Pharmacogenetic testing, informed consent and the problem of secondary information

Numerous benefits for patients have been predicted if prescribing decisions were routinely accompanied by pharmacogenetic testing. So far, little attention has been paid to the possibility that the routine application of this new technology could result in considerable harm to patients. This article emphasises that pharmacogenetic testing shares both the opportunities and the pitfalls with 'conventional' disease-genetic testing. It demonstrates that performing pharmacogenetic tests as well as interpreting the results are extraordinarily complex issues requiring a high level of expertise. It further argues that pharmacogenetic testing can have a huge impact on clinical decisions and may influence the therapeutic strategy as well as the clinical monitoring of a patient. This view challenges the predominant paradigm that pharmacogenetic testing will predict patients' responses to medicines, but that it will not provide any other significant disease-specific predictive information about the patient or family members. The article also questions published proposals to reduce the consent procedure for pharmacogenetic testing to a simple statement that the physician wishes to test a sample of the patient's DNA to see if a drug will be safe or whether it will work, and presents an alternative model that is better suited to protect patient's interests and to obtain meaningful informed consent. The paper concludes by outlining conditions for the application of pharmacogenetic testing in clinical practice in a way that can make full use of its potential benefits while minimising possible harm to patients and their families.     

Taking due care: moral obligations in dual use research

In the past decade, the perception of a bioterrorist threat has increased and created a demand on life scientists to consider the potential security implications of dual use research. This article examines a selection of proposed moral obligations for life scientists that have emerged to meet these concerns and the extent to which they can be considered reasonable. It also describes the underlying reasons for the concerns, how they are managed, and their implications for scientific values. Five criteria for what constitutes preventable harm are suggested and a number of proposed obligations for life scientists are considered against these criteria, namely, the obligations to prevent bioterrorism; to engage in response activities; to consider negative implications of research; not to publish or share sensitive information; to oversee and limit access to dangerous material; and to report activities of concern. Although bioterrorism might be perceived as an imminent threat, the analysis illustrates that this is beyond the responsibility of life scientists either to prevent or to respond to. Among the more reasonable obligations are duties to consider potential negative implications of one's research, protect access to sensitive material, technology and knowledge, and report activities of concern. Responsibility, therefore, includes obligations concerned with preventing foreseeable and highly probable harm. A central conclusion is that several of the proposed obligations are reasonable, although not unconditionally.     

A cross-cultural study of physician treatment decisions in relation to demented nursing home patients who develop pneumonia

This qualitative interview study in The Netherlands and North Carolina (US) found that physician treatment decisions are influenced by contextual differences in physician training and healthcare delivery in the US and The Netherlands. Dutch physicians treating nursing home residents with dementia and pneumonia assumed active, primary responsibility for treatment decisions while US physicians were more passive and deferential to family preferences, even in cases where they considered the families' wishes inappropriate. Dutch physicians knew their patients well and made treatment decisions based on what they perceived was in the best interest of the patient while US physicians reported limited knowledge of their nursing home patients due to a lack of contact time. Efforts to improve care for patients with poor quality of life who lack decision-making capacity must consider the context of societal values, physician training, and the processes by which physicians negotiate patient and family preferences.     

Right to die with dignity?

The right to die with dignity is an ill-defined concept, with multiple, often inappropriate, interpretations. The current proposition is that the physician take full responsibility for protecting the patients rights, for ensuring a rational use of resources and for overseeing the decision-making process such that the information is adequate and the steps proportioned. This responsibility extends not only to the health status of the patient situation, to the patients prognosis, and to his/her expectations and wishes, but also to the benefits foreseen and to the cost-benefit ratio. Emphasis is placed on two aspects of this relationship. First, dignity can be interpreted in many ways and sometimes, in the name of dignity, the patient is exposed (or exposes him/herself) to suffering, pain and complications that can be avoided. Second, when no reasonable probability of survival is present and a better quality of life is impossible, efforts are better redirected to offering a better quality of death.     

