The ethical issues regarding consent to clinical trials with pre-term or sick neonates: a systematic review (framework synthesis) of the analytical (theoretical/philosophical) research

BackgroundConducting clinical trials with pre-term or sick infants is important if care for this population is to be underpinned by sound evidence. Yet, approaching the parents of these infants at such a difficult time raises challenges to obtaining valid informed consent for such research. In this study, we asked, What light does the analytical literature cast on an ethically defensible approach to obtaining informed consent in perinatal clinical trials?MethodsIn a systematic search, we identified 30 studies. We began our analysis by applying philosophical frameworks, which were then refined as concepts emerged from the analytical studies, to present a coherent picture of a broad literature.ResultsBetween them, the studies addressed four themes. The first three were the ethical basis for parental informed consent for neonatal and/or perinatal research, the validity of parental consent in this context, and the range of possible options in methods for gaining consent. The last was the issue of risk and the possibility of a double-standard or asymmetry in the current approaches to the requirement for consent for research and consent for clinical treatment.ConclusionsIn addressing these issues, the analysed studies showed that, whilst there are a variety of possible defences for seeking parental ‘consent’ to neonatal and/or perinatal clinical trials, these are all consistent with the strongly and widely held view that it is important that parents do give (or decline) consent for such research. So far as the method of obtaining consent is concerned, none of the existing consent processes reviewed by the research is satisfactory, and there are philosophical reasons for supposing that at least some parents will fail to give valid consent in a neonatal context. Furthermore, in giving parental ‘consent’ in a perinatal context, parents are authorising infant participation, not giving ‘proxy consent’. Finally, there are reasons for giving weight to both parental ‘consent’ and the infant’s best interests in both research and clinical treatment. However, there are also reasons to treat these factors differently in the two contexts, and this may be partly due to the differing relevance of risk in each case. A significant gap is the lack of any detailed discussion of a process of emergency and/or urgent ‘assent’, in which parents assent or refuse their baby’s participation as best they can during the emergency and later give full consent to continuing participation and follow-up.

Electronic supplementary material

The online version of this article (doi:10.1186/s13063-016-1562-3) contains supplementary material, which is available to authorized users.     

The traits of “trait ecologists”: An analysis of the use of trait and functional trait terminology

Trait and functional trait approaches have revolutionized ecology improving our understanding of community assembly, species coexistence, and biodiversity loss. Focusing on traits promotes comparability across spatial and organizational scales, but terms must be used consistently. While several papers have offered definitions, it remains unclear how ecologists operationalize “trait” and “functional trait” terms. Here, we evaluate how researchers and the published literatures use these terms and explore differences among subdisciplines and study systems (taxa and biome). By conducting both a survey and a literature review, we test the hypothesis that ecologists’ working definition of “trait” is adapted or altered when confronting the realities of collecting, analyzing and presenting data. From 486 survey responses and 712 reviewed papers, we identified inconsistencies in the understanding and use of terminology among researchers, but also limited inclusion of definitions within the published literature. Discrepancies were not explained by subdiscipline, system of study, or respondent characteristics, suggesting there could be an inconsistent understanding even among those working in related topics. Consistencies among survey responses included the use of morphological, phonological, and physiological traits. Previous studies have called for unification of terminology; yet, our study shows that proposed definitions are not consistently used or accepted. Sources of disagreement include trait heritability, defining and interpreting function, and dealing with organisms in which individuals are not clearly recognizable. We discuss and offer guidelines for overcoming these disagreements. The diversity of life on Earth means traits can represent different features that can be measured and reported in different ways, and thus, narrow definitions that work for one system will fail in others. We recommend ecologists embrace the breadth of biodiversity using a simplified definition of “trait” more consistent with its common use. Trait‐based approaches will be most powerful if we accept that traits are at least as diverse as trait ecologists.     

Dogs (Canis familiaris) Evaluate Humans on the Basis of Direct Experiences Only

Reputation formation is a key component in the social interactions of many animal species. An evaluation of reputation is drawn from two principal sources: direct experience of an individual and indirect experience from observing that individual interacting with a third party. In the current study we investigated whether dogs use direct and/or indirect experience to choose between two human interactants. In the first experiment, subjects had direct interaction either with a “nice” human (who played with, talked to and stroked the dog) or with an “ignoring” experimenter who ignored the dog completely. Results showed that the dogs stayed longer close to the “nice” human. In a second experiment the dogs observed a “nice” or “ignoring” human interacting with another dog. This indirect experience, however, did not lead to a preference between the two humans. These results suggest that the dogs in our study evaluated humans solely on the basis of direct experience.     

