In a typical comparative clinical trial the randomization scheme is fixed at the beginning of the study, and maintained throughout the course of the trial. A number of researchers have championed a randomized trial design referred to as ‘outcome-adaptive randomization.’ In this type of trial, the likelihood of a patient being enrolled to a particular arm of the study increases or decreases as preliminary information becomes available suggesting that treatment may be superior or inferior. While (...) the design merits of outcome-adaptive trials have been debated, little attention has been paid to significant ethical concerns that arise in the conduct of such studies. These include loss of equipoise, lack of processes for adequate informed consent, and inequalities inherent in the research design which could lead to perceptions of injustice that may have negative implications for patients and the research enterprise. This article examines the ethical difficulties inherent in outcome-adaptive trials. (shrink)

Outcome-adaptive randomization (OAR) has been proposed as a corrective to certain ethical difficulties inherent in the traditional randomized clinical trial (RCT) using fixed-ratio randomization. In particular, it has been suggested that OAR redresses the balance between individual and collective ethics in favour of the former. In this paper, I examine issues of welfare and autonomy arising in relation to OAR. A central issue in discussions of welfare in OAR is equipoise, and the moral status of OAR is crucially influenced (...) by the way in which this concept is construed. If OAR is based on a model of equipoise that demands strict indifference between competing interventions throughout the trial, such equipoise is disturbed by accruing data favouring one treatment over another; OAR seeks to redress this by weighting randomization to the seemingly superior treatment. However, this is a partial response, as patients continue to be allocated to the inferior therapy. Moreover, it rests upon considerations of aggregate harms and benefits, and does not therefore uphold individual ethics. Issues of fairness also arise, as early and late enrollees are randomized on a different basis. Fixed-ratio randomization represents a fuller and more consistent response to a loss of equipoise, as so construed. With regard to consent, the complexity of OAR poses challenges to adequate disclosure and comprehension. Additionally, OAR does not offer a remedy to the therapeutic misconception—participants’ tendency to attribute treatment allocation in an RCT to individual clinical judgments, rather than to scientific considerations—and, if anything, accentuates rather than alleviates this misconception. In relation to these issues, OAR fails to offer ethical advantages over fixed-ratio randomization. More broadly, the ethical basis of OAR can be seen to lie more in collective than in individual ethics, and overall it fares worse in this territory than fixed-ratio randomization. (shrink)

BackgroundImplementation science research, especially when using participatory and co-design approaches, raises unique challenges for research ethics committees. Such challenges may be poorly addressed by approval and governance mechanisms that were developed for more traditional research approaches such as randomised controlled trials.DiscussionImplementation science commonly involves the partnership of researchers and stakeholders, attempting to understand and encourage uptake of completed or piloted research. A co-creation approach involves collaboration between researchers and end users from the onset, in question framing, research design (...) and delivery, and influencing strategy, with implementation and broader dissemination strategies part of its design from gestation. A defining feature of co-creation is its emergent and adaptive nature, making detailed pre-specification of interventions and outcome measures impossible. This methodology sits oddly with ethics committee protocols that require precise pre-definition of interventions, mode of delivery, outcome measurements, and the role of study participants. But the strict requirements of ethics committees were developed for a purpose – to protect participants from harm and help ensure the rigour and transparency of studies. We propose some guiding principles to help square this circle. First, ethics committees should acknowledge and celebrate the diversity of research approaches, both formally and informally ; without active support, their members may not understand or value participatory designs. Second, ground rules should be established for co-design applications and communicated to committee members and stakeholders. Third, the benefits of power-sharing should be recognised and credit given to measures likely to support this important goal, especially in research with vulnerable communities. Co-design is considered best practice, for example, in research involving indigenous peoples in New Zealand, Australia and Canada. (shrink)

Key messages The research environment has changed since clinical equipoise was first proposed 30 years ago New trial designs—such as umbrella and basket trials, adaptive platform trials, and cluster randomised trials—raise new ethical challenges for evaluating the state of scientific uncertainty and communicating about risks with patients and participants Clinical equipoise needs to evolve We propose the design of specific guidelines to provide ethics committees and trialists with instructions for how to evaluate equipoise in the context of new (...) designs and biomarkers and how to optimise communication with participants. (shrink)

Background: Chronic Pain (CP) has serious medical and social consequences, and leads to economic burden that threatens the sustainability of healthcare services. Thus, optimized management of pain tools to support CP patients in adjusting to their condition and improving quality of life is timely. Although Acceptance and Commitment Therapy (ACT) is considered an evidence-based psychological approach for CP, evidence for the efficacy of online-delivered ACT for CP is still scarce. At the same time, studies suggest that self-compassion mediates the change (...) in disability and psychopathological symptoms in ACT interventions for CP, although self-compassion is not a specific target in ACT. Thus, an explicit focus on self-compassion might increase the efficacy of ACT interventions for CP, although this hypothesis has not been tested. This study aims to develop an eHealth ACT and compassion-based self-management intervention for CP, the iACTwithPain, and to compare its efficacy in improving health outcomes to a similar ACT-only intervention and a waiting list group. Methods: The eHealth platform that will host the interventions will be developed using a flat design identity and will be interactive. The iACTwithPain intervention will comprise 8 weekly self-management sessions, and will be developed taking into consideration the psychological flexibility model applied to CP, with the addition of explicit compassion-based components. To analyse whether the iACTwithPain intervention will present superiority in improving CP’s impact and related health markers over the two other conditions, this study will follow a RCT design with three arms. CP patients will be recruited through direct contact with patient associations and healthcare services and a national press release in Portugal. Outcome measurement will be conducted at baseline, post-intervention and at 3- and 6-months follow-ups. The interventions’ acceptability will also be assessed. Discussion: The iACTwithPain intervention is expected to improve CP patients’ psychosocial functioning, quality of life, and empowerment, by promoting adaptive disease management and regulation of pain-related internal experiences. Results will contribute to a better understanding on the pertinence of adding compassion elements to ACT for CP and to reach an optimized intervention for CP. (shrink)

Clinical trials play a crucial role in generating evidence about healthcare interventions and improving outcomes for current and future patients. For individual trial participants, however, there are inevitably trade‐offs involved in clinical trial participation, given that trials have traditionally been designed to benefit future patient populations rather than to offer personalised care. Failure to understand the distinction between research and clinical care and the likelihood of benefit from participation in clinical trials has been termed the ‘therapeutic misconception’. The (...) evolution of the clinical trials landscape, including greater integration of clinical trials into healthcare and development of novel trial methodologies, may reinforce the significance of the therapeutic misconception and other forms of misunderstanding while at the same time (paradoxically) challenging its salience. Using cancer clinical trials as an exemplar, we describe how methodological changes in early‐ and late‐phase clinical trial designs, as well as changes in the design and delivery of healthcare, impact upon the therapeutic misconception. We suggest that this provides an impetus to re‐examine the ethics of clinical research, particularly in relation to trial access, participant selection, communication and consent, and role delineation. (shrink)

