Modelling PK/QT relationships from Phase I dose‐escalation trials for drug combinations and developing quantitative risk assessments of clinically relevant QT prolongations

In current industry practice, it is difficult to assess QT effects at potential therapeutic doses based on Phase I dose‐escalation trials in oncology due to data scarcity, particularly in combinations trials. In this paper, we propose to use dose‐concentration and concentration‐QT models jointly to model the exposures and effects of multiple drugs in combination. The fitted models then can be used to make early predictions for QT prolongation to aid choosing recommended dose combinations for further investigation. The models consider potential correlation between concentrations of test drugs and potential drug–drug interactions at PK and QT levels. In addition, this approach allows for the assessment of the probability of QT prolongation exceeding given thresholds of clinical significance. The performance of this approach was examined via simulation under practical scenarios for dose‐escalation trials for a combination of two drugs. The simulation results show that invaluable information of QT effects at therapeutic dose combinations can be gained by the proposed approaches. Early detection of dose combinations with substantial QT prolongation is evaluated effectively through the CIs of the predicted peak QT prolongation at each dose combination. Furthermore, the probability of QT prolongation exceeding a certain threshold is also computed to support early detection of safety signals while accounting for uncertainty associated with data from Phase I studies. While the prediction of QT effects is sensitive to the dose escalation process, the sensitivity and limited sample size should be considered when providing support to the decision‐making process for further developing certain dose combinations. Copyright © 2016 John Wiley & Sons, Ltd.     

Linear Increments with Non‐monotone Missing Data and Measurement Error

Linear increments (LI) are used to analyse repeated outcome data with missing values. Previously, two LI methods have been proposed, one allowing non‐monotone missingness but not independent measurement error and one allowing independent measurement error but only monotone missingness. In both, it was suggested that the expected increment could depend on current outcome. We show that LI can allow non‐monotone missingness and either independent measurement error of unknown variance or dependence of expected increment on current outcome but not both. A popular alternative to LI is a multivariate normal model ignoring the missingness pattern. This gives consistent estimation when data are normally distributed and missing at random (MAR). We clarify the relation between MAR and the assumptions of LI and show that for continuous outcomes multivariate normal estimators are also consistent under (non‐MAR and non‐normal) assumptions not much stronger than those of LI. Moreover, when missingness is non‐monotone, they are typically more efficient.     

Urban ecosystem Services in Latin America: mismatch between global concepts and regional realities?

Urban Ecosystems - Latin America and the Caribbean (LAC) is one of the most urbanized and biologically diverse regions in the world but is often characterized by weak environmental governance and...     

Advertising ‘Happy’ Children: The Settler Family,Happiness and the Indigenous Child Removal System

We analyse 4300 advertisements of children featured in the Today's Child column, a daily written by Helen Allen in The Toronto Telegram and The Toronto Star from 1964 to 1982, to understand how the Canadian public became accepting of the adoption of Indigenous children. While children of all ethnic backgrounds were featured, the Indigenous children who were displayed were part of a larger system of child removal, known as the ‘Sixties Scoop’. We demonstrate the ways Indigenous children are described with a specific form of happiness that is conjoined with colonial conceptions of the family and nation.     

Protecting and Benchmarking Migrants’ Rights: An Analysis of the Global Compact for Safe,Orderly and Regular Migration

The Global Compact for Safe, Orderly, and Regular Migration (GCM) was to be “guided by human rights law and standards” in recognition of the rights of international migrants, who are currently protected by an overlapping patchwork of treaties and international law. The GCM contains many laudable commitments that, if implemented, will ensure that states more consistently respect, protect, and fulfil the rights of all migrants and also that states incorporate data on migration into a more cohesive governance regime that does more to promote cooperation on the issue of international migration. However, many concerns remain. Using a legal analysis and cross‐national policy data, we find that the GCM neither fully articulates existing law nor makes use of international consensus to expand the rights of migrants. In its first section, this article provides a concise analysis of the GCM's compliance with a set of core principles of existing international human rights law regarding migrants. In the second section, we apply a novel instrument to create an objective, cross‐national accounting of the laws protecting migrants’ rights in various national legal frameworks. Focusing on a sample of five diverse destination and sending countries, the results suggest we are close to an international consensus on the protection of a core set of migrants’ rights. This analysis should help prioritize the work necessary to implement the GCM.     

