Returning negative results to individuals in a genomic screening program: lessons learned

PurposeIn genomics, the return of negative screening results for rare, medically actionable conditions in large unselected populations with low prior risk of disease is novel and may involve important and nuanced concerns for communicating their meaning. Recruitment may result in self-selection because of participants’ personal or family history, changing the characteristics of the screened population and interpretation of both positive and negative findings; prior motivations may also affect responses to results.MethodsUsing data from GeneScreen, an exploratory adult screening project that targets 17 genes related to 11 medically actionable conditions, we address four questions: (1) Do participants self-select based on actual or perceived risk for one of the conditions? (2) Do participants understand negative results? (3) What are their psychosocial responses? (4) Are negative results related to changes in reported health-related behaviors?ResultsWe found disproportionate enrollment of individuals at elevated prior risk for conditions being screened, and a need to improve communication about the nature of screening and meaning of negative screening results. Participants expressed no decision regret and did not report intention to change health-related behaviors.ConclusionThis study illuminates critical challenges to overcome if genomic screening is to benefit the general population.     

Establishing the value of genomics in medicine: the IGNITE Pragmatic Trials Network

PurposeA critical gap in the adoption of genomic medicine into medical practice is the need for the rigorous evaluation of the utility of genomic medicine interventions.MethodsThe Implementing Genomics in Practice Pragmatic Trials Network (IGNITE PTN) was formed in 2018 to measure the clinical utility and cost-effectiveness of genomic medicine interventions, to assess approaches for real-world application of genomic medicine in diverse clinical settings, and to produce generalizable knowledge on clinical trials using genomic interventions. Five clinical sites and a coordinating center evaluated trial proposals and developed working groups to enable their implementation.ResultsTwo pragmatic clinical trials (PCTs) have been initiated, one evaluating genetic risk APOL1 variants in African Americans in the management of their hypertension, and the other to evaluate the use of pharmacogenetic testing for medications to manage acute and chronic pain as well as depression.ConclusionIGNITE PTN is a network that carries out PCTs in genomic medicine; it is focused on diversity and inclusion of underrepresented minority trial participants; it uses electronic health records and clinical decision support to deliver the interventions. IGNITE PTN will develop the evidence to support (or oppose) the adoption of genomic medicine interventions by patients, providers, and payers.     

Regenerative medicine, resource and regulation: lessons learned from the remedi project

The successful commercialization of regenerative medicine products provides a unique challenge to the manufacturer owing to a lack of suitable investment/business models and a constantly evolving regulatory framework. The resultant slow translation of scientific discovery into safe and clinically efficacious therapies is preventing many potential products from reaching the market. This is despite of the need for new therapies that may reduce the burden on the world's healthcare systems and address the desperate need for replacement tissues and organs. The collaborative Engineering and Physical Sciences Research Council (EPSRC)-funded remedi project was devised to take a holistic but manufacturing-led approach to the challenge of translational regenerative medicine in the UK. Through strategic collaborations and discussions with industry and other academic partners, many of the positive and negative issues surrounding business and regulatory success have been documented to provide a remedi-led perspective on the management of risk in business and the elucidation of the regulatory pathways, and how the two are inherently linked. This article represents the findings from these discussions with key stakeholders and the research into best business and regulatory practices.     

Creating sustainable curricular change: lessons learned from an alternative therapies educational initiative.

The authors describe the process by which a curriculum was developed to introduce complementary and alternative medicine topics at multiple levels from health professional students to faculty, as part of a five-year project, funded by a grant from the National Institutes of Health, at the University of Texas Medical Branch in Galveston, Texas, from 2001 to 2005. The curriculum was based on four educational goals that embrace effective communication with patients, application of sound evidence, creation of patient-centered therapeutic relationships, and development of positive perspectives on wellness. The authors analyze the complex and challenging process of gaining acceptance for the curriculum and implementing it in the context of existing courses and programs. The developmental background and context of this curricular innovation at this institution is described, with reference to parallel activities at other academic health centers participating in the Consortium of Academic Health Centers for Integrative Medicine. The authors hold that successful curricular change in medical schools must follow sound educational development principles. A well-planned process of integration is particularly important when introducing a pioneering curriculum into an academic health center. The process at this institution followed six key principles for successful accomplishment of curriculum change: leadership, cooperative climate, participation by organization members, politics, human resource development, and evaluation. The authors provide details about six analogous elements used to design and sustain the curriculum: collaboration, communication, demonstration, evaluation, evolution, and dissemination.     

Immunity to intestinal pathogens: lessons learned from Salmonella

Salmonella are a common source of food- or water-borne infection and cause a wide range of clinical disease in human and animal hosts. Salmonella are relatively easy to culture and manipulate in a laboratory setting, and the infection of laboratory animals induces robust innate and adaptive immune responses. Thus, immunologists have frequently turned to Salmonella infection models to expand understanding of host immunity to intestinal pathogens. In this review, I summarize current knowledge of innate and adaptive immunity to Salmonella and highlight features of this response that have emerged from recent studies. These include the heterogeneity of the antigen-specific T-cell response to intestinal infection, the prominence of microbial mechanisms to impede T- and B-cell responses, and the contribution of non-cognate pathways for elicitation of T-cell effector functions. Together, these different issues challenge an overly simplistic view of host–pathogen interaction during mucosal infection, but also allow deeper insight into the real-world dynamic of protective immunity to intestinal pathogens.     