“Liking” as an early and editable draft of long-run affective value

Psychological and neural distinctions between the technical concepts of “liking” and “wanting” pose important problems for motivated choice for goods. Why could we “want” something that we do not “like,” or “like” something but be unwilling to exert effort to acquire it? Here, we suggest a framework for answering these questions through the medium of reinforcement learning. We consider “liking” to provide immediate, but preliminary and ultimately cancellable, information about the true, long-run worth of a good. Such initial estimates, viewed through the lens of what is known as potential-based shaping, help solve the temporally complex learning problems faced by animals.

What is the distinction between ’liking’ and ’wanting’? Why could we ’want’ something that we do not ’like,’ or ’like’ something but be unwilling to exert effort to acquire it? This Essay argues that the primary hedonic phenomenon called ’liking’ might solve the temporal credit assignment problem for learning that arises when true reinforcement values are available slowly or late.     

An assessment of terminology for intraspecific diversity in fishes,with a focus on “ecotypes” and “life histories”

Understanding and preserving intraspecific diversity (ISD) is important for species conservation. However, ISD units do not have taxonomic standards and are not universally recognized. The terminology used to describe ISD is varied and often used ambiguously. We compared definitions of terms used to describe ISD with use in recent studies of three fish taxa: sticklebacks (Gasterosteidae), Pacific salmon and trout (Oncorhynchus spp., “PST”), and lampreys (Petromyzontiformes). Life history describes the phenotypic responses of organisms to environments and includes biological parameters that affect population growth or decline. Life‐history pathway(s) are the result of different organismal routes of development that can result in different life histories. These terms can be used to describe recognizable life‐history traits. Life history is generally used in organismal‐ and ecology‐based journals. The terms paired species/species pairs have been used to describe two different phenotypes, whereas in some species and situations a continuum of phenotypes may be expressed. Our review revealed overlapping definitions for race and subspecies, and subspecies and ecotypes. Ecotypes are genotypic adaptations to particular environments, and this term is often used in genetic‐ and evolution‐based journals. “Satellite species” is used for situations in which a parasitic lamprey yields two or more derived, nonparasitic lamprey species. Designatable Units, Evolutionary Significant Units (ESUs), and Distinct Population Segments (DPS) are used by some governments to classify ISD of vertebrate species within distinct and evolutionary significant criteria. In situations where the genetic or life‐history components of ISD are not well understood, a conservative approach would be to call them phenotypes.

The terminology used to describe intraspecific diversity is varied and often used ambiguously. “Ecotype” was originally used to describe patterns in genes and ecology, and recent studies employing this term tend to report a genetic basis in ISD. By contrast, “life history” describes biological parameters that affect demography, and this term tends to be used in organismal‐ and ecology‐based journals.     

A “New” low incidence “Hutterite” blood group antigen waldner (Wda)

A “new” red cell antigen has been found so far only in members of Hutterite kindreds with the surname Waldner. The antigen, Wd^a, is inherited as an autosomal dominant and is not part of the ABO, Chido, Colton, Dombrock, Duffy, Kidd, MN, P, or Rh blood group systems.     

Short Peptide Induces an “Uncultivable” Microorganism To Grow In Vitro

Microorganisms comprise the bulk of biodiversity, but only a small fraction of this diversity grows on artificial media. This phenomenon was noticed almost a century ago, repeatedly confirmed, and termed the “great plate count anomaly.” Advances in microbial cultivation improved microbial recovery but failed to explain why most microbial species do not grow in vitro. Here we show that at least some of such species can form domesticated variants capable of growth on artificial media. We also present evidence that small signaling molecules, such as short peptides, may be essential factors in initiating growth of nongrowing cells. We identified one 5-amino-acid peptide, LQPEV, that at 3.5 nM induces the otherwise “uncultivable” strain Psychrobacter sp. strain MSC33 to grow on standard media. This demonstrates that the restriction preventing microbial in vitro growth may be different from those offered to date to explain the “great plate count anomaly,” such as deficiencies in nutrient composition and concentrations in standard media, medium toxicity, and inappropriate incubation time. Growth induction of MSC33 illustrates that some microorganisms do not grow in vitro because they are removed from their native communities and the signals produced therein. “Uncultivable” species represent the largest source of unexplored biodiversity, and provide remarkable opportunities for both basic and applied research. Access to cultures of some of these species should be possible through identification of the signaling compounds necessary for growth, their addition to standard medium formulations, and eventual domestication.     

