The Vulnerability of Study Participants in the Context of Transnational Biomedical Research: From Conceptual Considerations to Practical Implications

Outsourcing clinical trials sponsored by pharmaceutical companies from industrialized countries to low‐ (middle)‐income countries – summarized as transnational biomedical research (TBR) – has lead to many concerns about ethical standards. Whether study participants are particularly vulnerable is one of those concerns. However, the concept of vulnerability is still vague and varies in its definition. Despite the fact that important international ethical guidelines such as the Declaration of Helsinki by the World Medical Association or the Ethical Guidelines for Biomedical Research Involving Human Subjects by the Council of International Organizations of Medical Sciences refer to vulnerability as ethical principle, each of their approaches are different. To overcome these shortcomings, we analyze and unite different approaches of vulnerability and develop practical criteria in order to operationalize the concept especially for the context of TBR. These criteria refer to the context of a study as well as the characteristics and the current living situation of study participants. Based on a case study of an HIV‐vaccine‐trial conducted in India we demonstrate how those criteria can be applied in a retrospective way to identify potential ethical conflicts. The criteria can also indicate a prospective function for ethical pre‐assessment. For this, we provide an outlook for three major topics: 1. Vulnerability as a normative concept: Different ways of protection; 2. The relevance of transparency and 3. Vulnerability as an instrument to increase decision participation of human subjects.     

PRENATAL GENETIC TESTING KITS SOLD AT YOUR LOCAL PHARMACY: PROMOTING AUTONOMY OR PROMOTING CONFUSION?

Research groups around the world are developing non‐invasive methods of prenatal genetic diagnosis, in which foetal cells are obtained by maternal blood test. Meanwhile, an increasing number of genetic tests are sold directly to the public. I extrapolate from these developments to consider a scenario in which PNGD self‐testing kits are sold directly to the public. Given the opposition to over‐the‐counter genetic tests and the continuing controversy surrounding PNGD, it is reasonable to expect objections to PNGD self‐testing kits. I focus on one potential objection, that PNGD self‐testing kits would undermine the autonomy of potential test subjects. More specifically, that ‘direct to the public’ PNGD would fail to ensure that consumers exercise autonomy in the following PNGD‐related choices:

• ? Should I use PNGD?
• ? Based on the results of the PNGD test, should I continue or terminate my pregnancy?

Under the current system, PNGD is provided by health care practitioners, who are required to counsel women both before and after the test. In contrast, ‘direct to the public’ PNGD would allow women to make their PNGD‐related decisions outside the context of the health care system. I compare these two decision‐making contexts, arguing that the health care system is not unequivocally better at promoting the autonomy of potential test subjects. Therefore the promotion of autonomy does not constitute a strong argument against such test kits. Other objections may be more persuasive, so I do not offer an overall assessment of the acceptability of ‘direct to the public’ PNGD.     

Variation in floral morphology and plant reproductive success in four Ipomoea species (Convolvulaceae) with contrasting breeding systems

• This study tested the hypothesis that self‐compatibility would be associated with floral traits that facilitate autonomous self‐pollination to ensure reproduction under low pollinator visitation. In a comparison of two pairs of Ipomoea species with contrasting breeding systems, we predicted that self‐compatible (SC) species would have smaller, less variable flowers, reduced herkogamy, lower pollinator visitation and higher reproductive success than their self‐incompatible (SI) congeners.
• We studied sympatric species pairs, I. hederacea (SC)– I. mitchellae (SI) and I. purpurea (SC)–I. indica (SI), in Mexico, over two years. We quantified variation in floral traits and nectar production, documented pollinator visitation, and determined natural fruit and seed set. Hand‐pollination and bagging experiments were conducted to determine potential for autonomous self‐pollination and apomixis.
• Self‐compatible Ipomoea species had smaller flowers and lower nectar production than SI species; however, floral variation and integration did not vary according to breeding system. Bees were primary pollinators of all species, but visitation rates were seven times lower in SC than SI species. SC species had a high capacity for autonomous self‐pollination due to reduced herkogamy at the highest anther levels. Self‐compatible species had two to six times higher fruit set than SI species.
• Results generally support the hypothesis that self‐compatibility and autonomous self‐pollination ensure reproduction under low pollinator visitation. However, high variation in morphological traits of SC Ipomoea species suggests they maintain variation through outcrossing. Furthermore, reduced herkogamy was associated with high potential for autonomous self‐pollination, providing a reproductive advantage that possibly underlies transitions to self‐compatibility in Ipomoea.

