Learning from failure--rationale and design for a study about discontinuation of randomized trials (DISCO study)

Background Randomized controlled trials (RCTs) may be discontinued because of apparent harm, benefit, or futility. Other RCTs are discontinued early because of insufficient recruitment. Trial discontinuation has ethical implications, because participants consent on the premise of contributing to new medical knowledge, Research Ethics Committees (RECs) spend considerable effort reviewing study protocols, and limited resources for conducting research are wasted. Currently, little is known regarding the frequency and characteristics of discontinued RCTs. Methods/Design Our aims are, first, to determine the prevalence of RCT discontinuation for specific reasons; second, to determine whether the risk of RCT discontinuation for specific reasons differs between investigator- and industry-initiated RCTs; third, to identify risk factors for RCT discontinuation due to insufficient recruitment; fourth, to determine at what stage RCTs are discontinued; and fifth, to examine the publication history of discontinued RCTs. We are currently assembling a multicenter cohort of RCTs based on protocols approved between 2000 and 2002/3 by 6 RECs in Switzerland, Germany, and Canada. We are extracting data on RCT characteristics and planned recruitment for all included protocols. Completion and publication status is determined using information from correspondence between investigators and RECs, publications identified through literature searches, or by contacting the investigators. We will use multivariable regression models to identify risk factors for trial discontinuation due to insufficient recruitment. We aim to include over 1000 RCTs of which an anticipated 150 will have been discontinued due to insufficient recruitment. Discussion Our study will provide insights into the prevalence and characteristics of RCTs that were discontinued. Effective recruitment strategies and the anticipation of problems are key issues in the planning and evaluation of trials by investigators, Clinical Trial Units, RECs and funding agencies. Identification and modification of barriers to successful study completion at an early stage could help to reduce the risk of trial discontinuation, save limited resources, and enable RCTs to better meet their ethical requirements.

Pathogenesis of pulmonary edema: learning from high-altitude pulmonary edema

Pulmonary edema is a problem of major clinical importance resulting from a persistent imbalance between forces that drive water into the airspace of the lung and the biological mechanisms for its removal. Here, we will review the fundamental mechanisms implicated in the regulation of alveolar fluid homeostasis. We will then describe the perturbations of pulmonary fluid homeostasis implicated in the pathogenesis of pulmonary edema in conditions associated with increased pulmonary capillary pressure, namely cardiogenic pulmonary edema and high-altitude pulmonary edema (HAPE), with particular emphasis on the latter that has provided important new insight into underlying mechanisms of pulmonary edema. We will provide evidence that impaired pulmonary endothelial and epithelial nitric oxide synthesis and/or bioavailability may represent a central underlying defect predisposing to exaggerated hypoxic pulmonary vasoconstriction, and, in turn, capillary stress failure and alveolar fluid flooding. We will then demonstrate that exaggerated pulmonary hypertension, while possibly a prerequisite, may not always be sufficient to cause HAPE, and how defective alveolar fluid clearance may represent a second important pathogenic mechanism. Finally, we will outline, how this new insight gained from studies in HAPE, may be translated into the management of pulmonary edema and hypoxemia related disease states in general.

From text to codings: intercoder reliability assessment in qualitative content analysis

BACKGROUND: High intercoder reliability (ICR) is required in qualitative content analysis for assuring quality when more than one coder is involved in data analysis. The literature is short of standardized procedures for ICR procedures in qualitative content analysis. OBJECTIVE: To illustrate how ICR assessment can be used to improve codings in qualitative content analysis. METHODS: Key steps of the procedure are presented, drawing on data from a qualitative study on patients' perspectives on low back pain. RESULTS: First, a coding scheme was developed using a comprehensive inductive and deductive approach. Second, 10 transcripts were coded independently by two researchers, and ICR was calculated. A resulting kappa value of .67 can be regarded as satisfactory to solid. Moreover, varying agreement rates helped to identify problems in the coding scheme. Low agreement rates, for instance, indicated that respective codes were defined too broadly and would need clarification. In a third step, the results of the analysis were used to improve the coding scheme, leading to consistent and high-quality results. DISCUSSION: The quantitative approach of ICR assessment is a viable instrument for quality assurance in qualitative content analysis. Kappa values and close inspection of agreement rates help to estimate and increase quality of codings. This approach facilitates good practice in coding and enhances credibility of analysis, especially when large samples are interviewed, different coders are involved, and quantitative results are presented.

