When families cannot "let go": ethical decision-making at the bedside.

Shared decision-making at the bedside is now a regular feature of medical practice. When disagreements arise between a patient and family members caregivers sometimes find themselves caught in a complex tangle of human relationships that strains monochrome ethical thinking. The patient''s expressed wishes are often compromised for the sake of the family''s needs. Conversely, a unilateral appeal for patient autonomy may prove insensitive to the hurt and the needs of the family. We describe a relatively unsuccessful attempt by a patient''s caregivers to buy time to maximize the interests of the patient and her family and discuss the way in which the family dynamics militated against the rather obvious solution of promoting the patient''s right to refuse treatment. The purpose of this article is not to evoke sympathy for health care professionals in dealing with such conflicts but rather to heighten awareness of the issues at stake and to stimulate thinking about ways and means to bring about a more favourable outcome than the one described here.     

When biotech proteins go off-patent

The patents of the first generation of biopharmaceuticals derived from recombinant DNA such as interferons, growth hormone and epoietins are expiring, opening up the possibility for competitors to introduce biosimilar products. The concept of generics that applies to classical drugs and allows market admission on limited documentation cannot be extrapolated to these "off-patent biologics". Physicochemical characterization, bioassays and animals studies do not predict completely the efficacy and safety of therapeutic proteins. Clinical studies will nearly always be necessary to obtain marketing authorization for off-patent biologics. Immunogenicity is considered to be the main problem with therapeutic proteins. The recent upsurge of pure red cell aplasia (PRCA), a severe form of anemia associated with the use of epoietin-alpha, highlights both the unpredictability and the severe consequences of immunogenicity. A risk-based approach can be used to evaluate the potential induction of antibodies by off-patent biologics.     

When two trees go to war

Rooted phylogenetic networks are used to model non-treelike evolutionary histories. Such networks are often constructed by combining trees, clusters, triplets or characters into a single network that in some well-defined sense simultaneously represents them all. We review these four models and investigate how they are related. Motivated by the parsimony principle, one often aims to construct a network that contains as few reticulations (non-treelike evolutionary events) as possible. In general, the model chosen influences the minimum number of reticulation events required. However, when one obtains the input data from two binary (i.e. fully resolved) trees, we show that the minimum number of reticulations is independent of the model. The number of reticulations necessary to represent the trees, triplets, clusters (in the softwired sense) and characters (with unrestricted multiple crossover recombination) are all equal. Furthermore, we show that these results also hold when not the number of reticulations but the level of the constructed network is minimised. We use these unification results to settle several computational complexity questions that have been open in the field for some time. We also give explicit examples to show that already for data obtained from three binary trees the models begin to diverge.     

When good organs go to bad people

A number of philosophers have argued that alcoholics should receive lower priority for liver transplantations because they are morally responsible for their medical conditions. In this paper, I argue that this conclusion is false. Moral responsibility should not be used as a criterion for the allocation of medical resources. The reason I advance goes further than the technical problem of assessing moral responsibility. The deeper problem is that using moral responsibility as an allocation criterion undermines the functioning of medicine.     

Knowing when to let go: endosomal release of LDL from the LDL-Receptor

In this issue of Molecular Cell, Blacklow and colleagues use NMR structural analyses and the combination of deletion mapping, site-directed mutagenesis and LDL release assays to examine the molecular basis for low pH-induced release of LDL from the LDL receptor.