From the earliest application of modern randomized controlled trials in medical research, scientists and observers have deliberated the ethics of randomly allocating study participants to trial control arms. Adaptive RCT designs have been promoted as ethically advantageous over conventional RCTs because they reduce the allocation of subjects to what appear to be inferior treatments. Critical assessment of this claim is important, as adaptive designs are changing medical research, with the potential to significantly shift how clinical trials are conducted. Policy-makers (...) are swiftly moving to encourage greater use of adaptive designs. In 2016, the newly enacted 21st Century Cures Act instructed the Food and Drug Administration to help product sponsors incorporate adaptive methods into proposed clinical trial protocols and applications for investigational drugs and also biological products. In this article, we review the ethical justifications commonly offered for adaptive designs, explore these arguments in the context of actual trials, and contend that clinical equipoise is a useful standard for adaptive-trial ethics. We distinguish between theoretical and clinical equipoise and explain why ethical arguments related to adaptive trials tend to focus on the former. Yet we contend that theoretical equipoise can be an unreliable standard for adaptive ethics. While we contend that clinical equipoise is the most critical principle for the primary ethical concerns posed by adaptive trials, we suggest ethical approaches to deal with some additional concerns unique to adaptive designs. (shrink)

Many drugs used in paediatric medicine are off-label. There is a rising call for the use of adaptive clinical trial designs in responding to the need for safe and effective drugs given their potential to offer efficiency and cost-effective benefits compared with traditional clinical trials. ADs have a strong appeal in paediatric clinical trials given the small number of available participants, limited understanding of age-related variability and the desire to limit exposure to futile or unsafe interventions. Although the ethical (...) value of adaptive trials has increasingly come under scrutiny, there is a paucity of literature on the ethical dilemmas that may be associated with paediatric adaptive designs. This paper highlights some of these ethical concerns around safety, scientific/social value and caregiver/guardian comprehension of the trial design. Against this background, the paper develops a non-static conceptual lens for understanding PADs. It shows that ADs are epistemically open and reduce some of the knowledge-associated uncertainties inherent in clinical trials as well as fast-track the time to draw conclusions about the value of evaluated drugs/treatments. On this note, the authors argue that PADs are ethically justifiable given they have multiple layers of safety, exposing enrolled children to lesser potential risks, create social/scientific value generally and for paediatric populations in particular, specifically foster the flourishing of paediatric populations and can significantly improve paediatric trial efficiency when properly designed and implemented. However, because PADs are relatively new and their regulatory, ethical and logistical characteristics are yet to be clarified in some jurisdictions, the cooperation of various public and private stakeholders is required to ensure that the interests of children, their caregivers and parents/guardians are best served while exposing paediatric research subjects to the most minimal of risks when they are enrolled in paediatric trials that use ADs. Data sharing not applicable as no datasets generated and/or analysed for this study. Not applicable. (shrink)

BackgroundRandomized Controlled Trials are the gold standard for assessing whether an intervention is effective; however, they require large sample sizes in order to detect small effects. For rare or complex populations, we advocate a case series approach as a more realistic and useful first step for intervention evaluation. We consider the importance of randomization to such designs, and advocate for the use of Randomization Tests and Between Case Effect Sizes to provide a robust and statistically powerful evaluation of outcomes. In (...) this tutorial, we describe the method, procedures, and analysis code necessary to conduct robust single case series, using an empirical example with minimally verbal autistic children.MethodWe applied a pre-registered randomized baseline design with between-case effect size to a case series, to test the efficacy of a novel, parent-mediated, app-based speech production intervention for minimally verbal autistic children. Parent-rated probe scores were used to densely sample performance accuracy over time.ResultsParents were able to reliably code their children’s speech productions using BabbleBooster. A non-significant Randomization Test and small Between-Case Effect Size, suggested there was no evidence that BabbleBooster improved speech production in minimally verbal autistic children, relative to baseline scores, during this brief period of intervention.ConclusionThe current analyses exemplify a more robust approach to examining treatment effects in rare or complex populations, where RCT may be difficult or premature to implement. To facilitate adoption of this method by researchers and practitioners, we provide analysis code that can be adapted using open source R packages. Future studies could use this case series design to evaluate interventions aiming to improve speech and language outcomes for minimally verbal autistic children, and other heterogeneous and hard to reach populations. (shrink)

In an adaptive clinical trial , key trial characteristics may be altered during the course of the trial according to predefined rules in response to information that accumulates within the trial itself. In addition to having distinguishing scientific features, adaptive trials also may involve ethical considerations that differ from more traditional randomized trials. Better understanding of clinical trial experts’ views about the ethical aspects of adaptive designs could assist those planning ACTs. Our aim was to (...) elucidate the opinions of clinical trial experts regarding their beliefs about ethical aspects of ACTs. (shrink)

Ethically permissible clinical trials must not expose subjects to risks that are unreasonable in relation to anticipated benefits. In the research ethics literature, this moral requirement is typically understood in one of two different ways: as requiring the existence of a state of clinical equipoise, meaning a state of honest, professional disagreement among the community of experts about the preferred treatment; or as requiring an equilibrium between individual and collective ethics. It has been maintained that this second interpretation makes it (...) mandatory to minimize the number of patients receiving the treatment that will eventually be shown to be inferior by the trial. This requirement has led to the development of adaptive trials, i.e., trials in which treatment allocation is determined by data accumulated during interim analysis. Many statisticians argue that in some circumstances—typically with potentially high benefits, as in the much discussed ECMO trial—adaptive design is the only ethically permissible experimental design. Nevertheless, some proponents of clinical equipoise argue that adaptive trials are neither ethically required nor permissible. More specifically, they argue that clinical trials using adaptive designs fail to meet the moral requirement of clinical equipoise, since these trials presuppose an epistemic state that is incompatible with a physician’s duty of care to her subjects. This paper emphasizes that the debate is to a large extent resting on an epistemological confusion. Specifically, I argue that this response conflates two different conceptions of statistical evidence, and that recognizing this distinction elucidates an epistemological framework in which adaptive trials are both consistent with and recommended by the moral requirement of clinical equipoise. (shrink)

A key role in inference is played by randomization, which has been extensively used in clinical trials designs. Randomization is primarily intended to prevent the source of bias in treatment allocation by producing comparable groups. In the frequentist framework of inference, randomization allows also for the use of probability theory to express the likelihood of chance as a source for the difference of end outcome. In the Bayesian framework, its role is more nuanced. The Bayesian analysis of clinical trials can (...) afford a valid rationale for selective controls, pointing out a more limited role for randomization than it is generally accorded. This paper is aimed to offer a view of randomization from the perspective of both frequentist and Bayesian statistics and discussing the role of randomization also in theoretical decision models. (shrink)

The West African Ebola epidemic has set in motion a collective endeavour to conduct accelerated clinical trials, testing unproven but potentially lifesaving interventions in the course of a major public health crisis. This unprecedented effort was supported by the recommendations of an ad hoc ethics panel convened in August 2014 by the WHO. By considering why and on what conditions the exceptional circumstances of the Ebola epidemic justified the use of unproven interventions, the panel's recommendations have challenged conventional thinking about (...) therapeutic development and clinical research ethics. At the same time, unanswered ethical questions have emerged, in particular: the specification of exceptional circumstances, the specification of unproven interventions, the goals of interventional research in terms of individual versus collective interests, the place of adaptive trial designs and the exact meaning of compassionate use with unapproved interventions. Examination of these questions, in parallel with empirical data from research sites, will help build pragmatic foundations for disaster research ethics. Furthermore, the Ebola clinical trials signal an evolution in the current paradigms of therapeutic research, beyond the case of epidemic emergencies. (shrink)