“Third‐wave” cognitive and behavioral therapies and the emergence of a process‐based approach to intervention in psychiatry

For decades, cognitive and behavioral therapies (CBTs) have been tested in randomized controlled trials for specific psychiatric syndromes that were assumed to represent expressions of latent diseases. Although these protocols were more effective as compared to psychological control conditions, placebo treatments, and even active pharmacotherapies, further advancement in efficacy and dissemination has been inhibited by a failure to focus on processes of change. This picture appears now to be evolving, due both to a collapse of the idea that mental disorders can be classified into distinct, discrete categories, and to the more central attention given to processes of change in newer, so‐called “third‐wave” CBTs. Here we review the context for this historic progress and evaluate the impact of these newer methods and models, not as protocols for treating syndromes, but as ways of targeting an expanded range of processes of change. Five key features of “third‐wave” therapies are underlined: a focus on context and function; the view that new models and methods should build on other strands of CBT; a focus on broad and flexible repertoires vs. an approach to signs and symptoms; applying processes to the clinician, not just the client; and expanding into more complex issues historically more characteristic of humanistic, existential, analytic, or system‐oriented approaches. We argue that these newer methods can be considered in the context of an idiographic approach to process‐based functional analysis. Psychological processes of change can be organized into six dimensions: cognition, affect, attention, self, motivation and overt behavior. Several important processes of change combine two or more of these dimensions. Tailoring intervention strategies to target the appropriate processes in a given individual would be a major advance in psychiatry and an important step toward precision mental health care.     

Informed consent and collaborative research: perspectives from the developing world

Introduction: Informed consent has been recognized as an important component of research protocols and procedures of disclosure and consent in collaborative research have been criticized, as they may not be in keeping with cultural norms of developing countries. This study, which is part of a larger project funded by the United States National Bioethics Advisory Commission, explores the opinions of developing country researchers regarding informed consent in collaborative research. Methods: A survey of developing country researchers, involved in human subject research, was conducted by distributing a questionnaire with 169 questions, which included questions relating to informed consent. In addition, six focus group discussions, eight in-depth interviews and 78 responses to open-ended questions in the questionnaire provided qualitative data. Results: 203 surveys were considered complete and were included in the analysis. Written consent was not used by nearly 40% of the researchers in their most recent studies. A large proportion of respondents recommended that human subject regulations should allow more flexibility in ways of documenting informed consent. 84% of researchers agreed that a mechanism to measure understanding should be incorporated in research studies as part of the process of informed consent. Discussion: This paper is an empirical step in highlighting the ethical issues concerning disclosure. Health researchers in developing countries are well aware of the importance of consent in health research, and equally value the significance of educating human subjects regarding study protocols and associated risks and benefits. However, respondents emphasize the need for modifying ethical regulations in collaborative research.     

Ultrastructure of Thiothrix spp. and “Type 021N” Bacteria

The ultrastructural features of two groups of filamentous sulfur bacteria, Thiothrix spp. and an unnamed organism designated “type 021N,” were examined by transmission electron microscopy. Negative staining of whole cells and filaments with uranyl acetate revealed the presence of tufts of fimbriae located at the ends of individual gonidia of Thiothrix sp. strain A1 and “type 021N” strain N7. Holdfast material present at the center of mature rosettes was observed in thin sections stained with ruthenium red. A clearly defined sheath enveloped the trichomes of two of three Thiothrix strains but was absent from “type 021N” filaments. The outer cell wall appeared more complex in “type 021N” strains than in Thiothrix isolates. Bulbs or clusters of irregularly shaped cells, often present in filaments of “type 021N” bacteria, appeared to result from crosswalls which formed at angles oblique to the filament axis. The multicellular nature of these sulfur bacteria was apparent in that only the cytoplasmic membrane and peptidoglycan layer of the cell wall were involved in the septation process. Sulfur inclusions which developed in the presence of sodium thiosulfate were enclosed by a single-layered envelope and located within invaginations of the cytoplasmic membrane.     

