‘Complementary & alternative medicine’ (CAM): ethical and policy issues

Editorial for Bioethics 2016. 30:(2)

Integrative motivation and global language (English) acquisition in Poland

This study investigated the consistency of a measure of integrative motivation in the prediction of achievement in English as a foreign language in 18 samples of Polish school students. The results are shown to have implications for concerns expressed that integrative motivation might not be appropriate to the acquisition of English because it is a global language and moreover that other factors such as the gender of the student or the environment of the class might also influence its predictability. Results of a hierarchical linear modeling analysis indicated that for the older samples, integrative motivation was a consistent predictor of grades in English, unaffected by either the gender of the student or class environment acting as covariates. Comparable results were obtained for the younger samples except that student gender also contributed to the prediction of grades in English. Examination of the correlations of the elements of the integrative motivation score with English grades demonstrated that the aggregate score is the more consistent correlate from sample to sample than the elements themselves. Such results lead to the hypothesis that integrative motivation is a multi-dimensional construct and different aspects of the motivational complex come into play for each individual. That is, two individuals can hold the same level of integrative motivation and thus attain the same level of achievement but one might be higher in some elements and lower in others than another individual, resulting in consistent correlations of the aggregate but less so for the elements.

Career choice in medicine

Background: Career Choice in Medicine is an important and problematic topic. Medical education has been framed as professional identity development, yet career choice has not been viewed as a matter of identity. My primary aim was to offer new insights by exploring career choice using Figured Worlds theory, a socio-cultural theory of identity. Graduate retention is a challenge for many countries, including Ireland. My secondary aim was to address a gap in the data on postgraduate trainees in Ireland and to use the Irish case to illustrate points transferable to other contexts. Methodology & Methods: This was a predominantly qualitative Mixed Methods programme of research. My qualitative studies were oriented towards social constructionism. I collated existing data from the Royal College of Physicians of Ireland (RCPI) and HSE-MET to describe trainees and their career paths. I surveyed Basic Specialist Training trainees (n=333) about their career plans. I surveyed new trainees (n=527) about their expectations of training and all RCPI trainees about their experiences of training (n=1246). I conducted semi-structured interviews with 18 medical students and doctors. A subgroup (n=6) provided longitudinal data. Figured Worlds theory and Gee’s discourse tools were used for analysis. Results: I have used the case of medical training and career choice in Ireland to explain how social, political and cultural context, and day to day experiences in the cultural world of medicine, shaped doctors’ career choices. My qualitative findings described a unifying model of career choice, consisting of priming, exposure, positioning and open-endedness, which can guide the design of interventions to shape and support career choice. Conclusion: My original contribution has been to demonstrate the fruitfulness of framing career choice in terms of identity development. This represents a turn in the conversation about career choice, which brings new starting points and moves the dialogue forward.

A strategy to advance the evidence base in palliative medicine: formation of a palliative care research cooperative group.

BACKGROUND: Palliative medicine has made rapid progress in establishing its scientific and clinical legitimacy, yet the evidence base to support clinical practice remains deficient in both the quantity and quality of published studies. Historically, the conduct of research in palliative care populations has been impeded by multiple barriers including health care system fragmentation, small number and size of potential sites for recruitment, vulnerability of the population, perceptions of inappropriateness, ethical concerns, and gate-keeping. METHODS: A group of experienced investigators with backgrounds in palliative care research convened to consider developing a research cooperative group as a mechanism for generating high-quality evidence on prioritized, clinically relevant topics in palliative care. RESULTS: The resulting Palliative Care Research Cooperative (PCRC) agreed on a set of core principles: active, interdisciplinary membership; commitment to shared research purposes; heterogeneity of participating sites; development of research capacity in participating sites; standardization of methodologies, such as consenting and data collection/management; agile response to research requests from government, industry, and investigators; focus on translation; education and training of future palliative care researchers; actionable results that can inform clinical practice and policy. Consensus was achieved on a first collaborative study, a randomized clinical trial of statin discontinuation versus continuation in patients with a prognosis of less than 6 months who are taking statins for primary or secondary prevention. This article describes the formation of the PCRC, highlighting processes and decisions taken to optimize the cooperative group's success.

