Experience of a multidisciplinary task force with exome sequencing for Mendelian disorders.

BACKGROUND: In order to optimally integrate the use of high-throughput sequencing (HTS) as a tool in clinical diagnostics of likely monogenic disorders, we have created a multidisciplinary "Genome Clinic Task Force" at the University Hospitals of Geneva, which is composed of clinical and molecular geneticists, bioinformaticians, technicians, bioethicists, and a coordinator. METHODS AND RESULTS: We have implemented whole exome sequencing (WES) with subsequent targeted bioinformatics analysis of gene lists for specific disorders. Clinical cases of heterogeneous Mendelian disorders that could potentially benefit from HTS are presented and discussed during the sessions of the task force. Debate concerning the interpretation of identified variants and the content of the final report constitutes a major part of the task force's work. Furthermore, issues related to bioethics, genetic counseling, quality control, and reimbursement are also addressed. CONCLUSIONS: This multidisciplinary task force has enabled us to create a platform for regular exchanges between all involved experts in order to deal with the multiple complex issues related to HTS in clinical practice and to continuously improve the diagnostic use of HTS. In addition, this task force was instrumental to formally approve the reimbursement of HTS for molecular diagnosis of Mendelian disorders in Switzerland.

Just care: should doctors give priority to patients of low socioeconomic status?

Growing data on the socioeconomic determinants of health pose a challenge to analysis and application of fairness in health. In Just health: meeting health needs fairly, Norman Daniels argues for a change in the population end of our thinking about just health. What about clinical care? Given our knowledge of the importance of wealth, education or social status to health, is fairness in medicine served better by continuing to avoid considering our patients' social status in setting clinical priorities, or by attempting to equalise existing health inequalities by giving priority to the socioeconomically disadvantaged at the point of care? In this article, I argue that doctors should not attempt the latter. Granted, giving priority to low status would go some way towards compensating unjust health inequalities and the impression of being left aside in other social spaces. It would represent reverse discrimination, but could still be justified inasmuch as disadvantaged groups could be identifiable, and as long as the intent was compensation rather than retribution. However, under current circumstances such priority would risk being attributed arbitrarily, would represent a form of medical proselytising, risk leaving the worst-off with less by alienating the powerful, and require teaching doctors to act in strongly counter-cultural ways--possibly at great cost. Crucially, however, we protect both equal health and equal regard by treating all alike: priority to low status would promote the first somewhat, but at the expense of sacrificing the second.

Should ethics consultants help clinicians face scarcity in their practice?

In an international survey of rationing we have found that European physicians encounter scarcity-related ethical difficulties, and are dissatified with the resolution of many of these cases. Here we further examine survey results to explore whether ethics support services would be potentially useful in addressing scarcity related ethical dilemmas. Results indicate that while the type of help offered by ethics support services was considered helpful by physicians, they rarely referred difficulties regarding scarcity to ethics consultation. We propose that ethics consultants could assist physicians by making the process less difficult, and by contributing to decisions being more ethically justifiable. Expertise in bringing considerations of justice to bear on real cases could also be useful in recognising an unjust limit, as opposed to a merely frustrating limit. Though these situations are unlikely to be among the most frequently referred to ethics support services, ethics consultants should be prepared to address them.

Ethical difficulties in clinical practice: experiences of European doctors.

BACKGROUND: Ethics support services are growing in Europe to help doctors in dealing with ethical difficulties. Currently, insufficient attention has been focused on the experiences of doctors who have faced ethical difficulties in these countries to provide an evidence base for the development of these services. METHODS: A survey instrument was adapted to explore the types of ethical dilemma faced by European doctors, how they ranked the difficulty of these dilemmas, their satisfaction with the resolution of a recent ethically difficult case and the types of help they would consider useful. The questionnaire was translated and given to general internists in Norway, Switzerland, Italy and the UK. RESULTS: Survey respondents (n=656, response rate 43%) ranged in age from 28 to 82 years, and averaged 25 years in practice. Only a minority (17.6%) reported having access to ethics consultation in individual cases. The ethical difficulties most often reported as being encountered were uncertain or impaired decision-making capacity (94.8%), disagreement among caregivers (81.2%) and limitation of treatment at the end of life (79.3%). The frequency of most ethical difficulties varied among countries, as did the type of issue considered most difficult. The types of help most often identified as potentially useful were professional reassurance about the decision being correct (47.5%), someone capable of providing specific advice (41.1%), help in weighing outcomes (36%) and clarification of the issues (35.9%). Few of the types of help expected to be useful varied among countries. CONCLUSION: Cultural differences may indeed influence how doctors perceive ethical difficulties. The type of help needed, however, did not vary markedly. The general structure of ethics support services would not have to be radically altered to suit cultural variations among the surveyed countries.