“Ecology of fear” in ungulates: Opportunities for improving conservation

Because ungulates are important contributors to ecosystem function, understanding the “ecology of fear” could be important to the conservation of ecosystems. Although studying ungulate ecology of fear is common, knowledge from ungulate systems is highly contested among ecologists. Here, we review the available literature on the ecology of fear in ungulates to generalize our current knowledge and how we can leverage it for conservation. Four general focus areas emerged from the 275 papers included in our literature search (and some papers were included in multiple categories): behavioral responses to predation risk (79%), physiological responses to predation risk (15%), trophic cascades resulting from ungulate responses to predation risk (20%), and manipulation of predation risk (1%). Of papers focused on behavior, 75% were about movement and habitat selection. Studies were biased toward North America (53%), tended to be focused on elk (Cervus canadensis; 29%), and were dominated by gray wolves (40%) or humans (39%) as predators of interest. Emerging literature suggests that we can utilize predation risk for conservation with top‐down (i.e., increasing predation risk) and bottom‐up (i.e., manipulating landscape characteristics to increase risk or risk perception) approaches. It is less clear whether fear‐related changes in physiology have population‐level fitness consequences or cascading effects, which could be fruitful avenues for future research. Conflicting evidence of trait‐mediated trophic cascades might be improved with better replication across systems and accounting for confounding effects of ungulate density. Improving our understanding of mechanisms modulating the nature of trophic cascades likely is most important to ensure desirable conservation outcomes. We recommend future work embrace the complexity of natural systems by attempting to link together the focal areas of study identified herein.     

“Jack‐of‐all‐trades” is parthenogenetic

Sex is evolutionarily more costly than parthenogenesis, evolutionary ecologists therefore wonder why sex is much more frequent than parthenogenesis in the majority of animal lineages. Intriguingly, parthenogenetic individuals and species are as common as or even more common than sexuals in some major and putative ancient animal lineages such as oribatid mites and rotifers. Here, we analyzed oribatid mites (Acari: Oribatida) as a model group because these mites are ancient (early Paleozoic), widely distributed around the globe, and include a high number of parthenogenetic species, which often co‐exist with sexual oribatid mite species. There is evidence that the reproductive mode is phylogenetically conserved in oribatid mites, which makes them an ideal model to test hypotheses on the relationship between reproductive mode and species'' ecological strategies. We used oribatid mites to test the frozen niche variation hypothesis; we hypothesized that parthenogenetic oribatid mites occupy narrow specialized ecological niches. We used the geographic range of species as a proxy for specialization as specialized species typically do have narrower geographic ranges than generalistic species. After correcting for phylogenetic signal in reproductive mode and demonstrating that geographic range size has no phylogenetic signal, we found that parthenogenetic lineages have a higher probability to have broader geographic ranges than sexual species arguing against the frozen niche variation hypothesis. Rather, the results suggest that parthenogenetic oribatid mite species are more generalistic than sexual species supporting the general‐purpose genotype hypothesis. The reason why parthenogenetic oribatid mite species are generalists with wide geographic range sizes might be that they are of ancient origin reflecting that they adapted to varying environmental conditions during evolutionary history. Overall, our findings indicate that parthenogenetic oribatid mite species possess a widely adapted general‐purpose genotype and therefore might be viewed as “Jack‐of‐all‐trades.”     

Research, Informed Consent, and the Limits of Disclosure

According to this paper, respect for informed consent implies that subjects should often be told a good deal more than ethical guidelines explicitly or implicitly require. Unless subjects are informed of the researchers' personal characteristics, views, and sponsors whenever they would be likely to consider them significant, their autonomy is being overridden. However, overriding subjects' autonomy is sometimes required by the interests of researchers in not being discriminated against or suffering intrusions into their privacy. This paper resolves the conflict between informed consent and the interests of researchers by recommending that (i) subjects generally should be told of the personal characteristics of researchers when relevant as part of the researchers' job and (ii) that subjects should be told of researchers' views when conceptually connected to the research and (iii) that subjects should almost always be told about sponsorship. While the paper explicitly limits the role of informed consent, these recommendations go significantly beyond most guidelines in their requirements about what information should be disclosed.     

