Cluster randomization and political philosophy

In this paper, I will argue that, while the ethical issues raised by cluster randomization can be challenging, they are not new. My thesis divides neatly into two parts. In the first, easier part I argue that many of the ethical challenges posed by cluster randomized human subjects research are clearly present in other types of human subjects research, and so are not novel. In the second, more difficult part I discuss the thorniest ethical challenge for cluster randomized research--cases where consent is genuinely impractical to obtain. I argue that once again these cases require no new analytic insight; instead, we should look to political philosophy for guidance. In other words, the most serious ethical problem that arises in cluster randomized research also arises in political philosophy.     

The clinical characterization of the adult patient with depression aimed at personalization of management

Depression is widely acknowledged to be a heterogeneous entity, and the need to further characterize the individual patient who has received this diagnosis in order to personalize the management plan has been repeatedly emphasized. However, the research evidence that should guide this personalization is at present fragmentary, and the selection of treatment is usually based on the clinician's and/or the patient's preference and on safety issues, in a trial‐and‐error fashion, paying little attention to the particular features of the specific case. This may be one of the reasons why the majority of patients with a diagnosis of depression do not achieve remission with the first treatment they receive. The predominant pessimism about the actual feasibility of the personalization of treatment of depression in routine clinical practice has recently been tempered by some secondary analyses of databases from clinical trials, using approaches such as individual patient data meta‐analysis and machine learning, which indicate that some variables may indeed contribute to the identification of patients who are likely to respond differently to various antidepressant drugs or to antidepressant medication vs. specific psychotherapies. The need to develop decision support tools guiding the personalization of treatment of depression has been recently reaffirmed, and the point made that these tools should be developed through large observational studies using a comprehensive battery of self‐report and clinical measures. The present paper aims to describe systematically the salient domains that should be considered in this effort to personalize depression treatment. For each domain, the available research evidence is summarized, and the relevant assessment instruments are reviewed, with special attention to their suitability for use in routine clinical practice, also in view of their possible inclusion in the above‐mentioned comprehensive battery of measures. The main unmet needs that research should address in this area are emphasized. Where the available evidence allows providing the clinician with specific advice that can already be used today to make the management of depression more personalized, this advice is highlighted. Indeed, some sections of the paper, such as those on neurocognition and on physical comorbidities, indicate that the modern management of depression is becoming increasingly complex, with several components other than simply the choice of an antidepressant and/or a psychotherapy, some of which can already be reliably personalized.     

Widening gap between expectations and practice in Australian minesite rehabilitation

The basic methods for rehabilitating degraded land left after mining are reasonably well‐understood and there are examples across Australia of these being currently implemented. But there are many other situations where further research will be needed to achieve rehabilitation objectives. In addition, a number of mines are yet to embark on any sustained program of rehabilitation and there is a disappointing number of cases of mines ceasing operations before rehabilitation is completed leaving sites in a badly degraded state. Overall there appear to be surprisingly few examples in Australia of post‐ mining rehabilitation that has reached a successful conclusion. In part, this may be simply a matter of time and the problem will be resolved as more mines reach the end of their working lives. But there is an apparent trend for mines to be placed into ‘care and maintenance’ or sold to other entities, to avoid the costs of rehabilitation. Thus, we are concerned there is a widening gap between what should be possible and what is being done in practice. We review some of the experiences of rehabilitating post‐mining landscapes in Australia and conclude that problems have arisen because of (i) the inherently difficult task of restoring ecosystems at highly modified mine sites, (ii) institutional and management weaknesses and (iii) loose regulatory frameworks that allow a high level of company self‐regulation. A key problem is that the importance of rehabilitation appears to rank below that of production in the minds of many mine managers and is not accorded the level of priority that the community expects. The scale of the mining industry and its capacity to cause environmental damage means that there is a need to improve the way mine rehabilitation is currently undertaken. We suggest that this might be achieved by improving research programs as well as better institutional and regulatory arrangements. The present situation represents a major ecological and financial risk to the nation as a whole and regulatory authorities need to develop more rigorous approaches to ensure effective rehabilitation standards are achieved.     

