biotically, is irrefutable. The evidence is strongest in the European, Middle East, Himalayan, North American and Japanese successions, but not always so clear in South America, Antarctica and Australia. The eruption of the Wrangellia Large Igneous Province and global warming (causing increased evaporation in the Tethyan and Panthalassic oceans) are suggested as causes for the humid episode.

Proportioning variability in the dispensation of hand-mixed dental cements

Objectives: The purpose of this investigation was to determine for dispensed multiples (1 through 4) of powder (P) and liquid (L) in hand-mixed dental cement whether: (1) the mean (P/L) ratio (m/m) and (2) the maximum difference in (P/L) ratio is dependent on the number of multiples dispensed. The Null hypotheses were: (a) mean (P/L) ratio is independent of the number of multiples dispensed and (b) maximum difference in (P/L) ratio is independent of the number of multiples dispensed.
Methods: The materials investigated are listed in the Table. The masses of dispensed aliquots of powder and liquid were measured by a single operator (n=10, for multiples 1 through 4) on a 4-place analytical balance. All measurements were made independently and all possible (P/L) ratios calculated for each sample. The effect of multiple dispensations on (P/L) ratios and maximum (P/L) differences was by one-way ANOVA and linear regression, respectively, with the Tukey post-hoc correction for multiple comparisons.MULTIPLE DISPENSEDDISPENSED MU(x1)(x2)(x3)(x4)Zinc phosphateHeraeus12.271(0.691)a13.051(1.269)b13.215(0.824)b13.118(1.149)bFuji IXGC4.209(0.373)a4.085(0.275)b4.095(0.226)b4.095(0.217)bIRMDentsply7.933(0.767)a7.430(0.451)b7.977(0.729)a8.186(0.929)aKetac-Cem3M Espe9.6206(0.613)a9.714(0.523)a9.298(0.314)b9.321(0.292)bMean (SD) powder/liquid ratio (m/m). Superscript letters represent significances (α = 0.05) within each material
Results: Mean (SD) (P/L) ratios are presented in the Table. Null hypothesis (a) is rejected: either (x1) or (x2) dispensation yields a different (P/L) ratio to (x3) or (x4) (p < 0.05). Null hypothesis (b) is rejected: a negative correlation is observed in max (P/L) ratio difference with dispensed multiple for Ketac Cem (p = 0.029).
Conclusion: For hand-mixed dental cements: (1) more consistent (P/L) ratios may be observed with multiple dispensations of powder & liquid; (2) maximum differences in (P/L) ratio may be negatively correlated with dispensation multiple in some materials.

Defining Democracy: Voting Procedures in Decision-making, Elections and Governance

Book Review: Emerson, Peter, Defining Democracy: Voting Procedures in Decision-making, Elections and
Governance (2nd edn), Springer, London, 2012,

Developing an information booklet to meet the needs of intensive care patients and relatives

Changes in the economic climate and the delivery of health care require that pre-operative information programmes are effective and efficiently implemented. In order to be effective the pre-operative programme must meet the information needs of intensive care unit (ICU) patients and their relatives. Efficiency can be achieved through a structured pre-operative programme which provides a framework for teaching. The need to develop an ICU information booklet in a large teaching hospital in Northern Ireland has become essential to provide relevant information and improve the quality of service for patients and relatives, as set out in the White Paper, ‘Working for Patients’, (DoH, 1989). The first step in establishing a patient education programme was to ascertain patients' and relatives' informational needs. A ‘needs assessment’ identified the pre-operative information needs of ICU patients and their relatives (McGaughey, 1994) and the findings were used to plan and publish an information booklet. The ICU booklet provides a structure for pre-operative visits to ensure that patients and relatives information needs are met.

Book review. Cartographies of Time: a history of the timeline.

A review of 'Cartographies of Time: a history of the timeline' by Daniel Rosenberg and Anthony Grafton. Princeton, NJ: Princeton Architectural Press, 2010. (272pp. ISBN: 9781568987637). Keywords: timeline, chronographics

EU water framework directive: will the nitrate load reduction from diffuse sources produce the same results in all estuaries?

The impact of urban waste-water and non-point nitrate discharges in estuarine and near-shore coastal waters are analyzed. The study is focused on the effects of applying the European directives 91/271/EEC and 91/676/EEC to these systems. 4 Portuguese estuaries and two coastal lagoons with different characteristics are studied. A modelling system is applied and calibrated in each system. Three nitrate load scenarios are examined. It is shown that the morphologic and hydrodynamic characteristics of the domain largely control the ecological processes in these systems. The primary production limitation factors are split into “biologic” and “hydrodynamic” components. The physical limitation due to hydrodynamic and residence time is the most important factor. The combined limitation of “biologic” factors (temperature, light and nutrients availability) control productivity only in the systems where physical limitation is not important.