     

General principles regarding the use of adult stem cells

Abstract.  With only a few, almost inevitable exceptions, biomedical research has developed within the last 50 years under the tutelage of ethical standards of notable precision. In the vast world of scientific investigation, few disciplines can boast of having realized documents of such ethical rigour, and respect for the integrity and intrinsic value of the human person has been one of the cardinal principles of the researcher. Research is intrinsic to the medical profession; the reward of research is knowledge and its techniques are ordered towards maintenance of human health. Since this end concerns human beings, it demands an extremely rigorous ethical approach. Ethical aspects are present from the first moments of the experimental project and occur on three levels: choice of the objectives, selection and use of the appropriate means for the study, and application of resultant new discoveries. Today, our moral attention cannot be reduced to a cost–benefit analysis. Biomedical sciences and medicine have overlapping areas of interest that can be sources of tension: the good of the subject versus scientific utility; profit versus complexity of research; liberty versus ethical and juridical bonds; the public versus the private; and the individual versus the community. Here, I attempt to formulate some essential principles that should guarantee humane measures for research on humans.     

Molecular characterization of swine leukocyte antigen gene diversity in purebred Pietrain pigs

The porcine major histocompatibility complex (MHC) harbors the highly polymorphic swine leukocyte antigen (SLA) class I and II gene clusters encoding glycoproteins that present antigenic peptides to T cells in the adaptive immune response. In Austria, the majority of commercial pigs are F ₂ descendants of F ₁ Large White/Landrace hybrids paired with Pietrain boars. Therefore, the repertoire of SLA alleles and haplotypes present in Pietrain pigs has an important influence on that of their descendants. In this study, we characterized the SLA class I ( SLA‐1 , SLA‐2 , SLA‐3 ) and class II ( SLA‐DRB1 , SLA‐DQB1 , SLA‐DQA ) genes of 27 purebred Pietrain pigs using a combination of the high‐resolution sequence‐based typing (SBT) method and a low‐resolution (Lr) PCR‐based method using allele‐group, sequence‐specific primers (PCR‐SSP). A total of 15 class I and 13 class II haplotypes were identified in the studied cohort. The most common SLA class I haplotype Lr‐43.0 ( SLA‐1 *11XX– SLA‐3 *04XX– SLA‐2 *04XX) was identified in 11 animals with a frequency of 20%. For SLA class II, the most prevalent haplotype, Lr‐0.14 [ SLA‐DRB1 *0901– SLA‐DQB1 *0801– SLA‐DQA *03XX], was found in 14 animals with a frequency of 26%. Two class II haplotypes, tentatively designated as Lr‐Pie‐0.1 [ SLA‐DRB1 *01XX/be01/ha04– SLA‐DQB1 *05XX– SLA ‐ DQA*blank] and Lr‐Pie‐0.2 [ SLA‐DRB1 *06XX– SLA‐DQB1 *03XX– SLA‐DQA *03XX], appeared to be novel and have never been reported so far in other pig populations. We showed that SLA genotyping using PCR‐SSP‐based assays represents a rapid and cost‐effective way to study SLA diversity in outbred commercial pigs and may facilitate the development of more effective vaccines or identification of disease‐resistant pigs in the context of SLA antigens to improve overall swine health.     