Experimentation is at the heart of scientific inquiry. In the behavioral and neural sciences, where only a limited number of observations can often be made, it is ideal to design an experiment that leads to the rapid accumulation of information about the phenomenon under study. Adaptive experimentation has the potential to accelerate scientific progress by maximizing inferential gain in such research settings. To date, most adaptive experiments have relied on myopic, one-step-ahead strategies in which the stimulus on each (...) class='Hi'>trial is selected to maximize inference on the next trial only. A lingering question in the field has been how much additional benefit would be gained by optimizing beyond the next trial. A range of technical challenges has prevented this important question from being addressed adequately. This study applies dynamic programming, a technique applicable for such full-horizon, “global” optimization, to model-based perceptual threshold estimation, a domain that has been a major beneficiary of adaptive methods. The results provide insight into conditions that will benefit from optimizing beyond the next trial. Implications for the use of adaptive methods in cognitive science are discussed. (shrink)

Research conducted during epidemics may warrant adaptations or adaptive designs owing to practical constraints, time pressures, uncertainty, the importance of flexibility, and the potential for research to detract from epidemic response. Adapting research entails choosing different research designs or methods if research goals, contexts or constraints justify or require a different approach. Adaptive research, by contrast, is a type of research that prospectively plans for modifications after research has been initiated, while maintaining the validity and integrity of the research. While (...) adaptation and adaptive designs introduce an important degree of flexibility to research conducted during epidemics and help to address research objectives and constraints, adaptation and adaptive designs require close ethical scrutiny and are no different from other research in that they are expected to align with universally accepted ethical standards. Important ethical questions exist regarding the conditions that justify adaptations to research, the kinds of adaptive research designs that can be ethically justified, and how ethics review bodies ought to evaluate such novel approaches to research in epidemic contexts. The five cases included in this chapter prompt reflection on the ethical considerations and implications of adapting research in response to epidemic-related risks and the public health measures deployed in response to those risks, as well as the ethical implications of not adapting research in such contexts. These cases also highlight ethical questions and issues arising during the conduct of adaptive trials, including when treatments under study, treatment doses, sample size, and other study features are reviewed in response to evolving evidence. This chapter invites reflection on these key ethical dimensions when considering adaptive designs and adaptations to standard research procedures during epidemics. What these cases make clear is that adaptive designs and adaptations to research do not reduce the need for rigorous scientific evaluation and adherence to universal ethical standards, and must be explicitly ethically justified and reviewed through transparent and inclusive processes. (shrink)

Neurobiology-based interventions for mental diseases and searches for useful biomarkers of treatment response have largely failed. Clinical trials should assess interventions related to environmental and social stressors, with long-term follow-up; social rather than biological endpoints; personalized outcomes; and suitable cluster, adaptive, and n-of-1 designs. Labor, education, financial, and other social/political decisions should be evaluated for their impacts on mental disease.

A non-inferiority design accepts the possibility of some efficacy loss, as part of a “successful”, statistically significant result. That loss may be excessive when the non-inferiority threshold is lenient. However, even stringent significance thresholds and safety monitoring may fail to adequately protect study participants when the primary outcome is death. The OPTIMAAL trial, a large randomized clinical trial performed in high-risk patients, is discussed as an example, using the Belmont Report principles as an ethical frame of reference. (...) OPTIMAAL compared losartan, a new drug, to captopril, a drug known to reduce the risk of death in patients with heart failure after a myocardial infarction. Serious ethical challenges occurred in that study. Firstly, subjects had to tolerate captopril to participate, meaning that participation implied the possibility of higher risk of death if randomized to the losartan arm, as compared to the standard of care. Additionally, the stopping rules had to ensure enough powe... (shrink)

Background We report a randomised controlled clinical trial of neurofeedback therapy intervention for ADHD/ADD in adults. We focus on internal mechanics of neurofeedback learning, to elucidate the primary role of cortical self-regulation in neurofeedback. We report initial results; more extensive analysis will follow. Methods Trial has two phases: intervention and follow-up. The intervention consisted of neurofeedback treatment, including intake and outtake measurements, using a waiting-list control group. Treatment involved $\sim$40 hour-long sessions 2-5 times per week. Training involved either (...) theta/beta or sensorimotor-rhythm regimes, adapted by adding a novel 'inverse-training' condition to promote self-regulation. Follow-up (ongoing) will consist of self-report and executive function tests. Setting Intake and outtake measurements were conducted at University of Helsinki. Treatment was administered at partner clinic Mental Capital Care, Helsinki. Randomisation We randomly allocated half the sample then adaptively allocated the remainder to minimise baseline differences in prognostic variables. Blinding Waiting-list control design meant trial was not blinded. Participants 54 adult Finnish participants (mean age 36 years; 29 females) were recruited after screening by psychiatric review. 44 had ADHD diagnoses, 10 had ADD. Measurements Symptoms were assessed by computerised attention test (T.O.V.A.) and self-report scales, at intake and outtake. Performance during neurofeedback trials was recorded. Results Participants were recruited and completed intake measurements during summer 2012, before assignment to treatment and control, September 2012. Outtake measurements ran April-August 2013. After dropouts, 23 treatment and 21 waiting-list participants remained for analysis. Initial analysis showed that, compared to waiting-list control, neurofeedback promoted improvement of self-reported ADHD symptoms, but did not show transfer of learning to T.O.V.A. Comprehensive analysis will be reported elsewhere. Trial Registration "Computer Enabled Neuroplasticity Treatment (CENT)", ISRCTN13915109. Partly funded by Finnish science agency TEKES, project #440078. (shrink)

Flipped learning could improve the learning effectiveness of students. However, some studies have pointed out the limitations related to flipped classrooms because the content of the flipped course does not vary according to the needs of the students. On the other hand, adaptive teaching, which customizes the learning mode according to the individual needs of students, can make up for some of the shortcomings of flipped teaching. This study combines adaptive teaching with flipped teaching and applies it to face-to-face classroom (...) activities. The purpose of this research is to explore whether the implementation of flipping and adaptive learning in a computer programming course can improve the learning effectiveness of students. The experimental subjects of this study are the sophomore students in the Department of Information Management. The flipped classroom with adaptive instruction has been realized in the limited course time. This study uses questionnaires to collect pre- and post-test data on the “learning motivation” of students. The learning effectiveness was evaluated based on the students' previous programming course and the semester scores of this course. Research results show that the post-test “learning motivation” has improved overall compared with the pre-test, and the learning effect is significant. The results of this research not only prove the effectiveness of modern teaching theories in programming courses but also lay the foundation for future teaching design. (shrink)

