Treatment switching in cancer trials: Issues and proposals

Objectives: Treatment switching occurs when patients in a randomized clinical trial switch from the treatment initially assigned to them to another treatment, typically from the control to experimental treatment. This study discusses the issues this raises and possible approaches to addressing them in trials of cancer drugs. Methods: Stakeholders from around the world were invited to a 1.5-day Workshop in Adelaide, Australia. This study attempts to capture the key points from the discussion and the perspectives of the various stakeholder groups, but is not a formal consensus statement. Results: Treatment switching raises challenging ethical issues with arguments for and against allowing it. It is increasingly common in cancer drug trials and presents challenges for the interpretation of results by regulators, clinicians, patients, and payers. Proposals are offered for good practice in the design, management, and analysis of trials and wider development programs for cancer drugs in which treatment switching has occurred or is likely to. Recommendations are also offered for further action to improve understanding of the importance and challenges of treatment switching and to promote agreement between key stakeholders on guidelines and other steps to address these challenges. Conclusions: The handling of treatment switching in trials is of concern to all stakeholders. On the basis of the discussions at the Adelaide International Workshop, there would appear to be common ground on approaches to addressing treatment switching in cancer trials and scope for the development of formal guidelines to inform the work of regulators, payers, industry, trial designers and other stakeholders

Impact Exercise Increases BMC During Growth: An 8-Year Longitudinal Study

Our aim was to assess BMC of the hip over 8 yr in prepubertal children who participated in a 7-mo jumping intervention compared with controls who participated in a stretching program of equal duration. We hypothesized that jumpers would gain more BMC than control subjects. The data reported come from two cohorts of children who participated in separate, but identical, randomized, controlled, school-based impact exercise interventions and reflect those subjects who agreed to long-term follow-up (N = 57; jumpers = 33, controls = 24; 47% of the original participants). BMC was assessed by DXA at baseline, 7 and 19 mo after intervention, and annually thereafter for 5 yr (eight visits over 8 yr). Multilevel random effects models were constructed and used to predict change in BMC from baseline at each measurement occasion. After 7 mo, those children that completed high-impact jumping exercises had 3.6% more BMC at the hip than control subjects whom completed nonimpact stretching activities (p \u3c 0.05) and 1.4% more BMC at the hip after nearly 8 yr (BMC adjusted for change in age, height, weight, and physical activity; p \u3c 0.05). This provides the first evidence of a sustained effect on total hip BMC from short-term high-impact exercise undertaken in early childhood. If the benefits are sustained into young adulthood, effectively increasing peak bone mass, fracture risk in the later years could be reduced

Barriers to colonoscopy in UK colorectal cancer screening programmes: Qualitative interviews with ethnic minority groups

OBJECTIVE: People from ethnic minority backgrounds are less likely to attend colonoscopy, following faecal immunochemical test screening, and are more likely to be diagnosed with colorectal cancer at an advanced stage as a result. The aim of this research was to explore the barriers and facilitators to attending colonoscopy, perceived by ethnic minority groups living in the United Kingdom. METHODS: Semi-structured online and telephone interviews were conducted with thirty men and women of Black-African(n=5), Black-Caribbean(n=5), South Asian(n=10) and White British(n=10) descent. Participants were eligible for screening, but had not necessarily been invited for colonoscopy. All interviews were conducted in the participant's first language and were assessed using Framework-analysis, in line with a conceptual framework developed from previous interviews with healthcare professionals. RESULTS: Five thematic groups of barriers and facilitators were developed: 'Locus of control', 'Cultural attitudes and beliefs', 'Individual beliefs, knowledge and personal experiences with colonoscopy and cancer', 'Reliance on family and friends' and 'Health concerns'. Differences were observed, between ethnic groups, for: 'Locus of control', 'Cultural attitudes and beliefs' and 'Reliance on family and friends'. Black and South Asian participants frequently described the decision to attend colonoscopy as lying with 'God' (Muslims, specifically), 'the doctor', or 'family' (Locus of control). Black and South Asian participants also reported relying on friends and family for 'language, transport and emotional support' (Reliance on family and friends). Black-African participants, specifically, described cancer as 'socially taboo' (Cultural attitudes and beliefs). CONCLUSIONS: The results highlight several targets for culturally-tailored interventions to make colonoscopy more equitable. This article is protected by copyright. All rights reserved