Anaerobic Aryl Reductive Dehalogenation of Halobenzoates by Cell Extracts of “Desulfomonile tiedjei”

We studied the transformation of halogenated benzoates by cell extracts of a dehalogenating anaerobe, “Desulfomonile tiedjei.” We found that cell extracts possessed aryl reductive dehalogenation activity. The activity was heat labile and dependent on the addition of reduced methyl viologen, but not on that of reduced NAD, NADP, flavin mononucleotide, flavin adenine dinucleotide, desulfoviridin, cytochrome c₃, or benzyl viologen. Dehalogenation activity in extracts was stimulated by formate, CO, or H₂, but not by pyruvate plus coenzyme A or by dithionite. The pH and temperature optima for aryl dehalogenation were 8.2 and 35°C, respectively. The rate of dehalogenation was proportional to the amount of protein in the assay mixture. The substrate specificity of aryl dehalogenation activity for various aromatic compounds in “D. tiedjei” cell extracts was identical to that of whole cells, except differences were observed in the relative rates of halobenzoate transformation. Dehalogenation was 10-fold greater in “D. tiedjei” extracts prepared from cells cultured in the presence of 3-chlorobenzoate, suggesting that the activity was inducible. Aryl reductive dehalogenation in extracts was inhibited by sulfite, sulfide, and thiosulfate, but not sulfate. Experiments with combinations of substrates suggested that cell extracts dehalogenated 3-iodobenzoate more readily than either 3,5-dichlorobenzoate or 3-chlorobenzoate. Dehalogenation activity was found to be membrane associated. This is the first report characterizing aryl dehalogenation activity in cell extracts of an obligate anaerobe.     

Induction of Respiratory-Deficient Nonchromosomal “Petites” of Saccharomyces cerevisiae by Sodium Dodecyl Sulfate

Nonchromosomal “petites” can be produced in Saccharomyces cerevisiae by treatment with sodium dodecyl sulfate, an anionic surface active agent.     

Genetic Diversity of Porphyromonas gingivalis Isolates Recovered from Single “Refractory” Periodontitis Sites

Multilocus sequence typing and fimA genotyping were performed on Porphyromonas gingivalis isolates from 15 subjects with “refractory” periodontitis. Several sequence types were detected for most individual pockets. The variation indicated recombination at the recA and pepO genes. The prevalence of fimA genotypes II and IV confirmed their association with periodontitis.     

The “ideal protein” concept is not ideal in animal nutrition

Amino acids (AAs) are required for syntheses of proteins and low-molecular-weight substances with enormous physiological importance. Since 1912, AAs have been classified as nutritionally essential amino acids (EAAs) or nonessential amino acids (NEAAs) for animals. EAAs are those AAs that are either not synthesized or insufficiently synthesized de novo in the organisms. It was assumed that all NEAAs (now known as AAs that are synthesizable in animal cells de novo [AASAs]) were formed sufficiently in animals and were not needed in diets. However, studies over the past three decades have shown that sufficient dietary AASAs (e.g. glutamine, glutamate, glycine, and proline) are necessary for the maximum growth and optimum health of pigs, chickens, and fish. Thus, the concept of “ideal protein” (protein with an optimal EAA pattern that precisely meets the physiological needs of animals), which was originally proposed in the 1950s but ignored AASAs, is not ideal in animal nutrition. Ideal diets must provide all physiologically and nutritionally essential AAs. Improved patterns of AAs in diets for swine and chickens as well as zoo and companion animals have been proposed in recent years. Animal-sourced feedstuffs supply abundant EAAs and AASAs (including glutamate, glutamine, glycine, proline, 4-hydroxyproline, and taurine) for diets of swine, poultry, fish, and crustaceans to improve their growth, development, reproduction, and health, while sustaining global animal production. Nutritionists should move beyond the “ideal protein” concept to consider optimum ratios and amounts of all proteinogenic AAs in diets for mammals, birds, and aquatic animals, and, in the case of carnivores, also taurine.