Background: Although ethics consultation has been introduced to clinical practice for many years, the results of empirical studies to evaluate the effectiveness of ethics consultation are still controversial. The design of randomised controlled trials is considered the best research design to evaluate the effect of a clinical practice on the outcomes of interests. In order to understand the effects of ethics consultation, we conducted this search for studies with the design of randomised controlled trials to evaluate ethics (...) consultation.Objective: To provide an integrated review of studies with the design of randomised controlled trials to evaluate the effectiveness of ethics consultation.Methods: PubMed was used to search for studies using the randomised controlled trial design to evaluate the effectiveness of ethics consultation. The search term used was “ethics consultation”. The selection criterion was limited to “randomised controlled trial”.Results: Four articles that met both search criteria were retrieved. One of these articles reported a study that did not actually use the design of a randomised controlled trial and is excluded from the following discussion.Conclusions: To apply randomised controlled trials to evaluate the effectiveness of ethics consultation is extremely difficult as long as two issues are not resolved: the standardisation of ethics consultation and a placebo for ethics consultation to eliminate the placebo effect. Thus, the results generated by the design of randomised controlled trials are always problematic. Furthermore, as long as the two issues exist, the results generated by the design of quantitative research methods always pose problems. (shrink)

Coronavirus disease 2019 (COVID-19) is a fast-developing viral pandemic spreading across the globe. Due to lack of availability of proven medicines against COVID-19, physicians have resorted to treatments through large trials of investigational drugs with poor evidence or those used for similar diseases. Large trials randomize 100–500+ patients at multiple hospitals in different countries to either receive these drugs or standard treatment. In order to expedite the process, some regulatory agencies had also given permission to use drugs approved for other (...) diseases, despite a lack of evidence of efficacy in COVID-19. In this review, we highlight the potential ethical issues that should be addressed during the use of investigational drugs with little prior evidence as a treatment options during a pandemic. We discuss the impact of design of randomized clinical trials using LOTUS trial as an example and that of off-label use of drugs like chloroquine/hydroxychloroquine (CQ/HQ) on the safety of patients during COVID-19. We conclude that the adaptive randomized clinical trial designs offer a flexible and efficient approach, enabling patients to quickly switch to successful treatments, while minimizing the number of patients on standard of care. Randomized clinical trial design should consider blinding of investigators and only representative patients who can provide consent should be included. We also conclude the emergency approvals of drugs should be carefully issued and off-label use should be restricted in pandemics. Streamlined regulatory guidelines for emergency drug use in a pandemic can also help in providing benefit and minimizing harm to patients in the future. (shrink)

This article illustrates how a collaborative research process can successfully engage an underserved minority community to address health disparities. Pacific Islanders, including the Marshallese, are one of the fastest growing US populations. They face significant health disparities, including extremely high rates of type 2 diabetes. This article describes the engagement process of designing patient‐centered outcomes research with Marshallese stakeholders, highlighting the specific influences of their input on a randomized control trial to address diabetes. Over 18 months, an interdisciplinary research (...) team used community‐based participatory principles to conduct patient‐engaged outcomes research that involved 31 stakeholders in all aspects of research design, from defining the research question to making decisions about budgets and staffing. This required academic researcher flexibility, but yielded a design linking scientific methodology with community wisdom. (shrink)

To give substance to the rhetoric of ‘learning health systems’, a variety of novel trial designs are being explored to more seamlessly integrate research with medical practice, reduce study duration and reduce the number of participants allocated to ineffective interventions. Many of these designs rely on response adaptive randomisation. However, critics charge that RAR is unethical on the grounds that it violates the principle of equipoise. In this paper, I reconstruct critiques of RAR as holding that it is inconsistent (...) with five important ethical principles. I then argue that these criticisms rest on a faulty view of equipoise encouraged by the idea that a RAR study models the beliefs of a single rational agent about the relative merits of the interventions being studied. I outline a view in which RAR models an idealised health system in which diverse communities of fully informed experts shrink or grow as their constituent members update their expert opinions in light of reliable medical evidence. I show how a proper understanding of clinical equipoise can reconcile this conception of RAR with these five ethical principles. This analysis removes an in-principle objection to RAR and sheds important light on the relationship between clinical equipoise and transient diversity in the scientific community. (shrink)

BackgroundIndividuals with early phase cognitive impairment are frequently affected by existential distress, social avoidance and associated health issues. The demand for efficient psychological support is crucial from both an individual and a societal perspective. We have developed a novel psychological intervention manual for providing a non-medical path to enhanced psychological health in the cognitively impaired population. The current article provides specific information on the randomized controlled trial -design and methods. The main hypothesis is that participants receiving PIPCI will (...) increase their psychological flexibility compared to participants in the active control group and the waiting list control group. The secondary hypotheses are that participants receiving PIPCI will improve psychological health compared to participants in the active control group and the waiting list control group.Materials and MethodsThis three-arm RCT will recruit participants from the cognitive centers at Karolinska University Hospital in Stockholm and randomize approximately 120 individuals in the early phase of cognitive impairment to either an experimental group, an active control group or a waiting list control group. Intervention outcome will be evaluated with self-report questionnaires on physical and psychological aspects of health, cognitive assessment, biological markers and health care costs. Assessments will be performed at pre- and post-intervention, as well as at a 6-month follow-up.DiscussionThe development of a potentially feasible and effective psychological intervention tailored for early phase cognitive impairment has the potential to advance the non-pharmacological intervention field. This is especially important given the extensive burden for many affected individuals and their families and the current lack of effective treatments. If the psychological intervention discussed here shows feasibility and efficacy, there is potential for far-reaching healthcare implications for patients with early cognitive impairment at risk of developing dementia.Clinical Trial RegistrationClinicalTrials.gov: NCT04356924. Date of registration: April 22, 2020. URL: https://clinicaltrials.gov/ct2/show/NCT04356924. (shrink)

ObjectiveThis study aims to evaluate the effectiveness of the MotivAir program—a phone-based intervention based on Motivational Interviewing principles and techniques—in enhancing adherence to Continuous Positive Airway Pressure therapy among patients with Obstructive Sleep Apnea Syndrome.MethodsA multicenter randomized controlled trial design with random allocation at the level of the individual will be conducted to compare the impact of the experimental program with a control group receiving usual care only in improving selected clinical and psychological parameters in the patients. A (...) minimum sample of 80 participants will be recruited in each center according to the inclusion criteria. After the initial screening, participants will be randomly assigned to either the experimental group or the control condition. The program will last 180 days and will be delivered by a trained nurse. The impact of the MotivAir program on selected primary and secondary outcomes will be measured at baseline, and after 1-, 3-, and 6-month from CPAP initiation.DiscussionParticipants are expected to show an increased level of adherence to CPAP and to acquire the skills and self-confidence necessary to deal with the psychological consequences of their chronic condition. (shrink)