Office treatment of ambulatory schizophrenics

There are many advantages of treating schizophrenic patients outside a hospital setting, if it can be managed. These advantages include the lesser pecuniary cost to the family and patient and the maintenance of the patient's self-esteem by his continued life in the community, particularly if he can be kept at some sort of gainful occupation. There is also a tendency for schizophrenic persons to increase their loss of contact with reality if, as in a hospital, they are taken care of and not expected to assume any responsibility for themselves. The office treatment of a schizophrenic person entails special problems not only of therapy but of dealing with relatives and the community. It is felt that attention to these matters results in the successful social restoration of patients who formerly would have been thought too ill to remain outside a hospital setting. Although this is among the most demanding work a psychiatrist can engage in, the rewards are great.     

Ecological Risk Assessment and Regulation for Genetically-Modified Ornamental Plants

Classic plant breeding has increased the beauty and utility of ornamental plants, but biotechnology can offer completely new traits for plants used in homes and gardens. The creation of blue petal color in carnations and roses are examples where biotechnology has created novelty that conventional hybridization cannot match. However, all innovations have benefits and risks, and future commercialization of transgenic ornamental plants raises complex questions about potential negative impacts to managed landscapes and natural ecosystems. Predictive ecological risk assessment is a process that uses current knowledge to estimate future environmental harms or benefits arising from direct or indirect exposure to a genetically-modified (GM) plant, its genes, or gene products. This article considers GM ornamental plants in the context of current ecological risk assessment principles, research results, and current regulatory frameworks. The use of ecological risk assessment by government agencies to support decision-making is reviewed in the context of ornamental plants. Government risk assessments have usually emphasized the potential for pollen-mediated gene flow, weediness in managed areas, invasion of natural areas, and direct harm to nontarget organisms. Some of the major challenges for predictive risk assessment include characterizing gene flow over time and space, plant fitness in changing environments, and impacts to nontarget organisms, communities and ecosystems. The lack of baseline information about the ecology and biodiversity of urban areas, gardens, and natural ecosystems limits the ability to predict potential hazards, identify exposure pathways, and design hypothesis-driven research. The legacy of introduced ornamental plants as invasive species generates special concern about future invasions, especially for GM plants that exhibit increased stress tolerance or adaptability. While ecological risk assessments are a valuable tool and have helped harmonize regulation of GM plants, they do not define the acceptable level of risk or uncertainty. That responsibility belongs to regulators, stakeholders and citizens.     

The role of pharmacogenetics in treating central nervous system disorders

Symptoms of central nervous system (CNS) disorders include abnormalities in both physical and psychological domains. Many drugs indicated for the treatment of CNS disorders are fraught with side effects and/or poor efficacy which impact patients' quality of life and drives non-compliance. Moreover, for many CNS drugs such as antidepressants and antipsychotics, it takes time to determine whether a particular drug is efficacious in an individual patient. To optimize drug treatment for each patient, prescribing physicians often need to raise or lower doses, switch drug classes, or prescribe additional drugs to mitigate side effects, often in a "trial and error" fashion. Pharmacogenetic (PGx) testing, particularly in the realm of CNS therapy, can reduce the unpredictability of this process. By determining a patient's genetic profile, individual therapy parameters may be predicted pre-treatment for drug efficacy, optimal drug dose, and the risk of adverse drug reactions (ADRs). The intent of this review is to highlight the power of PGx testing to predict the likelihood of ADRs and efficacy during the treatment of the following CNS disorders: epilepsy, bipolar disorder, schizophrenia and depression.     

Een cultuurvergelijkend onderzoek naar behandelbesluiten van artsen met betrekking tot demente verpleeghuispatiënten met pneumonie

A cross-cultural study of physician treatment decisions for demented nursing home patients who develop pneumoniaThis qualitative interview study in the Netherlands and North Carolina (US) found that physician treatment decisions are influenced by contextual differences in physician training and healthcare delivery in the US and the Netherlands. Dutch physicians treating nursing home residents with dementia and pneumonia assumed active, primary responsibility for treatment decisions while US physicians were more passive and deferential to family preferences, even in cases where they considered the families’ wishes inappropriate. Dutch physicians knew their patients well and made treatment decisions based on what they perceived was in the best interest of the patient while US physicians reported limited knowledge of their nursing home patients due to a lack of contact time. Efforts to improve care for patients with poor quality of life who lack decision-making capacity must consider the context of societal values, physician training, and the processes by which physicians negotiate patient and family preferences.     