‘Bioethical Realism’: A Framework for Implementing Universal Research Ethics

Implementation of existing ethical guidelines for international collaborative medical and health research is still largely controversial in sub‐Saharan Africa for two major reasons: One, they are seen as foreign and allegedly inconsistent with what has been described as an ‘African worldview’, hence, demand for their strict implementations reeks of ‘bioethical imperialism’. Two, they have other discernible inadequacies – lack of sufficient detail, apparent as well as real ambiguities, vagueness and contradictions. Similar charges exist(ed) in other non‐Western societies. Consequently, these guidelines have been correctly judged as an inadequate response to the complex and ever shifting dilemmas met by researchers and research regulators in the field. This paper proposes a framework for effective implementation of existing guidelines without much worry about bioethical imperialism and other inadequacies. This framework is proposed using an analogy of Legal Realism, specifically its key assertions on how, in reality, judicial systems operate using general legal rules to settle specific cases. Legal realists assert that in judicial decision‐making, general legal rules do not totally dictate court decisions in specific cases. This analogy is used to coin a new term, ‘Bioethical Realism.’ The framework suggests that local Research Ethics Committees ought to be construed as analogues of judicial courts with the resulting implications. Consequently, just like legal rules are general rules that do not always dictate court decisions, similarly international bioethical guidelines are general ethical rules that should not always dictate local RECs’ decisions and such decisions (ought to) enjoy considerable immunity from outsiders.     

The effect of multiple natural enemies on a shared herbivore prey

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News and ISN

• Journal of Neurochemistry announces the move to Online Only publication as of January 2014 (issue 128‐1), with the recent release of the new App for iPad. Versions for iPhone and Android will follow soon.
• The App can be downloaded from https://itunes.apple.com/us/app/journal-neurochemistry-for/id655612235

• Special Issues have been published on:
  • 150 Years of Friedreich Ataxia Research
  • Virtual Issue on Molecular Imaging
  • Mini article series featuring Model systems for Neurodegenerative Diseases (yeast, drosophila, zebrafish) with an accompanying Editorial Highlight
• In addition to the Society for Neuroscience (SfN) and the Federation of European Neuroscience Societies (FENS), the ISN has become a member of the global advocacy initiative recently launched by International Brain Research Organization (IBRO) , with a first panel discussion and poster presentation held at SfN in San Diego this November.
• The ISN council has decided to launch two new exciting ventures:
  • A joint ISN‐JNeurochem Flagship School envisioned to be a recurring school that focuses on high impact research, to be launched in celebration of ISN's 50th anniversary celebration
  • A junior investigator committee to provide a voice for our junior researchers in society and biennial meeting issues.

     

Not Fit for Purpose: The Ethical Guidelines of the Indian Council of Medical Research

In 2006, the Indian Council of Medical Research (ICMR) published its ‘Ethical guidelines for Biomedical Research on human participants’. The intention was to translate international ethical standards into locally and culturally appropriate norms and values to help biomedical researchers in India to conduct ethical research and thereby safeguard the interest of human subjects. Unfortunately, it is apparent that the guideline is not fit for purpose. In addition to problems with the structure and clarity of the guidelines, there are several serious omissions and contradictions in the recommendations. In this paper, we take a close look at the two key chapters and highlight some of the striking flaws in this important document. We conclude that ethics committees and national authorities should not lose sight of international ethical standards while incorporating local reality and cultural and social values, as focusing too much on the local context could compromise the safety of human subjects in biomedical research, particularly in India.     