The volume of clinical research is increasing exponentially—far beyond our ability to process and absorb the results. Given this situation, it may be beneficial to consider reducing the flow at its source. In what follows, I will motivate and critically evaluate the following proposal: researchers should conduct fewer clinical trials. More specifically, I c onsider whether researchers should be permitted to conduct only clinical research of very high quality and, in turn, whether research ethics committees should prohibit all other, lower-quality (...) research, even when it might appear to meet some minimal ethical standard. Following a close analysis of the social-value requirement of ethical clinical research, I argue that this proposal is defensible. The problem identified in this paper has two parts, quantity and quality, and some clarification is needed about the latter because “quality” is a highly contested term in the medical literature. When some scholars advocate for high-quality trials, they mean large-scale, simple, explanatory randomized controlled trials. Others, including myself, have defended a different characterization of high-quality research that tends more toward pragmatic trial design and the use of methods other than RCTs. Pragmatic trials aim to provide evidence that directly supports clinical decision-making in “usual” care settings. Unlike explanatory trials, which aim to abstract away from particular settings and patients, in the hopes of creating ideal conditions for the success of an intervention, pragmatic trials deliberately pursue knowledge of high applicability, through the use of representative subjects, clinically important questions, flexible treatment protocols, patient-oriented outcome measures, and so on. I see applicability as a marker of high-quality research. The context in which research is meant to be applied should be the context in which new interventions are evaluated. (shrink)

Adaptive training adjusts a training task with the goal of improving learning outcomes. Adaptive training has been shown to improve human performance in attention, working memory capacity, and motor control tasks. Additionally, correlations have been observed between neural EEG spectral features (4–13 Hz) and the performance of some cognitive tasks. This relationship suggests some EEG features may be useful in adaptive training regimens. Here, we anticipated that adding a neural measure into a behavioral-based adaptive training system would improve human performance (...) on a subsequent transfer task. We designed, developed, and conducted a between-subjects study of 44 participants comparing three training regimens: Single Item Fixed Difficulty (SIFD), Behaviorally Adaptive Training (BAT), and Combined Adaptive Training (CAT) using both behavioral and EEG measures. Results showed a statistically significant transfer task performance advantage of the CAT-based system relative to SIFD and BAT systems of 6 and 9 percentage points, respectively. Our research shows a promising pathway for designing closed-loop BCI systems based on both users' behavioral performance and neural signals for augmenting human performance. (shrink)

BackgroundStreet-connected children and youth in low- and middle-income countries have multiple vulnerabilities in relation to participation in research. These require additional considerations that are responsive to their needs and the social, cultural, and economic context, while upholding core ethical principles of respect for persons, beneficence, and justice. The objective of this paper is to describe processes and outcomes of adapting ethical guidelines for SCCY’s specific vulnerabilities in LMIC.MethodsAs part of three interrelated research projects in western Kenya, we created procedures to (...) address SCCY’s vulnerabilities related to research participation within the local context. These consisted of identifying ethical considerations and solutions in relation to community engagement, equitable recruitment, informed consent, vulnerability to coercion, and responsibility to report.ResultsSubstantial community engagement provided input on SCCY’s participation in research, recruitment, and consent processes. We designed an assent process to support SCCY to make an informed decision regarding their participation in the research that respected their autonomy and their right to dissent, while safeguarding them in situations where their capacity to make an informed decision was diminished. To address issues related to coercion and access to care, we worked to reduce the unequal power dynamic through street outreach, and provided access to care regardless of research participation.ConclusionsAlthough a vulnerable population, the specific vulnerabilities of SCCY can to some extent be managed using innovative procedures. Engaging SCCY in ethical research is a matter of justice and will assist in reducing inequities and advancing their health and human dignity. (shrink)

Importance Informed consent is essential to ethical, rigorous research and is important to recruitment and retention in cancer trials.Objective To examine cancer clinical trial (CCT) participants’ perceptions of informed consent processes and variations in perceptions by cancer type.Design and Setting and Participants Cross-sectional survey from mixed-methods study at National Cancer Institute–designated Northeast comprehensive cancer center. Open-ended and forced-choice items addressed: (1) enrollment and informed consent experiences and (2) decision-making processes, including risk-benefit assessment. Eligibility: CCT participant with gastro-intestinal or (...) genitourinary, hematologic-lymphatic malignancies, lung cancer, and breast or gynecological cancer (N = 334).Main Outcome Measures Percentages satisfied with consent process and information provided; and assessing participation’s perceptions of risks/benefits. Multivariable logistic or ordinal regression examined differences by cancer type.Results Most patient-participants felt well informed by the consent process (more than 90% overall and by cancer type) and. most (87.4%) reported that the consent form provided all the information they wanted, although nearly half (44.8%) reported that they read the form somewhat carefully or less. More than half (57.9%) said that talking to research staff (i.e., the consent process) had a greater impact on participation decisions than reading the consent form (2.1%). A third (31.1%) were very sure of joining in research studies before the informed consent process (almost half of lung cancer patients did—47.1%). Most patients personally assessed the risks and benefits before consenting. However, trust in physicians played an important role in the decision to enroll in CCT.Conclusions and Relevance Cancer patients rely less on written features of the informed consent process than on information obtained from the research staff and their own physicians. Research should focus on information and communication strategies that support informed consent from referring physicians, researchers, and others to improve patient risk-benefit assessment and decision-making. (shrink)

The use of transcranial Electrical Stimulation in the modulation of cognitive brain functions to improve neuropsychiatric conditions has extensively increased over the decades. tES techniques have also raised new challenges associated with study design, stimulation protocol, functional specificity, and dose-response relationship. In this paper, we addressed challenges through the emerging methodology to investigate the dose-response relationship of High Definition-transcranial Direct Current Stimulation, identifying the role of negative valence in tinnitus perception. In light of the neurofunctional testable framework and tES (...) application, hypotheses were formulated to measure clinical and surrogate endpoints. We posited that conscious pairing adequately pleasant stimuli with tinnitus perception results in correction of the loudness misperception and would be reinforced by concurrent active HD-tDCS on the left Dorsolateral Prefrontal Cortex. The dose-response relationship between HD-tDCS specificity and the loudness perception is also modeled. We conducted a double-blind, randomized crossover pilot study with six recruited tinnitus patients. Accrued data was utilized to design a well-controlled adaptive seamless Bayesian dose-response study. The sample size and optimum interims were anticipated for adaptive decision-making about efficacy, safety, and single session dose parameters. Furthermore, preliminary pilot study results were sufficient to show a significant difference within the longitudinally detected self-report tinnitus loudness between before and under positive emotion induction. This study demonstrated a research methodology used to improve emotion regulation in tinnitus patients. In the projected method, positive emotion induction is essential for promoting functional targeting under HD-tDCS anatomical specificity to indicate the efficacy and facilitate the dose-finding process. The continuous updating of prior knowledge about efficacy and dose during the exploratory stage adapts the anticipated dose-response model. Consequently, the effective dose range to make superiority neuromodulation in correcting loudness misperception of tinnitus will be redefined. Highly effective dose adapts the study to a standard randomized trial and transforms it into the confirmatory stage in which active HD-tDCS protocol is compared with a sham trial. Establishing the HD-tDCS intervention protocols relying on this novel method provides reliable evidence for regulatory agencies to approve or reject the efficacy and safety. Furthermore, this paper supports a technical report for designing multimodality data-driven complementary investigations in emotion regulation, including EEG-driven neuro markers, Stroop-driven attention biases, and neuroimaging-driven brain network dynamics. (shrink)