Low Penetrance Germline Genetic Testing: Role for Risk Stratification in Prostate Cancer Screening and Examples From Clinical Practice

Broad-based prostate-specific antigen (PSA) screening has saved lives but at a substantial human and financial cost. One way of mitigating this harm, while maintaining and possibly improving the benefit, is by focusing screening efforts on men at higher risk. With age, race, and family history as the only risk factors, many men lack any reliable data to inform their prostate cancer (PCa) screening decisions. Complexities including history of previous negative biopsies, interpretation of negative and/or equivocal mpMRI findings, and patient comorbidities further compound the already complicated decisions surrounding PCa screening and early detection. The authors present cases that provide real-world examples of how a single nucleotide polymorphism-based test can provide patients and providers with personalized PCa risk assessments and allow for development of improved risk-stratified screening regimens.     

Challenges of Work–Life Balance for Women Physicians/Mothers Working in Leadership Positions

BackgroundFemale leadership in medicine is still disproportionately small, which might be due to the barriers of combining work and family.ObjectivesThe aim of this study was, first, to perform a strengths, weakness, opportunities, and threats (SWOT) analysis and, second, to create a strategic concept for career development.MethodsIn this study, all women in leadership positions in the health care system in Vienna, Austria, with at least 1 child (n = 8), were interviewed about the advantages and disadvantages of gender with regard to career development, the strengths and weaknesses of female leadership, and their work–life balance. Different factors that influenced the work–life balance were specified, and career strategies to realize adequate solutions were developed.ResultsThe sporadic focus on career advancement, time-consuming child care, responsibility for family life, and a woman's tendency toward understatement were barriers to career development. Work–family enrichment has a positive spillover effect that spreads positive energy and helps to balance the work–life relationship. For each individual, the allocation and interaction of different resources such as time, money, scope of decision making, and physical, emotional, and social resources, were essential to maintain the individual work–life balance.ConclusionsIn addition to the existing “glass ceiling,” the predominant responsibility for child care is still borne by the woman. However, mentoring programs, coaching, networking, and support of the partner or of other people help to strengthen female “soft” skills and achieve a work–life balance.     

Ion channels in smooth muscle: regulators of intracellular calcium and contractility

Smooth muscle (SM) is essential to all aspects of human physiology and, therefore, key to the maintenance of life. Ion channels expressed within SM cells regulate the membrane potential, intracellular Ca2+ concentration, and contractility of SM. Excitatory ion channels function to depolarize the membrane potential. These include nonselective cation channels that allow Na+ and Ca2+ to permeate into SM cells. The nonselective cation channel family includes tonically active channels (Icat), as well as channels activated by agonists, pressure-stretch, and intracellular Ca2+ store depletion. Cl--selective channels, activated by intracellular Ca2+ or stretch, also mediate SM depolarization. Plasma membrane depolarization in SM activates voltage-dependent Ca2+ channels that demonstrate a high Ca2+ selectivity and provide influx of contractile Ca2+. Ca2+ is also released from SM intracellular Ca2+ stores of the sarcoplasmic reticulum (SR) through ryanodine and inositol trisphosphate receptor Ca2+ channels. This is part of a negative feedback mechanism limiting contraction that occurs by the Ca2+-dependent activation of large-conductance K+ channels, which hyper polarize the plasma membrane. Unlike the well-defined contractile role of SR-released Ca2+ in skeletal and cardiac muscle, the literature suggests that in SM Ca2+ released from the SR functions to limit contractility. Depolarization-activated K+ chan nels, ATP-sensitive K+ channels, and inward rectifier K+ channels also hyperpolarize SM, favouring relaxation. The expression pattern, density, and biophysical properties of ion channels vary among SM types and are key determinants of electrical activity, contractility, and SM function.     

Clinical trial of common treatments for low back pain in family practice.