100 key research questions for the post‐2015 development agenda

The Sustainable Development Goals (SDGs) herald a new phase for international development. This article presents the results of a consultative exercise to collaboratively identify 100 research questions of critical importance for the post‐2015 international development agenda. The final shortlist is grouped into nine thematic areas and was selected by 21 representatives of international and non‐governmental organisations and consultancies, and 14 academics with diverse disciplinary expertise from an initial pool of 704 questions submitted by 110 organisations based in 34 countries. The shortlist includes questions addressing long‐standing problems, new challenges and broader issues related to development policies, practices and institutions. Collectively, these questions are relevant for future development‐related research priorities of governmental and non‐governmental organisations worldwide and could act as focal points for transdisciplinary research collaborations.     

Betting Decision Under Break-Streak Pattern: Evidence from Casino Gaming

Cognitive bias is prevalent among gamblers, especially those with gambling problems. Grounded in the heuristics theories, this study contributes to the literature by examining a cognitive bias triggered by the break streak pattern in the casino setting. We postulate that gamblers tend to bet on the latest outcome when there is a break-streak pattern. Moreover, three determinants of the betting decision under break-streak pattern, including the streak length of the alternative outcome, the frequency of the latest outcome, and gender, were identified and examined in this study. A non-participatory observational study was conducted among the Cussec gamblers in a casino in Macao. An analysis of 1229 bets confirms our postulation, particularly when the streak of the alternative outcome is long, the latest outcome is frequent, and the gamblers are females. The findings provide meaningful implications for casino management and public policymakers regarding the minimization of gambling harm.     

Avian haemosporidian parasites in an urban forest and their relationship to bird size and abundance

Urbanization has been identified as a threat to biodiversity due to landscape modifications. Studies of parasite ecology in urbanized areas lagged behind those made on macro organisms. Here we studied infection prevalence of haemosporidian parasites in an avian community of an urban forest from Germany, and its relationship with bird abundance and body mass. We used PCR to amplify a fragment of the mtDNA cyt b gene to determine the infection status of birds, and bird point counts to determine bird relative abundances. The avifauna was dominated by two small sized insectivore passerines (Parus major, Cyanistes caeruleus), representing ~40 % of the total bird records. The highest haemosporidian prevalence was recorded for Turdus philomelos (100 %) and for Fringilla coelebs (75 %). Bird abundance and body mass were positively associated with infection status for two haemosporidian genera: Plasmodium and Leucocytozoon. Infection rate was lower in juveniles compared to adult birds. We recorded a total of 7 Plasmodium, 26 Haemoproteus, and 10 Leucocytozoon lineages. Avian malaria (P. relictum) was detected infecting 5 individuals of P. major, the most abundant species in the community. These results, together with those of previous studies at the same site, suggest that potentially any of the genetic haemosporidian lineages detected in this urban forest can be transmitted across native and pet bird species, and to species of conservation concern housed at aviaries.     

Peeking into the past to plan the future: Assessing bird species richness in a neotropical city

Urbanization has been considered as a major threat to biodiversity, making its ecology of increasing interest. Many urban ecology studies have been developed in a short time-scale, measuring real-time patterns. However, long-term studies are imperative to understand the responses of some species to the urbanization process. In this study, we aimed to assess the information provided by a recent one-year citywide bird survey when compared to a published ‘historical’ bird list of a neotropical city (Xalapa, Mexico) that compiles information of the past three decades, mainly from urban greenspaces. Specifically, we contrasted species richness values and assessed differences in species composition between both lists. We recorded 51 species in the one-year citywide survey, representing ~15 % of those reported in the historical list. Nonetheless, the upper-bound confidence interval of the citywide survey richness prediction represented ~66 %. Most of the species recorded in the one-year citywide survey are insectivores and granivores, a pattern that agrees with previous findings that underline the importance of insectivores as part of urban bird communities in the Neotropics. Although we used robust methods to compare our one-year citywide bird list and the historical list for the city of Xalapa, we acknowledge the limitations of comparing them. However, our results shed some light on the kind and type of information that one-year citywide surveys can provide and the importance of long-term studies for comprehending the processes involved in biodiversity changes within urban areas over time. Undoubtedly, establishing long-term citywide surveys sampling birds and other biodiversity groups will allow us to better understand the response of biodiversity to urbanization over time.