Objective: To systematically analyze the effectiveness of technology-based interventions for reducing loneliness in older adults.Methods: We searched relevant electronic databases from inception to April 2021, which included Cochrane Library, PubMed, Web of Science, SpringerLink, EMBASE, CNKI, and Wanfang. The following criteria were used: study design—randomized controlled trial designs, people—older adults, intervention—technology-based interventions in which a core component involved the use of technology to reduce loneliness in older adults; and outcome—reduction of loneliness level in terms of rating scale scores. (...) Two reviewers independently identified eligible studies, extracted data, and assessed the risk of bias in the included studies. A third reviewer resolved any conflicts. The Cochrane Collaboration's bias assessment tool was used to evaluate the risk of bias for the included studies, and Review Manager 5.4 software was used for the meta-analysis. A random effects model was adopted to measure estimates of loneliness reduction, and standard mean differences with a 95% confidence interval were calculated for each intervention-control contrast, and the I2 statistic was applied to examine heterogeneity.Results: A total of 391 participants from six RCTs were included in the review. Of these, three studies were rated as low-quality, and the remaining three were rated as moderate-quality studies. The meta-analysis showed that the evidence regarding the effects on loneliness of technology-based interventions compared with control groups was uncertain, and suggested that technology-based interventions resulted in little to no difference in loneliness reduction compared to control groups. Two types of technology-based interventions were identified: smartphone-based video calls and computer-based training with Internet usage. The subgroup analysis found low-quality evidence to support the effectiveness of both intervention types.Conclusions: We found no current evidence to support that technology-based interventions were effective compared to different control conditions in reducing loneliness in older adults. This suggests that more research is needed to investigate the effects of technology-based interventions on loneliness in older adults. (shrink)

Value Sensitive Design (VSD) is an established method for integrating values into technical design. It has been applied to different technologies and, more recently, to artificial intelligence (AI). We argue that AI poses a number of challenges specific to VSD that require a somewhat modified VSD approach. Machine learning (ML), in particular, poses two challenges. First, humans may not understand how an AI system learns certain things. This requires paying attention to values such as transparency, explicability, and accountability. (...) Second, ML may lead to AI systems adapting in ways that ‘disembody’ the values embedded in them. To address this, we propose a threefold modified VSD approach: 1) integrating a known set of VSD principles (AI4SG) as design norms from which more specific design requirements can be derived; 2) distinguishing between values that are promoted and respected by the design to ensure outcomes that not only do no harm but also contribute to good; and 3) extending the VSD process to encompass the whole life cycle of an AI technology in order to monitor unintended value consequences and redesign as needed. We illustrate our VSD for AI approach with an example use case of a SARS-CoV-2 contact tracing app. (shrink)

Knives, birds' wings, and mountain slopes are used for certain purposes: cutting, flying, and climbing. A bird's wings have in common with knives that they have been 'designed' for the purpose they serve, which purpose accounts for their existence, whereas mountain slopes have come about by geological processes independently of their uses for climbing. A bird's wings differ from a knife in that they have not been designed or produced by any conscious agent; rather, the wings, like the slopes, are (...) outcomes of natural processes without any intentional causation. Evolutionary biologists use teleological language and teleological explanations. I propose that this use is appropriate, because teleological explanations are hypotheses that can be subject to empirical testing. The distinctiveness of teleological hypotheses is that they account for the existence of a feature in terms of the function it serves; for example, wings have evolved and persist because flying is beneficial to birds by increasing their chances of surviving and reproducing. Features of organisms that are explained with teleological hypotheses include structures, such as wings; processes, such as development from egg to adult; and behaviours, such as nest building. A proximate explanation of these features is the function they serve; an ultimate explanation that they all share is their contribution to the reproductive fitness of the organisms. I distinguish several kinds of teleological explanations, such as natural and artificial, as well as bounded and unbounded, some of which but not others apply to biological explanations. (shrink)

The Safe by Design conceptual initiative being developed for nanomaterials offers a template for a new sustainable innovation approach for advanced materials with four important sustainability characteristics. Firstly, it requires potential toxicity risks to be evaluated earlier in the innovation cycle simultaneously with its chemical functionality and possible commercial applications. Secondly, it offers future options for reducing animal laboratory testing by early assessment using in silico predictive toxicological approaches, minimizing the number that reaches in vitro and in vivo trials. (...) Thirdly, it promotes a culture of shared responsibility for ethical and sustainable outcomes in the innovation process by promoting early dialogue between groups with vested interests. Finally, it offers the prospect of a more democratized innovation process by including civil society actors in decisions on product safety, commercial applications, and social utility. Collectively, these four characteristics offer the prospect for a new social contract between science, technology, and society for the societal alignment and sustainable innovation of advanced materials. (shrink)

The “practice turn” in philosophy of science has strengthened the connections between philosophy and scientific practice. Apart from reinvigorating philosophy of science, this also increases the relevance of philosophical research for science, society, and science education. In this paper, we reflect on our extensive experience with teaching mandatory philosophy of science courses to science students from a range of programs at University of Copenhagen. We highlight some of the lessons we have learned in making philosophy of science “fit for teaching” (...) outside of philosophy circles by taking selected cases from the students’ own field as the starting point. We argue for adapting philosophy of science teaching to particular audiences of science students, and discuss the benefits of drawing on research within science education to inform curriculum and course design. This involves reconsidering teaching resources, assumptions about students, intended learning outcomes, and teaching formats. We also argue that to make philosophy of science relevant and engaging to science students, it is important to consider their potential career trajectories. By anticipating future contexts and situations in which methodological, conceptual, and ethical questions could be relevant, philosophy of science can demonstrate its value in the education of science students. (shrink)

In clinical and agricultural trials, there is the danger that an experimental outcome appears to arise from the causal process or treatment one is interested in when, in reality, it was produced by some extraneous variation in the experimental conditions. The remedy prescribed by classical statisticians involves the procedure of randomization, whose effectiveness and appropriateness is criticized. An alternative, Bayesian analysis of experimental design, is shown, on the other hand, to provide a coherent and intuitively satisfactory solution to the (...) problem. (shrink)

The article explores the challenges of ensuring voluntary and informed consent which is obtained from potential research subjects in the north‐eastern part of Romania. This study is one of the first empirical papers of this nature in Romania. The study used a quantitative survey design using the adapted Quality of Informed Consent (QuIC) questionnaire. The target population consisted of 100 adult persons who voluntarily enrolled in clinical trials. The informed consent form must contain details regarding the potential risks and (...) benefits, the aim of the clinical trial, study design, confidentiality, insurance and contact details in case of additional questions. Our study confirmed that although all required information was included in the ICF, few clinical trial participants truly understood it. We also found that the most important predictive factor for a good subjective and objective understanding of the clinical trial was the level of education. Our study suggests that researchers should consider putting more effort in order to help clinical trials participants achieve a better understanding of the informed consent. In this way they will ensure that participants’ decision‐making is meaningful and that their interests are protected. (shrink)