The results of a multicentered randomised clinical trial are reported of bed rest and of a physiotherapy and education programme for patients who presented in family practice with an acute episode of low back pain. No beneficial effect of either treatment was observed on several clinical outcome measures, including straight leg raising, lumbar flexion, activities of daily living, and pain. In fact the results favoured early mobilisation over bed rest and suggested that the physiotherapy and education programme was doing more harm than good. Moreover, additional analyses, which focused on clinically interesting patient subgroups, discovered no subset of patients who benefited from either of the treatments under study. Having failed to identify any clinically important benefits, or other explanations for these negative results, we can only conclude that family doctors have little reason to prescribe either bed rest or isometric exercises to patients who suffer from low back pain.     

Understanding potential barriers and enablers to a perioperative early phase cell therapy trial

Background aimsEarly-phase cell therapy clinical trials depend on patient and physician involvement, yet barriers can impede their participation.MethodsTo optimize engagement for a planned cell therapy trial to prevent perioperative cardiac complications, the authors conducted semi-structured interviews with at-risk patients and physicians who could potentially be involved in the study. The authors used the theoretical domains framework to systematically identify potential barriers and enablers.ResultsForty-one interviews were conducted to reach data saturation, and four overall potential barriers to participation (themes) were identified. Theme 1 emphasizes that patients and physicians need accessible information to better understand the benefits and risks of the novel therapy and trial procedures and to address misconceptions. Theme 2 underscores the need for clarity on whether the trial's primary purpose is safety or efficacy, as this may influence patient and physician decisions. Theme 3 recognizes the resource and logistic realities for patients (e.g., convenient follow-up appointments) and physicians (e.g., personnel to assist in trial procedures, competing priorities). Theme 4 describes the importance of social influences (e.g., physicians and family, peers/colleagues) that may affect decisions to participate and the importance of patient preferences (e.g., availability of physicians to discuss the trial, including caregivers in discussions).ConclusionsProspectively addressing these issues may help optimize feasibility prior to conducting an expensive, resource-intensive trial.     

Implications of the human genome initiative for the primary care physician

... Despite the need for physicians to be knowledgeable about and open to advances in genetic technology, little is known about the level of preparedness of primary care physicians to offer new genetic tests. Evidence suggests that several barriers exist to physicians adopting genetic tests. These include lack of knowledge, inability to interpret probabilistic information, low tolerance for uncertainty, negative attitudes about their responsibility for genetic counseling and testing, lack of confidence in their clinical skills, and unfamiliarity with ethical issues raised by testing. This paper will explore some of these barriers in further depth, discuss the ethical impact of physician unpreparedness on both patient care and the diffusion of genetic tests, and describe a study that is currently underway to investigate some of these issues.     

An economic theory of patient decision-making

Patient autonomy, as exercised in the informed consent process, is a central concern in bioethics. The typical bioethicist's analysis of autonomy centers on decisional capacity--finding the line between autonomy and its absence. This approach leaves unexplored the structure of reasoning behind patient treatment decisions. To counter that approach, we present a microeconomic theory of patient decision-making regarding the acceptable level of medical treatment from the patient's perspective. We show that a rational patient's desired treatment level typically departs from the level yielding an absence of symptoms, the level we call ideal. This microeconomic theory demonstrates why patients have good reason not to pursue treatment to the point of absence of physical symptoms. We defend our view against possible objections that it is unrealistic and that it fails to adequately consider harm a patient may suffer by curtailing treatment. Our analysis is fruitful in various ways. It shows why decisions often considered unreasonable might be fully reasonable. It offers a theoretical account of how physician misinformation may adversely affect a patient's decision. It shows how billing costs influence patient decision-making. It indicates that health care professionals' beliefs about the 'unreasonable' attitudes of patients might often be wrong. It provides a better understanding of patient rationality that should help to ensure fuller information as well as increased respect for patient decision-making.     