Role of the embryology laboratory in the human embryonic stem cell line derivation process

With the introduction of regenerative medicine and cell therapy programmes by means of human embryonic stem cells (hESC), several research centres have begun projects of derivation of hESC lines. In some stem cell banks, such as the Andalusian Stem Cell Bank, the law also permits the creation of these cell lines. Therefore, the recovery of cryopreserved embryos, their culture and the subsequent derivation to hESC lines requires a suitable embryology laboratory and specialized and highly qualified staff. Moreover, new techniques, from therapeutic nuclear transfer, need this type of laboratory and staff, too. Several International Associations have drawn up some guidelines for laboratories where embryos are manipulated and they reflect the physical space, the staff and the equipment needed in these kinds of laboratories. Nevertheless, we can see that these guidelines do not distinguish between IVF laboratories and other laboratories that obtain hESC lines, so it would be convenient to make a distinction. Following these guidelines, we have tried to draw up concurrent aspects applicable to areas of embryology within stem cell banks. So, the design and the specific implementation programmes for these areas and other research centres with this area but which do not use IVF techniques is vital to develop embryonic cell lines in optimum conditions for future therapeutic applications, although maybe it is rather premature to standardize this type of research.     

Regional collection planning for speciose taxonomic groups

Regional collection planning and implementation are essential if professional zoological parks and aquariums are to achieve their collective conservation and animal management goals. Several regional associations currently have taxon advisory groups (TAGs) in place whose primary role is to develop taxon‐specific collection plans. During their planning process, TAGs review all known taxa of interest and evaluate them based on relevant criteria. TAGs also evaluate the total amount of captive space available to determine the number of priority taxa that can be maintained. In addition, some TAGs heighten their impact on conservation by producing an action plan of select conservation and research projects to be supported by participating institutions. Although current guidelines for regional collection plan (RCP) development are extremely useful for some TAGs, such as those for most mammalian taxa, they do not address the needs of other more speciose TAGs, such as those for fish, invertebrates, and amphibians. These TAGs, characterized by their numerous taxa and more flexible space requirements, still need to develop plans for the species they manage. We recommend that highly speciose TAGs make development of an action plan their highest priority and use it to direct the RCP process. This will limit the number of taxa they need to consider, while ensuring that their RCPs are directly relevant to conservation. Once their action plans have been developed, speciose TAGs can then determine which species are most important to zoological collections and at what level they should be managed. This strategy represents a departure from the current processes used to develop RCPs for many mammalian and avian species and, as such, has not yet been addressed. An action plan‐driven approach will result in more practical and relevant planning for speciose TAGs. Zoo Biol 21:313–320, 2002. © 2002 Wiley‐Liss, Inc.     

ON USING PEOPLE MERELY AS A MEANS IN CLINICAL RESEARCH

It is often argued that clinical research should not violate the Kantian principle that people must not be used merely as a means for the purposes of others. At first sight, the practice of clinical research itself, however, seems to violate precisely this principle: clinical research is often beneficial to future people rather than to participants; even if participants benefit, all things considered, they are exposed to discomforts which are absent both in regular care for their diseases and in other areas of daily life. Therefore, in this paper we will consider whether people are used merely as a means by being enrolled in clinical research. On the basis of recent studies of Kantian scholars we will argue that clinical research is compatible with the Kantian principle if the conditions of possible consent and end‐sharing have been met. Participants are not used merely as a means if they have sufficient reasons to consent to being enrolled in clinical research and can share the ends of the researchers who use them. Moreover, we will claim that even if people are used merely as a means by participating in clinical research, it may not always be morally wrong to use them in this way.     

Infants,Children, and Informed Consent

Obtaining informed consent for non-therapeutic experimentation on infants and children has ethical and legal implications that cause great controversy. There is some danger that worthy research will be inhibited if current ethical codes are interpreted too strictly, yet infants, children, and other vulnerable groups clearly must be protected from exploitation as research subjects. It is suggested that permission from parents coupled with integrity of the investigator will remain the child''s best protection, but several additional protective mechanisms are available and should be used. Some guidelines for non-therapeutic research are suggested which should not only provide adequate protection for infants and young children involved in research projects, but allow investigators reasonable freedom to prosecute worthy research vital to continued improvements in child care.     

Expanding the moral circle: farmed fish as objects of moral concern

Until recently fish welfare attracted little attention, but international and national legislation and standards of fish welfare are now emerging and an overview of these developments is presented in this study. Whereas animal welfare legislation is based on public morality, animal ethics does not automatically accept public morality as normative and elaborates arguments regarding the way humans should treat animals (referred to as moral standards). In this study we present the most common animal ethics theories. For most of these, sentience is considered a demarcation line for moral concern: if an animal is sentient, then it should be included in the moral circle, i.e. receive moral consideration in its own right and some basic welfare should be ensured. As for fish, research has revealed that the sensory system of teleosts can detect noxious stimuli, and that some kind of phenomenal consciousness, allowing the fish to feel pain, seems to be present. This raises the ethical question as to how much evidence we need in order to act on such indications of fish sentience. A simple risk analysis shows that the probability that fishes can feel pain is not negligible and that if they do indeed experience pain the consequences in terms of the number of suffering individuals are great. We conclude that farmed fish should be given the benefit of the doubt and we should make efforts that their welfare needs are met as well as possible. Finally, the way forward is briefly discussed: efforts must be made to understand what fish welfare means in practical fish farming. This will involve the development of research and education, greater accountability and transparency, compliance with and control of policies, and quality assurance schemes.     