What do coaches orchestrate? Unravelling the 'quiddity' of practice

The general purpose of this article is threefold. Firstly, it is to further the notion of coaching as orchestration through developing insight into precisely how and what coaches orchestrate. Secondly, it is to firmly position coaching as a relational practice, whilst thirdly it is to better define coaching’s complex nature and how it can be somewhat ordered. Following an introduction where the purpose and value of the paper are outlined, we present the reflective method of critical companionship through which we explored and addressed the aforementioned purposes. The case for the quiddity, or the 'just whatness' (i.e., the inherent nature or essence) of coaching as involving complex, relational acts which can be somewhat explained through recourse to the developing theory of orchestration is subsequently made. In doing so, two precise examples of how we as coaches orchestrate sporting practice are presented. The paper concludes with both a summary of the principal argument(s) made, and some reflective considerations for future directions

Activity theory, complexity and sports coaching: An epistemology for a discipline

The aim of this article is two-fold. Firstly, it is to advance the case for Activity Theory (AT) as a credible and alternative lens to view and research sports coaching. Secondly, it is to position this assertion within the wider debate about the epistemology of coaching. Following a framing introduction, a more comprehensive review of the development and current conceptualisation of AT is given. Here, AT’s evolution through three distinct phases and related theorists, namely Vygotsky, Leont’ev and Engeström, is initially traced. This gives way to a more detailed explanation of AT’s principal conceptual components, including ‘object’, ‘subject’, ‘tools’ (mediating artefacts), ‘rules’, a ‘community’ and a ‘division of labour’. An example is then presented from empirical work illustrating how AT can be used as a means to research sports coaching. The penultimate section locates such thinking within coaching’s current ‘epistemological debate; arguing that the coaching ‘self’ is not an autonomous individual, but a relative part of social and cultural arrangements. Finally, a conclusion summarises the main points made, particularly in terms in presenting the grounding constructivist epistemology of AT as a potential way forward for sports coaching

“Cultural Security Is an On-Going Journey … ” Exploring Views from Staff Members on the Quality and Cultural Security of Services for Aboriginal Families in Western Australia

Cultural security is a key element of accessible services for Indigenous peoples globally, although few studies have examined this empirically. We explored the scope, reach, quality, and cultural security of health and social services available to Aboriginal and/or Torres Strait Islander families in Western Australia (WA), from the point of view of staff from the services. We recruited staff from health and social services for Aboriginal people in the Perth, Kalgoorlie, Great Southern, and South West regions of WA between December 2015 and September 2017 to complete online surveys. We examined the proportions of participants that responded saying the service was culturally secure, the reasons for the response, and perceived factors related to a high-quality service. Sixty participants from 21 services responded to the survey. Seventy-three percent stated the service was culturally secure; however, only 36% stated that the staff employed at the service had sufficient knowledge on cultural security. Participants suggested having Aboriginal staff and better cultural awareness training as methods to improve cultural security within the service. Participants highlighted that staffing, funding for resources, and patient financial difficulties in accessing care as key areas for quality improvement. Much greater effort is required in improving knowledge through on-going training of staff in the practice of culturally safe care. Organisations must also be required to meet specific standards in cultural safety

The under-ice microbiome of seasonally frozen lakes

Compared to the well-studied open water of the “growing” season, under-ice conditions in lakes are characterized by low and rather constant temperature, slow water movements, limited light availability, and reduced exchange with the surrounding landscape. These conditions interact with ice-cover duration to shape microbial processes in temperate lakes and ultimately influence the phenology of community and ecosystem processes. We review the current knowledge on microorganisms in seasonally frozen lakes. Specifically, we highlight how under-ice conditions alter lake physics and the ways that this can affect the distribution and metabolism of auto- and heterotrophic microorganisms. We identify functional traits that we hypothesize are important for understanding under-ice dynamics and discuss how these traits influence species interactions. As ice coverage duration has already been seen to reduce as air temperatures have warmed, the dynamics of the under-ice microbiome are important for understanding and predicting the dynamics and functioning of seasonally frozen lakes in the near future