Integrative Genomics Reveals a Role for GNA13 in Lymphomagenesis

Lymphomas comprise a diverse group of malignancies derived from immune cells. High throughput sequencing has recently emerged as a powerful and versatile method for analysis of the cancer genome and transcriptome. As these data continue to emerge, the crucial work lies in sorting through the wealth of information to hone in on the critical aspects that will give us a better understanding of biology and new insight for how to treat disease. Finding the important signals within these large data sets is one of the major challenges of next generation sequencing.

In this dissertation, I have developed several complementary strategies to describe the genetic underpinnings of lymphomas. I begin with developing a better method for RNA sequencing that enables strand-specific total RNA sequencing and alternative splicing profiling in the same analysis. I then combine this RNA sequencing technique with whole exome sequencing to better understand the global landscape of aberrations in these diseases. Finally, I use traditional cell and molecular biology techniques to define the consequences of major genetic alterations in lymphoma.

Through this analysis, I find recurrent silencing mutations in the G alpha binding protein GNA13 and associated focal adhesion proteins. I aim to describe how loss-of-function mutations in GNA13 can be oncogenic in the context of germinal center B cell biology. Using in vitro techniques including liquid chromatography-mass spectrometry and knockdown and overexpression of genes in B cell lymphoma cell lines, I determine protein binding partners and downstream effectors of GNA13. I also develop a transgenic mouse model to study the role of GNA13 in the germinal center in vivo to determine effects of GNA13 deletion on germinal center structure and cell migration.

Thus, I have developed complementary approaches that span the spectrum from discovery to context-dependent gene models that afford a better understanding of the biological function of aberrant events and ultimately result in a better understanding of disease.

Sea Urchin Body Plan Development and Evolution: An Integrative Transcriptomic Approach

My dissertation work integrates comparative transcriptomics and functional analyses to investigate gene expression changes underlying two significant aspects of sea urchin evolution and development: the dramatic developmental changes associated with an ecologically significant shift in life history strategy and the development of the unusual radial body plan of adult sea urchins.

In Chapter 2, I investigate evolutionary changes in gene expression underlying the switch from feeding (planktotrophic) to nonfeeding (lecithotrophic) development in sea urchins. In order to identify these changes, I used Illumina RNA-seq to measure expression dynamics across 7 developmental stages in three sea urchin species: the lecithotroph Heliocidaris erythrogramma, the closely related planktotroph Heliocidaris tuberculata, and an outgroup planktotroph Lytechinus variegatus. My analyses draw on a well-characterized developmental gene regulatory network (GRN) in sea urchins to understand how the ancestral planktotrophic developmental program was altered during the evolution of lecithotrophic development. My results suggest that changes in gene expression profiles occurred more frequently across the transcriptome during the evolution of lecithotrophy than during the persistence of planktotrophy. These changes were even more pronounced within the GRN than across the transcriptome as a whole, and occurred in each network territory (skeletogenic, endomesoderm and ectoderm). I found evidence for both conservation and divergence of regulatory interactions in the network, as well as significant changes in the expression of genes with known roles in larval skeletogenesis, which is dramatically altered in lecithotrophs. I further explored network dynamics between species using coexpression analyses, which allowed me to identify novel players likely involved in sea urchin neurogenesis and endoderm patterning.

In Chapter 3, I investigate developmental changes in gene expression underlying radial body plan development and metamorphosis in H. erythrogramma. Using Illumina RNA-seq, I measured gene expression profiles across larval, metamorphic, and post-metamorphic life cycle phases. My results present a high-resolution view of gene expression dynamics during the complex transition from pre- to post-metamorphic development and suggest that distinct sets of regulatory and effector proteins are used during different life history phases.

Collectively, my investigations provide an important foundation for future, empirical studies to investigate the functional role of gene expression change in the evolution of developmental differences between species and also for the generation of the unusual radial body plan of sea urchins.

The IGNITE network: a model for genomic medicine implementation and research.