AGAINST RISK-BENEFIT REVIEW OF PRISONER RESEARCH

The 2006 Institute of Medicine (IOM) report, 'Ethical Considerations for Research Involving Prisoners', recommended five main changes to current US Common Rule regulations on prisoner research. Their third recommendation was to shift from a category-based to a risk-benefit approach to research review, similar to current guidelines on pediatric research. However, prisoners are not children, so risk-benefit constraints on prisoner research must be justified in a different way from those on pediatric research. In this paper I argue that additional risk-benefit constraints on prisoner research are unnecessary: the current Common Rule regulations, omitting category-based restrictions but conjoined with the IOM report's other four main recommendations, ensure that prisoner research is as ethical as non-prisoner research is. I explain why four problems which which may be more prevalent in prisons and which risk-benefit constraints may seem to address – coercion, undue inducements, exploitation, and protection from harm – are in fact not solved by adding further risk-benefit constraints on prisoner research.     

The Disclosure of Genetic Information: A Human Research Ethics Perspective

Increasing emphasis on genetic research means that growing numbers of human research projects in Australia will involve complex issues related to genetic privacy, familial information and genetic epidemiology. The Office of Population Health Genomics (Department of Health, Western Australia) hosted an interactive workshop to explore the ethical issues involved in the disclosure of genetic information, where researchers and members of human research ethics committees (HRECs) were asked to consider several case studies from an ethical perspective. Workshop participants used a variety of approaches to examine the complex ethical issues encountered, but did not consistently refer to the values and principles outlined in the National Statement on Ethical Conduct in Human Research (NHMRC 2007) or apply rational ethical approaches. Overall, the data suggested that both researchers and HREC members may benefit from further education and support regarding the application of ethical frameworks to the issues encountered in genetic research.     

Primates in traditional folk medicine: a world overview

• 1 Almost 50% of primate species are in danger of becoming extinct, according to the criteria of the International Union for Conservation of Nature (IUCN) Red List of Threatened Species. This is partly because of their consumption by humans. The reasons for hunting vary by region. One pretext is the medicinal or magical value of products derived from these animals.
• 2 In this paper, we provide an overview of the global use of primates in traditional folk medicines as well as identifying the species used as remedies associated with folk beliefs. Some important questions relating to the conservation of primates are addressed.
• 3 Our results revealed that at least 101 species of primates, which belong to 38 genera and 10 families, were used in traditional folk practices and in magic–religious rituals throughout the world.
• 4 Of the 101 species of primates recorded in our review, 12 species were classified as Critically Endangered, 23 as Endangered, 22 as Vulnerable, seven as Near Threatened, 36 as Least Concern and one as Data Deficient in the IUCN Red List. All species were also included in The Convention on International Trade in Endangered Species of Wild Fauna and Flora Appendices I or II, although the reasons for their inclusion were not necessarily related to their medicinal use.
• 5 The widespread utilization of primates in traditional medicine is evidence of the importance of understanding such uses in the context of primate conservation as well as the need for considering socio‐cultural factors when establishing management plans concerning the sustainable use of these mammals.

     

Inferring insect feeding patterns from sugar profiles: a comparison of statistical methods

1. Investigations in nutritional ecology often require the identification of animal feeding patterns in natural conditions (what, where, and when do animals eat). Thus, methods are needed to trace not only individual resource uptake but also the relative use of different resources in a population or community.
2. Recent biochemical developments allow predicting the use of sugar‐rich resources from insects in the field. Individual feeding status (feeding history, food sources) is inferred by comparing insect sugar profiles with those of individuals fed on controlled diets. Individual assignations are then used to predict the relative consumption of different resources at the population or community level. As both steps may generate error, accurate prediction rules are needed. However, research from other domains (e.g., protein‐marking studies) suggests that classical decision rules used for such tasks may sometimes induce bias.
3. This study evaluated the performance of these rules and compared them to alternative methods on simulated, realistic datasets. It tested different methods for individual classification but also introduced methods for prevalence estimation, whose specific purpose is to estimate the relative frequency of different classes.
4. Alternative methods substantially outperformed the traditional algorithms to predict insect individual feeding status and population class distribution (relative frequency of insects with different feeding status). This study provided a simple decision tool to choose a method according to dataset size, variance, and biochemical method used.
5. Alternative methods should increase prediction confidence in future studies. Such approaches should easily be generalized to a wider range of systems.