Upsetting the balance on sex selection

It is widely assumed that the strongest case for permitting non‐medical sex selection is where parents aim at family balance. This piece criticizes one representative attempt to justify sex selection for family balance. Kluge (2007) assumes that some couples may seek sex selection because they hold discriminatory values, but this need not impugn those who merely have preferences, without evaluative commitments, for a particular sex. This is disputed by those who see any sex selection as inherently sexist because it upholds stereotypes about the sexes. This article takes an alternative approach. I argue that, even if we accept that preference‐based selection is unobjectionable, a policy permitting selection for family balancing does a poor job of distinguishing between value‐based and preference‐based selection. If we wish to permit only preference‐based sex selection we should seek to identify parents’ motives. If we wish to justify a family balancing policy, other arguments are needed.     

A Trust‐Based Pact in Research Biobanks. From Theory to Practice

Traditional Informed Consent is becoming increasingly inadequate, especially in the context of research biobanks. How much information is needed by patients for their consent to be truly informed? How does the quality of the information they receive match up to the quality of the information they ought to receive? How can information be conveyed fairly about future, non‐predictable lines of research? To circumvent these difficulties, some scholars have proposed that current consent guidelines should be reassessed, with trust being used as a guiding principle instead of information. Here, we analyse one of these proposals, based on a Participation Pact, which is already being offered to patients at the Istituto Europeo di Oncologia, a comprehensive cancer hospital in Milan, Italy.     

WHICH BENEFITS OF RESEARCH PARTICIPATION COUNT AS ‘DIRECT’?

It is widely held that individuals who are unable to provide informed consent should be enrolled in clinical research only when the risks are low, or the research offers them the prospect of direct benefit. There is now a rich literature on when the risks of clinical research are low enough to enroll individuals who cannot consent. Much less attention has focused on which benefits of research participation count as ‘direct’, and the few existing accounts disagree over how this crucial concept should be defined. This disagreement raises concern over whether those who cannot consent, including children and adults with severe dementia, are being adequately protected. The present paper attempts to address this concern by considering first what additional protections are needed for these vulnerable individuals. This analysis suggests that the extant definitions of direct benefits either provide insufficient protection for research subjects or pose excessive obstacles to appropriate research. This analysis also points to a modified definition of direct benefits with the potential to avoid these two extremes, protecting individuals who cannot consent without blocking appropriate research.     

Mind the gap: An empirical study of post‐trial access in HIV biomedical prevention trials

The principle of providing post‐trial access for research participants to successful products of that research is widely accepted and has been enshrined in various declarations and guidelines. While recent ethical guidelines recognise that the responsibility to provide post‐trial access extends to sponsors, regulators and government bodies as well as to researchers, it is the researchers who have the direct duty of care to participants. Researchers may thus need to act as advocates for trial participants, especially where government bodies, sponsors, and regulatory bodies have complex interests vested in decisions about whether or not new interventions are made available, how, and to whom. This paper provides an empirical account of post‐trial access in the context of HIV prevention research. It describes both access to the successful products of research and the provision antiretroviral drugs for trial participants who acquire HIV. First, we provide evidence that, in the current system, there is considerable variation in the duration and timeliness of access. We then argue that by analysing the difficulties faced by researchers to this point, and their efforts to meet this obligation, much can be learned about how to secure post‐trial access in HIV biomedical preventions trials. While researchers alone have a limited obligation, their advocacy on behalf of trial participants may be necessary to call the other parties to account.     

How the CIOMS guidelines contribute to fair inclusion of pregnant women in research

As early as 2002, CIOMS stated that pregnant women should be presumed eligible for participation in research. Despite this position and calls of other well‐recognized organizations, the health needs of pregnant women in research remain grossly under‐researched. Although the presumption of eligibility remains unchanged, the revision of the 2002 CIOMS International ethical guidelines for biomedical research involving human subjects involved a substantive rewrite of the guidance on research with pregnant women and related guidelines, such as those on fair inclusion and vulnerability. However, close reading of the guidelines reveals morally relevant different approaches to fair inclusion of pregnant women and other under‐represented groups, such as children and incompetents. Where CIOMS sets out that children and adolescents must be included unless a good scientific reason justifies their exclusion, no such claim of having to justify exclusion appears in the guideline on pregnant women. Instead, CIOMS claims that research relevant to pregnant women’s health needs must be promoted. This paper analyses how and to what extent the guideline on pregnant women differs from other guidance on fair inclusion in the document. Accordingly, the paper evaluates to what extent the current phrasing may contribute to fair inclusion of pregnant women in research. We will conclude that a system change towards a learning health system is essential to break down the status quo of knowledge generation in the field of medication use during pregnancy and argue that the CIOMS guidelines allow for this system change.     

