The perils of proxy outcomes in evidence-based medicine: the case of recombinant factor VIIa.

There is currently a major controversy surrounding the off-label use of recombinant activated Factor VII (rFVIIa). The literature offers at best inconclusive support for its use in the management of bleeding in any situation other than in patients with Factor VII deficiency or hemophilia A or B with antibodies to factor VIII or factor IX respectively. This evidence has not, however, slowed the growth in off-label prescribing of rFVIIa in other situations including intracranial hemorrhage, cardiac surgery, trauma, transplantation and prostatectomy. We argue that the controversy surrounding such off-label use of rFVIIa stems in part from different understandings of the purposes and methods of evidence-based medicine (EBM) - in particular the use of gross, proxy outcomes such as mortality to determine the effectiveness of an intervention. We then argue that clinical impression and expert opinion should not be dismissed outright on the basis of inconclusive evidence of ineffectiveness. Those who advocate its continued use, however, have a responsibility to demonstrate the benefits that may be missed in current manifestations of EBM. We suggest that the only justified verdict in the case of rFVIIa is currently 'Not Proven'. Keywords Clinical experience, evidence, evidence-based medicine, outcomes, proxy outcomes, recombinant Factor VIIaNHMR

Journal peer review in context: A qualitative study of the social and subjective dimensions of manuscript review in biomedical publishing

Peer- and editorial review of research submitted to biomedical journals (‘manuscript review’) is frequently argued to be essential for ensuring scientific quality and the dissemination of important ideas, but there is also broad agreement that manuscript review is often unsuccessful in achieving its goals. Problems with manuscript review are frequently attributed to the social and subjective dimensions of the process (e.g. bias and conflict of interest). While there have been numerous efforts to improve the process, these have had limited success. This may be because these efforts do not account sufficiently for all of the social and subjective dimensions of the process. We set out, therefore, to characterise the most salient social and subjective dimensions of the manuscript review process, from the perspective of practicing reviewers and editors. Open-ended interviews were carried out with 35 journal editors, and peer reviewers in the UK, USA and Australia. It emerged from these interviews that reviewers and editors were conscious of a number of social and subjective influences on the review process including: a wide variety of motivations for participation, complex relations of power, epistemic authority and moral responsibility, and unavoidable prejudice and intuition. Importantly, these social and subjective influences were often viewed positively and were seen as expressions of, rather than threats to, editors’ and reviewers’ epistemic authority and expertise. From this we conclude that the social and subjective dimensions of biomedical manuscript review should be made more explicit, accommodated and even encouraged, not only because these dimensions of human relationships and judgments are unavoidable, but because their explicit presence is likely to enrich, rather than threaten the manuscript review process. We suggest a ‘dialectical’ model which can simultaneously accommodate, and embrace, all dimensions of the manuscript review process. Keywords: United Kingdom, USA, Australia, Peer review, Biomedical publishing, Bioethics, Publication ethics, JournalsNHMR

Evidence and desperation in off-label prescribing: recombinant factor VIIa

Wendy Lipworth and colleagues explore why clinicians prescribe recombinant f actor VIIa off-label for major haemorrhage, despite a lack of supporting evidence—and why this matter

Evidence and desperation in off-label prescribing: recombinant factor VIIa

Wendy Lipworth and colleagues explore why clinicians prescribe recombinant f actor VIIa off-label for major haemorrhage, despite a lack of supporting evidence—and why this matter

Journal peer review in context: A qualitative study of the social and subjective dimensions of manuscript review in biomedical publishing

Peer- and editorial review of research submitted to biomedical journals (‘manuscript review’) is frequently argued to be essential for ensuring scientific quality and the dissemination of important ideas, but there is also broad agreement that manuscript review is often unsuccessful in achieving its goals. Problems with manuscript review are frequently attributed to the social and subjective dimensions of the process (e.g. bias and conflict of interest). While there have been numerous efforts to improve the process, these have had limited success. This may be because these efforts do not account sufficiently for all of the social and subjective dimensions of the process. We set out, therefore, to characterise the most salient social and subjective dimensions of the manuscript review process, from the perspective of practicing reviewers and editors. Open-ended interviews were carried out with 35 journal editors, and peer reviewers in the UK, USA and Australia. It emerged from these interviews that reviewers and editors were conscious of a number of social and subjective influences on the review process including: a wide variety of motivations for participation, complex relations of power, epistemic authority and moral responsibility, and unavoidable prejudice and intuition. Importantly, these social and subjective influences were often viewed positively and were seen as expressions of, rather than threats to, editors’ and reviewers’ epistemic authority and expertise. From this we conclude that the social and subjective dimensions of biomedical manuscript review should be made more explicit, accommodated and even encouraged, not only because these dimensions of human relationships and judgments are unavoidable, but because their explicit presence is likely to enrich, rather than threaten the manuscript review process. We suggest a ‘dialectical’ model which can simultaneously accommodate, and embrace, all dimensions of the manuscript review process. Keywords: United Kingdom, USA, Australia, Peer review, Biomedical publishing, Bioethics, Publication ethics, JournalsNHMR

Induction of dc voltage, proportional to the persistent current, by external ac current on system of inhomogeneous superconducting loops