Human genome project: a federator program of genomic medicine

The Human Genome Project improves our understanding of the molecular genetics basis of the inherited and complex diseases such as diabetes, schizophrenia, and cancer. Information from the human genome sequence is essential for several antenatal and neonatal screening programmes. The new genomic tools emerging from this project have revolutionized biology and medicine and have transformed our understanding of health and the provision of healthcare. Its implications pervade all areas of medicine, from disease prediction and prevention to the diagnosis and treatment of all forms of disease. Increasingly, it will be possible to drive predisposition testing into clinical practice, to develop new treatments or to adapt available treatments more specifically to an individual's genetic make-up. This genomic information should transform the traditional medications that are effective for every members of the population to personalized medicine and personalized therapy. The pharmacogenomics could give rise to a new generation of highly effective drugs that treat causes, not just symptoms.     

SARS: lessons learned from other coronaviruses

The identification of a new coronavirus as the etiological agent of severe acute respiratory syndrome (SARS) has evoked much new interest in the molecular biology and pathogenesis of coronaviruses. This review summarizes present knowledge on coronavirus molecular biology and pathogenesis with particular emphasis on mouse hepatitis virus (MHV). MHV, a member of coronavirus group 2, is a natural pathogen of the mouse; MHV infection of the mouse is considered one of the best models for the study of demyelinating disease, such as multiple sclerosis, in humans. As a result of the SARS epidemic, coronaviruses can now be considered as emerging pathogens. Future research on SARS needs to be based on all the knowledge that coronavirologists have generated over more than 30 years of research.     

Translating costimulation blockade to the clinic: lessons learned from three pathways

Summary:  As the recognition that costimulatory signals are critical for optimal T-cell activation, proliferation, and differentiation, there has been an explosion in the study of costimulatory molecules and their roles in enhancing anti-donor T-cell responses following transplantation. Here, we focus on the bench-to-beside translation of blocking agents designed to target three critical costimulatory pathways: the CD28/CD80/CD86 pathway, the CD154/CD40 pathway, and the lymphocyte function associated antigen-1/intercellular adhesion molecule pathway. While blockade of each of these pathways proved promising in inhibiting donor-reactive T-cell responses and promoting long-term graft survival in murine models of transplantation, the progression of development of therapeutic agents to block these pathways has each taken a slightly different course. Both logistical and biological pitfalls have accompanied the translation of blockers of all three pathways into clinically applicable therapies, and the development of costimulatory blockade as a substitute for current standard-of-care calcineurin inhibitors has by no means reached completion. Collaboration between both the basic and clinical arenas will further propel the development of costimulation blockers currently in the pipeline, as well as of novel methods to target these critical pathways during transplantation.     

Immunity against cancer: lessons learned from melanoma

Most major advances in human cancer immunology and immunotherapy have come from studies in melanoma. We are beginning to understand the immune repertoire of T cells and antibodies that are active against melanoma, with recent glimpses of the CD4(+) T cell repertoire. The view of what the immune system can see is extending to mutations and parts of the genome that are normally invisible.     

Gifts from the grave: lessons learned for living well

Often expected to work institutional miracles although under resourced, most hospice and palliative care nurses excel in meeting consistently intense and demanding clinical and human challenges. They do so by staying focused and being grounded, highly accountable, responsive, and empathetic. With time and experience, they often master the art of advocacy, and through developing a capacity for "organization-with-heart," they navigate very complex institutional, systemic, cultural, and societal waters. Nurses are present to patient and familial wounds; the sights, sounds, smells of chaos and beauty; gladness and grief; intimacy and numbness. Our guest author today distills years of nursing experience into a very few words that can be shared in classrooms, homes, and clinics. It is clear that she not only knows of what she speaks, but, having died many times to that which is not fruitful, she separates the essential from the nonessential and, in so doing, is renewed and full of life. Isn't this an ultimate demonstration of integration and embodiment? Therese Schroeder-Sheker, The Chalice of Repose Project.     

Opportunities and challenges for the integration of massively parallel genomic sequencing into clinical practice: lessons from the ClinSeq project

PurposeThe debate surrounding the return of results from high-throughput genomic interrogation encompasses many important issues including ethics, law, economics, and social policy. As well, the debate is also informed by the molecular, genetic, and clinical foundations of the emerging field of clinical genomics, which is based on this new technology. This article outlines the main biomedical considerations of sequencing technologies and demonstrates some of the early clinical experiences with the technology to enable the debate to stay focused on real-world practicalities.MethodsThese experiences are based on early data from the ClinSeq project, which is a project to pilot the use of massively parallel sequencing in a clinical research context with a major aim to develop modes of returning results to individual subjects.ResultsThe study has enrolled >900 subjects and generated exome sequence data on 572 subjects. These data are beginning to be interpreted and returned to the subjects, which provides examples of the potential usefulness and pitfalls of clinical genomics.ConclusionThere are numerous genetic results that can be readily derived from a genome including rare, high-penetrance traits, and carrier states. However, much work needs to be done to develop the tools and resources for genomic interpretation. The main lesson learned is that a genome sequence may be better considered as a health-care resource, rather than a test, one that can be interpreted and used over the lifetime of the patient.Genet Med 2012:14(4):393–398