Controlling morpholino experiments: don't stop making antisense

One of the most significant problems facing developmental biologists who do not work on an organism with well-developed genetics - and even for some who do - is how to inhibit the action of a gene of interest during development so as to learn about its normal biological function. A widely adopted approach is to use antisense technologies, and especially morpholino antisense oligonucleotides. In this article, we review the use of such reagents and present examples of how they have provided insights into developmental mechanisms. We also discuss how the use of morpholinos can lead to misleading results, including off-target effects, and we suggest controls that will allow researchers to interpret morpholino experiments correctly.     

On the Alleged Right to Participate in High‐Risk Research

Reigning regulatory frameworks for biomedical research impose on researchers and research ethics committees an obligation to protect research participants from risks that are unnecessary, disproportionate to potential research benefits, and non‐minimized. Where the research has no potential to produce results of direct benefit to the subjects and the subjects are unable to give consent, these requirements are strengthened by an additional condition, that risks should not exceed a certain minimal threshold. In this article, I address the question of whether there should be limits of permissible risks in non‐therapeutic research involving competent and healthy subjects. Some commentators argue that competent and informed individuals should have a right to participate even in extremely risky research and that research ethics committees should never reject studies because they are too dangerous. To use David Shaw's expression, competent volunteers should have ‘a right to participate in high‐risk research’. I argue that this idea is ill‐founded, as it does not take into account the social mission and complex collaborative nature of research practice as well as the inequity of power between researchers and subjects. Imposition of limits on permissible risks for healthy volunteers is justified by the need to protect research enterprise and the need to protect the weaker party, namely the subjects. Also, I suggest that the best way to set boundaries on research risks is to leave the judgment of risk acceptability to research ethics committees.     

Guidelines for the use and interpretation of assays for monitoring autophagy

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.     

Guidelines for the use and interpretation of assays for monitoring autophagy

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.     

Measuring and improving the quality of mental health care: a global perspective

Mental disorders are common worldwide, yet the quality of care for these disorders has not increased to the same extent as that for physical conditions. In this paper, we present a framework for promoting quality measurement as a tool for improving quality of mental health care. We identify key barriers to this effort, including lack of standardized information technology‐based data sources, limited scientific evidence for mental health quality measures, lack of provider training and support, and cultural barriers to integrating mental health care within general health environments. We describe several innovations that are underway worldwide which can mitigate these barriers. Based on these experiences, we offer several recommendations for improving quality of mental health care. Health care payers and providers will need a portfolio of validated measures of patient‐centered outcomes across a spectrum of conditions. Common data elements will have to be developed and embedded within existing electronic health records and other information technology tools. Mental health outcomes will need to be assessed more routinely, and measurement‐based care should become part of the overall culture of the mental health care system. Health care systems will need a valid way to stratify quality measures, in order to address potential gaps among subpopulations and identify groups in most need of quality improvement. Much more attention should be devoted to workforce training in and capacity for quality improvement. The field of mental health quality improvement is a team sport, requiring coordination across different providers, involvement of consumer advocates, and leveraging of resources and incentives from health care payers and systems.     

Depression screening as a quality indicator

Objective Although practice guidelines for depression screening are evidence based, with their development relying on reviews of controlled studies, their adaptation and use as quality indicators have not been subject to rigorous study. This paper will therefore review the evidence supporting this practice.Methods A rational evaluation was carried out on both controlled studies and other sources of evidence related to the technical, clinical and policy assumptions underlying the use of depression screening guidelines as quality indicators.Results 1) Technical assumptions: depression screening could be used as a quality indicator. Current information technology does not allow accurate determination of who would benefit from being screened, whether they actually were screened, or the optimal percentage that should be screened. 2) Clinical assumptions: depression screening would improve outcomes. The evidence suggests that although depression screening might increase the diagnosis of depression, depressed patients so recognised tend to be less ill, less in need of treatment, or less likely to benefit from treatment, while screening, in the absence of other interventions, does not improve outcomes. 3) Policy assumptions: depression screening should be a focus of quality improvement. However, relative to other preventative measures, depression screening is a low priority. It does not meet usual cost-effectiveness criteria. There are more robust interventions for depression (i.e. collaborative care) that could be a focus of quality improvement efforts.Conclusion Although routine depression screening may be an acceptable practice guideline, its use as a quality measure is not supported.