A dc voltage induced by an external ac current is observed in system of asymmetric mesoscopic superconducting loops. The value and sign of this dc voltage, like the one of the persistent current, depend in a periodical way on a magnetic field with period corresponded to the flux quantum within the loop. The amplitude of the oscillations does not depend on the frequency of the external ac current (in the investigated region 100 Hz - 1 MHz) and depends on its amplitude. The latter dependence is not monotonous. The observed phenomenon of rectification is interpreted as a consequence of a dynamic resistive state induced by superposition of the external current and the persistent current. It is shown that the dc voltage can be added in system of loops connected in series: the dc voltage oscillations with amplitude up to 0.00001 V were observed in single loop, up to 0.00004 V in a system of 3 loops and up to 0.0003 V in a system of 20 loops.Comment: 5 pages, 6 figure

Should biomedical publishing be ‘opened-up’? Towards a values-based peer-review process.

Peer review of manuscripts for biomedical journals has become a subject of intense ethical debate. One of the most contentious issues is whether or not peer review should be anonymous. This study aimed to generate a rich, empirically-grounded understanding of the values held by journal editors and peer reviewers with a view to informing journal policy. Qualitative methods were used to carry out an inductive analysis of biomedical reviewers’ and editors’ values. Data was derived from indepth, open-ended interviews with journal editors and peer reviewers. Data was “read for” themes relevant to reviewer anonymisation and interactions among editors, reviewers, and authors. Editors and peer reviewers provided three arguments that would support a more open and interactive peerreview process. First, a number of participants emphasised the importance of not only ensuring the scientific quality of published research but also nurturing their colleagues and supporting their communities. Second, many spoke about the ongoing moral responsibilities that reviewers and editors felt toward authors. Finally, participants spoke at length about their enjoyment of social interactions and of the value of collective, rather than isolated, reasoning processes. Whether or not journal editors decide to allow anonymous review, the values of editors and reviewers need to be seriously addressed in codes of publication ethics, in the management of biomedical journals, and in the establishment of journal policies. Keywords: Peer review, Social values, Qualitative research, Research ethics, Bioethics: Medical ethics Research (humans)National Health and Medical Research Council (NHMRC) postgraduate scholarshi

Cancer As Rubbish: Donation of tumor tissue for research.

Tissue banking (or biobanking), thought by many to be an essential form of medical research, has raised a number of ethical issues that highlight a need to understand the beliefs and values of tissue donors, including the motivations underlying consent or refusal to donate. Data from our qualitative study of the legal, social and ethical issues surrounding tumor banking in New South Wales, Australia, shows that participants’ attitudes to donation of tumor tissue for research are partially captured by theories of weak altruism and social exchange. However, we argue that the psychological rewards of value transformation described by Thompson’s rubbish theory provide additional insights into participants’ attitudes to tumor donation. We believe our data provides sufficient justification for an approach to regulation of tumor banking that is aimed at fostering a relationship based on the notions of virtuous reassignment and social exchange. Keywords Ethics; genetics; research participation; risk perceptionsUniversity of Sydney Cancer Research Fun

Overcoming entrenched disagreements. the case of misoprostol for post-partum haemorrhage.

The debate about whether misoprostol should be distributed to low resource communities to prevent post-partum haemorrhage (PPH), recognised as a major cause of maternal mortality, is deeply polarised. This is in spite of stakeholders having access to the same evidence about the risks and benefits of misoprostol. To understand the disagreement, we conducted a qualitative analysis of the values underpinning debates surrounding community distribution of misoprostol. We found that different moral priorities, epistemic values, and attitudes towards uncertainty were the main factors sustaining the debate. With this understanding, we present a model for ethical discourse that might overcome the current impasse

Values as ‘modest foundations’ for medicine

Medicine and healthcare have been around for thousands of years, but we seldom ask why they are so important. It seems self-evident that we should seek relief of suffering from some institution in the society in which we live and equally selfevident that each society should provide healthcare for its people at some level. Yet when we inquire further, we are driven to seek foundational answers to iterative questions, seeking answers at deeper and deeper levels. Ultimately, it seems best to accept the Humean refuge [1] and finish with some such statement as "Humans are like that" or "Societies can't function in any other way". These Humean questions suggest that survival, security and flourishing are endpoints for such an inquiry and that medical (and many other) systems are built on these implicit foundations. The ways in which societies build relevant systems (such as medicine, welfare, law, transport, housing and so on) will differ strikingly, but common ground will still exist at the foundational level. Acknowledging a commonality of foundations does not commit one either to a conservative normativity, nor to a loose relativism. Increasing activity at the level of the International Court of Justice makes clear that there is a possibility of consensus for judging the validity of the interpretations and enactments of foundational values in any society. The ideals of the American Declaration of Independence — life, liberty and the pursuit of happiness — are principles very similar to the foundational values of survival, security and flourishing. Person-centered medicine is inescapably based on theories of the person and must therefore be able to offer an account of what personhood is. Values underpin the philosophy and practice of medicine, including person-centered medicine, because they are foundations of personhood, as well as foundations of the societies in which each person lives. Keywords: Discourse, evidence-based medicine, foundationalism, medical epistemology, narrative-based medicine, person-centered medicine, reform, values-based medicinen/