A Knowledge Brokering Framework for Integrated Landscape Management

Sustainable land management is at the heart of some of the most intractable challenges facing humanity in the 21st century. It is critical for tackling biodiversity loss, land degradation, climate change and the decline of ecosystem services. It underpins food production, livelihoods, dietary health, social equity, climate change adaptation, and many other outcomes. However, interdependencies, trade-offs, time lags, and non-linear responses make it difficult to predict the combined effects of land management decisions. Policy decisions also have to be made in the context of conflicting interests, values and power dynamics of those living on the land and those affected by the consequences of land use decisions. This makes designing and coordinating effective land management policies and programmes highly challenging. The difficulty is exacerbated by the scarcity of reliable data on the impacts of land management on the environment and livelihoods. This poses a challenge for policymakers and practitioners in governments, development banks, non-governmental organisations, and other institutions. It also sets demands for researchers, who are under ever increasing pressure from funders to demonstrate uptake and impact of their work. Relatively few research methods exist that can address such questions in a holistic way. Decision makers and researchers need to work together to help untangle, contextualise and interpret fragmented evidence through systems approaches to make decisions in spite of uncertainty. Individuals and institutions acting as knowledge brokers can support these interactions by facilitating the co-creation and use of scientific and other knowledge. Given the patchy nature of data and evidence, particularly in developing countries, it is important to draw on the full range of available models, tools and evidence. In this paper we review the use of evidence to inform multiple-objective integrated landscape management policies and programmes, focusing on how to simultaneously achieve different sustainable development objectives in diverse landscapes. We set out key success factors for evidence-based decision-making, which are summarised into 10 key principles for integrated landscape management knowledge brokering in integrated landscape management and 12 key skills for knowledge brokers. We finally propose a decision-support framework to organise evidence that can be used to tackle different types of land management policy decision

GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of Linerixibat in Primary Biliary Cholangitis Patients With Pruritus

Background & aims: GLIMMER assessed dose-response, efficacy, and safety of linerixibat, an ileal bile acid transporter inhibitor in development for cholestatic pruritus associated with primary biliary cholangitis (PBC). Methods: GLIMMER was a Phase 2b, multicenter, randomized, parallel-group study in adults with PBC and moderate-to-severe pruritus (≥4 on 0-10 numerical rating scale [NRS]). After 4 weeks of single-blind placebo, patients with NRS ≥3 were randomized (4:1) to double-blind linerixibat/placebo for 12 weeks (to week 16), followed by single-blind placebo (to week 20). The primary objective was to investigate dose-related changea in mean worst daily itch (MWDI) score. Results: One hundred forty-seven patients received placebo (n = 36) or linerixibat (once daily: 20 mg, n = 16; 90 mg, n = 23; 180 mg, n = 27; twice daily: 40 mg, n = 23; 90 mg, n = 22). Linerixibat groups exhibited ≥2-point mean reductions in MWDI from baseline at week 16; however, differences from placebo were not significant. Post hoc analysis of change from baseline in monthly itch score over the treatment period (Phase 3 endpoint) showed significant differences between placebo and linerixibat 180 mg once daily (P = .0424), 40 mg twice daily (P = .0105), and 90 mg twice daily (P = .0370). A significant relationship between total daily dose and response was observed post hoc in the per protocol population (P = .0542). Consistent with mechanism of action, diarrhea was the most frequent adverse event, and incidence increased with dose. Conclusions: Linerixibat effect on itch was not significantly different versus placebo in the primary intent-to-treat analysis but was associated with a significant dose-dependent reduction in itch in the per protocol population. A well-tolerated dose was identified for Phase 3 investigation for cholestatic pruritus in PBC. Clinicaltrials: gov ID: NCT02966834. Keywords: Bile Acids; Cholestatic Pruritus; Clinical Trial; IBAT Inhibitor; Patient-Reported Outcomes