Sustainable Wastewater Management: Is it Possible to Regulate Micropollution in the Future by Learning from the Past? A Policy Analysis

This paper applies a policy analysis approach to the question of how to effectively regulate micropollution in a sustainable manner. Micropollution is a complex policy problem characterized by a huge number and diversity of chemical substances, as well as various entry paths into the aquatic environment. It challenges traditional water quality management by calling for new technologies in wastewater treatment and behavioral changes in industry, agriculture and civil society. In light of such challenges, the question arises as to how to regulate such a complex phenomenon to ensure water quality is maintained in the future? What can we learn from past experiences in water quality regulation? To answer these questions, policy analysis strongly focuses on the design and choice of policy instruments and the mix of such measures. In this paper, we review instruments commonly used in past water quality regulation. We evaluate their ability to respond to the characteristics of a more recent water quality problem, i.e., micropollution, in a sustainable way. This way, we develop a new framework that integrates both the problem dimension (i.e., causes and effects of a problem) as well as the sustainability dimension (e.g., long-term, cross-sectoral and multi-level) to assess which policy instruments are best suited to regulate micropollution. We thus conclude that sustainability criteria help to identify an appropriate instrument mix of end-of-pipe and source-directed measures to reduce aquatic micropollution.

Spatio-Temporal Credit Assignment in Neuronal Population Learning

n learning from trial and error, animals need to relate behavioral decisions to environmental reinforcement even though it may be difficult to assign credit to a particular decision when outcomes are uncertain or subject to delays. When considering the biophysical basis of learning, the credit-assignment problem is compounded because the behavioral decisions themselves result from the spatio-temporal aggregation of many synaptic releases. We present a model of plasticity induction for reinforcement learning in a population of leaky integrate and fire neurons which is based on a cascade of synaptic memory traces. Each synaptic cascade correlates presynaptic input first with postsynaptic events, next with the behavioral decisions and finally with external reinforcement. For operant conditioning, learning succeeds even when reinforcement is delivered with a delay so large that temporal contiguity between decision and pertinent reward is lost due to intervening decisions which are themselves subject to delayed reinforcement. This shows that the model provides a viable mechanism for temporal credit assignment. Further, learning speeds up with increasing population size, so the plasticity cascade simultaneously addresses the spatial problem of assigning credit to synapses in different population neurons. Simulations on other tasks, such as sequential decision making, serve to contrast the performance of the proposed scheme to that of temporal difference-based learning. We argue that, due to their comparative robustness, synaptic plasticity cascades are attractive basic models of reinforcement learning in the brain.

Retraining of interjoint arm coordination after stroke using robot-assisted time-independent functional training

We have developed a haptic-based approach for retraining of interjoint coordination following stroke called time-independent functional training (TIFT) and implemented this mode in the ARMin III robotic exoskeleton. The ARMin III robot was developed by Drs. Robert Riener and Tobias Nef at the Swiss Federal Institute of Technology Zurich (Eidgenossische Technische Hochschule Zurich, or ETH Zurich), in Zurich, Switzerland. In the TIFT mode, the robot maintains arm movements within the proper kinematic trajectory via haptic walls at each joint. These arm movements focus training of interjoint coordination with highly intuitive real-time feedback of performance; arm movements advance within the trajectory only if their movement coordination is correct. In initial testing, 37 nondisabled subjects received a single session of learning of a complex pattern. Subjects were randomized to TIFT or visual demonstration or moved along with the robot as it moved though the pattern (time-dependent [TD] training). We examined visual demonstration to separate the effects of action observation on motor learning from the effects of the two haptic guidance methods. During these training trials, TIFT subjects reduced error and interaction forces between the robot and arm, while TD subject performance did not change. All groups showed significant learning of the trajectory during unassisted recall trials, but we observed no difference in learning between groups, possibly because this learning task is dominated by vision. Further testing in stroke populations is warranted.

Knowledge Management and Decision Support for Sustainable Land Management

Much research has focused on desertification and land degradation assessments without putting sufficient emphasis on prevention and mitigation, although the concept of sustainable land management (SLM) is increasingly being acknowledged. A variety of SLM measures have already been applied at the local level, but they are rarely adequately recognised, evaluated, shared or used for decision support. WOCAT (World Overview of Technologies and Approaches) has developed an internationally recognised, standardised methodology to document and evaluate SLM technologies and approaches, including spatial distribution, allowing the sharing of SLM knowledge worldwide. The recent methodological integration into a participatory process allows now analysing and using this knowledge for decision support at the local and national level. The use of the WOCAT tools stimulates evaluation (self-evaluation as well as learning from comparing experiences) within SLM initiatives where all too often there is not only insufficient monitoring but also a lack of critical analysis. The comprehensive questionnaires and database system facilitate to document, evaluate and disseminate local experiences of SLM technologies and their implementation approaches. This evaluation process - in a team of experts and together with land users - greatly enhances understanding of the reasons behind successful (or failed) local practices. It has now been integrated into a new methodology for appraising and selecting SLM options. The methodology combines a local collective learning and decision approach with the use of the evaluated global best practices from WOCAT in a concise three step process: i) identifying land degradation and locally applied solutions in a stakeholder learning workshop; ii) assessing local solutions with the standardised WOCAT tool; iii) jointly selecting promising strategies for implementation with the help of a decision support tool. The methodology has been implemented in various countries and study sites around the world mainly within the FAO LADA (Land Degradation Assessment Project) and the EU-funded DESIRE project. Investments in SLM must be carefully assessed and planned on the basis of properly documented experiences and evaluated impacts and benefits: concerted efforts are needed and sufficient resources must be mobilised to tap the wealth of knowledge and learn from SLM successes.