     

Community‐based native seed production for restoration in Brazil – the role of science and policy

• Large‐scale restoration programmes in the tropics require large volumes of high quality, genetically diverse and locally adapted seeds from a large number of species. However, scarcity of native seeds is a critical restriction to achieve restoration targets.
• In this paper, we analyse three successful community‐based networks that supply native seeds and seedlings for Brazilian Amazon and Cerrado restoration projects. In addition, we propose directions to promote local participation, legal, technical and commercialisation issues for up‐scaling the market of native seeds for restoration with high quality and social justice.
• We argue that effective community‐based restoration arrangements should follow some principles: (i) seed production must be based on real market demand; (ii) non‐governmental and governmental organisations have a key role in supporting local organisation, legal requirements and selling processes; (iii) local ecological knowledge and labour should be valued, enabling local communities to promote large‐scale seed production; (iv) applied research can help develop appropriate techniques and solve technical issues.
• The case studies from Brazil and principles presented here can be useful for the up‐scaling restoration ecology efforts in many other parts of the world and especially in tropical countries where improving rural community income is a strategy for biodiversity conservation and restoration.

     

Anatomical and phenological implications of the relationship between Schinus polygama (Cav.) (Cabrera) and the galling insect Calophya rubra (Blanchard)

• The success of galling insects could be determined by synchronisation with host plant phenology and climate conditions, ensuring suitable oviposition sites for gall induction and food resources for their survival. The anatomical, histochemical and phenological synchronisation strategies between Calophya rubra (Blanchard) (Hemiptera: Psylloidea) and its host, the evergreen plant Schinus polygama (Cav.) (Cabrera) (Anacardiaceae), in the Mediterranean climate of southern Chile was evaluated and compared to that of the congeneric C. cf. duvauae (Scott) from Brazil and closely related host plant S. engleri in a subtropical climate.
• Anatomical, histometric, histochemical and vegetative phenology studies of the stem and galls were conducted from June 2015 to December 2016.
• Based on the anatomical, histometric and histochemical analysis, the conical stem gall traits imply gains over the non‐galled stem toward the galling insect survival, but the maintenance of phellem, secretory ducts and pith indicate conservative developmental traits that cannot be manipulated by C. rubra. Our results indicate that the conditions of the Mediterranean climate zone limit C. rubra immature activity during unfavourable periods, probably determining a diapause period and a univoltine life cycle, which are peculiarities of the S. polygama– C. rubra system.
• The synchronisation between development and seasonality confers peculiarities to the S. polygama– C. rubra system in the Mediterranean climate zone.

     

Addressing the challenge for expedient ethical review of research in disasters and disease outbreaks

Guideline 20 of the updated International Ethics Guidelines for Health‐related Research Involving Humans (2016) by the Council for International Organizations of Medical Sciences (CIOMS) provides guidance on research in disasters and disease outbreaks against the background of the need to generate knowledge quickly, overcome practical impediments to implementing such research, and the need to maintain public trust. The guideline recommends that research ethics committees could pre‐screen study protocols to expedite ethical reviews in a situation of crisis, that pre‐arrangements be made regarding data sharing and biomedical sample sharing, and that sponsors and research ethics committees seek to minimize risk to researchers conducting research during a disaster. This paper critiques these recommendations against the background of the findings of a survey of public health officials and chairs of research ethics committees in the Caribbean during 2016, which sought to determine the best template for the expeditious ethical review of research proposals in emergency and epidemic situations in the Caribbean, and whose findings can serve as a model for other low‐ and middle‐income countries.     