Avaliação e gestão do desempenhos dos professores

Tese de dout., Psicologia, Faculdade de Ciências Humanas e Sociais, Universidade do Algarve, 2005

Primary production in systems subject to natural and anthropogenic eutrophication

Tese dout., Química, Universidade do Algarve, 2005

Entscheidungshilfe bei Internationalisierungsstrategien in der Nutzfahrzeugindustrie durch Competitive Intelligence - am Anwendungsbeispiel Afrika

Die nachhaltige Verschiebung der Wachstumsmärkte in Richtung Emerging Markets (und hier insbesondere in die BRIC-Staaten) infolge der Wirtschaftskrise 2008/2009 hat die bereits weit reichend konsolidierte Nutzfahrzeugindustrie der Triadenmärkte in Nordamerika, Europa und Japan vor eine Vielzahl von Herausforderungen gestellt. Strategische Ziele wie die Festigung und Steigerung von Absatzvolumina sowie eine bessere Ausbalancierung von zyklischen Marktentwicklungen, die die Ertragssicherung und eine weitestgehend kontinuierliche Auslastung existenter Kapazitäten sicherstellen soll, sind in Zukunft ohne eine Marktbearbeitung in den ex-Triade Wachstumsmärkten kaum noch erreichbar. Dies verlangt eine Auseinandersetzung der betroffenen Unternehmen mit dem veränderten unternehmerischen Umfeld. Es gilt neue, bisher größtenteils unbekannte Märkte zu erobern und sich dabei neuen – teilweise ebenfalls wenig bekannten - Wettbewerbern und deren teilweise durchaus unkonventionellen Strategien zu stellen. Die Triade-Unternehmen sehen sich dabei Informationsdefiziten und einer zunehmenden Gesamtkomplexität ausgesetzt, die zu für sie zu nachteiligen und ungünstigen nformationsasymmetrien führen können. Die Auswirkungen, dieser Situation unangepasst gegenüberzutreten wären deutlich unsicherheits- und risikobehaftetere Marktbearbeitungsstrategien bzw. im Extremfall die Absenz von Internationalisierungsaktivitäten in den betroffenen Unternehmen. Die Competitive Intelligence als Instrument zur unternehmerischen Umfeldanalyse kann unterstützen diese negativen Informationsasymmetrien zu beseitigen aber auch für das Unternehmen günstige Informationsasymmetrien in Form von Informationsvorsprüngen generieren, aus denen sich Wettbewerbsvorteile ableiten lassen. Dieser Kontext Competitive Intelligence zur Beseitigung von Informationsdefiziten bzw. Schaffung von bewussten, opportunistischen Informationsasymmetrien zur erfolgreichen Expansion durch Internationalisierungsstrategien in den Emerging Markets wird im Rahmen dieses Arbeitspapieres durch die Verbindung von wissenschaftstheoretischen und praktischen Implikationen näher beleuchtet. Die sich aus dem beschriebenen praktischen Anwendungsbeispiel Competitive intelligence für afrikanische Marktbearbeitung ergebenden Erkenntnisse der erfolgreichen Anwendung von Competitive Intelligence als Entscheidungshilfe für Internationalisierungsstrategien sind wie folgt angelegt: - Erweiterung der Status-quo, häufig Stammmarkt-zentristisch angelegten Betrachtungsweisen von Märkten und Wettbewerbern in Hinblick auf das reale Marktgeschehen oder Potentialmärkte - bias-freie Clusterung von Märkten bzw. Wettbewerbern, oder Verzicht auf den Versuch der Simplifizierung durch Clusterbildung - differenzierte Datenerhebungsverfahren wie lokale vs. zentrale / primäre vs. sekundäre Datenerhebung für inhomogene, unterentwickelte oder sich entwickelnde Märkte - Identifizierung und Hinzuziehung von Experten mit dem entscheidenden Wissensvorsprung für den zu bearbeitenden Informationsbedarf - Überprüfung der Informationen durch Datentriangulation

Before identity, gender and human rights

This is the beginning of an exploration of before as the thesis ‘before’ (temporally) and ‘be-fore’ (spatially) difference. Before denotes the origin and the desired destination. Before (in the double sense of ‘before’ and ‚be-in-the-fore’) opens up a space of pre-difference, of origin and of forgotten memory, as well as a space of desire, objective, illusion of teleology, unity, completion. Applied to the two domains of Human Rights and Sex/Gender, the space of ‘before’ yields two slightly different vistas: in human rights, a premodern, functionally undifferentiated society which had to invent human rights as its safeguards of functional differentiation. In Sex/Gender, 'before' brings a self-referential construction: that of ipseity, as the form of identity beyond comparison that does not play with id but with ipsum. Ipseity is inoperable but not useless. It is inoperable because it cannot be observed from anywhere without suffering rupture. It is not useless because it offers a ground for the reconceptualisation of difference, both through awe and desire.