While the HVTN 505 trial showed no overall efficacy of the tested vaccine to prevent HIV infection over placebo, markers measuring immune response to vaccination were strongly correlated with infection. This finding generated the hypothesis that some marker-defined vaccinated subgroups were partially protected whereas others had their risk increased. This hypothesis can be assessed using the principal stratification framework (Frangakis and Rubin, 2002) for studying treatment effect modification by an intermediate response variable, using methods in the sub-field of principal (...) surrogate (PS) analysis that studies multiple principal strata. Unfortunately, available methods for PS analysis require an augmented study design not available in HVTN 505, and make untestable structural risk assumptions, motivating a need for more robust PS methods. Fortunately, another sub-field of principal stratification, survivor average causal effect (SACE) analysis (Rubin, 2006) – which studies effects in a single principal stratum – provides many methods not requiring an augmented design and making fewer assumptions. We show how, for a binary intermediate response variable, methods developed for SACE analysis can be adapted to PS analysis, providing new and more robust PS methods. Application to HVTN 505 supports that the vaccine partially protected individuals with vaccine-induced T-cells expressing certain combinations of functions. (shrink)

In clinical trials, it is common practice to follow up significant interactions between the factors under investigation with subgroup analyses. Such analyses pose at least two analytical and interpretational challenges. The first challenge is that performing multiple subgroup analyses increases the likelihood of obtaining spuriously significant results. This has been acknowledged and relevant guidance exists in the medical literature. The second challenge is that the effects that are obtained at the level of subgroup are composite. This has yet to be (...) fully acknowledged and discussed in the context of medical research. This paper aims to fill this lacuna. Using a simple additive model, we use recent findings from the CHARISMA trial on the efficacy of clopidogrel in addition to aspirin in the treatment of patients at risk for atherothrombotic events to demonstrate quantitatively the composition of effects at the level of subgroups. In the simplest case of a design involving an interaction (two crossed factors, with two levels each, i.e. a 2 x 2 design), effects at the level of subgroup consist of influences that stem (i) from the incidence of the measured outcome in the study population as a whole; (ii) from the factor of interest (e.g. treatment vs. placebo); (iii) from the second factor (e.g. patient group membership); (iv) from the interaction between the two factors; and (v) from random error in the measured outcome. The value of the approach illustrated here is that it is generalizable to any research design irrespective of its complexity and that it prompts clinicians to consider the multiple causality underlying medical research findings. (shrink)

Objective: Ethical guidelines are designed to ensure benefits, protection and respect of participants in clinical research. Clinical trials must now be registered on open-access databases and provide details on ethical considerations. This systematic survey aimed to determine the extent to which recently registered clinical trials report the use of standard of care and post-trial obligations in trial registries, and whether trial characteristics vary according to setting. Methods: We selected global randomized trials registered on http://www.clinicaltrials.gov and http://www.controlled-trials.com. We (...) searched for intervention trials of HIV/AIDS, malaria, and tuberculosis from 9 October 2004, the date of the most recent version of the Helsinki Declaration, to 10 April 2007. Results: We collected data from 312 trials. Fifty-eight percent (58%, 95% CI = 53 to 64) of trial protocols report informed consent. Fifty-eight percent (58%, 95% CI = 53 to 64) of trials report active controls. Almost no trials (1%, 95% CI = 0.5 to 3) mention post-trial provisions. Most trials measure surrogate outcomes. Twenty percent (20%, 95% CI = 16 to 25) of trials measure patient-important outcomes, such as death; and the odds that these outcomes are in a low income country are five times greater than for a developed country (odds ratio (OR) 5.03, 95% CI = 2.70 to 9.35, p = < 0.001). Pharmaceutical companies are involved in 28% (CI = 23 to 33) of trials and measure surrogate outcomes more often than nonpharmaceutical companies (OR 2.45, 95% CI = 1.18 to 5.09, p = 0.31). Conclusion: We found a large discrepancy in the quality of reporting and approaches used in trials in developing settings compared to wealthier settings. (shrink)

Research on authentic learning has been predominantly focussed on skills-based training: there is a paucity of research on models of authentic learning available for adaptation in the humanities undergraduate classroom. In this article, I will seek to address this gap by proposing that legal trials are ideal models for designing authentic learning scenarios in undergraduate teaching and learning contexts, with a specific focus on the humanities. First, I discuss why and how the structure of legal trials can produce authentic learning (...) environments. Second, I present an undergraduate classroom project that combined two disciplinary fields – Shakespearean drama and criminal law – in an effort to enhance student learning and engagement. I outline how the authentic learning scenario was implemented and evaluated and, finally, reflect on the barriers, challenges and potentially transformative effect of authentic learning environments on students and educators. This new intervention combines legal studies... (shrink)

ObjectiveMost young adults diagnosed with breast or gynecologic cancers experience adverse reproductive or sexual health outcomes due to cancer and its treatment. However, evidence-based interventions that specifically address the RSH concerns of young adult and/or LGBTQ+ survivor couples are lacking. Our goal is to develop a feasible and acceptable couple-based intervention to reduce reproductive and sexual distress experience by young adult breast and gynecologic cancer survivor couples with diverse backgrounds.MethodsWe systematically adapted an empirically supported, theoretically grounded couple-based intervention to address (...) the RSH concerns of young couples coping with breast or gynecologic cancer through integration of stakeholder perspectives. We interviewed 11 couples with a history of breast or gynecologic cancer to review and pretest intervention materials. Three of these couples were invited to review and comment on intervention modifications. Content experts in RSH and dyadic coping, clinicians, and community advisors participated throughout the adaptation process.ResultsFindings confirmed the need for an online, couple-based intervention to support young couples experiencing RSH concerns after breast or gynecologic cancer. Qualitative themes suggested intervention preferences for: A highly flexible intervention that can be tailored to couples’ specific RSH concerns; Active steps to help members of a dyad “get on the same page” in their relationship and family building plans; A specific focus on raising partners’ awareness about how cancer can affect body image and physical intimacy; and Accessible, evidence-based information about RSH for both partners. These results, along with feedback from stakeholders, informed adaptation and finalization of the intervention content and format. The resulting virtual intervention, Opening the Conversation, includes five weekly sessions offering training to couples in communication and dyadic coping skills for addressing RSH concerns.ConclusionThe systematic adaptation process yielded a theory-informed intervention for young adult couples facing breast and gynecological cancers, which will be evaluated in a randomized controlled trial. The long-term goal is to implement and disseminate Opening the Conversation broadly to reach young adult couples with diverse backgrounds who are experiencing RSH concerns in cancer survivorship. (shrink)

Well-designed pragmatic clinical trials (PCTs) are critical for improving healthcare delivery and patient outcomes (Haff and Choudhry 2018), and the article written by Garland et al. (2023) advance...