Mainstreaming a Decade's Experiences in Watershed Management to Meet the Challenges of Environmental Change in the Hindu Kush-Himalayas

Like other mountain areas in the world, the Hindu Kush-Himalayan (HKH) region is particularly vulnerable to climate change. Ongoing climate change processes are projected to have a high impact on the HKH region, and accelerated warming has been reported in the Himalayas. These climate change impacts will be superimposed on a variety of other environmental and social stresses, adding to the complexity of the issues. The sustainable use of natural resources is crucial to the long-term stability of the fragile mountain ecosystems in the HKH and to sustain the socio-ecological resilience that forms the basis of sustainable livelihoods in the region. In order to be prepared for these challenges, it is important to take stock of previous research. The ‘People and Resource Dynamics Project’ (PARDYP), implemented by International Centre for Integrated Mountain Development (ICIMOD), provides a variety of participatory options for sustainable land management in the HKH region. The PARDYD project was a research for development project that operated in five middle mountain watersheds across the HKH – two in Nepal and one each in China, India, and Pakistan. The project ran from 1996 to 2006 and focused on addressing the marginalisation of mountain farmers, the use and availability of water, issues relating to land and forest degradation and declining soil fertility, the speed of regeneration of degraded land, and the ability of the natural environment to support the growing needs of the region’s increasing population. A key learning from the project was that the opinion of land users is crucial to the acceptance (and, therefore, successful application) of new technologies and approaches. A major challenge at the end of every project is to promote knowledge sharing and encourage the cross-fertilization of ideas (e.g., in the case of PARDYP, with other middle mountain inhabitants and practitioners in the region) and to share lessons learned with a wider audience. This paper will highlight how the PARDYP findings, including ways of addressing soil fertility and water scarcity, have been mainstreamed in the HKH region through capacity building (international, regional, and national training courses), networking, and the provision of backstopping services. In addition, in view of the challenges in watershed management in the HKH connected to environmental change, the lessons learned from the PARDYP are now being used by ICMOD to define and package climate change proof technology options to address climate change adaptation.

Taking up national safety alerts to improve patient safety in hospitals: The perspective of healthcare quality and risk managers.

BACKGROUND National safety alert systems publish relevant information to improve patient safety in hospitals. However, the information has to be transformed into local action to have an effect on patient safety. We studied three research questions: How do Swiss healthcare quality and risk managers (qm/rm(1)) see their own role in learning from safety alerts issued by the Swiss national voluntary reporting and analysis system? What are their attitudes towards and evaluations of the alerts, and which types of improvement actions were fostered by the safety alerts? METHODS A survey was developed and applied to Swiss healthcare risk and quality managers, with a response rate of 39 % (n=116). Descriptive statistics are presented. RESULTS The qm/rm disseminate and communicate with a broad variety of professional groups about the alerts. While most respondents felt that they should know the alerts and their contents, only a part of them felt responsible for driving organizational change based on the recommendations. However, most respondents used safety alerts to back up their own patient safety goals. The alerts were evaluated positively on various dimensions such as usefulness and were considered as standards of good practice by the majority of the respondents. A range of organizational responses was applied, with disseminating information being the most common. An active role is related to using safety alerts for backing up own patient safety goals. CONCLUSIONS To support an active role of qm/rm in their hospital's learning from safety alerts, appropriate organizational structures should be developed. Furthermore, they could be given special information or training to act as an information hub on the issues discussed in the alerts.

The Role for Virtual Patients in the Future of Medical Education

The medical education community is working-across disciplines and across the continuum-to address the current challenges facing the medical education system and to implement strategies to improve educational outcomes. Educational technology offers the promise of addressing these important challenges in ways not previously possible. The authors propose a role for virtual patients (VPs), which they define as multimedia, screen-based interactive patient scenarios. They believe VPs offer capabilities and benefits particularly well suited to addressing the challenges facing medical education. Well-designed, interactive VP-based learning activities can promote the deep learning that is needed to handle the rapid growth in medical knowledge. Clinically oriented learning from VPs can capture intrinsic motivation and promote mastery learning. VPs can also enhance trainees' application of foundational knowledge to promote the development of clinical reasoning, the foundation of medical practice. Although not the entire solution, VPs can support competency-based education. The data created by the use of VPs can serve as the basis for multi-institutional research that will enable the medical education community both to better understand the effectiveness of educational interventions and to measure progress toward an improved system of medical education.