How physicians face ethical difficulties: a qualitative analysis.

BACKGROUND: Physicians face ethical difficulties daily, yet they seek ethics consultation infrequently. To date, no systematic data have been collected on the strategies they use to resolve such difficulties when they do so without the help of ethics consultation. Thus, our understanding of ethical decision making in day to day medical practice is poor. We report findings from the qualitative analysis of 310 ethically difficult situations described to us by physicians who encountered them in their practice. When facing such situations, the physicians sought to avoid conflict, obtain assistance, and protect the integrity of their conscience and reputation, as well as the integrity of the group of people who participated in the decisions. These goals could conflict with each other, or with ethical goals, in problematic ways. Being aware of these potentially conflicting goals may help physicians to resolve ethical difficulties more effectively. This awareness should also contribute to informing the practice of ethics consultation. OBJECTIVE: To identify strategies used by physicians in dealing with ethical difficulties in their practice. DESIGN, SETTING, AND PARTICIPANTS: National survey of internists, oncologists, and intensive care specialists by computer assisted telephone interviews (n = 344, response rate = 64%). As part of this survey, we asked physicians to tell us about a recent ethical dilemma they had encountered in their medical practice. Transcripts of their open-ended responses were analysed using coding and analytical elements of the grounded theory approach. MAIN MEASUREMENTS: Strategies and approaches reported by respondents as part of their account of a recent ethical difficulty they had encountered in their practice. RESULTS: When faced with ethical difficulties, the physicians avoided conflict and looked for assistance, which contributed to protecting, or attempting to protect, the integrity of their conscience and reputation, as well as the integrity of the group of people who participated in the decisions. These efforts sometimes reinforced ethical goals, such as following patients' wishes or their best interests, but they sometimes competed with them. The goals of avoiding conflict, obtaining assistance, and protecting the respondent's integrity and that of the group of decision makers could also compete with each other. CONCLUSION: In resolving ethical difficulties in medical practice, internists entertained competing goals that they did not always successfully achieve. Additionally, the means employed were not always the most likely to achieve those aims. Understanding these aspects of ethical decision making in medical practice is important both for physicians themselves as they struggle with ethical difficulties and for the ethics consultants who wish to help them in this process.

Inhibitors of protein kinase C. 2. Substituted bisindolylmaleimides with improved potency and selectivity.

A hypothetical mode of inhibition of protein kinase C (PKC) by the natural product staurosporine has been used as a basis for the design of substituted bisindolylmaleimides with improved potency over the parent compound. Structure-activity relationships were consistent with the interaction of a cationic group in the inhibitor with a carboxylate group in the enzyme, and the most potent compound had a Ki of 3 nM. The inhibitors were competitive with ATP but inhibited cAMP-dependent protein kinase (PKA) only at much higher concentrations despite the extensive sequence homology between the ATP-binding regions of PKA and PKC. Three compounds were evaluated further and found to inhibit a human allogeneic mixed lymphocyte reaction pointing to the potential utility of PKC inhibitors in immunosuppressive therapy. One of these compounds was orally absorbed in the rat and represents an attractive lead in the development of PKC inhibitors as drugs.

Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides.

The design and synthesis of a series of novel inhibitors of protein kinase C (PKC) is described. These 2,3-bisarylmaleimides were derived from the structural lead provided by the indolocarbazoles, staurosporine and K252a. Optimum activity required the imide NH, both carbonyl groups, and the olefinic bond of the maleimide ring. 2,3-Bisindolylmaleimides were the most active, and the potency of these was improved by a chloro substituent at the 5-position of one indole ring (compound 28, IC50 0.11 microM). In a series of (phenylindolyl)maleimides, nitro compound 74 was most active (IC50 0.67 microM). Naphthalene 19 and benzothiophene 21 showed greater than 100-fold selectivity for inhibition of PKC over the closely related cAMP-dependent protein kinase (PKA).