BACKGROUND: Patients, clinicians, researchers and payers are seeking to understand the value of using genomic information (as reflected by genotyping, sequencing, family history or other data) to inform clinical decision-making. However, challenges exist to widespread clinical implementation of genomic medicine, a prerequisite for developing evidence of its real-world utility. METHODS: To address these challenges, the National Institutes of Health-funded IGNITE (Implementing GeNomics In pracTicE; www.ignite-genomics.org ) Network, comprised of six projects and a coordinating center, was established in 2013 to support the development, investigation and dissemination of genomic medicine practice models that seamlessly integrate genomic data into the electronic health record and that deploy tools for point of care decision making. IGNITE site projects are aligned in their purpose of testing these models, but individual projects vary in scope and design, including exploring genetic markers for disease risk prediction and prevention, developing tools for using family history data, incorporating pharmacogenomic data into clinical care, refining disease diagnosis using sequence-based mutation discovery, and creating novel educational approaches. RESULTS: This paper describes the IGNITE Network and member projects, including network structure, collaborative initiatives, clinical decision support strategies, methods for return of genomic test results, and educational initiatives for patients and providers. Clinical and outcomes data from individual sites and network-wide projects are anticipated to begin being published over the next few years. CONCLUSIONS: The IGNITE Network is an innovative series of projects and pilot demonstrations aiming to enhance translation of validated actionable genomic information into clinical settings and develop and use measures of outcome in response to genome-based clinical interventions using a pragmatic framework to provide early data and proofs of concept on the utility of these interventions. Through these efforts and collaboration with other stakeholders, IGNITE is poised to have a significant impact on the acceleration of genomic information into medical practice.

Challenges in integrative approaches to modelling the marine ecosystems of the North Atlantic: Physics to fish and coasts to ocean

It has long been recognised that there are strong interactions and feedbacks between climate, upper ocean biogeochemistry and marine food webs, and also that food web structure and phytoplankton community distribution are important determinants of variability in carbon production and export from the euphotic zone. Numerical models provide a vital tool to explore these interactions, given their capability to investigate multiple connected components of the system and the sensitivity to multiple drivers, including potential future conditions. A major driver for ecosystem model development is the demand for quantitative tools to support ecosystem-based management initiatives. The purpose of this paper is to review approaches to the modelling of marine ecosystems with a focus on the North Atlantic Ocean and its adjacent shelf seas, and to highlight the challenges they face and suggest ways forward. We consider the state of the art in simulating oceans and shelf sea physics, planktonic and higher trophic level ecosystems, and look towards building an integrative approach with these existing tools. We note how the different approaches have evolved historically and that many of the previous obstacles to harmonisation may no longer be present. We illustrate this with examples from the on-going and planned modelling effort in the Integrative Modelling Work Package of the EURO-BASIN programme.

Components of the peptidome and transcriptome persist in lin wa pi: the dried skin of the Heilongjiang brown frog Rana amurensis as used in Traditional Chinese Medicine

Although the ancient practice of traditional Chinese medicine (TCM) utilizes predominantly herbal ingredients, many of which are now the subject of intense scientific scrutiny, significant quantities of animal tissue-derived materials are also employed. Here we have used contemporary molecular techniques to study the material known as lin wa pi, the dried skin of the Heilongjiang brown frog, Rana amurensis, that is used commonly as an ingredient of many medicines, as a general tonic and as a topical antimicrobial/wound dressing. Using a simple technology that has been developed and validated over several years, we have demonstrated that components of both the skin granular gland peptidome and transcriptome persist in this material. Interrogation of the cDNA library constructed from the dried skin by entrapment and amplification of polyadenylated mRNA, using a "shotgun" primer approach and 3'-RACE, resulted in the cloning of cDNAs encoding the precursors of five putative antimicrobial peptides. Two (ranatuerin-2AMa and ranatuerin-2AMb) were obvious homologs of a previously described frog skin peptide family, whereas the remaining three were of sufficient structural novelty to be named amurins 1-3. Mature peptides were each identified in reverse phase HPLC fractions of boiling water extracts of skin and their structures confirmed by MS/MS fragmentation sequencing. Components of traditional Chinese medicines of animal tissue origin may thus contain biologically active peptides that survive the preparation procedures and that may contribute to therapeutic efficacy.