Adjusting the focus: A public health ethics approach to data research

This paper contends that a research ethics approach to the regulation of health data research is unhelpful in the era of population‐level research and big data because it results in a primary focus on consent (meta‐, broad, dynamic and/or specific consent). Two recent guidelines – the 2016 WMA Declaration of Taipei on ethical considerations regarding health databases and biobanks and the revised CIOMS International ethical guidelines for health‐related research involving humans – both focus on the growing reliance on health data for research. But as research ethics documents, they remain (to varying degrees) focused on consent and individual control of data use. Many current and future uses of health data make individual consent impractical, if not impossible. Many of the risks of secondary data use apply to communities and stakeholders rather than individual data subjects. Shifting from a research ethics perspective to a public health lens brings a different set of issues into view: how are the benefits and burdens of data use distributed, how can data research empower communities, who has legitimate decision‐making capacity? I propose that a public health ethics framework – based on public benefit, proportionality, equity, trust and accountability – provides more appropriate tools for assessing the ethical uses of health data. The main advantage of a public health approach for data research is that it is more likely to foster debate about power, justice and equity and to highlight the complexity of deciding when data use is in the public interest.     

Effect of plant patch shape on the distribution and abundance of three lepidopteran species associated with Brassica oleracea

• 1 Plant patch shape may affect the abundance of herbivorous insects. Patches of the same size but longer or irregular have a higher perimeter/area relationship (P/A) than square or regular ones, which may determine the immigration, emigration and abundance of individuals in the patch.
• 2 Only specialist species should be affected by plant patch shape. Those species that are more abundant in smaller patches should be more abundant in patches with higher P/A, whereas those that are more abundant in larger patches should be more abundant in patches with lower P/A.
• 3 We studied the density of eggs, larvae and pupae of Pieris brassicae, Plutella xylostella and Trichoplusia ni in square (low P/A) and I‐shaped (high P/A) patches of 144 plants of Brassica oleracea. We also estimated their immigration to these patches, and the final plant weight.
• 4 Plant patch shape affected the abundance, but not the distribution, of the two specialist species. Whereas P. brassicae was denser in I‐shaped patches, P. xylostella was more abundant in square patches. The generalist T. ni was not affected by patch shape. Immigration of P. brassicae was higher in I‐shaped patches, but immigration of P. xylostella and T. ni was not affected by patch shape. Plants were heavier in the centre of square patches.
• 5 Our results suggest that plant patch shape affects the density of herbivorous insects and should be considered independently from other plant patch variables when studying the population dynamics of these organisms.

     

Road kills of non‐human primates: a global view using a different type of data

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The forgotten whale: a bibliometric analysis and literature review of the North Atlantic sei whale Balaenoptera borealis

• 1 A bibliometric analysis of the literature on the sei whale Balaenoptera borealis is presented. Research output on the species is quantified and compared with research on four other whale species. The results show a significant increase in research for all species except the sei whale. Research output is characterized chronologically and by oceanic basin.
• 2 The species' distribution, movements, stock structure, feeding, reproduction, abundance, acoustics, mortality and threats are reviewed for the North Atlantic, and the review is complemented with previously unpublished data.
• 3 Knowledge on the distribution and movements of the sei whale in the North Atlantic is still mainly derived from whaling records. Movement patterns and winter distribution are not clear. Surveys in some known summering areas show that the species has changed its distribution in parts of its previously known range.
• 4 With the present information, it is impossible to determine whether or not the North Atlantic sei whale population is subdivided into biological units. Abundance estimates are fragmentary and cover a restricted part of the summering habitat.
• 5 In the North Atlantic, sei whales seem to be stenophagous, feeding almost exclusively on calanoid copepods and euphausiids. On feeding grounds, they are associated with oceanic frontal systems, but how they find and explore these structures has not been fully investigated.
• 6 The available data on vital rates are based on whaling‐derived studies and are 25 years old or older. Despite increasing human and environmentally induced pressures, there are no current estimates for mortality and population trends.
• 7 Current research needs include the clear definition of stock units, reliable abundance estimates, studies of distribution and migration that incorporate the identification of wintering areas, acquisition of up‐to‐date data on reproduction and mortality, and investigations into the consequences of environmental changes for the species.