Sequestration revisited: integrating traditional electron microscopy, de novo assembly and new results

Electron microscopy analysis of the autophagic sequestration membrane (SM) in various metazoan cell types after different fixation methods shows that: (1) the growing SM cannot derive from preformed rough surfaced endoplasmic reticulum (RER) membranes by transformation; (2) the empty cleft between the two layers of the SM after aldehyde fixation is an artifact of sample preparation; (3) the SM emerges from and grows de novo in cytoplasmic areas where membranous precursors cannot be identified by traditional electron microscopy; (4) the growing SM consists of two tightly packed membrane layers with a sharp bend at the edge; (5) changes in the environment of the growing SM participate in the determination of the size and shape of the autophagosome. We suggest that expansion as well as regression takes place at the edge of the growing SM. Stabilization and irreversibility of formation of the SM is achieved by closure. The immediate source of lipids for the SM must be in the cytoplasmic matrix, supposedly in the form of special phospholipid carrying vesicles that might involve the transmembrane Atg9 protein. To explain the apparent lack of such vesicles by electron microscopy we suggest that they are too small, have a similar density to other frequently occurring structures, or are destroyed during sample preparation.     

Three-dimensional structure of the rSly1 N-terminal domain reveals a conformational change induced by binding to syntaxin 5

Sec1/Mun18-like (SM) proteins and soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) play central roles in intracellular membrane fusion. Diverse modes of interaction between SM proteins and SNAREs from the syntaxin family have been described. However, the observation that the N-terminal domains of Sly1 and Vps45, the SM proteins involved in traffic at the endoplasmic reticulum, the Golgi, the trans-Golgi network and the endosomes, bind to similar N-terminal sequences of their cognate syntaxins suggested a unifying theme for SM protein/SNARE interactions in most internal membrane compartments. To further understand this mechanism of SM protein/SNARE coupling, we have elucidated the structure in solution of the isolated N-terminal domain of rat Sly1 (rSly1N) and analyzed its complex with an N-terminal peptide of rat syntaxin 5 by NMR spectroscopy. Comparison with the crystal structure of a complex between Sly1p and Sed5p, their yeast homologues, shows that syntaxin 5 binding requires a striking conformational change involving a two-residue shift in the register of the C-terminal beta-strand of rSly1N. This conformational change is likely to induce a significant alteration in the overall shape of full-length rSly1 and may be critical for its function. Sequence analyses indicate that this conformational change is conserved in the Sly1 family but not in other SM proteins, and that the four families represented by the four SM proteins found in yeast (Sec1p, Sly1p, Vps45p and Vps33p) diverged early in evolution. These results suggest that there are marked distinctions between the mechanisms of action of each of the four families of SM proteins, which may have arisen from different regulatory requirements of traffic in their corresponding membrane compartments.     

The human amygdala and the induction and experience of fear

Although clinical observations suggest that humans with amygdala damage have abnormal fear reactions and a reduced experience of fear, these impressions have not been systematically investigated. To address this gap, we conducted a new study in a rare human patient, SM, who has focal bilateral amygdala lesions. To provoke fear in SM, we exposed her to live snakes and spiders, took her on a tour of a haunted house, and showed her emotionally evocative films. On no occasion did SM exhibit fear, and she never endorsed feeling more than minimal levels of fear. Likewise, across a large battery of self-report questionnaires, 3 months of real-life experience sampling, and a life history replete with traumatic events, SM repeatedly demonstrated an absence of overt fear manifestations and an overall impoverished experience of fear. Despite her lack of fear, SM is able to exhibit other basic emotions and experience the respective feelings. The findings support the conclusion that the human amygdala plays a pivotal role in triggering a state of fear and that the absence of such a state precludes the experience of fear itself.     

Precision agriculture: a challenge for crop nutrition management

Precision agriculture was initiated in the mid 1980s, using newly available technologies, to improve the application of fertilizers by varying rates and blends as needed within fields. Presently, the concept has been adapted to a variety of practices, crops, and countries. Its adoption varies significantly by cropping system, regions, and countries but it is progressively introduced or evaluated around the world. Several types of challenges limit a broader adoption: socio-economical, agronomical, and technological. Socio-economical barriers are principally costs and lack of skills. Agronomical challenges are lack of basic information, inadequate sampling and scouting procedures, absence of site-specific fertilizer recommendations, misuse of information, and lack of qualified agronomic services. There are multiple technological barriers that relate to machinery, sensor, GPS, software, and remote sensing. However, these barriers will be progressively lifted and precision agriculture will be a significant component of the agricultural system of the future. It offers a variety of potential benefits in profitability, productivity, sustainability, crop quality, food safety, environmental protection, on-farm quality of life, and rural economic development.