Social anxiety disorders (SAD) are among the most prevalent mental disorders (lifetime prevalence: 7–12%), with high impact on the life of an affected social system and its individual social system members. We developed a manualized disorder-specific integrative systemic and family therapy (ISFT) for SAD, and evaluated its feasibility in a pilot randomized controlled trial (RCT). The ISFT is inspired by Helm Stierlin’s concept of related individuation developed during the early 1980s, which has since continued to be refined. It integrates (...) solution-focused language, social network diagnostics, and genogram work, as well as resource- and problem orientation for both case conceptualization and therapy planning. Post-Milan symptom prescription to fluidize the presented symptoms is one of the core interventions in the ISFT. Theoretically, the IFST is grounded in radical constructivism and “Cybern-Ethics,” multi-directional partiality, and a both/and attitude toward a disorder-specific vs. non-disorder-specific therapy approach. SAD is understood from the viewpoint of social systems theory, especially in adaptation to a socio-psycho-biological explanatory model of social anxiety. In a prospective multicenter, assessor-blind pilot RCT, we included 38 clients with SAD (ICD F40.1; Liebowitz Social Anxiety Scale, LSAS-SR > 30): 18 patients participated in the ISFT, and 20 patients in Cognitive Behavioral Therapy (CBT; age:M = 36 years,SD = 14). Within-group, simple-effect intention-to-treat analyses showed significant reduction in social anxiety (LSAS-SR; ISFT:d = 1.67; CBT:d = 1.04), while intention-to-treat mixed-design ANOVA demonstrated the advantage of ISFT (d = 0.81). Per-protocol analyses supported these results. The remission rate based on blind diagnosticians’ ratings was good to satisfactory (Structured Clinical Interview, SCID; 78% in ST, 45% in CBT,p = 0.083); this has yet to be verified in a subsequent confirmatory RCT. The article will present the ISFT rationale and manual, including a special focus on multi-person settings, and the central findings from our pilot RCT. (shrink)

Research that is initiated, designed or funded by sponsor agencies based in countries with relatively high social and economic development, and conducted in countries that are relatively less developed, gives rise to many important ethical challenges. Although clinical trials of HIV vaccines began ten years ago in the US and Europe, an increasing number of trials are now being conducted or planned in other countries, including several that are considered “developing” countries. Safeguarding the rights and welfare of individuals participating as (...) research subjects in developing countries is a priority. In September, 1997, the Joint United Nations Programme on HIV/AIDS embarked on a process of international consultation; its purpose was further to define the important ethical issues and to formulate guidance that might facilitate the ethical design and conduct of HIV vaccine trials in international contexts. This paper summarises the major outcomes of the UNAIDS consultative process. (shrink)

ABSTRACTMajor depressive disorder is a prevalent condition with high relapse rates. There is evidence that cognitive reactivity is an important vulnerability factor for the recurrence of depression. Mindfulness-based interventions are designed to reduce relapse rates, with cognitive reactivity as one of the proposed working mechanisms. In a randomised controlled trial we compared the effect of mindfulness-based cognitive therapy with treatment-as-usual on cognitive reactivity in recurrently depressed patients. Depressive symptoms, cognitive reactivity, and mindfulness skills were assessed pre and post treatment. (...) Patients in the MBCT group reported a significantly greater reduction in cognitive reactivity than those in the TAU group. The reduction of cognitive reactivity appeared to mediate the association between MBCT/TAU and decrease of depressive symptoms, using pre and post scores. The current study provides evidence that MBCT reduces cognitive reactivity and preliminar... (shrink)

Use of a placebo control in surgical trials is a divisive issue. We argue that, in principle, placebo controls for surgery are necessary in the same way as for medicine. However, there are important differences between these types of trial, which both increase justification and limit application of surgical studies. We propose that surgical randomised placebo-controlled trials are ethical if certain conditions are fulfilled: the presence of equipoise, defined as a lack of unbiased evidence for efficacy of an intervention; (...) clinically important research question; the risk to patients is minimised and reasonable; there is uncertainty about treatment allocation rather than deception; there is preliminary evidence for efficacy, which justifies a placebo-controlled design; and ideally, the placebo procedure should have some direct benefit to the patient, for example, as a diagnostic tool. Placebo-controlled trials in surgery will most often be justified when surgery is performed to improve function or relieve symptoms and when objective outcomes are not available, while the risk of mortality or significant morbidity is low. In line with medical placebo-controlled trials, the surgical trial should be sufficiently powered and standardised so that its results are valid, consent should be valid, the standard treatment or rescue medication should be provided if possible, and after the trial, the patients should be told which treatment they received and there should be provision for post-trial care if the study may result in long-term negative effects. We comment and contrast our guidelines with those of the American Medical Association. (shrink)

Stroke is one of the most common causes of acquired disability, leaving numerous adults with cognitive and motor impairments, and affecting patients’ capability to live independently. Virtual Reality (VR) based methods for stroke rehabilitation have mainly focused on motor rehabilitation but there is increasing interest toward the integration of cognitive training for providing more effective solutions. Here we investigate the feasibility for stroke recovery of a virtual cognitive-motor task, the Reh@Task, which combines adapted arm reaching, and attention and memory training. (...) 24 participants in the chronic stage of stroke, with cognitive and motor deficits, were allocated to one of two groups (VR, Control). Both groups were enrolled in conventional occupational therapy, which mostly involves motor training. Additionally, the VR group underwent training with the Reh@Task and the control group performed time-matched conventional occupational therapy. Motor and cognitive competences were assessed at baseline, end of treatment (1 month) and at a 1-month follow-up through the Montreal Cognitive Assessment, Single Letter Cancelation, Digit Cancelation, Bells Test, Fugl-Meyer Assessment Test, Chedoke Arm and Hand Activity Inventory, Modified Ashworth Scale, and Barthel Index. Our results show that both groups improved in motor function over time, but the Reh@Task group displayed significantly higher between-group outcomes in the arm subpart of the Fugl-Meyer Assessment Test. Improvements in cognitive function were significant and similar in both groups. Overall, these results are supportive of the viability of VR tools that combine motor and cognitive training, such as the Reh@Task. Trial Registration: This trial was not registered because it is a small clinical study that addresses the feasibility of a prototype device. (shrink)

Background Research in children is essential for them to benefit from the outcomes of research but involvement must be weighed against potential harms. In many countries and circumstances, medical research legally requires parental consent until the age of 18 years, with poorly defined recommendations for assent prior to this. However, there is little research exploring how these decisions are made by families and the ethical implications of this. Aim To explore key ethical debates in decision-making for participation of children and (...) adolescents in a human papillomavirus (HPV) vaccine trial. Methods Semi-structured interviews were undertaken with Tanzanian girls (aged 9–16 years) who had participated in an HPV vaccine trial (n = 13), their parents or guardians (n = 12), and girls together with their parents (in paired parent-child interviews) (n = 6). The interviews were analysed using thematic analysis. Interview data came from a qualitative acceptability study undertaken as part of the Dose Reduction Immunobridging and Safety Study of Two Human Papillomavirus (HPV) Vaccines in Tanzanian Girls (DoRIS) trial. Results Girls and parents desired collaborative decision-making, with parents ultimately making the decision to consent. However, girls wanted a larger part in decision-making. Decisions to consent involved many people, including extended social networks, the trial team, media outlets and healthcare professionals and this resulted in conflicts to be negotiated. Deciding where to place trust was central in participants and parents considering decisions to consent and overcoming rumours about trial involvement. Conclusions Existing models of decision-making help to understand dynamics between parents, adolescents and researchers but neglect the important wider social impacts and the fundamental nature of trust. Children’s roles in discussions can be evaluated using the principles of consent: autonomy, freedom and information. Concepts such as relational autonomy help to explain mechanisms families use to negotiate complex consent decisions. Whilst interviewees supported the maintenance of legal parental consent, researchers must design consent processes centring the child to ensure that whole family decision-making processes are supported. (shrink)